Eur Child Adolesc Psychiatry (2015) 24:619634
DOI 10.1007/s00787-015-0702-8
REVIEW
Genetics inchild andadolescent psychiatry: methodological
advances andconceptual issues
SarahHohmann NicolettaAdamo
BenjaminB.Lahey StephenV.Faraone
TobiasBanaschewski
Received: 25 April 2014 / Accepted: 6 March 2015 / Published online: 8 April 2015
Springer-Verlag Berlin Heidelberg 2015
Abstract Discovering the genetic basis of early-onset
psychiatric disorders has been the aim of intensive research
during the last decade. We will first selectively summarize
results of genetic research in child and adolescent psychia-
try by using examples from different disorders and dis-
cuss methodological issues, emerging questions and future
directions. In the second part of this review, we will focus
on how to link genetic causes of disorders with physiologi-
cal pathways, discuss the impact of genetic findings on
diagnostic systems, prevention and therapeutic interven-
tions. Finally we will highlight some ethical aspects con-
nected to genetic research in child and adolescent psychia-
try. Advances in molecular genetic methods have led to
insights into the genetic architecture of psychiatric disor-
ders, but not yet provided definite pathways to pathophysi-
ology. If replicated, promising findings from genetic stud-
ies might in some cases lead to personalized treatments. On
the one hand, knowledge of the genetic basis of disorders
may influence diagnostic categories. On the other hand,
S. Hohmann and N. Adamo contributed equally to this work.
S.Hohmann N.Adamo T.Banaschewski(*)
Department ofChild andAdolescent Psychiatry
andPsychotherapy, Central Institute ofMental Health, Medical
Faculty Mannheim/Heidelberg University, Mannheim, Germany
e-mail: tobias.banaschewski@zimannheim.de
B.B.Lahey
Departments ofHealth Studies andPsychiatry andBehavioral
Neuroscience, University ofChicago, Chicago, IL, USA
S.V.Faraone
Department ofPsychiatry andBehavioral Sciences, State
University ofNew York (SUNY) Upstate Medical University,
Syracuse, NY, USA
models also suggest studying the genetic architecture of
psychiatric disorders across diagnoses and clinical groups.
Keywords Gene-environment interactions
Neurodevelopmental disorders Copy number variations
Genome-wide association studies Taxonomy
Introduction
An increasing number of studies have reported that most
early-onset psychiatric disorders run within families.
Adoption and twin studies have found high heritability
estimates for most disorders including ADHD [44], autism
spectrum disorders [121] and schizophrenia [137] indicat-
ing a strong genetic influence on their etiology [21, 100,
111]. However, in some disorders like e.g., depression
and anxiety disorders [46, 56], heritability estimates are
lower. But as heritability estimates are necessarily popu-
lation- and time-specific, one needs to be cautious when
making comparisons among heritability estimates for dif-
ferent traits or across different samples. Segregation analy-
sis studies have led to the suggestion of major suscepti-
bility loci for e.g., ADHD [42, 79], obsessivecompulsive
disorder (OCD) [55, 99], schizophrenia [118, 124], bipolar
disorder [18, 104], and Tourette syndrome [105]. In some
neurodevelopmental disorders, specific single genetic risk
factors have been identified. For example, approximately
40% of cases of intellectual disability associated to frag-
ile X syndrome are caused by single X-linked gene muta-
tions [36, 122]. Yet, most psychiatric disorders are not
solely influenced by single genetic risk factors with large
effect sizes (monogenic effects) but are complex traits of
heterogeneous and polygenic origin (and the single genes
do not have large effect sizes). Additionally, difficulties in
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identifying specific genetic factors might stem from the
neglect of broader and pleiotropic factors (as described in
Sect.Implications of genetic findings for prevention and
therapeutic approaches).
Due to the rapid advances in biotechnology and molec-
ular genetics, the methods for detecting the genetic basis
of psychiatric disorders have changed substantially over
time [41]. Initially, most groups either scanned the entire
genome for new possible risk variants involved in the
pathophysiology of disorders using genetic linkage analysis
or followed the candidate-gene approach.
This review was structured to provide an overview about
methodological advances and emerging issues in genetics
of early-onset psychiatric disorders. Due to the complexity
of the subject and the large amount of literature associated
with it, we decided to selectively review the literature and
choose examples from different disorders to illustrate cer-
tain approaches.
Linkage, association studies andthe introduction ofGWAS
Linkage studies
The concept of linkage studies (genome-wide linkage
mapping) pertains to the identification of disease-related
sequence variation based on their location in the genome
[114]. It is based on the principle, that genetic loci are
linked if they are transmitted together from parent to off-
spring more often than anticipated under circumstances of
independent inheritance. One refers to linkage disequilib-
rium if a combination of two loci is detected on the same
haplotype more often than expected (when looking at the
population as a whole) (for a review see [35]). Genetic
linkage studies have proven very successful in discovering
genes associated with simple mendelian traits but seem not
to be as effective in complex diseases like psychiatric dis-
orders [20, 47]. This could be primarily attributed to limita-
tions in statistical power as compared to association studies
[119] but also to difficulties in defining clear phenotypes
for these disorders.
