Original Article

Fifteen Genetic Loci Associated

WiththeElectrocardiographic P Wave
Ingrid E. Christophersen, MD, PhD*; Jared W. Magnani, MD, MSc*; Xiaoyan Yin, PhD*;
John Barnard, PhD; Lu-Chen Weng, PhD; Dan E. Arking, PhD; Maartje N. Niemeijer, MD;
Steven A. Lubitz, MD, MPH; Christy L. Avery, PhD; Qing Duan, PhD; Stephan B. Felix, MD;
Joshua C. Bis, PhD; Kathleen F. Kerr, PhD; Aaron Isaacs, PhD;
Martina Mller-Nurasyid, PhD; Christian Mller, MSc; Kari E. North, PhD;
Alex P. Reiner, MD, MSc; Lesley F. Tinker, PhD, RD; Jan A. Kors, PhD;
Alexander Teumer, PhD; Astrid Petersmann, MD; Moritz F. Sinner, MD, MPH;
Petra Buzkova, PhD; Jonathan D. Smith, PhD; David R. Van Wagoner, PhD;
Uwe Vlker, PhD; Melanie Waldenberger, PhD; Annette Peters, PhD; Thomas Meitinger, MD;
Marian C. Limacher, MD; Kirk C. Wilhelmsen, MD, PhD; Bruce M. Psaty, MD, PhD;
Downloaded from http://circgenetics.ahajournals.org/ by guest on August 10, 2017

Albert Hofman, MD, PhD; Andre Uitterlinden, PhD; Bouwe P. Krijthe, MD, PhD;
Zhu-Ming Zhang, MD, MPH; Renate B. Schnabel, MD, MSc; Stefan Kb, MD;
Cornelia van Duijn, PhD; Jerome I. Rotter, MD; Nona Sotoodehnia, MD, PhD;
Marcus Drr, MD; Yun Li, PhD; Mina K. Chung, MD; Elsayed Z. Soliman, MD, MSc, MS;
Alvaro Alonso, MD, PhD; Eric A. Whitsel, MD, MPH; Bruno H. Stricker, MMed, PhD;
Emelia J. Benjamin, MD, ScM; Susan R. Heckbert, MD, PhD; Patrick T. Ellinor, MD, PhD

BackgroundThe P wave on an ECG is a measure of atrial electric function, and its characteristics may serve as predictors
for atrial arrhythmias. Increased mean P-wave duration and P-wave terminal force traditionally have been used as markers
for left atrial enlargement, and both have been associated with increased risk of atrial fibrillation. Here, we explore the
genetic basis of P-wave morphology through meta-analysis of genome-wide association study results for P-wave duration
and P-wave terminal force from 12 cohort studies.
Methods and ResultsWe included 44456 individuals, of which 6778 (16%) were of African ancestry. Genotyping,
imputation, and genome-wide association study were performed at each study site. Summary-level results were meta-
analyzed centrally using inverse-variance weighting. In meta-analyses of P-wave duration, we identified 6 significant
(P<5108) novel loci and replicated a prior association with SCN10A. We identified 3 loci at SCN5A, TBX5, and CAV1/
CAV2 that were jointly associated with the PR interval, PR segment, and P-wave duration. We identified 6 novel loci
in meta-analysis of P-wave terminal force. Four of the identified genetic loci were significantly associated with gene
expression in 329 left atrial samples. Finally, we observed that some of the loci associated with the P wave were linked
to overall atrial conduction, whereas others identified distinct phases of atrial conduction.
ConclusionsWe have identified 6 novel genetic loci associated with P-wave duration and 6 novel loci associated with P-wave
terminal force. Future studies of these loci may aid in identifying new targets for drugs that may modify atrial conduction
or treat atrial arrhythmias.(Circ Cardiovasc Genet. 2017;10:e. DOI: 10.1161/CIRCGENETICS.116.001667.)
Key Words:arrhythmia atrial function electrocardiography genetic variation
genome-wide association study

T he electrocardiographic P wave is a measure of electric

activation of the atria and was first described by Bayliss
and Starling over 120 years ago.1 P-wave indices (PWI)
describe atrial electric function and are quantified as measures
of duration and voltage from the surface ECG. The clinical
utility of PWI has been demonstrated by their relation to atrial
electrophysiology using invasive intracardiac studies2,3 and by
their assessment as risk factors for atrial fibrillation (AF).47

Received November 10, 2016; accepted May 15, 2017.

Guest Editor for this article was Christopher Semsarian, MBBS, PhD, MPH.
*Drs Christophersen, Magnani, and Yin contributed equally to this work.
The Data Supplement is available at http://circgenetics.ahajournals.org/lookup/suppl/doi:10.1161/CIRCGENETICS.116.001667/-/DC1.
Correspondence to Jared W. Magnani, MD, MSc, Department of Medicine, Division of Cardiology, UPMC Heart and Vascular Institute, University of
Pittsburgh, Pittsburgh, Pennsylvania, USA. E-mail magnanijw@upmc.edu or Patrick T. Ellinor, MD, PhD, Broad Institute of Harvard and MIT, 75 Ames
St, Cambridge, MA 02124. E-mail ellinor@mgh.harvard.edu
2017 American Heart Association, Inc.
Circ Cardiovasc Genet is available at http://circgenetics.ahajournals.org DOI: 10.1161/CIRCGENETICS.116.001667

1
 2 Christophersen et al Genetic Basis of the P Wave
P-wave terminal forcederived from the product of the dura-
tion of the negative phase of the P wave in lead V1 and its
terminal depth (Figure1)has been used as an ECG marker
for the presence of left atrial enlargement.8 In addition to ter-
minal force, P-wave duration has been used widely because of
its accessibility from the ECG. Elucidation of the associations
of genetic variants related to PWI may improve our under-
standing of the biology underlying atrial conduction and fur-
ther inform the genetic determinants of risk of arrhythmias,
including AF.
See Editorial by Bezzina
See Clinical Perspective
We sought to enhance our understanding of atrial elec-
tric function by conducting large genome-wide association
studies (GWAS) of PWI in individuals of European and
African ancestry. Prior GWAS have distinguished genetic loci
uniquely associated with P-wave duration from those associ-
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ated with the PR interval and the PR segment.9,10 The larg-
est study evaluating common variants associated with P-wave
maximal duration, to date, included 16468 individuals of
European ancestry and identified 3 significant genetic loci.10
There have been no reports on common genetic variants asso-
ciated with P-wave terminal force.
In the present investigation, we examined the genome-wide
associations of maximum P-wave duration and P-wave terminal
force in 12 cohorts, including >44000 individuals of European
and African American ancestry. We hypothesized that the PWI
examined have novel genetic associations, distinct from those
previously identified as associated with the PR interval.
Materials and Methods
Study Cohorts
Participants of European or African ancestry from 12 studies contrib-
uted to the present analyses (Table I in the Data Supplement): ARIC
Study (Atherosclerosis Risk in Communities), CHS (Cardiovascular
Health Study), ERF Study (Erasmus Rucphen Family), FHS
(Framingham Heart Study), KORA (Cooperative Health Research in
the Augsburg Region), GHS I (Gutenberg Health Study I), MESA
(Multi-Ethnic Study of Atherosclerosis), RS I-III (Rotterdam
Studies I, II, and III), SHIP (Study of Health in Pomerania), and 3
distinct studies affiliated with the Womens Health Initiative (WHI)
clinical trials: GARNET (Genome-wide Association Research
Network), MOPMAP (Modification of Particulate MatterMediated
Arrhythmogenesis in Populations), and SHARe (SNP Health
Association Resource Project). The study was limited to participants
with available DNA and consent for genetics research. We excluded
individuals in whom we could not determine PWI and individuals
with a history of AF, an implanted pacemaker or ICD, WPW syn-
drome, and complete heart block or who received medication altering
atrioventricular nodal conduction (-blockers, dihydropyridine cal-
cium channel blockers, type I and III antiarrhythmic medication, and
digoxin). Individuals with mitral valve disease were not excluded. All
participants had given their written informed consent to participation,
and all studies were approved by their respective institutional review
boards or equivalent ethical committees.
PWI Measurement
Participants in all cohorts underwent a standardized, digital 12-lead
ECG at rest in the supine position as a component of the cohort ex-
amination. All PWI were quantified using contemporary software al-
gorithms from digitized tracings. Electrocardiograms from the ARIC,
CHS, and MESA and data from the 3 WHI clinical trials substudies were
automatically processed at the Epidemiological Cardiology Research
Center of Wake Forest University School of Medicine (Winston Salem,
NC) using General Electric (GE) 12-SL software (GE, Milwaukee,
WI) running under GE MUSE and Magellan Research Work Station.
ECGs in FHS were read independently at FHS and analyzed using GE
12-SL software. PWI calculated using GE 12-SL software have pre-
viously been reported as having a repeatability of 100%.4 In GHS I,
ECGs were recorded using the Welch Allyn CardioPerfect electrocar-
diograph (Skaneateles Falls, NY), and PWI were calculated using the
GE Healthcare software CASE, CardioSoft, version 6 (Palatine, IL). In
ERF and RSI-III, electrocardiograms were recorded using the ACTA
Gnosis IV ECG recorder (Esaote Biomedica, Florence, Italy), and in
SHIP, electrocardiograms were recorded using the Personal 120LD
(Esaote, Genova, Italy). In ERF, RSI-III, and SHIP, electrocardiograms
were analyzed with the Modular ECG Analysis System.11 KORA used
the AMEDTEC ECGpro system (AMEDTEC Medizintechnik Aue
GmbH, Aue, Germany) and analyzed tracings using the Hannover
ECG system (Corscience GmbH&Co. KG, Erlangen, Germany).
PWI were selected for their availability across cohorts. P-wave
duration in each lead was calculated by summing the durations of
the positive and negative phase of the P wave in each lead. The maxi-
mum P-wave duration was selected as the highest value among the
12 leads. P-wave terminal force, specific to right precordial lead V1,
was calculated as the product of the duration and voltage of the nega-
tive deflection of the P wave in lead V1. Distributions of the PWI
by cohort are presented in Table II in the Data Supplement. P-wave
terminal force was not available in KORA and GHS.
Genotyping
Details on genotyping methods, quality control, imputation, and soft-
ware are provided in detail in Table III in the Data Supplement. All
cohorts used genome-wide arrays for genotyping. Genotyping was
performed independently in each cohort using the following arrays:
Affymetrix 6.0 genome-wide array (ARIC, KORA, GHS, MESA,
SHIP, and WHI SHARe), Illumina 370 (CHS), Affymetrix 500K+50K
(FHS), Illumina Infinium (RSI-III), Illumina Quad (WHI GARNET),
and Affymetrix Titan (MOPMAP). Samples with call rates <95%
(ARIC, GHS, MESA, WHI MOPMAP, and WHI SHARe), <97%
(CHS, FHS), or <98% (KORA, Rotterdam, ERF, and GARNET) at
genotyped markers were excluded.
Expression Quantitative Trait Loci Analyses
A complete description is enclosed in Methods in the Data
Supplement. In brief, expression Quantitative Trait Loci (eQTL)
analyses were performed from human left atrial tissue samples and
from the Genotype-Tissue Expression (GTEx) database.
Figure 1. Calculation of P wave terminal force. ECG with the
P wave highlighted in green and calculation of P wave terminal
force depicted in lead V1.
 3 Christophersen et al Genetic Basis of the P Wave
Estimation of the Variance Explained by the
Significant Genetic Variants
Results from the meta-analyses were used to estimate the percentage
of the variance that can be explained by the most significant single
nucleotide polymorphism (SNP) at each genetic locus as described
by Hibar et al.12 We calculated estimated variance explained for SNPs
identified in both separate and combined ancestry analyses and ad-
justed for age, sex, RR interval, and the maximum number of princi-
pal components adjusted for in any of the ancestry-matched GWAS.
Evaluation of the Genetic Associations Between
P-Wave Duration and P-Wave Terminal Force
We performed a summary-level analysis to test the association be-
tween the genetic variants associated with P-wave duration and the
measured P-wave terminal force and vice versa in the European an-
cestry group. To define independent signals, we performed linkage
disequilibrium (LD) clumping by selecting SNPs with P<1105 and
assigning all SNPs within 250 kb in each direction in moderate LD
(r2>0.5) and P<0.05 to the same clump. LD clumping was iterated un-
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til all SNPs with P<1105 had been clumped, using PLINK v.1.9.13
To assess whether the selected LD threshold was sufficient to identify
independent variants, we also performed LD clumping using lower
thresholds (r2>0.1 and r2>0.05). LD information was obtained from the
Framingham Heart Study. Genetic risk scores (GRS) were then created
for both ECG traits, including only SNPs significantly associated with
the trait and that were not in LD with any other significant SNPs. The
scores were used to evaluate the association between the genetically
determined P-wave duration and measured P-wave terminal force and
between the genetically determined P-wave terminal force and mea-
sured P-wave duration, using the R-package gtx.14 The association re-
sults were then used to estimate the fraction of the total variance of each
trait that could be explained by the GRS of the other trait.
Statistical Analysis
Each cohort conducted an independent association analysis relating
genotype to P-wave duration and P-wave terminal force. Cohorts with
participants of African ancestry performed separate analyses by race.
Adjustment for principal components was performed in individual
studies if appropriate. Cohorts used linear regression models that
adjusted for participant age, sex, RR interval, and cohort or site in
a primary analysis and further adjusted for hypertension (defined as
systolic blood pressure 140 mmHg, diastolic blood pressure 90
mmHg, or treatment with an antihypertensive) and body mass index
(weight [kg]/height [m]2) in a secondary analysis.
Genetic variants were given a marker identifier (ID) consisting of
chromosome number and chromosomal position before meta-anal-
ysis to avoid inconsistencies in reference SNP ID numbers (rsIDs)
from the Single Nucleotide Polymorphism database (dbSNP) across
different builds. Cohort-specific summary statistics were pooled for
inverse-variance weighted fixed-effect meta-analyses, which were
performed separately for maximum P-wave duration and P-wave ter-
minal force. Both ancestry-specific and combined ancestry analyses
were performed for both traits. Variants that were not present in at
least 2 studies were excluded. Associations with 2-sided P<5108
were considered genome-wide significant.
Results
The study sample for maximum P-wave duration included
37678 individuals of European ancestry and 6778 of African
ancestry. Because KORA and GHS did not contribute to anal-
yses of the P-wave terminal force, the total number of individ-
uals of European ancestry for that meta-analysis was 33955.
Descriptive characteristics of the study participants are pro-
vided in Table II in the Data Supplement. The 3 WHI clini-
cal trial cohorts included only women, while the remaining
cohorts included both sexes. Mean age within study ranged
from 4616 to 725 years. Mean P-wave duration was highly
consistent across cohorts. In contrast, P-wave terminal force
had a wider range with proportionately larger standard devia-
tion. Details regarding study design, genotyping, GWAS, and
imputation are listed in Table III in the Data Supplement.
P-Wave Duration
In the primary analyses, we identified 9 loci associated with
P-wave duration, 5 of which have not been associated with
P-wave duration previously. The most significant variant from
each locus is listed in Tables IV and Table V in the Data Sup-
plement. Table VI in the Data Supplement displays a com-
parison of the genome-wide significant loci across P-wave
duration and P-wave terminal force analyses. Figure2 depicts
the Manhattan plots for the P-wave duration analysis, strati-
fied by ancestry. Figure IA in the Data Supplement shows
the Manhattan plot for pooled ancestries, and Figure II in the
Data Supplement shows the regional plots for all genetic loci
associated with P-wave duration in this study. Table VII in the
Data Supplement summarizes the relationship between sig-
nificant genetic loci in the present GWAS of P-wave duration
and previous PWI GWAS.
Genetic Loci Unique to P-Wave Duration
We identified an association between P-wave duration and a
variant on chromosome 5 (rs4276421) that resides 100 kb
upstream of HCN1. On chromosome 7, we identified a locus
comprising CAV1 and CAV2, with the most significant vari-
ant located intronic to CAV1. More than 40 variants at this
locus had significant or near significant eQTLs for CAV1/
CAV2 in European American left atrial samples (Table VIII
in the Data Supplement). The most significant variant in the
combined ancestry analysis (rs3801995) was in moderate LD
(Utah residents with Northern and Western European ances-
try from the Centre d'Etude du Polymorphisme Humain col-
lection [CEU] r2=0.56), with the most significant variants in
previous GWAS of PR interval,10,1517 which are in perfect LD
(rs3807989 and rs11773845; CEU r2=1) with each other. The
most significant variant in Europeans (rs13242816) was not
in LD (CEU r2=0.11) with previously identified variants at
this locus. A third locus was identified on chromosome 2, and
the top hit (rs11689011) was intronic to the gene EPAS1. On
chromosome 1, we identified a locus (most significant SNP
rs562408) surrounding the gene SSBP3. The lead SNP and 5
other variants were significant eQTLs for SSBP3 in European
American left atrial samples (Table VIII in the Data Supple-
ment), and the lead SNP in Europeans was the strongest cis
eQTL for this gene; similar results were found in the GTEx
database (Table IX in the Data Supplement). Another locus
was located on chromosome 4 with rs2285703 intronic to the
gene CAMK2D.
Last, in the meta-analysis of European and African-
American ancestries combined, we identified an additional
genetic locus associated with P-wave duration on chromo-
some 3. The top variant, rs1467026, was located upstream of
CAND2 and was in moderate LD (CEU r2=0.67) with a variant
associated with AF by Sinner et al18 in 2014. Rs1467026 has
been shown to be a significant eQTL for CAND2 (P=7.510
27
) in skeletal muscle in the GTEx database (Table IX in the
Data Supplement), though this was not found to be a signifi-
cant eQTL in left atrial tissues.
 4 Christophersen et al Genetic Basis of the P Wave
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Figure 2. Manhattan plot of meta-analysis results for genome-wide association of maximum P wave duration for European and African
American ancestry. A, European ancestry meta-analysis results. B, African American ancestry meta-analysis results. The dashed horizon-
tal lines represent the genome-wide significance threshold. Genetic loci that reached genome-wide significance are highlighted in red.
Genetic Loci Previously Associated With
Electrocardiographic Traits
We identified an association between P-wave duration and the
SCN5A region in both Europeans and African Americans. The
most significant European variant (rs41312411) at the SCN5A
locus was in strong LD with the most significant variant
(rs11708996; CEU r2=0.94) from the first PR interval GWAS
by Pfeufer et al15 and in moderate LD with a variant associated
with both PR segment10 and PR interval19 (rs6599222; CEU
r2=0.55). In African Americans, we replicated the association
between SNP rs3922844 and the PR interval observed in 2
previous GWAS in African Americans19,20; this variant also
has been associated with the PR segment in Europeans.10
In individuals of European ancestry, we identified an addi-
tional association signal in the adjacent SCN10A gene. The
most significant variant at the SCN10A locus (rs6790396) was
in strong LD with the following previously identified variants:
(1) rs6800541 (CEU r2=1), which was previously associated
with PR interval15; (2) rs6795970 (CEU r2=0.97), which was
associated with both PR interval and P-wave duration in an
Indian Asian population21 and PR interval in Europeans16; and
(3) rs6801957 (CEU r2=0.97), which was associated with PR
interval,20,22 PR segment,10 and P-wave duration.10 There also
was strong (CEU r2=0.87) and moderate (Yoruba in Ibadan,
Nigeria [YRI] r2=0.51) LD between our lead SCN10A variant
and a variant associated with PR interval in African Americans
(rs6798015).
In both Europeans and African Americans, we identified
a locus with the most significant variant located intronic
to the gene TBX5. The lead variants in all ancestry analy-
ses were significant eQTLs for TBX5 in both European
American and African American left atrial samples (Table
VIII in the Data Supplement). The most significant SNP in
the African American ancestry group (rs1895582) was also
an eQTL for TBX5 in left ventricular tissue in GTEx (Table
IX in the Data Supplement). The same SNP, rs1895582,
was in strong LD (YRI r2=0.81) with a variant previously
associated with PR interval in African Americans. The most
significant variant (rs148020424) in Europeans was sur-
rounded by an 300 kb LD block, bordered by 2 recombi-
nation hot spots. There were no LD data available between
rs148020424 and previously associated SNPs at this locus.
However, the most significant variant in our combined
ancestry analysis (rs7312625) was previously associated
with PR interval in African Americans. Rs7312625 was in
strong LD (YRI r2=0.81) with the most significant variant
in African Americans in our study and in moderate LD with
rs1895585 (YRI r2=0.78), the most significant variant in
the TBX5 region from a previous GWAS on PR interval in
African Americans.20 SNP rs7312625 was also in moderate
LD with rs3825214 (CEU r2=0.76), an intronic variant in
TBX5 previously associated with heart rate in Europeans.16
We identified an association between P-wave dura-
tion and variant rs452036 on chromosome 14 in a region
 5 Christophersen et al Genetic Basis of the P Wave

encompassing MYH6 and MYH7, and the same variant was
also significantly associated with P-wave terminal force in our
study. Rs452036 was the most significant variant in a GWAS
for heart rate by Eijgelsheim et al23 in 2010 and was in strong
LD with rs365990 (CEU r2=0.96, YRI r2=1), which has been
associated with heart rate in studies of both European and
African American ancestry.16,2325 Rs452036 was not in LD
(CEU r2=0.16) with the heart rateassociated SNP rs223116,
which is intronic to MYH7 and, thus, most likely represents an
independent locus for heart rate.23
P-Wave Terminal Force
In the primary analysis, we identified 6 loci associated with
P-wave terminal force. The most significantly associated
variants are listed in Tables X and XI in the Data Supple-
ment; Figure3 depicts the Manhattan plots, stratified by
ancestry. The Manhattan plot for the pooled analysis of
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In the African American population, one locus was
identified on chromosome 11. The most significant variant
(rs10832139) was located 44 kb upstream of the closest gene,
SPON1.
Genetic Loci Associated With Heart Rate, P-Wave Duration,
and P-Wave Terminal Force
On chromosome 14, we identified a locus with the most sig-
nificant variant located intronic to MYH6. Rs445754 was
in moderate LD with the most significant variant from the
P-wave duration analysis in the present study (rs452036;
CEU r2=0.7) and the most significant variant from the first
GWAS on heart rate (rs365990; CEU r2=0.6).16 The variant
rs365990 has been replicated in 3 subsequent GWAS of heart
rate.16,24,25
Variance Explained by the Genetic Loci Associated
With P-Wave Duration and P-Wave Terminal Force

Europeans and African Americans is shown in Figure IB

in the Data Supplement, and regional plots for all genetic
loci significantly associated with P-wave terminal force are
shown in Figure III in the Data Supplement. Table XII in
the Data Supplement summarizes the shared associations
of genetic loci between the present P-wave terminal force
analysis and previous GWAS of PWI.
Genetic Loci Unique to the P Wave Terminal Force
In the European study populations, the locus with the
strongest association was identified on chromosome 1
(rs12090194), intronic to KCND3. Rs12090194 was in weak
LD (CEU r2=0.2) with rs2798334, which has been associ-
ated with P-wave duration by Verweij et al10; thus, this locus
seems to be specific to P-wave terminal force. A second locus
was identified on chromosome 19, with the most signifi-
cant variant (rs4435363) intronic to the gene PPP5D1 and
downstream of the gene CALM3. On chromosome 15q25,
the most significant variant was an indel (rs201517563),
intronic to ALPK3. This variant was not present in the 1000
Genomes database reference, and so there were no available
LD data. However, LD data were available for the second
most significant variant at this locus (rs11073730), which
was located between ALPK3 and ZNF592. The 15q25 locus
spanned several other genes, including NMB, for which there
were multiple significant eQTLs in European American left
atrial samples (Table XIII in the Data Supplement), and
rs11073730 was also a significant eQTL for several genes
in various tissues in GTEx, including ALPK3 (Table IX in
the Data Supplement). In addition, 2 perfect proxies were
associated with increased expression of CSPG4P11 in tis-
sue from the tibial nerve (P=1.4106 and 2.2106) and
rs11073730, along with 14 proxies in strong LD (r2=0.81)
was associated with increased expression of WDR73 in the
muscular layer of the esophagus (P=3.3107 to 1.4109).
We identified another locus in an intergenic region on chro-
mosome 4, with the most significant variant (rs11099412)
700 kb downstream of the closest gene PCDH18. Finally, a
locus was identified on chromosome 6, 150 kb downstream
of the gene C6orf195. A strong proxy (r2=0.9) for the most
significant variant was previously associated with orthostatic
hypotension.26
The most significant SNPs associated with P-wave duration
explained 0.08% to 0.83% of the total variance (Tables IV and
V in the Data Supplement), while the variants associated with
P-wave terminal force explained 0.09% to 0.47% of the total
variance (Tables X and XI in the Data Supplement).
P-Wave Duration and P-Wave Terminal Force Are
Genetically Associated
After LD clumping (r2>0.5), 199 significant SNPs remained
from the P-wave duration analysis and 85 significant SNPs
remained from the P-wave terminal force analysis, which
were included in the respective GRS. The P-wave terminal
force GRS was associated with measured P-wave duration
(=0.00095; SE=0.00014; P=2.51011), and the P-wave
duration GRS was associated with measured P-wave termi-
nal force (=8.33; SE=1.64; P=3.6107). Using lower r2
thresholds for the LD clumping produced similar results, with
even lower P values (Results in the Data Supplement). One
unit increase in the genetically determined P-wave terminal
force was associated with a 0.00095 ms increase in P-wave
duration, whereas 1 U increase in the genetically determined
P-wave duration was associated with an 8.33 V x ms increase
in P-wave terminal force. The estimated percentage of total
variance of the measured P-wave terminal force explained by
the P-wave duration GRS is 0.07%, and conversely, the esti-
mated fraction of the total variance of the measured P-wave
duration explained by the P-wave terminal force GRS is 0.1%.
Discussion
In the current work, we sought to characterize the genetic basis
of the P wave and to integrate our findings with prior associa-
tion studies of electrocardiographic traits quantifying atrial con-
duction. Our results reveal both unique and overlapping genetic
loci for the different phases of atrial conduction (Figure4).
As expected, the phenotypic variance explained by the causal
SNP from each genetic locus associated with P-wave duration
and P-wave terminal force was small (0.08%0.83%). Similar
estimates have been reported for common variants associated
with other continuous traits, such as human height and BMI,
and reflect the often highly polygenic nature of common traits,
which are, thus, explained by a large number of variants with
 6 Christophersen et al Genetic Basis of the P Wave
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Figure 3. Manhattan plot of meta-analysis results for genome-wide association of P wave terminal force for European and African Ameri-
can ancestry. A, European ancestry meta-analysis results. B, African American ancestry meta-analysis results. The dashed horizontal lines
represent the genome-wide significance threshold. Genetic loci that reached genome-wide significance are highlighted in blue.
small effect sizes. The larger percentage of variance explained
by the variants identified in the African American ancestry
groups is caused by the large effect sizes of these SNPs.
In Discussion in the Data Supplement, we have provided a
detailed description of the loci that are unique to either P-wave
duration or P-wave terminal force, and we have discussed the
broad contribution of the sodium channels, caveolin, and
TBX5 to atrial conduction.
Interrelationship Between P-Wave Duration and
P-Wave Terminal Force
P-wave duration and P-wave terminal force are both endophe-
notypes for AF; however, they represent different aspects of
atrial conduction. P-wave duration reflects the depolarization of
both right and left atrium, while P-wave terminal force, which
is calculated from the last half portion of the P-wave, more
specifically represents left atrial activation. Soliman et al4 have
shown that the mutual PWI correlations are weak to moderate
in a study of more than 15000 individuals. In particular, P-wave
duration and P-wave terminal force displayed the weakest cor-
relation (Pearsons R=0.080.29). In this study, we found that
the genetically determined P-wave duration is highly associated
with the measured P-wave terminal force and vice versa but that
the percentage of explained variance between the 2 PWI was
small. Thus, we had expected to identify genetic loci uniquely
associated with either right or left atrial activation, in addition
to some overlap of genetic variants associated with both phe-
notypes in the present study. We did discover one genetic locus
associated with both P-wave duration and P-wave terminal
force, encompassing the gene MYH6. The 14q11 locus includes
MYH6, the gene encoding myosin heavy chain 6 protein, which
is important in actin and calmodulin binding in the sarcomere
of striated muscles. The most significant variant at this locus,
rs452036, and its proxy rs365990 (CEU r2=0.96) have been
associated with heart rate in multiple GWAS16,23,24 and most
likely represent the same locus. MYH6 has been implicated in
congenital heart defects,27 dilated and hypertrophic cardiomy-
opathy,28,29 AF,30 atrial septal defects,31,32 and sick sinus syn-
drome.33 All of these conditions may affect inter- or intra-atrial
conduction and modify P-wave duration.
According to reports that P-wave terminal force is a predic-
tor of left atrial enlargement,8 one might have expected to see
a predominance of structurally related genes associated with
P-wave terminal force and a preponderance of genes involved
in electric properties of the atrium associated with P-wave dura-
tion. Indeed, some of the genes identified in the analyses of
P-wave duration are more likely to produce electric disturbances
(SCN5A, SCN10A, HCN1, CAV1/CAV2, EPAS1, CAND2, and
CAMK2D), while a selection of the genes identified in the analy-
ses of P-wave terminal force are more likely to cause structural
changes (TBX5, ALPK3/NMB, MYH6, and SPON1). However,
recent studies have reported that P-wave terminal force was not
associated with left atrial enlargement on echocardiography34 or
computed tomography volume measurement.35 In a sample of
275 middle-aged Americans referred to cardiovascular magnetic
resonance imaging between 2001 and 2004, electrocardiographic
 7 Christophersen et al Genetic Basis of the P Wave
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Figure 4. Integrated view of the anatomic, electric, and genetic architecture of atrial conduction. Top, Heart, anterior 4-chamber view,
with the different phases of atrial conduction color-coded. Purple, sinoatrial node activity (heart rate); green, P wave duration; red, PR
segment; blue, PR interval; gray, P wave terminal force; and yellow, overall atrial conduction. Middle, ECG corresponding to the differ-
ent phases of atrial conduction. Bottom, All identified risk genes for heart rate (R-R), PR interval, and P wave indices. For each trait, only
genes uniquely associated with that trait are listed. Genes associated with multiple electrocardiographic traits are listed under multiple
atrial conduction traits. Red font, novel loci in the present study; green font, loci identified in both the present study and previous litera-
ture; black font, loci only identified in previous studies. AV indicates atrioventricular; LA, left atrium; LV, left ventricle; PTF, P-wave terminal
force; RA, right atrium; RV, right ventricle; and SA, sinoatrial.