Genome-wide linkage studies have been frequently used
in ADHD research [7, 8, 57, 101103, 120] and have led
to the identification of several loci potentially harboring
genes involved in the pathogenesis of the disorder. Unfor-
tunately, the overlap between linkage signals detected in
these studies is relatively small. A meta-analysis including
most available linkage scans on ADHD could identify only
one single significant genome-wide linkage signal cover-
ing chromosome 16q2116q24 [158]. A possible candidate
gene located in this region is Cadherin-13 (CDH13), a cell
adhesion molecule. For dyslexia, linkage studies have led to
the discovery of 9 risk loci (for a review see [106]), which
include several potential candidate genes. Also, linkage of
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Eur Child Adolesc Psychiatry (2015) 24:619634
22q11.2 microdeletions has been described in 1% of all
cases of schizophrenia [11, 12, 31]. However, while link-
age studies have led to the identification of several risk loci
potentially containing new candidate genes, in most cases
they could not provide genome-wide significant risk vari-
ants for early-onset psychiatric disorders. Nevertheless, the
loci identified by linkage studies could represent possible
targets or regions of interest for more advanced sequenc-
ing methods or could be related to panels like e.g., the
1000 genomes project (see below), which provides data
on almost all of the variants in specific disease-associated
regions with a frequency of at least 1% in the population
studied.
Candidate gene studies
Another commonly used method is represented by research
on candidate genes in association studies. Here, investiga-
tors choose polymorphisms within specific candidate
genes hypothesized to play a role in the pathophysiology
of the particular disorder and try to associate them with this
disorder, mostly using a case-control design. As the patho-
physiological underpinnings of nearly all psychiatric disor-
ders have still not been fully disentangled, candidate genes
have mostly been selected based on the mechanism of
action of psychopharmacological drugs. Several functional
polymorphisms of genes involved in neurotransmission
were intensively studied in this context (e.g., monoaminer-
gic genes in ADHD, schizophrenia and depression), several
being corroborated as risk genes for the particular disor-
der. For instance, a tandem repeat polymorphism in exon
III of the dopamine receptor D4 (DRD4-7r) was repeatedly
found to be significantly associated with ADHD in pooled
scores and meta-analyses (e.g., [44, 76]). However, current
results from candidate genes, including the DRD4-7r allele,
cannot sufficiently explain the high heritability estimates of
the disorders.
Genomewide association studies
Further development of technology resulted in the emer-
gence of genome-wide association studies (GWAS), which
combined the advantages of both, genome-wide approaches
and high resolution association studies (for a review on
methods see [114]). In contrast to candidate gene stud-
ies (and similar to linkage methods), GWAS are hypoth-
esis generating instead of hypothesis testing. Within a
GWAS analysis, large samples of patients and controls are
screened with DNA-chips (a collection of short DNA frag-
ments to detect either the wild type or the mutated allele,
on a solid surface like glass or plastic). Those allow to
assay large numbers of single nucleotide polymorphisms
(SNPs) within the genome of an individual in a rapid and
Eur Child Adolesc Psychiatry (2015) 24:619634 621
accurate way. Introduced for the first time during the 1990s
[26, 27], DNA-chip technology has rapidly advanced, ena-
bling todays researchers to test for more than a hundred
thousand variants at a time. However, the expectations that
GWAS would lead to findings of causal DNA variants for
psychiatric disorders were not completely fulfilled over
the last years. For example, in ADHD [98] and autism
spectrum disorders [3], none of the candidate genes pre-
viously endorsed by association or linkage studies could
reach genome-wide significance in GWAS analyses after
correction for multiple testing. This could either point to
insufficient power of the studies or indicate that those can-
didate genes might not truly be associated with the dis-
orders. Nonetheless, outcomes of GWAS have provided
some important new insights. By using the family based
associations test on data from the International Multi-cen-
tre ADHD Genetics (IMAGE) project, Lasky-Su and col-
leagues [72] were able to detect one significant SNP within
the gene encoding for CDH13. Interestingly, this gene lies
within the only significant linkage region for ADHD [158].
However, to detect common DNA variants of small effects,
further studies with much larger samples (e.g., more than
10,000 subjects) are necessary. As shown recently for
schizophrenia, an increase in sample sizes can lead to the
detection of more variants of genome-wide significance
[117].
Yet, to address the needs for larger samples, more
affordable methodologies are needed.
The implementation of different study designs can also
contribute to take advantage of the full potential of GWAS.
Most GWAS have involved the use of a case-control design
comparing patient cohorts and matched control cohorts.
This approach represents a powerful tool for investigat-
ing the etiology of complex human diseases, in such that
it allows for estimation of genotype and allele frequencies
in optimally defined clinical groups and controls. However,
the case-control design of association studies may present
confounds such as selection bias, ethnic distribution arti-
facts (population stratification), genetic heterogeneity and
phenotype complexity [84]. Collaborative groups have
started pooling together data from participants examined
in different centers and countries, which allows to control
for site effects. One example is the IMAGEN multicenter
study, designed to attain behavioral and neuropsychological
assessment and GWAS scans from 2000typically devel-
oping adolescents [128]. In particular, community (popu-
lation) twin designs unselected for phenotypic extremes
and comparisons of siblings within families may provide
a robust, alternative strategy for evaluating the etiology of
underlying complex disorders [67]. Consistent with high
phenotypic correlation among several major psychiatric
disorders [64], emerging hypotheses indeed suggest that
for most disorders little of the genetic influence on each
dimension of psychopathology is dimension-specific but
rather might constitute a risk factor for multiple condi-
tions [66, 69]. Therefore, case-control studies of one men-
tal disorder against healthy controls might miss most of
the genetic risk variants, which are often pleiotropic (see
also Sect.Implications for taxonomy and classification
systemsof this review).
The missing heritability problem andhow tosolve it
The problem of inconsistency between the heritability of a
trait and the variance accounted for in total by known gene
associations has been referred to as missing heritability
problem [95].
Rare variants
One of several possible explanations for this missing her-
itability could be the contribution of variants of low fre-
quency alleles, which have so far not been captured by
current GWAS arrays [85, 113]. Structural variants of the
genotype, such as copy number variations (CNVs) were
also not completely assessed by most of the earlier SNP
genotyping arrays and may therefore account for part of
the explanation of the missing heritability problem (see
also for review [81]).CNVs are defined as alterations of
the DNA with a length of at least one kb [28]) resulting
in a normal or abnormal variation in the number of copies
of one or more sections of the genome. They correspond
to relatively large regions of the genome that have either
been deleted or duplicated. An enrichment of rare CNVs
has been suggested for several neurodevelopmental disor-
ders (e.g., ADHD [152, 153], autism [107, 129] and child-
hood onset schizophrenia [1]). Recent findings also suggest
that biological pathways interrupted by CNVs overlap in
ADHD and autism [83]. The detection of over-represented
CNVs within genes encoding for metabotrobic glutamate
receptors has been recently reported in ADHD, indicating
that at leastin some of the individuals affected by ADHD
glutamatergic networks play a role in the pathophysiol-
ogy of the disorder [40]. However, the contribution of an
associated variant to the variation in the population reflects
both its frequency and its effect size (OR), and so despite
mostly high ORs, rare CNVs individually contribute less
than0.2% of the variance [147].
Rare single nucleotide variants (SNVs) (less than0.5%
minor allele frequency) can be detected via next genera-
tion sequencing of selected parts of the genome of patients
in comparison with healthy controls. To enable researchers
to focus on SNVs with low to very low allele frequencies
in patients and their families, a comprehensive catalogue
of these variants has been created by the 1000genomes
project (www.1000genomes.org). Using new sequencing
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methods, SNVs of relatively large effects have been
recently detected in individuals with autism and schizo-
phrenia [62, 97], among others, allowing conclusions
about the biological pathways underlying these disorders.
As methods are further advancing and the sequencing
of large parts or the whole genome of patients becomes
increasingly more affordable, this approach could con-
stitute one possibility to reduce the missing heritability
gap. The sequencing of trio families (i.e., two parents, one
affected child) has allowed for the detection of de novo
SNVs, mutations that occur in the affected child but not
the parents. This method has been applied successfully to
autism [97, 126].
In an attempt to increase the power of genetic studies,
investigators have proposed to screen larger populations
on common variants. However, even including larger sam-
ples, the common variants that can be discovered with this
method might still only account for a small part of the her-
itability of neurodevelopmental disorders [82]. The Exome
chip has been developed to allow for the detection of rare
coding SNVs that had been identified in prior sequencing
studies (for further details see http://genome.sph.umich.
edu/wiki/Exome_Chip_Design).
The PsychChip, developed by the Psychiatric Genom-
ics Consortium (PGC, https://pgc.unc.edu/) comprises the
Exome chip content, a low resolution GWAs and variants
relevant for psychiatric disorders. This is a comparatively
cheap method for the scanning of large numbers of both
psychiatric patients and healthy individuals.
Environmental influence
The interplay between environmental risk factors and genes
might also account for part of the missing heritability prob-
lem. Studies on gene-environment interactions are mostly
based on the assumption that environmental pathogens
cause disorders and that genes influence the susceptibility
to these pathogens [24, 125]. This implies that differences
between individuals, originating in the DNA sequence,
determine differences in their resilience or vulnerability
to environmental causes of many pathological conditions.
For example, Caspi and colleagues reported that maltreated
children with a genotype resulting in reduced expression
of the monoamine oxidase A (MAO-A) developed conduct
disorder, antisocial personality disorder and adult violent
criminality more often than children with another MAOA
genotype [23].
Environmental factors can also influence gene expres-
sion via epigenetic regulation. The term epigenetic regula-
tion describes different intracellular processes (including
histone acetylation or methylation of DNA), which influ-
ence gene activity without altering the genetic code and are
reversible (for a review see [143]).
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For instance, in mice, pre- or perinatal maternal stress or
grooming behavior (e.g., [25, 86, 159]) seems to influence
expression levels of specific genes via epigenetic regulation
and thereby can lead to a certain phenotype. Besides envi-
ronmental factors, mutations within proteins involved in the
regulation of gene expression can also cause alterations in
the activity of genes. One example for such an (at least in
part) epigenetically induced neurodevelopmental disor-
der is the Rett syndrome. It appears to be caused in part by
mutations within the gene encoding for the transcriptional
repressor methyl-CPG-binding protein 2 (MeCP2) which is
located on the X chromosome [25]. A deficiency of MeCP2
leads to an overactive gene transcription of, among other
factors, the brain derived neurotropic factor (BDNF) [159].
An overexpression of these gene products is thought to
cause a selective impairment in presynaptic excitatory func-
tion and Rett-like symptoms in animal models (e.g., [34]).
Epigenetic influences on pathophysiology have been
discussed for many psychiatric disorders like schizophre-
nia, depression or addiction. To date, further extensive
research in e.g., animal models or postmortem human brain
tissues is needed to identify the genes most likely targeted
by changes in histone modifications or DNA methylation.
Furthermore, growing evidence indicates that changes in
brain methylation might be reflected by methylation pat-
terns in mononuclear blood cells (e.g., [19, 141]). If blood
cells prove to be a suitable surrogate tissue for studying
epigenetic regulation in psychiatric disorders, this would
enable researchers to examine the impact of environmen-
tal changes on methylation patterns directly in the affected
individual. A recent genome-wide examination conducted
post-mortem in brains of individuals with autism spec-
trum disorders has shown differentially methylated DNA
regions, supporting the need to search for biomarkers of
environmental factors [65]. Longitudinal-prospective stud-
ies are likely to provide most informative findings in the
search for epigenetic associations with psychiatric diseases
[49, 91] and environmental factors acting during early
life [75]. One approach is using a longitudinal design that
measure samples of monozygotic (MZ) twin pairs both, in
the early years and when they become discordant for expo-
sure and/or presentation of disorders. Additionally, fol-
lowing individuals from pre- or peri-conception period to
adulthood typically allows for examination of the contribu-
tion of intra-uterine and early post-natal environmental fac-
tors to determining the disorder [13, 160].