P-wave terminal force (negative P terminal force in V1>0.04 s
x mm) had high specificity (88%) but low sensitivity (37%) and
positive predictive value (47%) for left atrial enlargement, com-
pared with volumetric assessment of left atrial size.36
Strengths and Limitations
Strengths of our study include the substantial power obtained
by including >44 000 individuals from established stud-
ies with carefully phenotyped participants. Further, the PWI
measurements were all measured digitally and calculated
automatically. Last, because AF is thought to originate pre-
dominantly from the left atrium and pulmonary veins, evalua-
tion of eQTLs in a large sample of left atrial samples provides
a suitable model for functional interrogation of the genetic
variants associated with AF in our study.
Our study was also subject to several limitations. First, both
P-wave duration and P-wave terminal force measurements are less
reproducible over time than PR interval, P-wave axis, and P-wave
 8 Christophersen et al Genetic Basis of the P Wave
area.37 Second, one could consider adjusting the P value for sig-
nificant results for the 2 traits considered (5108/2=2.5108);
however, the P-wave duration and P-wave terminal force are only
weakly correlated, and so we used a conventional threshold for
genome-wide significance of 5108. Third, associations with P
values in the range of 1108 to 1010 will require replication in
independent cohorts. Fourth, although we included individuals
of both European and African ancestry, our findings may not be
generalizable to other ancestries. Fifth, the analyses in African
Americans were underpowered compared with our analyses in
European-ancestry individuals and require replication as other
studies become available in the future. Finally, it is important
to remember that we have identified markers of genetic regions
involved in the P-wave indices. The genes outlined above are
the genes closest to the most significant variant in each genetic
region, yet it remains unclear whether they truly are the effec-
tor genes. Other genes in the same region or even more distantly
Downloaded from http://circgenetics.ahajournals.org/ by guest on August 10, 2017
located genes might actually be the causal genes. Future studies
including targeted mapping of these loci and functional analyses
of the implicated genes may shed light on the underlying biology.
Conclusion
We report 15 genetic loci associated with P-wave duration and
P-wave terminal force, 4 of which harbor significant eQTLs in left
atrial tissue. In the context of the existing knowledge of genetic
factors for atrial conduction, a genetic architecture is emerging, in
which specific genetic regions influence different phases of atrial
conduction. Functional characterization of the novel loci may
clarify the underlying pathophysiology and aid the discovery of
targets for new drugs, which may modulate atrial conduction and,
thus, potentially treat a range of arrhythmia disorders.
Web Resources
The Genotype-Tissue Expression (GTEx) browser, http://
www.gtexportal.org
SNAP proxy search, http://www.broadinstitute.org/mpg/
snap/
Locus zoom, https://statgen.sph.umich.edu/locuszoom/
Disclosures
Dr Ellinor is the PI on a grant from Bayer HealthCare to the Broad
Institute focused on the genetics and therapeutics of atrial fibrillation.
Dr Psaty serves on the DSMB of a clinical trial funded by Zoll LifeCor
and on the Steering Committee of the Yale Open Data Access Project
funded by Johnson & Johnson. The other authors report no conflicts.
Appendix
From the Cardiovascular Research Center, Massachusetts General
Hospital, Boston, MA (I.E.C., L.-C.W., S.A.L., P.T.E.); Program in
Medical & Population Genetics, The Broad Institute of Harvard & MIT,
Cambridge, MA (I.E.C., L.-C.W., S.A.L., P.T.E.); Department of Medical
Research, Brum Hospital, Vestre Viken Hospital Trust, Rud, Norway
(I.E.C.); Department of Medicine, Boston University School of Medicine,
Boston, MA (J.W.M., E.J.B.); Division of Cardiology, Department of
Medicine, University of Pittsburgh Medical Center Heart & Vascular
Institute University of Pittsburgh, Pittsburgh, PA (JWM); NHLBI &
Boston Universitys Framingham Heart Study Framingham, MA (J.W.M.,
X.Y., E.J.B.); Department of Biostatistics (X.Y.) and Department of
Epidemiology (E.J.B.), Boston University School of Public Health, Boston,
MA; Departments of Cardiovascular Medicine, Cellular & Molecular
Medicine, Molecular Cardiology & Quantitative Health Sciences,
Cleveland Clinic, OH (J.B., J.D.S., D.R.V.W., M.K.C.); McKusick-
Nathans Institute of Genetic Medicine, Johns Hopkins University School
of Medicine, Baltimore, MD (D.E.A.); Department of Epidemiology
(M.N.N., A.H., A.U., B.P.K., B.H.S.), Genetic Epidemiology Unit,
Department of Epidemiology (A.I., C.v.D.), Department of Medical
Informatics (J.A.K.), and Department of Internal Medicine (A.U., B.H.S.),
Erasmus University Medical Center, Rotterdam, the Netherlands; CARIM
School for Cardiovascular Diseases, Maastricht Centre for Systems
Biology (MaCSBio), Dept. of Biochemistry, Maastricht University,
Maastricht, the Netherlands (A.I.); Department of Epidemiology (C.L.A.,
K.E.N., E.A.W.), Department of Genetics (Q.D., K.C.W., Y.L.), Carolina
Center for Genome Sciences (K.E.N.), Department of Neurology
(K.C.W.), Departments of Biostatistics and Computer Science (Y.L.) and
Department of Medicine (E.A.W.), University of North Carolina, Chapel
Hill, NC; DZHK (German Center for Cardiovascular Research), Partner
Site Greifswald, Greifswald, Germany (S.B.F., U.V., M.D.); Department
of Internal Medicine B (S.B.F., M.D.), Institute for Community Medicine
(A.T.), Institute of Clinical Chemistry & Laboratory Medicine (A.
Petersmann), Department of Functional Genomics, Interfaculty Institute
for Genetics & Functional Genomics (U.V.), University Medicine
Greifswald, Greifswald, Germany; Cardiovascular Health Research
Unit, Department of Medicine (J.C.B., B.M.P., N.S.), Department of
Biostatistics (K.F.K., P.B.), Department of Epidemiology (A.P.R.), Fred
Hutchinson Cancer Research Center (A.P.R., L.F.T.), Department of
Epidemiology & Cardiovascular Health Research Unit (B.M.P., S.R.H.),
Department of Health Services (B.M.P.), and Cardiology Division (N.S.),
University of Washington, Seattle, WA; Institute of Genetic Epidemiology
(M.M.-N.), Research Unit of Molecular Epidemiology (M.W.), Institute of
Epidemiology II (M.W., A. Peters), Institute of Human Genetics (T.M.),
Helmholtz Zentrum Mnchen-German Research Center for Environmental
Health, Neuherberg, Germany; Department of Medicine I, University
Hospital Munich, Ludwig-Maximilians University, Munich, Germany
(M.M.-N., M.F.S., S.K.); German Centre for Cardiovascular Research
(DZHK), partner site: Munich Heart Alliance, Munich, Germany (M.M.-N.,
M.F.S., M.W., A. Peters, T.M., S.K.); Clinic for General & Interventional
Cardiology, University Heart Center Hamburg, Hamburg, Germany (C.M.,
R.B.S.); German Center for Cardiovascular Research (DZHK e.V.),
Partner Site Hamburg/Lbeck/Kiel, Germany (C.M., R.B.S.); German
Center for Diabetes Research, Neuherberg, Germany (A. Peters); Institute
of Human Genetics, Technische Universitt Mnchen, Munich, Germany
(T.M.); Department of Medicine, Division of Cardiovascular Medicine,
University of Florida, Gainesville, FL (M.C.L.); Kaiser Permanente
Washington Health Research Institute, Seattle, WA (B.M.P., S.R.H.);
Epidemiological Cardiology Research Center (EPICARE), Wake Forest
School of Medicine, Winston Salem, NC (Z.-M.Z., E.Z.S.); Institute for
Translational Genomics & Population Sciences, Los Angeles Biomedical
Research Institute & Department of Pediatrics at Harbor-UCLA Medical
Center, Torrance, CA (J.I.R.); and Department of Epidemiology, Rollins
School of Public Health, Emory University, Atlanta, GA (A.A.).
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CLINICAL PERSPECTIVE
The electrocardiographic P wave is a measure of electric activation of the atria that can be quantified by assessing the P-wave
duration or P-wave terminal force. Because measures of atrial activation have been associated with left atrial enlargement
and atrial fibrillation, we sought to determine the genetic basis of P-wave duration and P-wave terminal force. We identified
6 new genetic loci that contribute to the maximum P-wave duration and 6 genetic loci that contribute to the P-wave terminal
force. When integrating our results with prior work, we have identified a genetic architecture of the P wave in which some
genetic loci are uniquely associated with distinct electrocardiographic parameters and others are more broadly associated
with atrial conduction. Further studies evaluating the function of the genetic loci linked to atrial conduction may help eluci-
date the biology underlying atrial conduction, as well as provide new targets for antiarrhythmic drugs.
 Fifteen Genetic Loci Associated With the Electrocardiographic P Wave
Ingrid E. Christophersen, Jared W. Magnani, Xiaoyan Yin, John Barnard, Lu-Chen Weng, Dan
E. Arking, Maartje N. Niemeijer, Steven A. Lubitz, Christy L. Avery, Qing Duan, Stephan B.
Felix, Joshua C. Bis, Kathleen F. Kerr, Aaron Isaacs, Martina Mller-Nurasyid, Christian
Mller, Kari E. North, Alex P. Reiner, Lesley F. Tinker, Jan A. Kors, Alexander Teumer, Astrid
Downloaded from http://circgenetics.ahajournals.org/ by guest on August 10, 2017

Petersmann, Moritz F. Sinner, Petra Buzkova, Jonathan D. Smith, David R. Van Wagoner, Uwe
Vlker, Melanie Waldenberger, Annette Peters, Thomas Meitinger, Marian C. Limacher, Kirk
C. Wilhelmsen, Bruce M. Psaty, Albert Hofman, Andre Uitterlinden, Bouwe P. Krijthe,
Zhu-Ming Zhang, Renate B. Schnabel, Stefan Kb, Cornelia van Duijn, Jerome I. Rotter, Nona
Sotoodehnia, Marcus Drr, Yun Li, Mina K. Chung, Elsayed Z. Soliman, Alvaro Alonso, Eric
A. Whitsel, Bruno H. Stricker, Emelia J. Benjamin, Susan R. Heckbert and Patrick T. Ellinor

Circ Cardiovasc Genet. 2017;10:

doi: 10.1161/CIRCGENETICS.116.001667
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 SupplementalMaterial

Page Description
2 SupplementalMethods
4 SupplementalResults
5 SupplementalDiscussion
9 Funding/Support
15 TableS1.OverviewofparticipatingstudiesandPWImeasurements
16 TableS2.Summaryofparticipantcharacteristicsbycohort.
17 TableS3.Detailsregardingstudysamples,genotypinganddatacleaning.
20 TableS4.SummaryofgeneticassociationsforPwavemaximumdurationincombinedancestry
analysis.
21 TableS5.SummaryofsignificantgeneticassociationsforPwavemaximumdurationinparticipants
ofEuropeanandAfricanancestry.
22 TableS6.ComparisonofallgenomewidesignificantlociacrossPwavedurationandPwaveterminal
forceanalyses.
23 TableS7.SharedassociationsbetweenpresentandpreviousGWASofPwaveduration.
25 TableS8.SignificanteQTLsinleftatrialappendagesamplesforgeneticlociassociatedwithPwave
duration.
31 TableS9.SignificanteQTLsintheGTExdatabase
32 TableS10.SummaryofgeneticassociationsforPwaveterminalforceinparticipantsofEuropean
andAfricanancestry.
33 TableS11.SummaryofgeneticassociationsforPwaveterminalforceincombinedancestryanalysis.
34 TableS12.SharedassociationsbetweenpresentandpreviousGWASofPwaveterminalforce.
35 TableS13.SignificanteQTLsinleftatrialappendagesamplesforgeneticlociassociatedwithPwave
terminalforce.
38 FigureS1.ManhattanplotforcombinedEuropeanandAfricanancestryparticipants.
39 FigureS2.LocuszoomplotsPwaveduration.
41 FigureS3.LocuszoomplotsPwaveterminalforce.
43 SupplementalReferences

Page1of47

SUPPLEMENTALMETHODS

SelectionofECGs

Instudieswithmultiplevisits,ECGwereselectedfromfollowingvisits:baselinevisit(MESA,RSIIII),

exam20(FHSOriginalcohort),exam6(FHSOffspringcohort),andexam1(FHSGen3).

GeneexpressionandeQTLanalysesinleftatrialtissuesamples

HumanleftatrialtissuesampleswereobtainedfromtheClevelandClinicAtrialTissueBankand

ArrhythmiaBiorepository,processedontheIlluminaHumanHap550v3orHap610v1chipsandIllumina

HumanHT12v3orv4chipstoobtaingenotypeandRNAexpressiondata,respectively.Humanleftatrial

sampleswereobtainedfrom289individualsofEuropeanAmerican(EA)ethnicity;266sampleswere

fromleftatrialappendage(LAA)tissueand23theleftatrialpulmonaryveinjunctiontissue(LAPV).Of

the289subjects,80werefemales,70hadnohistoryofAF,and136camefrompatientsthatwereinAF

atthetimeoftissueacquisition.Of40individualsofAfricanAmerican(AA)ethnicity,25werefemales,

16hadnohistoryofAF,and12wereinAFatthetimeoftissueacquisition;34sampleswerefromLAA

and6fromLAPVtissue;Detailedmethodshavebeendescribedpreviously.1SNPgeneexpression

associationtests(eQTLanalyses)wereperformedforallgenomewidesignificantgeneticvariants

identifiedinanalysesofPwavedurationandPwaveterminalforce.Falsediscoveryrate(FDR)values

werecalculatedfromthepvaluesusingtheBenjaminiandHochbergmethod.2Cisprobevariantpairs

withanFDRvaluelessthan0.05weredeemedsignificantatthegenomewidelevel.Inaddition,for

eachvariantsetofinterest,FDRvalueswerecalculatedforthatset.

InsilicofunctionalannotationandeQTLanalyses

Weassessedthelinkagedisequilibrium(LD)betweenthemostsignificantvariantinourstudyand

previousstudies,forallgeneticlocireportedinpreviouspublishedGWASofPwaveindices,usingthe

Page2of47

pairwiseLDfunctionoftheSNAPsoftwareversion2.2.3LDwascategorizedasfollows;strongLD,r20.8;

moderateLD,r2<0.8and0.50;weakLD,r2<0.5and0.2;noLD,r2<0.2.Weusedthe1000Genomes

Pilot1SNPdataset,andchosetheEuropean(CEU)populationpanelforvariantsidentifiedinEuropean

studiesandtheAfrican(YRI)populationpanelforvariantsdiscoveredinAfricanAmericanstudies.We

alsousedtheSNAPsoftwaretoidentifyproxiesforthemostsignificantSNPfromeachgeneticlocus

identifiedintheGWAS,usingthesamesettingsasdescribedaboveinadditiontoadistancelimitof500

kbandanLDr2thresholdof0.8.

AlltophitsandtheirproxieswereselectedforeQTLandSNPfunctionanalyses.Weperformeda

lookupofstatisticallysignificanteQTLsincardiacandskeletalmuscletissues,usingtheGenomeTissue

Expressiondatabase(GTEx),4whichwasaccessedonOctober21,2015.WeassessedSNPfunction

throughtheNCBIdbSNPwebsiteonOctober30,2015.

Page3of47

SUPPLEMENTALRESULTS

PwavedurationandPwaveterminalforcearegeneticallyassociated

AfterLDclumpingusingr2>0.1,96significantSNPsremainedfromthePwavedurationanalysisand

75significantSNPsremainedfromthePwaveterminalforceanalysis,whichwereincludedinthe

respectiveGRS.ThePwaveterminalforceGRSwasassociatedwithmeasuredPwaveduration

(=0.007;SE=0.0005;p=1.2x1042)andthePwavedurationGRSwasassociatedwithmeasuredPwave

terminalforce(=11.2;SE=2.46,p=5.3x106).AfterLDclumpingusingr2>0.05,85significantSNPs

remainedfromthePwavedurationanalysisand66significantSNPsremainedfromthePwaveterminal

forceanalysis,whichwereincludedintherespectiveGRS.ThePwaveterminalforceGRSwas

associatedwithmeasuredPwaveduration(=0.007;SE=0.0005;p=1.2x1044)andthePwaveduration

GRSwasassociatedwithmeasuredPwaveterminalforce(=12.4;SE=2.67,p=3.3x106).Theestimated

percentageoftotalvarianceofthemeasuredPwaveterminalforceexplainedbythePwaveduration

GRSis0.06%,forbothr2thresholds,andconversely,theestimatedfractionofthetotalvarianceofthe

measuredPwavedurationexplainedbythePwaveterminalforceGRSis0.5%,forbothr2thresholds.

Page4of47

SUPPLEMENTALDISCUSSION

Thesodiumchannel(SCN5A/SCN10A),caveolin(CAV1/CAV2),andTBX5locibroadlycontributeto

atrialconduction.

Alimitednumberofgeneticlocihavebeenassociatedwithseveralatrialelectrocardiographictraits,

suggestingthattheyareimportantcontributorsinthepropagationofatrialelectricalactivityfromthe

sinoatrialnodethroughtheatrioventricularnode.