As inherited epigenetic changes that contribute to dis-
ease risk would not be captured by GWAS assays, they
may explain part of the missing heritability problem. Slat-
kin [135] proposed that epigenetic changes and mutations
will contribute equally to average risk when found in the
same population frequency, but the mutation will contribute
more to recurrence risk, implying that inherited epigenetic
Eur Child Adolesc Psychiatry (2015) 24:619634 623
changes can only account for the missing heritability prob-
lem if they are more common than the mutation or have
more pronounced effects on the disease risk.
However, it remains unclear to what extent and through
which exact mechanism epigenetic marks can actually be
passed on, as methylation marks seem to get largely lost dur-
ing gametogenesis. One explanation could be that there are
several ways of transmitting epigenetic information to the
offspring. Danchin and colleagues describe two contrasting
forms of transgenerational epigenetic inheritance (reviewed
in [33]), germline epigenetic inheritance, where the epige-
netic state is present in germline cells and is thus transmitted
to the offspring over generations, and experience-dependent
epigenetic inheritance, where an epigenetic state affects
parental behavior in a way that generates the same epigenetic
state in the offspring. Just recently, Cortijo etal. [30] have
identified so called epigenetic quantitative trait loci in a cer-
tain plant, through which epigenetic changes can be stably
inherited independent of DNA sequence changes. In sum-
mary, although increasing evidence seems to endorse the role
of transgenerational epigenetic inheritance in explaining part
of the heritability of complex disorders, the exact mecha-
nisms behind still need to be better understood.
Heterogeneity
Yet another explanation for the missing heritability problem
could be the heterogeneity of psychiatric traits. For instance,
some ADHD patients, though carrying rare CNVs of large
effect, do not differ from ADHD patients with another geno-
type concerning symptoms severity [70]. Also, a variant of
the COMT gene has been found to be associated with antiso-
cial behavior in a specific subgroup of ADHD patientsonly
[22]. Concerning autism spectrum disorders, genetic hetero-
geneity among the three autism symptom clusters has been
reported [121], with only a modest genetic overlap between
the clusters. Heterogeneity of complex disorders can also
be explained by the involvement of polygenic factors and
gene-gene interactions. For example, in spite of some incon-
sistencies, a potential interaction between the 7-repeat allele
of the DRD4 and the 10-repeat allele DAT1 has been ini-
tially reported in ADHD (for review [9]). Similarly, a recent
study evaluated the independent and combined contribution
of single SNPs to the genetic variance of autism spectrum
disorders in an Argentinian sample and revealed a potential
association of a gene-gene interactionbetweenGABAA-
receptor subunit geneswith an increased risk for autism
spectrum disorders [130].
Interactional effects
A recent study has shown that eight susceptibility genes
collectively accounted for 16% of the variance within
a measure of antisocial phenotypes [15]. These find-
ings, obtained in a general population sample, support the
hypothesis that interactional or additional effects of mul-
tiple genes may be responsible for the determination of
psychopathology. Indeed, an increasing number of studies
have also extended the genetic investigations to population-
based samples, which allow for measuring dimensional
behavioral traits in a continuum. This approach provides
the opportunity to assess the genetic risk in large repre-
sentative population samples, essential to quantify the
phenotypic variance of complex disorders accounted for
by genetic factors [115]. For example, a recent report has
suggested that a high genetic load for schizophrenia, as
indexed by number of relatives affected, increased the risk
of psychotic symptoms in subjects without clinically rel-
evant psychosis [17].
Other explanations
The application of polygenic methods (reviewed in [154])
to GWAS data of several psychiatric disorders has led to
estimations, that genetic variation tagged by common SNPs
accounts for between one-third and half of their heritability
(e.g., [59, 155]). This implies, that much of the heritability
might be merely hidden, meaning that most of the common
risk loci accounting for the variation do not surpass the
threshold for genome-wide significance in GWAS ([51]).
Eventually, part of the inconsistency between the esti-
mated heritability of a trait and the variance accounted for
by known gene associations might simply be explainable
by an overestimation of heritability. Family designs used
for heritability estimations include close relatives who
share a common environment as well as nonadditive gene
combinations, which can be difficult to separate ([148,
154]).
What do these findings tell us? How can we get
fromassociated SNPs andCNVs tounderstanding
pathophysiology ofpsychiatric disorders?
Ongoing advances in genetic research have led to the dis-
covery of several common SNPs, CNVs and rare variants
(e.g., large, functional relevant CNVs) which are associ-
ated with early-onset psychiatric disorders. However, most
risk variants detected so far have not allowed us to fully
disentangle the pathophysiological basis of the particular
disorders. The reported variants can rather indicate specific
genes on which to focus further intensive research concern-
ingaltered protein function and alterations in gene expres-
sionunderlying pathophysiology. A successful example for
this approach is the fat mass and obesity associated pro-
tein (FTO), the first obesity gene of the GWAS era (for
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a review see [78]). A common variant in the first intron
region of the FTO gene has been reported to be associated
with higher body mass index and a higher risk for obesity
in children and adults [48] for the first time in 2007. At
that time, FTO had neither been the focus of any research
within the area of appetite or body weight regulation, nor
had the function of the encoded protein been of any inter-
est to the scientific community. Since then, several groups
have addressed the question on how the gene product of
FTO might be involved in the complicated circuits of body
weight regulation. To date, structure and function of the
FTO gene product have been extensively studied [52, 78].
However, the exact mechanism by which the common vari-
ants within the first intron of FTO lead to disturbances in
body weight regulation still needs to be understood.
Concerning psychiatric disorders, neuroscientists are
currently focusing on the study of intermediate phenotypes
[89], which are heritable traits on the pathogenesis path
from genetic predisposition to psychopathology. These
intermediate phenotypes, also called endophenotypes, are
thought to be associated with more basic and proximal etio-
logical processes and should therefore be more amenable to
genetic investigation. For instance, one emerging approach
uses neurons generated from induced pluripotent stem cells
(ipsCs) of individuals carrying specific genetic risk vari-
ants. Using so generated neuronal cells may help study the
consequences of genetic variance on cellular development,
connectivity and synaptic function (e.g., [53]). Another
common method using endophenotypes [50] in psychi-
atric disorders at present is imaging genetics [89]. This
technique aims at analyzing the impact of genetic risk vari-
ants on specific functional or structural circuits in the brain
assessed through neuroimaging methods. Imaging genet-
ics has revealed the effects on brain function and struc-
ture of several genetic risk variants associated with ADHD
(reviewed by [38]), autism (e.g., [142]) and schizophrenia
(reviewed by [88]). However, focusing on endophenotypes
requires considerably larger financial resources and is more
time consuming than just studying categorical diagnoses.
As funding is limited, future researchers might therefore
have to choose between the collection of even larger sam-
ples and endophenotype research.
Recently, researchers have increasingly used bioin-
formatical methods such as pathway or network analyses
on GWAS data to gain insights into the cellular signaling
pathways involved in pathophysiology [149]. Thus, by
including the most significant findings from all disorder-
specific GWAS or either linkage studies into their analyses,
the work led by Poelmans and colleagues described path-
ways for neurodevelopmental disorders, including ADHD
[110], autism [109] and dyslexia [108]. In these stud-
ies,genes related to neurite outgrowth, neural migration
and synaptic function were thegenetic networks proposed
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Eur Child Adolesc Psychiatry (2015) 24:619634
to be predominantly involved in pathophysiology of these
disorders. In addition, advanced analytical methods used
on GWAs data from the IMAGE-study (see above) led to
the suggestion thataltered glutamatergic neurotransmis-
sion might be involved in the pathophysiology of ADHD
[40]. In a recent study, Yang and colleagues [156] analyzed
GWAS data from a large sample of Han Chinese individu-
als by using pathway and polygenic analysis techniques.
They reported three pathophysiological pathways relevant
for ADHD: cell adhesion, development of glutamatergic
synapses and transcriptional processes. There are already
some reports on approaches to use pathway techniques
for diagnostic issues, for example to identify autistic chil-
dren at a very early stage in development by using specific
genetic constellations as a biomarker [134]. Bioinformatics
methods have also been used to provide clues for finding
new pathways to psychiatric disorders that can be influ-
enced pharmacologically [45]. Thus, advancing new analy-
sis techniques might constitute a powerful tool to interpret
GWAS data and generate hypotheses about the biological
pathways involved in the pathogenesis of disorders, but
they are largely still lacking confirmation.
In summary, current findings of genetic studies can only
in part provide a better understanding of pathophysiology;
they rather constitute the basis for further investigationson
pathophysiological mechanisms.
Implications ofgenetic findings forprevention
andtherapeutic approaches
Many efforts to uncover the genetic basis of early emerg-
ing psychiatric disorders are driven by hopes that such
findings will provide us with new possible targets for ther-
apeutic interventions. The current pharmacological and
non-pharmacological treatment options for these disorders
have been developed on the basis of only little to barely any
knowledge of the underlying pathophysiology. Therefore, a
strong demand for more specific therapies exists. Awareness
of the precise genetic make-up of an individual could allow
specialists to draw conclusions about the best therapeutic
options. In other fields of medical science such as oncology,
this kind of personalized medicine is already widely used
for assigning the best possible treatment to the single patient.
While we are still far from using genes to predict treatment
outcomes in psychiatry, there are already some reports on
effects of genotypes on responses to therapeutic interven-
tions. Thus, pharmacogenetics aims at identifying clinical
relevant predictors for drug efficacy and/or side effect burden
(for a review see e.g., [80]). At present, information about
genetic influences on drug metabolism is predominantly
available and can provide useful evidence for the selection
and titration of pharmacological treatments. One example is
Eur Child Adolesc Psychiatry (2015) 24:619634 625
provided by the genetic variants of the gene encoding for the
cytochrome P450 2D6 enzyme, which is responsible for the
metabolism of several psychotropic agents. The combination
of more than 100 genetic variants within this gene leads to
four different phenotypes of CYP2D6, poor-, intermediate-,
rapid- and ultra-rapid metabolizers. In poor metabolizers,
reduced function of the enzyme can lead to accumulation of
the drug and thus cause greater side effects burden. By con-
trast, ultra-rapid metabolizers may require higher doses of
drugs to gain sufficient efficacy.
Besides these rather general genetic effects on pharma-
codynamic processes, several groups have recently focused
on the impact of specific genotypes on the response to cer-
tain treatments. For instance, a functional polymorphism
within the promotor of the dopamine D2 receptor (DRD2)
has been reported to significantly reduce antipsychotic drug
efficacy [157]. Current investigations on pharmacogenet-
ics have been using GWAS specifically designed to achieve
pharmacogenetic aims. Thus, the genome based therapeutic
drugs for depression (GENDEP) study has indicated that
several genetic variants within candidate genes (e.g., the
monoaminergic transporters) are relevant for the efficacy of
different sorts of antidepressant medication [145]. A poly-
morphism within the promotor of the interleukin-11 gene
has been reported by the same group to influence response
to antidepressant treatment [112, 146]. Several other net-
works of possible predictors for antidepressant treatment
response have been suggested by using pathway-analyses
on GWAS data [61]. However, a recent meta-analysis of
nearly all pharmacogenetic GWAS data on antidepressant
therapy could not identify common variants of genome-
wide significance [60]. A GWAS study of methylpheni-
date response in ADHD found no genome-wide significant
results, but did find suggestive evidence of association for a
glutamate receptor gene [90].