Thegeneticregionthatstandsoutasmostrobustlyassociatedwiththeoverallconductionproperties

oftheatriaandtheAVnodeinpreviousGWASisclearlytheSCN5A/SCN10Aregion.Thesewell

characterizedgenesencodethesodiumchannelsNaV1.5andNaV1.8,crucialfordepolarizationof

cardiomyocytesandtheinitializationoftheactionpotentialitself.Thesegeneshavebeenassociated

withthePRinterval,511Pwaveduration,5,10,12andPwavesegment5,12andbothwereassociatedwithP

wavedurationinthepresentstudy.Moreover,theSCN5AlocushasbeenassociatedwithQRS

duration13andBrugadasyndrome,14underscoringtherelevanceofthisregiontooverallcardiac

conduction.

Similarly,theTBX3/5andCAV1/CAV2locihavebeenassociatedwithPRinterval,PRsegment,69,11,12,

AF,1518andinthepresentstudywithPwaveduration.BothlocidisplayconvincingeQTLsinleftatrial

tissueinthisstudy.CAV1/CAV2alsohasbeenrelatedtoAVnodalautomaticityandQRSduration.7,13,19

ThegenesNKX25andSOX5,whichbothencodetranscriptionfactorsimportantintheembryonic

developmentoftheatria,havebeenassociatedwithbothPRinterval6andheartrate.20,21

GeneticlociuniquetoPwaveduration

The5p12locusisadjacenttoHCN1,whichencodesthehyperpolarizationactivatedcyclicnucleotide

gatedionchannel1,achannelcontributingtothepacemakercurrentincardiaccellsandneurons.22The

Page5of47

mostabundantHCNchannelinthehumansinoatrialnode(SAN)isHCN4;however,expressionofboth

HCN1andHCN4hasbeenshowninrabbitSANandPurkinjefibers23andHCN1cancoassemblewith

otherHCNchannelisoforms.24HCN1deficientmicedevelopseveresinoatrialdeficiency,including

bradycardia,sinusdysrhythmia,sinuspauses,andotherpropertiesofsicksinussyndrome.25

Themostsignificantvariantonchromosome2p21(rs11689011)wasintronictoEPAS1,which

encodesahypoxiainducibletranscriptionfactorexpressedmainlyinvascularendothelialcells,26but

alsointhecarotidbodyandincatecholamineproducingorgansinmice.27EPAS1deficientmicedisplay

reducedlevelsofcatecholaminesandpronouncedbradycardia,beforetheydiemidgestation,without

morphologicalchangesinthecirculatorysystem.27OverexpressionoftheEPAS1geneleadstoincreased

expressionofadrenomedullin,implicatingEPAS1intheadaptationofcardiacmyocytesduringheart

failure.28TwovariantsinstrongLDwithrs11689011(rs7579899,CEUr2=1andrs11894252,CEUr2=0.96)

werereportedinapreviousGWAStobeassociatedwithrenalcellcarcinoma.29,30Athirdproxy,

rs1867785(CEUr2=0.96),hasbeenassociatedwithretinopathyinprematureneonatesandpatent

ductusarteriosus.31,32However,thespecificmechanismbywhichgeneticvariantsattheEPAS1locus

altersPwavedurationremainsunclear.

ThegeneSSBP3,harboringthemostsignificantvariantat1p32,hasnotpreviouslybeendescribedin

relationtoanycardiacphenotype.However,AFassociatedvariantsintronictothisgenewerethe

strongesteQTLsidentifiedinleftatrialsamplesinthisstudy.SSBP3encodesthesinglestrandedDNA

bindingprotein3,whichisexpressedinhearttissueandhasbeensuggestedtobeanimportant

regulatorycomponentofdevelopmentalprogramsinthecell.33

Thelocusat4q26surroundsCAMK2D,whichencodestheCa2+/CalmodulinDependentProteinKinase

TypeIIDelta.Thisserine/threonineproteinkinaseisactivatedatincreasedCa2+levelsandisinvolvedin

theregulationofcalciumhomeostasisandtheexcitationcontractioncouplingincardiomyocytes.

Page6of47

CAMK2Dhasarangeofcardiacdownstreameffects,suchasregulationofsarcoplasmicreticulumCa2+

releasethroughtheryanodinereceptor34andCa2+uptakethroughphospholambaninhibitionof

SERCA,35regulationofvoltagegatedLtypeCa2+channels,36,37andregulationofNav1.538andKv4.3,39

whichmayleadtoarrhythmogenesis.Allofthesefunctionsmaybeinvolvedinatrialconductionand

modifyPwaveduration.

TheCAND2geneticlocuswasassociatedwithPwavedurationincombinedmetaanalysisof

EuropeanandAfricanAmericanancestries.CAND2waspreviouslyassociatedwithAFbySinneretal.15

ThemostsignificantAFvariant(rs4642101)isinmoderateLDwiththemostsignificantvariantinour

study(rs1467026,CEUr2=0.7),suggestingthatthevariantsrepresentthesamelocus.Rs1467026isa

significanteQTLforCAND2(p=7.5x1027),KRT18P17(p=9.2x1011),andRP11767C1.2(p=1.2x109)

expressioninskeletalmusclebasedonGTExdata.Sinnerandcolleaguesshowedthatrs4642101

increasedtheexpressionofCAND2inleftatrialtissuesamplesandthatknockdowninzebrafishledto

prolongationoftheatrialactionpotential.Takentogether,theassociationwithbothPwaveduration

andAF,andthefunctionalevidenceprovidedbySinneretal.,implicateCAND2inatrialconductionand

arrhythmogenesis,althoughfurtherworkisneededtoclarifytheunderlyingmechanism.

GeneticlociuniquetoPwaveterminalforce

Themostsignificantvariantat1p13isintronictoKCND3,whichencodesKv4.3,theporeformingsubunit

ofthetransientoutwardK+current,Ito.TheItocurrentisinstrumentalinphase1ofcardiac

repolarizationandaffectscalciumhandling.AnothervariantintheregionsurroundingKCND3has

previouslybeenassociatedwithPwaveduration,butdoesnotseemtorepresentthesamesignal(CEU

r2=0.2).12GainoffunctionmutationsinKCND3havebeenshowntobeassociatedwithearlyonsetAF,40

shorteningofactionpotentialduration,andBrugadasyndrome.41Althoughfurtherstudiesareneeded

toelucidatethemechanismunderlyingtheassociationbetweentheKCND3locusandincreasedPwave

Page7of47

terminalforce,wespeculatethatthePwaveterminalforcecouldbeaffectedbydownregulationof

Kv4.3thatleadstoaprolongationoftheAPD,witharesultingdelayedatrialrepolarization.

Onchromosome15q25,themostsignificantvariant(rs201517563)waslocatedintronictoALPK3,

whichencodestheproteinkinasealphakinase3,abundantlyexpressedincardiactissueandactivein

cardiomyocytedifferentiation.Interestingly,amongthemanytranscriptionfactorsthatbindtothe

promoterregionofthisgeneareNKX25andMEIS1,bothofwhichwerepreviouslyassociatedwithPR

interval.6ThegeneNeuromedinB(NMB),forwhichtherewereconvincingeQTLassociationsatthe

15q25locus,haspreviouslybeenassociatedwithECGdefinedleftventricularhypertrophy(rs2292462)42

andthesamevariantwasassociatedwithleftventricularhypertrophyintype2diabetics.43NMBhas

alsobeenassociatedwithobesityinchildren.44

InAfricanAmericansonly,thevariantrs10832139wasidentified44kbupstreamofSPON1on

chromosome11.SPON1encodesSpondin1ExtracellularMatrixProtein,whichwasfirstidentifiedasa

promoterofaxongrowthinthespinalcordandtheperipheralnervoussystem.45Later,SPON1was

showntobeastronggrowthpromotingfactorforvascularsmoothmusclecells46andithasbeen

suggestedasacandidatehypertensiongene.47Recently,anintronicvariant(rs2618516)inSPON1was

associatedwithbrainconnectivityinaGWASbyJahanshadandcolleagues,andolderindividualswith

thisvariantdisplayedmilderdementiasymptoms.48However,therewasnoLDbetweenthetwovariants

(CEUr2=0.01,YRIr2=0.02),andthebiologiclinkbetweenSPON1andPwaveterminalforceisunclear.

ThetwofinallociassociatedwithPwaveterminalforce,C6orf195andPPP5D1,haveanunclear

biologiclinkwiththeelectrocardiographicphenotypeandhavenotbeenreportedinanyprevious

GWAS.

Page8of47

FUNDING/SUPPORT

ARIC:TheAtherosclerosisRiskinCommunitiesStudyiscarriedoutasacollaborativestudysupportedby

theNationalHeart,Lung,andBloodInstitute[HHSN268201100005C,HHSN268201100006C,

HHSN268201100007C,HHSN268201100008C,HHSN268201100009C,HHSN268201100010C,

HHSN268201100011C,HHSN268201100012C,R01HL087641,R01HL59367,andR01HL086694];the

NationalHumanGenomeResearchInstitute[U01HG004402];andtheNationalInstitutesofHealth

[HHSN268200625226C].TheauthorsthankthestaffandparticipantsoftheARICstudyfortheir

importantcontributions.InfrastructurewaspartlysupportedbyNationalInstitutesofHealthandNIH

RoadmapforMedicalResearch[UL1RR025005].ThisworkwasadditionallysupportedbyNationalHeart,

Lung,andBloodInstitute[RC1HL099452]andtheAmericanHeartAssociation[09SDG2280087].

ClevelandClinic:ThisworkwassupportedbytheNationalInstitutesofHealth[RO1HL111314toMKC,

DVW,JB,andJDS],theNIHNationalCenterforResearchResourcesforCaseWesternReserveUniversity

andTheClevelandClinicClinicalandTranslationalScienceAward[UL1RR024989].

CHS:ThisCHSresearchwassupportedbyNHLBI[HHSN268201200036C,HHSN268200800007C,

N01HC55222,N01HC85079,N01HC85080,N01HC85081,N01HC85082,N01HC85083,N01HC85086,

HHSN268200960009C,U01HL080295,R01HL087652,R01HL105756,R01HL103612,andR01HL120393]

withadditionalcontributionfromtheNationalInstituteofNeurologicalDisordersandStroke(NINDS).

AdditionalsupportwasprovidedfromtheNationalInstituteonAging(NIA)[R01AG023629].Afulllistof

principalCHSinvestigatorsandinstitutionscanbefoundatCHSNHLBI.org.Theprovisionofgenotyping

datawassupportedinpartbytheNationalCenterforAdvancingTranslationalSciences,CTSI

[UL1TR000124],andtheNationalInstituteofDiabetesandDigestiveandKidneyDiseaseDiabetes

ResearchCenter(DRC)[DK063491]totheSouthernCaliforniaDiabetesEndocrinologyResearchCenter.

Page9of47

Thecontentissolelytheresponsibilityoftheauthorsanddoesnotnecessarilyrepresenttheofficial

viewsoftheNationalInstitutesofHealth.

ERF:TheERFstudyasapartofEUROSPAN(EuropeanSpecialPopulationsResearchNetwork)was

supportedbyEuropeanCommissionFP6STRPgrantnumber018947[LSHGCT200601947]andalso

receivedfundingfromtheEuropeanCommunity'sSeventhFrameworkProgramme[FP7/2007

2013/grantagreementHEALTHF42007201413]bytheEuropeanCommissionundertheprogramme

"QualityofLifeandManagementoftheLivingResources"of5thFrameworkProgramme(no.QLG2CT

200201254).TheERFstudywasfurthersupportedbyENGAGEconsortiumandCMSB.Highthroughput

analysisoftheERFdatawassupportedbyjointgrantfromNetherlandsOrganisationforScientific

ResearchandtheRussianFoundationforBasicResearch[NWORFBR047.017.043].ERFwasfurther

supportedbytheZonMwgrant[project91111025].Wearegratefultoallstudyparticipantsandtheir

relatives,generalpractitionersandneurologistsfortheircontributionsandtoP.Veraartforherhelpin

genealogy,J.Vergeerforthesupervisionofthelaboratorywork,andP.Snijdersforhishelpindata

collection.

FHS:ThisresearchwasconductedusingdataandresourcesfromFHSoftheNationalHeartLungand

BloodInstituteoftheNationalInstitutesofHealthandBostonUniversitySchoolofMedicinebasedon

analysesbyFraminghamHeartStudyinvestigatorsparticipatingintheSNPHealthAssociationResource

(SHARe)project.ThisworkwassupportedbyBostonUniversitysandtheNationalHeart,Lungand

BloodInstitute'sFraminghamHeartStudy[HHSN268201500001IandN01HC25195]anditscontract

withAffymetrix,Incforgenotypingservices[N02HL64278].Aportionofthisresearchutilizedthe

LinuxClusterforGeneticAnalysis(LinGAII)fundedbytheRobertDawsonEvansEndowmentofthe

DepartmentofMedicineatBostonUniversitySchoolofMedicineandBostonMedicalCenter.Other

supportcamefromtheAmericanHeartAssociation[09FTF2190028]andtheNationalInstitutesof

Page10of47

Health[5R21HL106092].Dr.BenjaminwassupportedbygrantsfromtheNationalInstitutesofHealth

[R01HL128914,2R01HL092577,and3R01HL09257706S1].

GHS:TheGutenbergHealthStudyisfundedthroughthegovernmentofRheinlandPfalz(Stiftung

RheinlandPfalzfrInnovation,[AZ961386261/733],theresearchprogramsWissenschafftZukunft

andSchwerpunktVaskulrePrventionoftheJohannesGutenbergUniversityofMainzandits

contractwithBoehringerIngelheimandPHILIPSMedicalSystemsincludinganunrestrictedgrantforthe

GutenbergHealthStudy.Dr.SchnabelissupportedbygrantsofDeutscheForschungsgemeinschaft

(GermanResearchFoundation)EmmyNoetherProgramSCHN1149/31,BundesministeriumfrBildung

undForschung[01ZX1408A],andEuropeanResearchCouncilconsolidatorgrant[648131].

KORA:TheKORAresearchplatform(KORA,CooperativeResearchintheRegionofAugsburg)was

initiatedandfinancedbytheHelmholtzZentrumMnchenGermanResearchCenterforEnvironmental

Health,whichisfundedbytheGermanFederalMinistryofEducationandResearchandbytheStateof

Bavaria.Furthermore,KORAresearchwassupportedwithintheMunichCenterofHealthSciences(MC

Health),LudwigMaximiliansUniversitt,aspartofLMUinnovativ,theDZHK(GermanCentrefor

CardiovascularResearch)andbytheBMBF(GermanMinistryofEducationandResearch).Supportfor

KORAisprovidedbytheGermanNationalGenomeResearchNetwork[NGFN01GS0838,01GR0803,

BMBF01EZ0874,01GR0803,NGFN01GI0204,01GR0103,NGFN2,NGFNPlus01GS0823,andNGFNPlus

01GS0834];GermanFederalMinistryofresearch[01EZ0874];GermanCompetenceNetworkonAF

(AFNET)[01GI0204/N];LeducqFoundation[07CVD03],BMBFspitzenclusterpersonalizedmedicine

m4[01EX1021E],LMUExcellenceInitiative[425956];MunichCenterofHealthSciences(MCHealth)as

partofLMUinnovativ.Dr.SinnerissupportedbytheGermanHeartFoundation.

MESA:MESAandtheMESASHAReprojectareconductedandsupportedbytheNationalHeart,Lung,

andBloodInstitute(NHLBI)incollaborationwithMESAinvestigators.SupportforMESAisprovidedby

Page11of47

contracts[N01HC95159,N01HC95160,N01HC95161,N01HC95162,N01HC95163,N01HC

95164,N01HC95165,N01HC95166,N01HC95167,N01HC95168,N01HC95169,UL1TR001079,

andUL1TR000040].FundingforSHARegenotypingwasprovidedbyNHLBI[N02HL64278].

GenotypingwasperformedatAffymetrix(SantaClara,California,USA)andtheBroadInstituteof

HarvardandMIT(Boston,Massachusetts,USA).

RotterdamStudy:TheRotterdamStudy(RSI)issupportedbytheErasmusMedicalCenterandErasmus

UniversityRotterdam;TheNetherlandsOrganizationforScientificResearch;TheNetherlands

OrganizationforHealthResearchandDevelopment(ZonMw);theResearchInstituteforDiseasesinthe

Elderly;TheNetherlandsHeartFoundation;theMinistryofEducation,CultureandScience;theMinistry

ofHealthWelfareandSports;theEuropeanCommission;andtheMunicipalityofRotterdam.Support

forgenotypingwasprovidedbyTheNetherlandsOrganizationforScientificResearch(NWO)

[175.010.2005.011and911.03.012]andResearchInstituteforDiseasesintheElderly(RIDE).Thisstudy

wassupportedbyTheNetherlandsGenomicsInitiative(NGI)/NetherlandsOrganizationforScientific

Research(NWO)[projectnr.050060810].

SHIP:SHIPispartoftheCommunityMedicineResearchnetoftheUniversityofGreifswald,Germany,

whichisfundedbytheFederalMinistryofEducationandResearch[grantsno.01ZZ9603,01ZZ0103,and

01ZZ0403],theMinistryofCulturalAffairsaswellastheSocialMinistryoftheFederalStateof

MecklenburgWestPomerania.GenerationofgenomewidedatahasbeensupportedbytheFederal

MinistryofEducationandResearch[grantno.03ZIK012]andajointgrantfromSiemensHealthcare,

Erlangen,GermanyandtheFederalStateofMecklenburgWestPomerania.TheUniversityof

GreifswaldisamemberoftheCachCampusprogramoftheInterSystemsGmbH.

WHICT:TheWomensHealthInitiativeclinicaltrialswerefundedbytheNationalHeart,Lung,andBlood

Institute,NationalInstitutesofHealth,U.S.DepartmentofHealthandHumanServices

Page12of47

[HHSN268201100046C,HHSN268201100001C,HHSN268201100002C,HHSN268201100003C,

HHSN268201100004C,andHHSN271201100004C].AllcontributorstoWHIsciencearelistedat

https://www.whi.org/researchers/Documents%20%20Write%20a%20Paper/WHI%20Investigator%20Lo

ng%20List.pdf.YLandQDarepartiallysupportedby[R01HG006292andR01HG006703awardedtoY.L.].

WHIGARNET:WithintheGenomicsandRandomizedTrialsNetwork,aGWASofHormoneTreatment

andCVDandMetabolicOutcomesintheWHIwasfundedbytheNationalHumanGenomeResearch

Institute,NationalInstitutesofHealth,U.S.DepartmentofHealthandHumanServicesthrough

cooperativeagreement[U01HG005152toA.P.R.].AllcontributorstoGARNETsciencearelisted@

https://www.garnetstudy.org/Home.

WHIMOPMAP:TheModificationofPMMediatedArrhythmogenesisinPopulationswasfundedbythe

NationalInstituteofEnvironmentalHealthSciences,NationalInstitutesofHealth,U.S.Departmentof

HealthandHumanServices[R01ES017794toE.A.W.].

WHISHARe:TheSNPHealthAssociationResourceprojectwasfundedbytheNationalHeart,Lungand

BloodInstitute,NationalInstitutesofHealth,U.S.DepartmentofHealthandHumanServicesthrough

contract[N02HL64278].

Otherfundingsources:Dr.ChristophersenissupportedbyamobilitygrantfromtheResearchCouncilof

Norway[240149/F20].Dr.LubitzissupportedbyNIH[K23HL114724]andaDorisDukeCharitable

FoundationClinicalScientistDevelopmentAward[2014105].Dr.MagnaniissupportedbyDorisDuke

CharitableFoundationClinicalScientistDevelopmentAward[2015084].Dr.Ellinorissupportedby

grantsfromtheNationalInstitutesofHealth[1R01HL092577,R01HL128914,and1K24HL105780],an

EstablishedInvestigatorAwardfromtheAmericanHeartAssociation[13EIA14220013]andthe

Page13of47

FondationLeducq[14CVD01].

RoleoftheSponsor:Noneofthefundingagencieshadanyroleinthestudydesign,datacollectionor

analysis,interpretationofthedata,writingofthemanuscript,orinthedecisiontosubmitthe

manuscriptforpublication.

Page14of47

 TableS1.OverviewofparticipatingstudiesandPWImeasurements
Pwave Pwaveterminal
Study Reference ECGanalysissoftware duration force
AtherosclerosisRiskinCommunities(ARIC) 49,50
GE12SLsoftware x x
Study
51
CardiovascularHealthStudy(CHS) GE12SLsoftware x x
52
ErasmusRucphenFamily(ERF)Study ModularECGAnalysisSystem x x
53,54
FraminghamHeartStudy(FHS) GE12SLsoftware x x
CooperativeHealthResearchintheAugsburg 55
TheHannoverECGsystem x NA
Region(KORA)

56 GEHealthcaresoftwareCASE,
GutenbergHealthStudyI(GHSI) x NA
CardioSoft,version6
57
MultiEthnicStudyofAtherosclerosis(MESA) GE12SLsoftware x x
58
RotterdamStudiesI,II,III ModularECGAnalysisSystem x x

59
StudyofHealthinPomerania(SHIP) ModularECGAnalysisSystem x x

WomensHealthInitiativeclinicaltrials(WHI 60

CT):
GenomewideAssociationResearch
GE12SLsoftware x x
Network(GARNET)
ModificationofParticulateMatter
MediatedArrhythmogenesisin GE12SLsoftware x x
Populations(MOPMAP)
SNPHealthAssociationResourceProject
GE12SLsoftware x x
(SHARe)
GE,GeneralElectric;NA,notavailable

Page15of47

TableS2.Summaryofparticipantcharacteristicsbycohort.
Bodymass Pwave
Participants Males HTN RR PR MaximumP
index terminal
Cohort Race Age interval, interval, wave
force,msx
n % % kg/m2 ms ms duration,ms
Va
EA 8151 46 536 19 275 915133 16023 10612 14901643
ARIC
AA 2799 37 536 50 296 920147 17127 11212 20091974
CHS EA 2415 36 725 46 264 948145 16627 11013 24591917
ERF EA 1651 42 4714 44 274 972157 15222 11112 14681545
FHS EA 5878 45 4714 20 275 971157 15823 10512 15611600
KORA EA 1519 49 529 33 274 935144 16224 10912 NA
EA 1907 50 6110 24 275 974148 16325 10413 19281677
MESA
AA 964 50 6010 37 306 977150 16927 10712 24631961
GHSI EA 2204 51 5411 41 274 1001159 16022 10912 NA
RSI EA 4552 40 689 49 264 865139 16725 11913 2217208
RSII EA 1453 45 648 56 274 871131 16523 11713 21751809
RSIII EA 2532 42 566 42 275 876131 16221 11512 11701415
SHIP EA 2680 49 4616 10 275 853148 15220 11011 7881237
WHICTGARNET EA 1617 0 657 31 286 920132 15924 10613 21961834
WHICTMOPMAP EA 1119 0 627 32 286 922132 15823 10613 22361900
WHICTSHARe AA 3015 0 607 50 316 913143 16625 11012 26712156
Summarystatisticsarereportedasmeanstandarddeviationunlessotherwisenoted.aPwaveterminalforceequalstheduration(ms)xthenegativevoltage
deflection(V)oftheterminalpartofthePwaveinleadV1.EA,EuropeanandEuropeanAmericanancestry;AA,AfricanandAfricanAmericanancestry;ARIC,
AtherosclerosisRiskinCommunitiesStudy;CHS,CardiovascularHealthStudy;ERF,ErasmusRucphenFamilyStudy;FHS,FraminghamHeartStudy;MESA,Multi
EthnicStudyofAtherosclerosis;RS,RotterdamStudy;SHIP,StudyofHealthinPomerania;WHICT,WomensHealthInitiativeClinicalTrialscohort;GARNET,
GenomicsandRandomizedTrialsNetwork;MOPMAP,ModificationofPMMediatedArrhythmogenesisinPopulations;SHARe,SNPHealthAssociation
Resource.

Page16of47

 TableS3.Detailsregardingstudysamples,genotyping,anddatacleaning.

GHSI ARIC CHS ERF FHS KORA MESA RSI,II,III SHIP WHICT

Genome
Modification
Kooperative wide
Atheroscleros Erasmus ofPM SNPHealth
Gesungheitsfo MultiEthnic TheStudyof Association
Gutenberg isRiskin Cardiovascula Rucphen Framingham Rotterdam Mediated Association
Study rschunginder Studyof Healthin Research
HealthStudy Communities rHealthStudy Family HeartStudy Study Arrhythmoge Resource
Region Atherosclerosis Pomerania Network
Study Study nesisin Project
Augsburg Effectsof
Populations
Treatment

Affymetrix
Affymetrix
Illumina370 Illumina GeneChip
Illumina Illumina GeneTitan,
CNV+ 318Kand 500KArray
Affymetrix Affymetrix Infinium Affymetrix HumanOmni Axiom Affymetrix
Array Illumina 370K, Set&50K Affymetrix6.0 Affymetrix6.0
6.0 6.0 HumanHap55 6.0 1Quadv10 Genome 6.0
ITMATBroad Affymetrix HumanGene
0chipv3.0 B WideHuman
CARe(IBC) 250K Focused
CEU1
Panel

Affymetrix
Calling BeadStudio
Birdseed Birdseed BeadStudio BeadStudio BRLMM Birdseedv2 Birdseedv2 BeadStudio Birdseedv2 PowerTools Birdseed
Algorithm v3.1.3.0
v1.14.3
PerSNPCall
<95% <95% <97% <98% <97% <93% <95% <98% ND 98% 95% 95%
rate
HWEpvalue <104 <105 <105 <106 <106 NA NA <106 ND <104 <106 <106
Genotypes
weresetto
Mendelian missingfor
NA NA 2 N>100 NA NA NA NA NA NA NA
errors problematic
familysub
units.
Subject
hetero
Excess
zygosity>5
heterozygosit NA NA ND ND ND >0.53 >0.336;n=21 ND NA NA NA
SDaway
y
fromthe
mean
EA:<0.5% Excluded
MAF <1% SNPswith0 <1% <1% NA NA <1% ND None <0.5% <1%
AA:<1% heterozygotes

Page17of47

 Usedlinear
Eigenstrat,
Analysis mixed Analysis Outliersas
Selection AllPCs MDSwith
committee effects Nopopulation committee identifiedby >6SDfrom
criteriafor unassociated HapMap
recommenda modelsto substructure recommendatio IBSclustering top10PCs
PCs p>0.05 reference
tions accountfor ns wereexcluded
population
relatedness
Numberof EA:4 EA:0
PCsinthe 0 0 0 0 0 4 0 3 3 10
model AA:10 AA:10

Numberof EA:711,589 EA:854,755

SNPsusedfor 662,405 678,524 EA:445,149 651,596 512,849 869,224 535,600 829,370
imputation AA:806,416 AA:861,124
Prephasing
IMPUTE
withShapeIt
MACH1 v.0.5.0
Imputation IMPUTE v.1.r53262 MACH1, MACH1 MACH1 IMPUTE MACH1 BEAGLE MACH1, MACH
v.1.0.15163, against
software v.2.1.061 Imputation minimac 63,64
64 v.1.0.151 63,64
v.1.0.15 63,64
v.2.1.0 61
v.1.0.151 63,64
v.3.3.165 minimac63,64 v.1.0.1663,64
HapMapII
withIMPUTE
61 CEUv.2261
v.2.1.0
1000 1000 Build36/
Genomes Genomes
EA:HapMapI+II
PhaseI PhaseI
Imputation CEUr24
integrated integrated
Backbone/ Build36 Build36 Build37 Build36 AA:HapMap Build36 Build36 Build37 Build36 Build36
variantset variantset
NCBIBuild I+II
release(v.3) release(v.3)
inNCBIbuild inNCBIbuild CEU+YRI+CHB+J
37(hg19) 37(hg19) PTr22
SNPposition
Hapmapr22 Hapmap2
fromNCBI Build36 Build37 Build37 Build36 Build37 Build36 Build36 Build36 Build36 1000GEUR
CEU YRI/CEU1:1
build
Mach2QTL,63,
GWAS GenABEL, Rpackages 64
66 67 68 Rpackage GenABEL+ QUICKTEST
Statistical SNPTEST FaSTLMM R ProbABEL, kinship,GEE, ProbABEL,R68 R68 R68 R68
GEE68 PLINK,69R,68 v.0.9571
Analysis R68 coxpH368
GRIMP70
RSI
EA:9,337,140 2,402,234 EA:2,592,133 8,818,618,RS
Totalnumber
8,522,176 II8,798,976,
ofSNPsused EA:9,403,802
2,320,937 (MAF>=0.01, RSIII
inthe 2,564,344 (noMAF 2,543,887 2,748,910 8,864,574 2,543,830 2,203,608
(0.005< imputation 8,846,227
analysis AA: filtering)
MAF< quality>0.3) AA:2,975,847 (MAF>0.01,
(MAF>0.005) 15,879,929 0.995) imputation
quality>0.3)

Page18of47

 Pmax:
EA: EA: RS1:1.025
Pmax:1.02 Pmax:1.029
RS2:1.013
PTF:1.01 PTF:1.036
RS3:1.013
Inflation Pmax:1.02 Pmax:1.00 Pmax:1.01
NA Pmax:1.01 PTF: Pmax:0.98 PTF:1.01 PTF:1.00 PTF:1.02
factor() PTF:1.01 PTF:1.03 PTF:1.02
RS1:0.992 PTF:1.01
AA: AA:
RS2:0.958
Pmax:1.01 Pmax:1.029
RS3:1.010
PTF:0.98 PTF:1.025

NA,notapplicable;ND,notdetermined;PC,principalcomponent;Pmax,maximumPwaveduration;PTF,Pwaveterminalforce

Page19of47

TableS4.SummaryofgenomewidesignificantgeneticassociationsforPwavemaximumdurationinparticipantsofEuropeanandAfrican
ancestry.

Location Variance
Closest MAF, Minorallele
SNP Chr relativeto Minor/majorallele Pvalue explained,
gene % effect,(SE)
gene %
Europeanancestry(n=37,678)
rs562408 1p32 Intronic SSBP3 A/G 44 0.53(0.09) 1.97x108 0.09
rs11689011 2p21 Intronic EPAS1 T/C 42 0.60(0.09) 1.18x1010 0.12
rs41312411 3p22 Intronic SCN5A G/C 15 1.91(0.15) 9.63x1040 0.43
rs6790396 3p22 Intronic SCN10A C/G 41 1.22(0.09) 2.17x1039 0.49
rs2285703 4q26 Intronic CAMK2D G/A 26 0.56(0.10) 3.77x108 0.08
rs4276421 5p12 Intergenic HCN1 C/T 42 0.61(0.09) 1.47x1011 0.12
rs13242816 7q31 Intronic CAV1/CAV2 T/C 8 1.21(0.19) 8.24x1011 0.11
rs148020424 12q24 Intronic TBX5 G/GGAAAGAAAGAAAAGAGAAA 27 0.85(0.12) 5.72x1013 0.13
rs452036 14q11 Intronic MYH6 A/G 36 0.59(0.10) 6.49x1010 0.09
Africanancestry(n=6778)
rs3922844 3p21 Intronic SCN5A T/C 47 1.66(0.22) 3.26x1014 0.83
rs1895582 12q24 Intronic TBX5 G/A 28 1.33(0.23) 1.41x108 0.49
Adjustedforageandsex.Chr,chromosome;MAF,Minorallelefrequency;SE,standarderror.

Page20of47


TableS5.SummaryofgeneticassociationsforPwavemaximumdurationincombinedancestryanalysis.