Furthermore, pharmacogenetic approaches can also pro-
vide indications of the burden of adverse events occurring
in the individual patient under pharmacological treatment.
One adverse event which occurs frequently especially
in young patients treated with atypical antipsychotics is
weight gain (e.g., [29]). It has been suggested that poly-
morphisms within the promoter region of the 5-HT2C
receptorgene influence weight gain under antipsychotic
treatment [116, 133]. If replicated, knowledge about the
higher susceptibility of patients carrying a risk allele for
weightgain and subsequent cardiometabolic effects may
provide clinicians with options to counteract this develop-
ment. As sufficient pharmacological treatment alternatives
for schizophrenia are lacking at the moment, it is recom-
mended that clinicians at least closely monitor patients at
risk and offer specific exercises and diet programmes or
implement supplementary pharmacological interventions
such as metformin [80].
The emerging field of therapy-genetics aims at study-
ing the genetic predictors of response to psychological
treatments like CBT. In a recent study, anxiety disordered
children carrying two copies of the s allele of the seroto-
nin transporter promoter polymorphism (5HTTLPR) were
20% more likely to be disorder free at follow-up after CBT
than l/l or s/l carriers [39]. The same group found a poly-
morphism in the gene for nerve growth factor (NGF) to be
relevant for psychotherapy treatment outcomes in children
suffering from anxiety disorder [74]. However, these find-
ings await replication.
To date, while we are still lacking deeper insights into
the pathophysiologic foundations of most psychiatric disor-
ders, we do indeed know about their high heritability. This
knowledge by itself does already provide us with possi-
bilities for preventive activities. Especially in disorders for
which it is known that environmental conditions can mod-
erate the impact of genetic risk factors (like e.g., in antiso-
cial behavior [14, 63]), one can identify high-risk families
and introduce parents and children to specific prevention
programs at an early stage of development.
Implications fortaxonomy andclassification systems
The difficulty in understanding the genetic determinants of
psychopathology might result from using psychiatric clas-
sification systems (DSM-V and ICD-10) that are predomi-
nantly based on phenomenologically defined categories of
symptoms rather than on knowledge about the etiology of
the disorders.
In some cases, integrating findings from basic research
into clinical practice has helped defining subtypes of the
disorders with a known etiology and facilitated the diag-
nostic processes. For example, for some neurodevelop-
mental disorders, which are caused by only one or a few
genes, clinical genetic testing is recommended by avail-
able guidelines [132]. Concerning developmental delay and
intellectual disabilities, karyotyping and molecular genetic
testing identify anomalies in 310% of individuals [132].
Additionally, genetic testing is increasingly used in the
diagnosis and research of intellectual disabilities since the
recent discovery of the etiological importance of abnormal
CNVs [77, 94, 95]. Examination of the karyotype for chro-
mosomal abnormalities, genetic testing for Fragile X, and
more recently, microarray-based genomic copy-number
testing has also been recommended for the clinical genetic
testing in autism spectrum disorders [92, 127]. Yet, the
genetic yield of these analyses only reaches up to 7% for
patients with autism spectrum disorders when using micro-
arrays-based CNV methodologies [131]. Among the com-
monly studied candidate findings, the 22q11 deletion has
the highest likelihood of identifying neurodevelopmental
13

626
disorders, and may represent a candidate marker to sup-
port prenatal screening and genetic counseling for predic-
tion of risk to develop psychiatric disorders at later ages
[93]. However, it should be considered that abnormalities
in this chromosomal region may not identify the risk for a
specific psychopathology and rather be associated with sev-
eral disorders [2, 46]. Important ethical aspects should be
also considered (see also below, Sect.Ethics of advancing
genetic studies).
Besides these limited examples, for most diagnostic cat-
egories described in our current nosology systems underly-
ing mechanisms of dysfunctionshave not been identified.
Therefore, different approaches have been proposed to
optimize current classification systems. For instance, Tsu-
ang and Faraone [144] suggested that a psychiatric genet-
ics nosologyshould be developed for genetic studies, as
the current systems seem less suitable for research than for
clinical purposes. This approach would discard traditional
diagnostic barriers and allow for overlap among disorders.
Another proposed approach, not limited to genetics, is the
Research Domain Criteria (RDoC) project of the NIMH
[58]. The RDoC classification hypothesizes that dys-
functionsunderlying mental disorders can be detectedin
defined brain circuits with the tools of clinical neurosci-
ence, including neuroimaging and imaging genetics. Thus,
bridging the link between clinical signs and genetic find-
ings will be facilitated by using biomarkers defined on the
basis of clinical neuroscience studies.The RDoCapproach
is mostly focused on neural circuits representing interme-
diate phenotypes [89], and suggests analyzing both the
effects of altered circuitry functions on clinical symptom-
atology and the genetic or molecular factors influencing
suchbrain functions. As most brain circuits are assumed to
be involved in the pathophysiology of more than just one
disorder, research samples might include patients with dif-
ferent disorders according to the current categorical nosol-
ogy [58].