Location Minor/major MAF, Minoralleleeffect, Variance

SNP Chr Closestgene Pvalue
relativetogene allele % (SE) explained,%
rs562408 1p32 Intronic SSBP3 A/G 43% 0.52(0.09) 2.78x109 0.08
rs11894252 2p21 Intronic EPAS1 T/C 43% 0.52(0.09) 1.43x109 0.08
8
rs1467026 3p25 Intergenic CAND2 G/A 39% 0.51(0.09) 1.61x10 0.07
40
rs41312411 3p22 Intronic SCN5A G/C 15% 1.90(0.14) 1.85x10 0.41
rs4276421 5p12 Intergenic HCN1 C/T 44% 0.58(0.08) 3.52x1012 0.12
10
rs3801995 7q31 Intronic CAV1/CAV2 T/C 26% 0.60(0.09) 1.04x10 0.10
rs7312625 12q24 Intronic TBX5 G/A 27% 0.80(0.09) 2.41x1018 0.18
13
rs452036 14q11 Intronic MYH6 A/G 38% 0.64(0.09) 3.99x10 0.11
Adjustedforageandsex.Chr,chromosome;MAF,minorallelefrequency;SD,standarderror.

Page21of47

TableS6.ComparisonofallgenomewidesignificantlociacrossPwavedurationandPwaveterminal
forceanalyses.
Location Pwavedurationanalysis Pwaveterminalforceanalysis
Closest
SNP Chr relativeto Minorallele Minorallele
gene Pvalue Pvalue
gene effect,(SE) effect,(SE)
SignificantinPwavedurationanalysis
Europeanancestry(n=37,678)
rs562408 1p32 Intronic SSBP3 0.53(0.09) 1.97x108 7.29(13.13) 0.58
rs11689011 2p21 Intronic EPAS1 0.60(0.09) 1.18x1010 7.25(13.11) 0.58
rs41312411 3p22 Intronic SCN5A 1.91(0.15) 9.63x1040 0.68(20.36) 0.97
39
rs6790396 3p22 Intronic SCN10A 1.22(0.09) 2.17x10 NA NA
8
rs2285703 4q26 Intronic CAMK2D 0.56(0.10) 3.77x10 19.21(14.55) 0.19
11
rs4276421 5p12 Intergenic HCN1 0.61(0.09) 1.47x10 2.19(12.65) 0.86
11
rs13242816 7q31 Intronic CAV1 1.21(0.19) 8.24x10 9.71(26.00) 0.71
13
rs148020424 12q24 Intronic TBX5 0.85(0.12) 5.72x10 NA NA
10
rs452036 14q11 Intronic MYH6 0.59(0.10) 6.49x10 112.32(13.37) 4.44x1017
Africanancestry(n=6778)
rs3922844 3p21 Intronic SCN5A 1.66(0.22) 3.26x1014 12.90(37.29) 0.73
8
rs1895582 12q24 Intronic TBX5 1.33(0.23) 1.41x10 21.67(39.67) 0.58
SignificantinPwaveterminalforceanalysis
Europeanancestry(n=33,955)
rs12090194 1p13 Intronic KCND3 0.28(0.10) 0.004 119(13) 5.56x1019
rs11242779 6p25 Intergenic C6orf195 0.37(0.09) 6.37x105 71(13) 2.10x108
rs445754 14q11 Intronic MYH6 0.54(0.11) 5.11x107 131(15) 3.22x1018
rs201517563 15q25 Intergenic ALPK3 NA NA 86(15) 3.95x109
rs4435363 19q13 Intronic PPP5D1 0.24(0.11) 0.039 93(16) 3.84x109
Africanancestry(n=6778)
rs10832139 11p15 Intergenic SPON1 0.50(0.22) 0.025 214(38) 2.44x108
VariantsthatreachedgenomewidesignificanceinbothPwavedurationandPwaveterminalforceanalysesare
indicatedbyboldfont.Chr,chromosome;SE,standarderror;NA,notavailable.

Page22of47

TableS7.SharedassociationsbetweenthepresentPwavedurationGWASandpreviousPWIGWAS.

rsIDpresent Closest rsIDprevious Pwave

Chr Ancestry LD,r2CEU/YRI PRinterval PRsegment Heartrate
study gene study duration
rs41312411 3p22 SCN5A EUR rs11708996 0.94/NA EUR6
rs6599222 0.55/NA AA72 EUR12
rs7638909 0.16/NA Kosrae5* Kosrae5* Kosrae5*
rs3922844 3p21 SCN5A AA rs3922844 1/1 AA9,72 EUR12
rs11708996 0.07/NA EUR6
rs6599222 0.001/0.24 AA72 EUR12
rs7638909 0.05/0.006 Kosrae5* Kosrae5* Kosrae5*
rs6790396 3p21 SCN10A EUR rs6800541 1/NA EUR6,AS11
rs6795970 0.97/0.07 EUR7,AS11 AS10
rs6801957 0.97/1 AA9,AS11 EUR12 EUR12
rs6798015 0.87/0.51 AA72
rs13242816 7q31 CAV1 EUR rs3807989 0.11/NA EUR6,7,AS8,11 EUR12
rs11773845 0.11/NA AA9
rs3801995 7q31 CAV1 EUR+AA rs3807989 0.56/0.17 EUR6,7,AS8,11 EUR12
rs11773845 0.56/0.17 AA9
rs148020424 12q24 TBX5 EUR rs7312625 NA/NA AA72
rs3825214 NA/NA EUR7
rs1895585 NA/NA AA9
rs1895582 12q24 TBX5 AA rs7312625 0.80/0.81 AA72
rs3825214 0.65/0.33 EUR7
rs1895585 NA/NA AA9
rs7312625 12q24 TBX5 EUR+AA rs7312625 1/1 AA72
rs3825214 0.76/0.23 EUR7
rs1895585 0.87/0.78 AA9
rs452036 14q11 MYH6 EUR rs452036 1/1 EUR ,AA73
20

rs365990 0.96/1 EUR7,20,21,AA73

Page23of47

 rsIDpresent Closest rsIDprevious Pwave
Chr Ancestry LD,r2CEU/YRI PRinterval PRsegment Heartrate
study gene study duration
rs223116** 0.16/0.002 EUR20
OverviewofsharedgeneticlocibetweenpresentandpreviousGWAS.ThevariantsidentifiedinpreviousstudyarereportedwithrsID,LD
information,previouslyassociatedelectrocardiographicphenotype,anddiscoveryancestrygroup.Chr,chromosome;LD,Linkagedisequilibrium;
CEU,UtahresidentswithNorthernandWesternEuropeanancestryfromthe1000Genomes;YRI,YorubainIbadan,Nigeria,Africanancestry
groupfromthe1000Genomes;NA,notavailableinSNAPLDsearch;EUR,Europeanancestry;AA,AfricanAmericanancestry;AS,Asianancestry.
*FounderpopulationinMicronesia,**IntronictoMYH7.

Page24of47

TableS8.SignificanteQTLsinleftatrialtissuesamplesforgeneticlociassociatedwithPwaveduration.

Fold TSS
IndexSNP Closestgene/s* Chr Position rsID ProbeID Gene MA change** distance r2 FDR_gw FDR_dur
VariantsidentifiedinEuropeanethnicityGWASanalysiseQTLsinEuropeanAmericanatrialsamples
rs562408 SSBP3 1 54742618rs562408 ILMN_1814165 SSBP3 A 1.112 136.534 0.062 0.007 0.003
rs562408 SSBP3 1 54742471rs590041 ILMN_1814165 SSBP3 T 1.111 136.681 0.061 0.008 0.003
rs41312411 SCN5A 3 38624253rs3922844 ILMN_1694956 SCN5A T 1.080 66.911 0.040 0.075 0.034
rs13242816 CAV1 7 116198621rs1997571 ILMN_1687583 CAV1 G 0.819 33.782 0.1847.90x1010 5.40x1010
rs13242816 CAV1 7 116198828rs1997572 ILMN_1687583 CAV1 A 0.819 33.989 0.1847.90x1010 5.40x1010
rs13242816 CAV1 7 116186241rs3807989 ILMN_1687583 CAV1 A 0.819 21.402 0.1848.07x1010 5.40x1010
rs13242816 CAV1 7 116191301rs11773845 ILMN_1687583 CAV1 C 0.819 26.462 0.1848.16x1010 5.40x1010
rs13242816 CAV1 7 116194228rs7804372 ILMN_1687583 CAV1 A 0.859 29.389 0.082 0.001 0.0005
rs13242816 CAV1 7 116197579rs3807994 ILMN_1687583 CAV1 A 0.860 32.74 0.080 0.001 0.0005
rs13242816 CAV1 7 116198466rs10953822 ILMN_1687583 CAV1 C 0.860 33.627 0.080 0.001 0.0005
rs13242816 CAV1 7 116198090rs6466588 ILMN_1687583 CAV1 T 0.860 33.251 0.080 0.001 0.0005
rs13242816 CAV1 7 116197245rs3807992 ILMN_1687583 CAV1 A 0.860 32.406 0.080 0.001 0.0005
rs13242816 CAV1 7 116196763rs3807990 ILMN_1687583 CAV1 T 0.860 31.924 0.080 0.001 0.0005
rs13242816 CAV1 7 116193705rs3757732 ILMN_1687583 CAV1 A 0.860 28.866 0.079 0.001 0.0005
rs13242816 CAV1 7 116193729rs3757733 ILMN_1687583 CAV1 A 0.860 28.89 0.079 0.001 0.0005
rs13242816 CAV1 7 116190597rs3801995 ILMN_1687583 CAV1 T 0.860 25.758 0.079 0.001 0.0005
rs13242816 CAV1 7 116190693rs3815412 ILMN_1687583 CAV1 C 0.860 25.854 0.079 0.001 0.0005
rs13242816 CAV1 7 116194905rs729949 ILMN_1687583 CAV1 A 0.860 30.066 0.079 0.001 0.0005
rs13242816 CAV1 7 116194384rs7789117 ILMN_1687583 CAV1 T 0.860 29.545 0.079 0.001 0.0005
rs13242816 CAV1 7 116191812rs9885998 ILMN_1687583 CAV1 A 0.860 26.973 0.079 0.001 0.0005
rs13242816 CAV1 7 116191697rs9886216 ILMN_1687583 CAV1 G 0.860 26.858 0.079 0.001 0.0005
rs13242816 CAV1 7 116198621rs1997571 ILMN_2149226 CAV1 G 1.043 33.782 0.071 0.002 0.001
rs13242816 CAV1 7 116198828rs1997572 ILMN_2149226 CAV1 A 1.043 33.989 0.071 0.002 0.001
rs13242816 CAV1 7 116191301rs11773845 ILMN_2149226 CAV1 C 1.043 26.462 0.071 0.003 0.001
rs13242816 CAV1 7 116186241rs3807989 ILMN_2149226 CAV1 A 1.043 21.402 0.070 0.003 0.001
rs13242816 CAV1 7 116198621rs1997571 ILMN_1735220 CAV2 G 1.051 271.187 0.053 0.019 0.009
rs13242816 CAV1 7 116198828rs1997572 ILMN_1735220 CAV2 A 1.051 271.394 0.053 0.019 0.009

Page25of47

rs13242816 CAV1 7 116191301rs11773845 ILMN_1735220 CAV2 C 1.051 263.867 0.052 0.020 0.010
rs13242816 CAV1 7 116186241rs3807989 ILMN_1735220 CAV2 A 1.051 258.807 0.052 0.021 0.010
rs13242816 CAV1 7 116197579rs3807994 ILMN_2149226 CAV1 A 1.037 32.74 0.040 0.074 0.034
rs13242816 CAV1 7 116196763rs3807990 ILMN_2149226 CAV1 T 1.037 31.924 0.040 0.074 0.034
rs13242816 CAV1 7 116198466rs10953822 ILMN_2149226 CAV1 C 1.037 33.627 0.040 0.075 0.034
rs13242816 CAV1 7 116198090rs6466588 ILMN_2149226 CAV1 T 1.037 33.251 0.040 0.075 0.034
rs13242816 CAV1 7 116197245rs3807992 ILMN_2149226 CAV1 A 1.037 32.406 0.040 0.075 0.034
rs13242816 CAV1 7 116193705rs3757732 ILMN_2149226 CAV1 A 1.037 28.866 0.040 0.075 0.034
rs13242816 CAV1 7 116193729rs3757733 ILMN_2149226 CAV1 A 1.037 28.89 0.040 0.075 0.034
rs13242816 CAV1 7 116190597rs3801995 ILMN_2149226 CAV1 T 1.037 25.758 0.040 0.075 0.034
rs13242816 CAV1 7 116190693rs3815412 ILMN_2149226 CAV1 C 1.037 25.854 0.040 0.075 0.034
rs13242816 CAV1 7 116194905rs729949 ILMN_2149226 CAV1 A 1.037 30.066 0.040 0.075 0.034
rs13242816 CAV1 7 116194384rs7789117 ILMN_2149226 CAV1 T 1.037 29.545 0.040 0.075 0.034
rs13242816 CAV1 7 116191812rs9885998 ILMN_2149226 CAV1 A 1.037 26.973 0.040 0.075 0.034
rs13242816 CAV1 7 116191697rs9886216 ILMN_2149226 CAV1 G 1.037 26.858 0.040 0.075 0.034
rs13242816 CAV1 7 116194228rs7804372 ILMN_1735220 CAV2 A 1.051 266.794 0.039 0.082 0.037
rs148020424 TBX5 12 114802361rs1946295 ILMN_1742362 TBX5 A 0.891 43.886 0.074 0.002 0.001
rs148020424 TBX5 12 114804898rs3825215 ILMN_1742362 TBX5 G 0.891 41.349 0.074 0.002 0.001
rs148020424 TBX5 12 114802138rs1895585 ILMN_1742362 TBX5 A 0.891 44.109 0.073 0.002 0.001
rs148020424 TBX5 12 114800813rs4767237 ILMN_1742362 TBX5 A 0.891 45.434 0.073 0.002 0.001
rs148020424 TBX5 12 114807035rs1895582 ILMN_1742362 TBX5 G 0.890 39.212 0.072 0.002 0.001
rs148020424 TBX5 12 114806885rs1895583 ILMN_1742362 TBX5 A 0.891 39.362 0.070 0.003 0.001
rs148020424 LOC255480;TBX5 12 114789226rs2384407 ILMN_1742362 TBX5 G 0.899 57.021 0.067 0.004 0.002
rs148020424 TBX5 12 114799974rs7312625 ILMN_1742362 TBX5 G 0.898 46.273 0.066 0.004 0.002
rs148020424 TBX5 12 114805057rs148020424 ILMN_1742362 TBX5 G 0.898 41.19 0.064 0.006 0.003
rs148020424 TBX5 12 114802760rs1946293 ILMN_1742362 TBX5 G 0.902 43.487 0.060 0.008 0.004
rs148020424 TBX5 12 114801772rs7135659 ILMN_1742362 TBX5 G 0.902 44.475 0.060 0.008 0.004
rs148020424 TBX5 12 114793240rs883079 ILMN_1742362 TBX5 C 0.905 53.007 0.060 0.008 0.004
rs148020424 TBX5 12 114797306rs7955405 ILMN_1742362 TBX5 A 0.908 48.941 0.054 0.017 0.008
rs148020424 TBX5 12 114797093rs10507248 ILMN_1742362 TBX5 G 0.908 49.154 0.054 0.017 0.008
rs148020424 LOC255480;TBX5 12 114789350rs2384408 ILMN_1742362 TBX5 A 0.899 56.897 0.048 0.032 0.016
rs148020424 TBX5 12 114766735rs10850315 ILMN_1742362 TBX5 G 0.916 79.512 0.044 0.048 0.027