Accordingly, higher order dimensions of psychopathol-
ogy that cut acrosspsychiatric disorders demarcated by
current diagnostic classification systems have also been
investigated. With such an approach, it was suggested that
onegeneral genetic risk factor contributes to internalizing
disorders such as anxiety disorders and major depression;
in parallel, another factor contributes to externalizing prob-
lems (conduct problems, antisocial personality disorder,
and substance abuse disorders) [68]. More recently, how-
ever, high (55%) shared genetic variance between com-
monly used dimensions of internalizing and externalizing
symptoms was identified [69]. According to these findings,
little genetic influence would be dimension-specific. In
contrast, environmental factors might have more specific
effects on the single disorders [66]. Lahey and colleagues
argued that these findings show that a broader or higher
13
Eur Child Adolesc Psychiatry (2015) 24:619634
order psychopathology phenotype may provide informa-
tion beyond diagnostic classifications [69]. These findings
challenge the current diagnostic nosology and suggest the
need for loosening diagnostic boundaries and for search-
ing the underlying mechanisms of symptoms or dimensions
instead.
Consistently, investigations focusing on single psychi-
atric disorders as defined by current nosological systems
might neglect the pleiotropy of some common genetic risk
factors andmight thereforepotentiallyoverlook genetic
overlap between several psychiatric disorders. Pleiotropy,
the observation that certain genetic variants can be involved
in the origins of different phenotypes, might explain the
high rates of comorbidity and familial overlap between
disorders (e.g., ADHD and bipolar disorder, [43]). In this
context, a large population-based analysis has recently
shown that first-degree relatives of individuals with ADHD
exhibit an increased risk for developing bipolar disorder
and schizophrenia, suggesting shared genetic factors under-
lying these disorders [71]. Specifically, recent efforts have
provided molecular evidence forthe contribution of pleio-
tropic genes to five major psychiatric disorders [32, 73]. By
pooling analyses across both neurodevelopmental disorders
(autism spectrum disorders and ADHD) and disorders usu-
ally diagnosed after childhood (schizophrenia, bipolar dis-
order and major depressive disorder), common risk loci
and potential neurobiological mechanisms contributing to
the risk of the different diseases could be identified [32].
Using the same sampling strategy, another study found that
heritability estimates based on common SNPs correlated
across disorders [73]. While failing to reveal the expected
genetic sharing between early neurodevelopmental disor-
ders (e.g., ADHD and autism) possibly due to low power,
such an approach has additionally identified a link between
these disorders and disorders emerging mostly in adulthood
such as bipolar disorder and schizophrenia [73]. Consist-
ently, shared common SNPs were found between adult
schizophrenia and childhood ADHD [54] in another recent
GWAS study. The discovery of genetic liability that cuts
across diagnostic categories confirms that symptom-based
diagnoses might not describe discrete biological entities.
Moving from the study of diagnoses as phenotypes to
examining single dimensions is also a promising approach.
For example, investigators have attempted to clarify the
role of emotional lability, a set of symptoms including
irritability, hot temper and low frustration tolerance, in
ADHD. Strong phenotypic [10, 16, 136, 138], familial [16,
139], and genetic association between emotional lability
and ADHD [87] has been shown. This relationship occurs
independently from the association with common ADHD-
related neuropsychological dysfunctions, suggesting that
the association between emotional lability and ADHD
might reflect the result of pleiotropic effects [10]. These
Eur Child Adolesc Psychiatry (2015) 24:619634 627
findings may also translate to a better diagnosis and treat-
ment of individuals who present withADHD and emo-
tional lability in the context of other disorders. Similarly, a
related construct, negative emotionality, has accounted for
a large proportion of the genetic influences on the comor-
bidity between depression and conduct disorder and has
been proposed as a dispositional trait underlying both dis-
orders [140].
The pros and cons of dissecting diagnostic categories
into constituting traits or dimensionsneed to be carefully
considered. The dimensional model could collide with
the clinical purposes of diagnoses, but it is probably use-
ful for disentangling the etiology of psychiatric disorders.
Taken together, implications for the clinical classification
systems still remain unclarified. A more accurate pheno-
type definition could helpto improve our understanding
of the comorbidity between disorders and result in a more
dimensional approach to the diagnosis and treatment of
psychopathology.
Ethics ofadvancing genetic studies
The development of the new genetic technologies and
advances in molecular genetics summarized above has
favored concrete progress in understanding some of the
genetic determinants of complex psychiatric disorders. This
has encouraged the possibility of testing individuals and
relatives of individuals suffering from psychiatric disorders
to inform them about their own genetic risk for develop-
ing psychiatric illness or the risk of their offspring, respec-
tively. Community surveys and systematic assessments
have been conducted on perceived benefits and limitations
of potential genetic testing for psychiatric disorders. For
example, investigations revealed a substantial interest in
obtaining a genotype to determine risk for depression (e.g.,
[150]) or schizophrenia [37] if such a test was to become
available. However, it has been reported that, beyond the
stigma typically associated with a psychiatric diagnosis,
the possibility of receiving a positive genotype result for
depression causes fear of potential insurance and employ-
ment discrimination [151]. In the field of intellectual disa-
bility, genetic testing has become widely used, particularly
since the recent discovery of the etiological importance of
abnormal CNVs [77, 94, 95]. Yet, there has been concern
about the potential for the new genetic tests to perpetuate
discrimination for those with these conditions by using pre-
natal testing to prevent the birth of children with disabilities
[96]. Another issue to consider is the high costs of research
caused by the screening of constantly increasing numbers
of patients. The genetic risk variants for early-onset psychi-
atric disorders to be discovered by todays techniques are
of low to very low allele frequency or account only for a
small part of the heritability. In most cases, these genetic
risk variants might not be sufficient alone to lead to the dis-
covery of relevant new drug targets or a better understand-
ing of pathophysiology. Thus, at the current stage, they
provide nearly no direct benefit for the individual patient.