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rs148020424 TBX5 12 114807655rs11378406 ILMN_1742362 TBX5 A
0.912 38.592 0.043 0.055 0.032
rs148020424 LOC255480;TBX5 12 114789810rs2891503 ILMN_1742362 TBX5 A 0.913 56.437 0.042 0.062 0.034
rs148020424 LOC255480;TBX5 12 114790884rs1895597 ILMN_1742362 TBX5 T 0.912 55.363 0.042 0.063 0.034
rs148020424 LOC255480;TBX5 12 114790500rs7977083 ILMN_1742362 TBX5 A 0.916 55.747 0.041 0.065 0.034
rs148020424 TBX5 12 114794057rs2113433 ILMN_1742362 TBX5 T 0.909 52.19 0.041 0.066 0.034
rs148020424 LOC255480;TBX5 12 114791455rs7316919 ILMN_1742362 TBX5 A 0.917 54.792 0.041 0.068 0.034
rs148020424 LOC255480;TBX5 12 114789046rs7308120 ILMN_1742362 TBX5 T 0.907 57.201 0.040 0.072 0.034
VariantsidentifiedincombinedethnicityGWASanalysiseQTLsinEuropeanAmericanatrialsamples
rs562408 SSBP3 1 54742618rs562408 ILMN_1814165 SSBP3 A 1.112 136.534 0.062 0.007 0.003
rs562408 SSBP3 1 54741767rs603901 ILMN_1814165 SSBP3 C 1.110 137.385 0.060 0.008 0.003
rs562408 SSBP3 1 54736800rs9662034 ILMN_1814165 SSBP3 C 1.106 142.352 0.056 0.014 0.006
rs562408 SSBP3 1 54735974rs1537430 ILMN_1814165 SSBP3 C 1.106 143.178 0.055 0.015 0.006
rs562408 SSBP3 1 54732940rs679200 ILMN_1814165 SSBP3 A 1.099 146.212 0.050 0.025 0.010
rs41312411 SCN5A 3 38624253rs3922844 ILMN_1694956 SCN5A T 1.080 66.911 0.040 0.075 0.030
rs3801995 CAV2 7 116145957rs4730743 ILMN_1687583 CAV1 A 0.805 18.882 0.2372.93x1013 2.25x1013
rs3801995 CAV2 7 116145849rs10271007 ILMN_1687583 CAV1 A 0.805 18.99 0.2372.95x1013 2.25x1013
rs3801995 CAV1 7 116198621rs1997571 ILMN_1687583 CAV1 G 0.819 33.782 0.1847.90x1010 4.20x1010
rs3801995 CAV1 7 116198828rs1997572 ILMN_1687583 CAV1 A 0.819 33.989 0.1847.90x1010 4.20x1010
rs3801995 CAV1 7 116186241rs3807989 ILMN_1687583 CAV1 A 0.819 21.402 0.1848.07x1010 4.20x1010
rs3801995 CAV1;CAV2 7 116118330rs926197 ILMN_1687583 CAV1 C 0.827 46.509 0.182 1.00x109 4.44x1010
rs3801995 CAV2 7 116145849rs10271007 ILMN_1735220 CAV2 A 1.088 218.415 0.161 2.09x108 8.56x109
rs3801995 CAV2 7 116145957rs4730743 ILMN_1735220 CAV2 A 1.088 218.523 0.161 2.10x108 8.56x109
rs3801995 CAV1;CAV2 7 116118330rs926197 ILMN_1735220 CAV2 C 1.079 190.896 0.133 9.91x107 4.89x107
rs3801995 CAV1 7 116194228rs7804372 ILMN_1687583 CAV1 A 0.859 29.389 0.082 0.001 0.0004
rs3801995 CAV1 7 116197579rs3807994 ILMN_1687583 CAV1 A 0.860 32.74 0.080 0.001 0.0004
rs3801995 CAV1 7 116198466rs10953822 ILMN_1687583 CAV1 C 0.860 33.627 0.080 0.001 0.0004
rs3801995 CAV1 7 116197245rs3807992 ILMN_1687583 CAV1 A 0.860 32.406 0.080 0.001 0.0004
rs3801995 CAV1 7 116196763rs3807990 ILMN_1687583 CAV1 T 0.860 31.924 0.080 0.001 0.0004
rs3801995 CAV1 7 116193705rs3757732 ILMN_1687583 CAV1 A 0.860 28.866 0.079 0.001 0.0004
rs3801995 CAV1 7 116193729rs3757733 ILMN_1687583 CAV1 A 0.860 28.89 0.079 0.001 0.0004
rs3801995 CAV1 7 116190597rs3801995 ILMN_1687583 CAV1 T 0.860 25.758 0.079 0.001 0.0004
rs3801995 CAV1 7 116190693rs3815412 ILMN_1687583 CAV1 C 0.860 25.854 0.079 0.001 0.0004

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rs3801995 CAV1 7 116194905rs729949 ILMN_1687583 CAV1 A 0.860 30.066 0.079 0.001 0.0004
rs3801995 CAV1 7 116194384rs7789117 ILMN_1687583 CAV1 T 0.860 29.545 0.079 0.001 0.0004
rs3801995 CAV1 7 116191812rs9885998 ILMN_1687583 CAV1 A 0.860 26.973 0.079 0.001 0.0004
rs3801995 CAV1 7 116191697rs9886216 ILMN_1687583 CAV1 G 0.860 26.858 0.079 0.001 0.0004
rs3801995 CAV1 7 116198621rs1997571 ILMN_2149226 CAV1 G 1.043 33.782 0.071 0.002 0.001
rs3801995 CAV1 7 116198828rs1997572 ILMN_2149226 CAV1 A 1.043 33.989 0.071 0.002 0.001
rs3801995 CAV1 7 116186241rs3807989 ILMN_2149226 CAV1 A 1.043 21.402 0.070 0.003 0.001
rs3801995 CAV2 7 116145957rs4730743 ILMN_2149226 CAV1 A 1.040 18.882 0.066 0.004 0.002
rs3801995 CAV2 7 116145849rs10271007 ILMN_2149226 CAV1 A 1.040 18.99 0.066 0.004 0.002
rs3801995 CAV1 7 116198621rs1997571 ILMN_1735220 CAV2 G 1.051 271.187 0.053 0.019 0.007
rs3801995 CAV1 7 116198828rs1997572 ILMN_1735220 CAV2 A 1.051 271.394 0.053 0.019 0.007
rs3801995 CAV1 7 116186241rs3807989 ILMN_1735220 CAV2 A 1.051 258.807 0.052 0.021 0.009
rs3801995 CAV1 7 116197579rs3807994 ILMN_2149226 CAV1 A 1.037 32.74 0.040 0.074 0.030
rs3801995 CAV1 7 116196763rs3807990 ILMN_2149226 CAV1 T 1.037 31.924 0.040 0.074 0.030
rs3801995 CAV1 7 116198466rs10953822 ILMN_2149226 CAV1 C 1.037 33.627 0.040 0.075 0.030
rs3801995 CAV1 7 116197245rs3807992 ILMN_2149226 CAV1 A 1.037 32.406 0.040 0.075 0.030
rs3801995 CAV1 7 116193705rs3757732 ILMN_2149226 CAV1 A 1.037 28.866 0.040 0.075 0.030
rs3801995 CAV1 7 116193729rs3757733 ILMN_2149226 CAV1 A 1.037 28.89 0.040 0.075 0.030
rs3801995 CAV1 7 116190597rs3801995 ILMN_2149226 CAV1 T 1.037 25.758 0.040 0.075 0.030
rs3801995 CAV1 7 116190693rs3815412 ILMN_2149226 CAV1 C 1.037 25.854 0.040 0.075 0.030
rs3801995 CAV1 7 116194905rs729949 ILMN_2149226 CAV1 A 1.037 30.066 0.040 0.075 0.030
rs3801995 CAV1 7 116194384rs7789117 ILMN_2149226 CAV1 T 1.037 29.545 0.040 0.075 0.030
rs3801995 CAV1 7 116191812rs9885998 ILMN_2149226 CAV1 A 1.037 26.973 0.040 0.075 0.030
rs3801995 CAV1 7 116191697rs9886216 ILMN_2149226 CAV1 G 1.037 26.858 0.040 0.075 0.030
rs3801995 CAV1 7 116194228rs7804372 ILMN_1735220 CAV2 A 1.051 266.794 0.039 0.082 0.033
rs3801995 CAV1;CAV2 7 116118330rs926197 ILMN_2149226 CAV1 C 1.029 46.509 0.036 0.109 0.049
rs7312625 TBX5 12 114802361rs1946295 ILMN_1742362 TBX5 A 0.891 43.886 0.074 0.002 0.001
rs7312625 TBX5 12 114804898rs3825215 ILMN_1742362 TBX5 G 0.891 41.349 0.074 0.002 0.001
rs7312625 TBX5 12 114802138rs1895585 ILMN_1742362 TBX5 A 0.891 44.109 0.073 0.002 0.001
rs7312625 TBX5 12 114800813rs4767237 ILMN_1742362 TBX5 A 0.891 45.434 0.073 0.002 0.001
rs7312625 TBX5 12 114807035rs1895582 ILMN_1742362 TBX5 G 0.890 39.212 0.072 0.002 0.001
rs7312625 TBX5 12 114806885rs1895583 ILMN_1742362 TBX5 A 0.891 39.362 0.070 0.003 0.001

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rs7312625 LOC255480;TBX5 12 114789226rs2384407 ILMN_1742362 TBX5 G 0.899 57.021 0.067 0.004 0.002
rs7312625 TBX5 12 114799974rs7312625 ILMN_1742362 TBX5 G 0.898 46.273 0.066 0.004 0.002
rs7312625 TBX5 12 114805057rs148020424 ILMN_1742362 TBX5 G 0.898 41.19 0.064 0.006 0.002
rs7312625 TBX5 12 114802760rs1946293 ILMN_1742362 TBX5 G 0.902 43.487 0.060 0.008 0.003
rs7312625 TBX5 12 114801772rs7135659 ILMN_1742362 TBX5 G 0.902 44.475 0.060 0.008 0.003
rs7312625 TBX5 12 114793240rs883079 ILMN_1742362 TBX5 C 0.905 53.007 0.060 0.008 0.003
rs7312625 TBX5 12 114797306rs7955405 ILMN_1742362 TBX5 A 0.908 48.941 0.054 0.017 0.007
rs7312625 TBX5 12 114797093rs10507248 ILMN_1742362 TBX5 G 0.908 49.154 0.054 0.017 0.007
rs7312625 LOC255480;TBX5 12 114789350rs2384408 ILMN_1742362 TBX5 A 0.899 56.897 0.048 0.032 0.014
rs7312625 TBX5 12 114766735rs10850315 ILMN_1742362 TBX5 G 0.916 79.512 0.044 0.048 0.023
rs7312625 TBX5 12 114807655rs11378406 ILMN_1742362 TBX5 A
0.912 38.592 0.043 0.055 0.027
rs7312625 LOC255480;TBX5 12 114789810rs2891503 ILMN_1742362 TBX5 A 0.913 56.437 0.042 0.062 0.030
rs7312625 LOC255480;TBX5 12 114790884rs1895597 ILMN_1742362 TBX5 T 0.912 55.363 0.042 0.063 0.030
rs7312625 LOC255480;TBX5 12 114789478rs2384409 ILMN_1742362 TBX5 A 0.908 56.769 0.041 0.064 0.030
rs7312625 LOC255480;TBX5 12 114790500rs7977083 ILMN_1742362 TBX5 A 0.916 55.747 0.041 0.065 0.030
rs7312625 TBX5 12 114794057rs2113433 ILMN_1742362 TBX5 T 0.909 52.19 0.041 0.066 0.030
rs7312625 LOC255480;TBX5 12 114791455rs7316919 ILMN_1742362 TBX5 A 0.917 54.792 0.041 0.068 0.030
rs7312625 LOC255480;TBX5 12 114789046rs7308120 ILMN_1742362 TBX5 T 0.907 57.201 0.040 0.072 0.030
rs7312625 TBX5 12 114792236rs6489956 ILMN_1742362 TBX5 T 0.912 54.011 0.039 0.085 0.035
rs7312625 TBX5 12 114814286rs7964303 ILMN_1742362 TBX5 T 0.919 31.961 0.037 0.102 0.044
rs7312625 LOC255480;TBX5 12 114791528rs1895596 ILMN_1742362 TBX5 A 0.905 54.719 0.036 0.110 0.049
rs452036 MYH6 14 23863802rs445754 ILMN_1702105 EFS T 1.091 28.841 0.036 0.113 0.050
VariantsidentifiedinAfricanAmericanethnicityGWASanalysiseQTLsinEuropeanAmericanatrialsamples
rs3922844 SCN5A 3 38624253rs3922844 ILMN_1694956 SCN5A T 1.080 66.911 0.040 0.075 0.003
rs1895582 TBX5 12 114807035rs1895582 ILMN_1742362 TBX5 G 0.890 39.212 0.072 0.002 0.0001
rs1895582 TBX5 12 114799974rs7312625 ILMN_1742362 TBX5 G 0.898 46.273 0.066 0.004 0.0001
rs1895582 TBX5 12 114807035rs1895582 ILMN_2376958 TBX5 G 0.947 39.212 0.024 0.303 0.022

FilteredatFDR_dur<0.05.GreyhighlightingofrowsindicateseQTLsthatdidnotreachgenomewideFDR.TherewerenosignificanteQTLsfor
variantsidentifiedintheAfricanAmericanancestryanalysisorthecombinedancestryanalysisintheAfricanAmericanatrialsamples.TSS,
transcriptionstartsite;SNP,singlenucleotidepolymorphism;Chr,chromosome.MA,minoralleleintheatrialtissuebiobank.*Boldtext
indicatesvariantlocatedingene,otherwiseclosestgene/s.**FoldchangeinexpressionwhendosageofMAincreasesby1.Explained

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(adjusted)variationinprobeIDbydosageofrsID/squaredadjustedPearsoncorrelation.Genomewidefalsediscoveryrate.Falsediscovery
ratespecifictovariantset.

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TableS9.SignificanteQTLsintheGTExdatabase.

Closest
SNP Chr Ancestry eQTLgene SmallesteQTLPvalue Tissue
gene

Pwaveduration
rs562408 1p32 SSBP3 EUR SSBP3 3.47x1012 Atrialappendage
EUR SSBP3 3.21x106 Leftventricle
EUR MRPL37 10
2.9x10 Atrialappendage
rs1895582 12q24 TBX5 AA TBX5 6
3.84x10 Leftventricle
rs1467026 3p25 CAND2 EA+AA CAND2 7.5x1027 Skeletalmuscle
KRT18P17 11
9.19x10 Skeletalmuscle
RP11767C1.2 9
1.2x10 Skeletalmuscle
Pwaveterminalforce
rs11073730 15q25 ALPK3 EUR RP11182J1.16 1.71x107 Atrialappendage
7
EUR CSPG4P11 1.79x10 Atrialappendage
EUR AC103965.1 2.82x108 Atrialappendage
8
EUR AC103965.1 9.04x10 Leftventricle
6
EUR RP11182J1.16 9.83x10 Leftventricle
EUR WDR73 1.12x107 Leftventricle
10
EUR AC103965.1 9.34x10 Skeletalmuscle
17
EUR ALPK3 1.12x10 Skeletalmuscle
EUR CSPG4P11 1.08x105 Skeletalmuscle
8
EUR WDR73 1.37x10 Skeletalmuscle
Chr,chromosome;EUR,Europeanancestry;AA,AfricanAmericanancestry

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TableS10.SummaryofgenomewidesignificantgeneticassociationsforPwaveterminalforceinparticipantsofEuropeanandAfrican
ancestry.

Location
Minor/major Minorallele Variance
SNP Chr relativeto Closestgene MAF,% Pvalue
allele effect,(SE) explained,%
gene
Europeanancestry(n=33,955)
rs12090194 1p13 Intronic KCND3 T/C 32 119(13) 5.56x1019 0.25
rs11242779 6p25 Intergenic C6orf195 C/T 49 71(13) 2.10x108 0.09
rs445754 14q11 Intronic MYH6 T/G 23 131(15) 3.22x1018 0.22
rs201517563 15q25 Intronic ALPK3/NMB TA/T 47 86(15) 3.95x109 0.10
rs4435363 19q13 Intronic PPP5D1 G/A 20 93(16) 3.84x109 0.10
Africanancestry(n=6778)
rs10832139 11p15 Intergenic SPON1 G/A 41 214(38) 2.44x108 0.47
Adjustedforageandsex.Chr,chromosome;MAF,Minorallelefrequency;SE,standarderror.

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TableS11.SummaryofgeneticassociationsforPwaveterminalforceincombinedancestryanalysis

Location
Closest Minor/ Minorallele Variance
SNP Chr relativeto MAF,% Pvalue
gene majorallele effect,(SE) explained,%
gene
rs4839185 1p13 Intronic KCND3 C/T 31% 117(13) 3.14x1020 0.20
rs11099412 4q28 Intergenic PCDH18 A/G 11% 244(41) 2.52x109 0.09
9
rs11242779 6p25 Intergenic C6orf195 C/T 48% 72(12) 7.90x10 0.09
rs445754 14q11 Intronic MYH6 T/G 24% 136(14) 4.20x1022 0.23
10
rs2115630 15q25 Intronic ALPK3/NMB T/C 46% 85(14) 6.38x10 0.09
9
rs4435363 19q13 Intronic PPP5D1 G/A 20% 96(16) 1.15x10 0.09
Adjustedforageandsex.Chr,chromosome;MAF,minorallelefrequency;SD,standarderror.

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 TableS12.SharedassociationsbetweenpresentandpreviousGWASofPwaveterminalforce.
rsID rsID
present Closest previous LD,r2 Pwave
study Chr gene Ancestry study CEU/YRI PRinterval duration PRsegment Heartrate
rs12090194 1p13 KCND3 EUR rs2798334 0.20/0.01 EUR 12
rs4839185 1p13 KCND3 EUR+AA rs2798334 NA/NA EUR12
rs445754 14q11 MYH6 EUR rs452036 0.65/0.26 EUR* EUR20,AA73
rs365990 0.62/0.26 EUR7,21,AA73
OverviewofsharedgeneticlocibetweenpresentandpreviousGWAS.ThevariantsidentifiedinpreviousstudiesarereportedwithrsID,LD
information,previouslyassociatedelectrocardiographicphenotype,andancestrygroup.Chr,chromosome;LD,Linkagedisequilibrium;CEU,
UtahresidentswithNorthernandWesternEuropeanancestryfromthe1000Genomes;YRI,YorubainIbadan,Nigeria,Africanancestrygroup
fromthe1000Genomes;NA,notavailableinSNAPLDsearch;EUR,Europeanancestry;AA,AfricanAmericanancestry.*Variantfromthe
presentstudyonPwaveduration.

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TableS13.SignificanteQTLsinleftatrialtissuesamplesforgeneticlociassociatedwithPwaveterminalforce.

Closest Fold TSS

IndexSNP gene/s* Chr Position eQTLSNP ProbeID Gene MA change** distance r2 FDR_gw FDR_dur
VariantsidentifiedinEuropeanancestryGWASanalysiseQTLsinEuropeanAmericanatrialsamples
rs201517563 ALPK3 15 85361960rs4633690 ILMN_2347592 NMB T 1.122 160.166 0.060 0.009 0.024
rs201517563 ALPK3 15 85363708rs11854291 ILMN_2347592 NMB C 1.123 161.914 0.060 0.009 0.024
rs201517563 ALPK3 15 85364516rs2115630 ILMN_2347592 NMB T 1.123 162.722 0.060 0.009 0.024
rs201517563 ALPK3 15 85355841rs35828350 ILMN_2347592 NMB A 0.874 154.047 0.058 0.011 0.024
rs201517563 ZNF592 15 85276935rs58581703 ILMN_2347592 NMB T 1.117 75.141 0.053 0.019 0.031
rs201517563 ZNF592 15 85318065rs11633377 ILMN_2347592 NMB G 0.888 116.271 0.051 0.024 0.031
rs201517563 ZNF592 15 85344550rs12912388 ILMN_2347592 NMB A 0.888 142.756 0.051 0.024 0.031
rs201517563 ZNF592 15 85343980rs35960805 ILMN_2347592 NMB G 0.888 142.186 0.051 0.024 0.031
rs201517563 ZNF592 15 85347709rs17601029 ILMN_2347592 NMB G 0.888 145.915 0.050 0.026 0.031
rs201517563 ALPK3 15 85373498rs35545192 ILMN_2347592 NMB CT 0.890 171.704 0.049 0.030 0.033
rs201517563 ALPK3 15 85377441rs35808647 ILMN_2347592 NMB A 0.891 175.647 0.048 0.033 0.035
rs201517563 ALPK3 15 85374112rs2340652 ILMN_2347592 NMB G 0.891 172.318 0.046 0.040 0.040
rs201517563 SEC11A 15 85242529rs8029660 ILMN_2347592 NMB A 1.112 40.735 0.045 0.046 0.044
VariantsidentifiedincombinedancestryGWASanalysiseQTLsinEuropeanAmericanatrialsamples
rs2115630 ALPK3 15 85361960rs4633690 ILMN_2347592 NMB T 1.122 160.166 0.060 0.009 0.011
rs2115630 ALPK3 15 85363708rs11854291 ILMN_2347592 NMB C 1.123 161.914 0.060 0.009 0.011
rs2115630 ALPK3 15 85364516rs2115630 ILMN_2347592 NMB T 1.123 162.722 0.060 0.009 0.011
rs2115630 SEC11A 15 85253258rs8033459 ILMN_2347592 NMB T 1.124 51.464 0.059 0.009 0.011
rs2115630 ALPK3 15 85372645rs6496452 ILMN_2347592 NMB T 1.124 170.851 0.059 0.010 0.011
rs2115630 ALPK3 15 85355841rs35828350 ILMN_2347592 NMB A 0.874 154.047 0.058 0.011 0.011
rs2115630 SEC11A 15 85255385rs8027779 ILMN_2347592 NMB C 1.118 53.591 0.054 0.017 0.011
rs2115630 ZNF592 15 85334952rs28595395 ILMN_2347592 NMB C 1.121 133.158 0.054 0.017 0.011
rs2115630 ALPK3 15 85357649rs56864281 ILMN_2347592 NMB A 0.882 155.855 0.054 0.017 0.011
rs2115630 ZNF592 15 85333396rs61074241 ILMN_2347592 NMB T 0.877 131.602 0.053 0.018 0.011
rs2115630 ZNF592 15 85282635rs1030863 ILMN_2347592 NMB T 1.118 80.841 0.053 0.018 0.011
rs2115630 ZNF592 15 85349231rs35630683 ILMN_2347592 NMB C 0.883 147.437 0.053 0.018 0.011
rs2115630 ZNF592 15 85318080rs9788687 ILMN_2347592 NMB T 1.117 116.286 0.053 0.019 0.011

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rs2115630 ZNF592 15 85276935rs58581703 ILMN_2347592 NMB T 1.117 75.141 0.053 0.019 0.011
rs2115630 ZNF592 15 85320924rs202221250ILMN_2347592 NMB AC 1.117 119.13 0.053 0.019 0.011
rs2115630 ZNF592 15 85323568rs55646601 ILMN_2347592 NMB T 1.117 121.774 0.052 0.020 0.011
rs2115630 ZNF592 15 85350081rs11073729 ILMN_2347592 NMB C 1.115 148.287 0.052 0.020 0.011
rs2115630 ZNF592 15 85297793rs6496401 ILMN_2347592 NMB T 1.116 95.999 0.052 0.020 0.011
rs2115630 ZNF592 15 85280212rs34570071 ILMN_2347592 NMB A 0.885 78.418 0.052 0.022 0.011
rs2115630 SEC11A 15 85273880rs12592554 ILMN_2347592 NMB A 1.116 72.086 0.052 0.022 0.011
rs2115630 ZNF592 15 85277888rs8028490 ILMN_2347592 NMB A 1.116 76.094 0.051 0.023 0.011
rs2115630 ZNF592 15 85318065rs11633377 ILMN_2347592 NMB G 0.888 116.271 0.051 0.024 0.011
rs2115630 ZNF592 15 85302373rs12899981 ILMN_2347592 NMB A 0.888 100.579 0.051 0.024 0.011
rs2115630 ZNF592 15 85337699rs12903134 ILMN_2347592 NMB A 0.888 135.905 0.051 0.024 0.011
rs2115630 ZNF592 15 85322351rs12908549 ILMN_2347592 NMB G 0.888 120.557 0.051 0.024 0.011
rs2115630 ZNF592 15 85344550rs12912388 ILMN_2347592 NMB A 0.888 142.756 0.051 0.024 0.011
rs2115630 ZNF592 15 85337800rs35726233 ILMN_2347592 NMB T 0.888 136.006 0.051 0.024 0.011
rs2115630 ZNF592 15 85311382rs35758837 ILMN_2347592 NMB T 0.888 109.588 0.051 0.024 0.011
rs2115630 ZNF592 15 85343980rs35960805 ILMN_2347592 NMB G 0.888 142.186 0.051 0.024 0.011
rs2115630 ZNF592 15 85319692rs36033486 ILMN_2347592 NMB G 0.888 117.898 0.051 0.024 0.011
rs2115630 ZNF592 15 85321220rs62019469 ILMN_2347592 NMB C 0.888 119.426 0.051 0.024 0.011
rs2115630 ZNF592 15 85288087rs62019463 ILMN_2347592 NMB A 0.888 86.293 0.051 0.024 0.011
rs2115630 ZNF592 15 85285536rs17599989 ILMN_2347592 NMB C 0.888 83.742 0.051 0.024 0.011
rs2115630 ZNF592 15 85280210rs35738019 ILMN_2347592 NMB C 0.888 78.416 0.051 0.024 0.011
rs2115630 ZNF592 15 85280792rs60957376 ILMN_2347592 NMB G 0.888 78.998 0.051 0.024 0.011
rs2115630 ZNF592 15 85316465rs12914760 ILMN_2347592 NMB T 0.887 114.671 0.051 0.024 0.011
rs2115630 ZNF592 15 85298662rs12910012 ILMN_2347592 NMB C 0.888 96.868 0.051 0.024 0.011
rs2115630 SEC11A 15 85268036rs62021226 ILMN_2347592 NMB C 0.888 66.242 0.050 0.025 0.011
rs2115630 ZNF592 15 85294469rs62019464 ILMN_2347592 NMB A 0.888 92.675 0.050 0.025 0.011
rs2115630 SEC11A 15 85264461rs58416181 ILMN_2347592 NMB A 0.888 62.667 0.050 0.025 0.011
rs2115630 ZNF592 15 85324467rs11633267 ILMN_2347592 NMB C 0.888 122.673 0.050 0.025 0.011
rs2115630 ZNF592 15 85347709rs17601029 ILMN_2347592 NMB G 0.888 145.915 0.050 0.026 0.011
rs2115630 ZNF592 15 85331271rs34342559 ILMN_2347592 NMB G 0.888 129.477 0.049 0.028 0.011
rs2115630 ZNF592 15 85331629rs35557864 ILMN_2347592 NMB G 0.888 129.835 0.049 0.028 0.011
rs2115630 ZNF592 15 85331493rs62019472 ILMN_2347592 NMB G 0.888 129.699 0.049 0.028 0.011

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rs2115630 ALPK3 15 85373498rs35545192 ILMN_2347592 NMB CT 0.890 171.704 0.049 0.030 0.012
rs2115630 ALPK3 15 85377441rs35808647 ILMN_2347592 NMB A 0.891 175.647 0.048 0.033 0.013
rs2115630 SEC11A 15 85258203rs35524990 ILMN_2347592 NMB C 0.890 56.409 0.048 0.034 0.013
rs2115630 SEC11A 15 85257599rs34900908 ILMN_2347592 NMB A 0.890 55.805 0.048 0.034 0.013
rs2115630 SEC11A 15 85256159rs62021219 ILMN_2347592 NMB T 0.890 54.365 0.047 0.034 0.013
rs2115630 SEC11A 15 85256303rs12907808 ILMN_2347592 NMB C 0.890 54.509 0.047 0.034 0.013
rs2115630 SEC11A 15 85250253rs4643294 ILMN_2347592 NMB T 0.890 48.459 0.047 0.035 0.013
rs2115630 SEC11A 15 85248133rs35316992 ILMN_2347592 NMB G 0.891 46.339 0.047 0.035 0.013
rs2115630 SEC11A 15 85240403rs12908699 ILMN_2347592 NMB T 0.891 38.609 0.047 0.036 0.013
rs2115630 SEC11A 15 85231585rs34028043 ILMN_2347592 NMB A 0.892 29.791 0.046 0.038 0.014
rs2115630 ALPK3 15 85374112rs2340652 ILMN_2347592 NMB G 0.891 172.318 0.046 0.040 0.014
rs2115630 ZNF592 15 85354596rs11073730 ILMN_2347592 NMB T 1.104 152.802 0.042 0.063 0.026

FilteredatFDR_ptf<0.05.GreyhighlightingofrowsindicateseQTLsthatdidnotreachgenomewideFDR.TherewerenosignificanteQTLsfor
variantsidentifiedintheAfricanAmericanandcombinedancestryanalysisintheAfricanAmericanatrialsamplesandnosignificanteQTLsfor
variantsidentifiedintheAfricanAmericanancestryanalysisintheEuropeanancestryatrialsamples.TSS,transcriptionstartsite;SNP,single
nucleotidepolymorphism;Chr,chromosome;MA,minoralleleintheatrialtissuebiobank.*Boldtextindicatesvariantlocatedingene,
otherwiseclosestgene/s.**FoldchangeinexpressionwhendosageofMAincreasesby1.Explained(adjusted)varia oninprobeIDbydosage
ofrsID/squaredadjustedPearsoncorrelation.Genomewidefalsediscoveryrate.Falsediscoveryratespecifictovariantset.

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SupplementalFigures

FigureS1.Manhattanplotsofmetaanalysesresultsforcombinedancestrygenomewideassociation
studiesofmaximumPwavedurationandPwaveterminalforce

A.Pwaveduration;significantgeneticlociarehighlightedinred.B.Pwaveterminalforce;
significantgeneticlociarehighlightedinblue.Dashedlinesrepresentthegenomewidesignificance
threshold(p=5x108).

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FigureS2.RegionalplotsofgeneticlocisignificantlyassociatedwithPwavemaximumdurationin
Europeans.

Page39of47

Ateachnovellocus,allSNPsinalimitedregionareplottedbychromosomallocationandpvalue(left
verticalaxis)fromthemetaanalysis.ThemostsignificantSNPisplottedasadiamondshape,andall
otherSNPsarecoloredaccordingtotheirlinkagedisequilibrium(LD)withthetopSNP.FortheTBX5
locus(G),thisistrueforthesecondmostsignificantvariant,duetomissingLDdataforthemost
significantvariant(grey).ReddepictsthehighestLDwhilebluedepictsthelowest,asshowninthe
legendineachplot.Estimatedrecombinationrateisdisplayedforeachregion(rightverticalaxis).Gene
annotationispresentedbelowtheplot.LDandrecombinationinformationisbasedonthe1000
GenomesNovember2014EURrelease.AllplotsweremadeusingLocusZoom.74AHshowsnovelloci,
whereasIJshowsreplicatedloci.A,SSBP3;B,EPAS1;C,CAND2;D,CAMK2D;E,HCN1;F,CAV1/2;G,
TBX5;H,MYH6;I,SCN5A;J,SCN10A.

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FigureS3.RegionalplotsofgeneticlocisignificantlyassociatedwithPwaveterminalforce.

Ateachnovellocus,allSNPsinalimitedregionareplottedbychromosomallocationandpvalue(left
verticalaxis)fromthemetaanalysis.ThemostsignificantSNPisplottedasadiamondshape,andall

Page41of47

otherSNPsarecoloredaccordingtotheirlinkagedisequilibrium(LD)withthetopSNP.Reddepictsthe
highestLDwhilebluedepictsthelowest,asshowninthelegendineachplot.Estimatedrecombination
rateisdisplayedforeachregion(rightverticalaxis).Geneannotationispresentedbelowtheplot.LD
andrecombinationinformationisbasedonthe1000GenomesNovember2014EURrelease.Allplots
weremadeusingLocusZoom.74A,KCND3;B,C6orf195;C,MYH6;D,ALPK3/NMB;E,PPP5D1;F,SPON1.

Page42of47

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