Therefore, critical opponents of genetic research in psychi-
atric disorders argue that parts of these funds would better
be spent on clinical studies on new treatment methods to
also consider the patients needs [123].
Conclusions
Advancing techniques in epidemiologic and molecu-
lar genetics represent a powerful research tool to provide
insight into the complex etiology of early-onset psychiatric
disorders. Results yielded from molecular genetic research
have provided an increasing number of candidate genes that
might be implicated in the pathophysiology of child and
adolescent psychopathology. These findings are promising
but require replication. At present, evidence for the specific
genetic underpinnings has not been conclusively reported
for any psychiatric disorders. One reason for the difficulty
to fully understand the relevant genetic risk variance for
psychiatric disorders might lie in the need for substantially
larger samples and more appropriate study designs.
Both epidemiological and molecular studies revealed
high heritability estimates and identified potential genetic
correlates of several psychiatric disorders. However, it is
still under debate what factors explain the gap between
estimates of heritability from family studies and the vari-
ance accounted for by the potentially correlated genetic
variants. Suggested explanation for this missing heritability
includes genetic heterogeneity, the involvement of rare sin-
gle nucleotide variants, gene-gene interaction, gene-envi-
ronment interaction and epigenetic regulation.
Findings from genetic studies do not necessarily provide
researchers with new insights into the pathophysiological
underpinnings of disorders. They rather represent starting
points for further studies on both the biomolecular or cel-
lular basis of disorders and on the impact of genetic vari-
ants on specific brain circuits. Equally, the use of new data
analysis methods such as network- or pathway-analyses
on GWAS data can contribute to a better understanding of
underlying pathophysiology.
While molecular genetics has the potential of helping
to define safety and tolerability of a specific pharmaco-
logical intervention, much more work is needed to under-
stand what genetic make-up helps predicting the treatment
response both for pharmacological and psychotherapeu-
tic interventions. In contrast, based on consistent findings
from twin, family and adoption studies, it is now possible
to identify risk families and put in place early intervention
13

628
or prevention programs for individuals at risk for develop-
ing psychiatric disorders when such a strategy is ethical.
Linkage, association and GWAS have permitted the dis-
covery of a number of possible genetic correlates of few
neurodevelopmental disorders, but evidence on the genetic
determinants underlying all early-onset psychiatric disor-
ders is yet not conclusive. Most investigations have used
case-control designs or community based samples, provid-
ing increasing evidence for candidate genes and potential
mechanisms of pathophysiology. Given emerging evidence
for pleiotropic effects of genes, models were suggested that
focus either on unitary functions (e.g., smaller dimensions
such as emotional lability) oron the neural circuitry under-
lying such functions. These models also suggest studying
the genetic architecture of psychiatric disorders across
diagnoses and clinical groups.
Despite the increasing knowledge on genes implicated
in the etiology of several psychiatric disorders, the poten-
tial for genetic testing in identifying and diagnosing indi-
viduals at risk for psychiatric illness (or their offspring and
relatives) is still limited. The genetic yield for most of the
candidate genes and for the GWAS detectable anomalies
is still low and the benefit for the single individual is lim-
ited. Additional concerns regarding potential ethics issues
related to knowing the genetic weakness of an individual
have been raised, together with concerns about high costs
yielded by the application of genetic testing and research.
Key Points
Genetic research has identified several risk variants for
early-onset psychiatric disorders. Yet, to conclusively
understand their genetic basis and overcome the miss-
ing heritability gap we have to combine the advantages
of different techniques within larger samples and with
modified study designs.
Current research focuses on the impact of the identified
genetic risk variants on cellular mechanisms, molecular
networks and functional or structural brain circuits.
Investigating psychopathology phenotypes and study-
ing psychiatric populations across diagnoses might help
clarifying the etiology of psychiatric disorders.
While it is possible to identify individuals at risk for
psychiatric illness and implement intervention/preven-
tion programs, further work is needed to characterize the
genetic sensitivity to pharmacological and psychothera-
peutic interventions.
The use of genetic testing in the individual patient is
currently limited for most psychiatric disorders by rela-
tively low diagnostic accuracy, ethical considerations
and elevated costs.
13
Eur Child Adolesc Psychiatry (2015) 24:619634
Conflict of interest Dr. Banaschewski served in an advisory
or consultancy role for Hexal Pharma, Lilly, Medice, Novartis,
Otsuka, Oxford outcomes, PCM scientific, Shire and Viforpharma.
He received conference attendance support and conference sup-
port or received speakers fee by Lilly, Medice, Novartis and Shire.
He is/has been involved in clinical trials conducted by Lilly, Shire &
Viforpharma. The present work is unrelated to the above grants and
relationships.
In the past year, Dr. Faraone received income, travel expenses and/
or research support from Pfizer, Ironshore, Shire, Akili Interactive
Labs, Alcobra, VAYA Pharma, and Neurovance, Impax and research
support from the National Institutes of Health (NIH). His institution is
seeking a patent for the use of sodium-hydrogen exchange inhibitors
in the treatment of ADHD. In previous years, he received consulting
fees or was on Advisory Boards or participated in continuing medical
education programs sponsored by: Shire, Alcobra, Otsuka, McNeil,
Janssen, Novartis, Pfizer and Eli Lilly. Dr. Faraone receives royalties
from books published by Guilford Press: Straight Talk about Your
Childs Mental Health and Oxford University Press: Schizophrenia:
The Facts.
Drs Lahey, Hohmann and Adamo report no biomedical financial
interests or potential conflicts of interest with respect to their author-
ship or the publication of this article.
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