Case Study Genetics of Schizophrenia

Key concepts: genome wide association studies (GWAS); SNP genotyping, nature vs. nurture,
multifactorial inheritance, heritable, heritability, genetic heterogeneity, linkage analysis,
positional cloning
Schizophrenia is a disease of the brain that causes split (schizo) thinking (phrenia),
leading to disorganized thoughtsincluding hallucinations, delusionsand depressive-like
symptoms (1). The diagnosis of schizophrenia, and clinical subtypes, is based on a constellation
of symptoms (1). The pathophysiology results from interactions of abnormal brain development
and environmental influences (2). Imaging studies of brains of individuals diagnosed with
schizophrenia show that there are distinctive, progressive changes in brain morphology (3).
The cause of schizophrenia has been subject to the classic nature vs. nurture debate. A
genetic component was first identified by research conducted in the 1960s, but it took until the
late 1980s to confirm the genetic basis of schizophrenia (4). Studies published in 2004 used
linkage analysis and positional cloning techniques to identify specific genes associated with
schizophrenia (5). In 2011, the Psychiatric Genome Consortium (PGC) conducted an extensive
Genome Wide Association Study (GWAS) of schizophrenia, and identified 5 schizophrenia
associated loci (6). The most recent GWAS study by the same consortium identified 108
schizophrenia-associated genetic loci (7).
Schizophrenia is not just highly heritable, but it is also a multifactorial inheritance. The
environmental components that contribute to schizophrenia have been equally difficult to
identify and confirm as the genetic components (8). Factors such as season of birth, prenatal
influenza, prenatal stress, and obstetric complications have been considered important
environmental influences (8).
A common misconception of many heritable conditions is the heritability of the
condition; similar words, but very different concepts. Heritability is a statistical value that refers
to the amount of phenotypic variation that is due to genetics or due to environment, not whether
the trait is inherited or not. A trait may be 100% heritable, but if there is no phenotypic
variability, then the heritability is 0% (9). Published estimates of the heritability of
schizophrenia have been as high as 0.8 (on a scale of 0-1), but is likely much lower (10).
However, any study estimating heritability in humans is fundamentally flawed by the small
population sample, and uncontrolled variables (9).
Questions.
Refer to the articles, Biological insights from 108 schizophrenia-associated genetic loci, and the
article Large-scale genomics unveils the genetic architecture of psychiatric disorders, to answer
question 1
1. The authors of the Biological insights study state that Schizophrenia is a highly heritable
disorder. Many family studies have been conducted to demonstrate the genetic component of
this disorder. Provide a brief explanation (2-3 sentences) for why the specific inheritance
pattern of schizophrenia cannot be determined. (1 point)
2. The GWAS on schizophrenic associated loci that was published in 2011
showed about 5 loci on different chromosomes were associated with
schizophenria. One of the loci was at the Major Histocompatibility
Complex. The SNP that was most statistically significant was rs9272105.

The rs is an abbreviation for Reference SNP, which is a nucleotide

sequence that surrounds the SNP, 25 bp on the 5 side of the SNP and 25
bp on the 3side of the SNP. (1 point)
Go to http://www.ncbi.nlm.nih.gov/SNP/, enter rs9272105 in the search
window.
What is the single nucleotide polymorphism (SNP) in the reference
sequence?
Click on the NC_000006.11:g.32599999G>A; What chromosome contains
this SNP? (Hint: look at the title of the image).
3. Linkage analysis and positional cloning are two molecular techniques used to map genes, i.e.,
identify the chromosomal location of a genes. Use the reference, Genetics Home Reference
(http://ghr.nlm.nih.gov/) to provide a brief response (1-2 sentences) comparing/contrasting
positional cloning vs. gene cloning. (1 point)
4. Use the same website to provided a brief response (1-2 sentences) on how are SNPs used in
linkage analysis. (1 point)
Read the article, Schizophrenias Genetic Skyline Rising, and answer questions 5, 6, 7.
5. What factor most influenced the rising of the Manhattan Plots shown in Figure 1. (1
point).

Figure 1. Comparison of the PGC 2011 and 2014 GWAS results. Source: NIMH. 2014. Press
Release. Schizophrenias Genetic Skyline Rising July 22, 2014. Retrieved October 4, 2015,
from
http://www.nimh.nih.gov/news/science-news/2014/schizophrenias-genetic-skyline-rising.shtml
6. Briefly (1-3 sentences) IN YOUR OWN WORDS, summarize the justification of the study,
Biological insights from 108 schizophrenia-associated genetic loci, as
explained Thomas R. Insel, M.D., director of the NIHs National Institute of
Mental Health. (1 point)
7. What are the genes that have variants associated with schizophrenia? (1 point)

Use any of the references provided, including the website Genetic Home Reference to provide
responses to Question 8 (3 points).
8. Compare and contrast the genetic concepts of: multifactorial inheritance, genetic
heterogeneity, heritable, and heritability.
References.
1. Schizophrenia. (2015, September 2). In Wikipedia, The Free Encyclopedia. Retrieved 22:03,
September 26, 2015, from https://en.wikipedia.org/w/index.php?
title=Schizophrenia&oldid=679043841
2. van Os J, Kapur S (August 2009). "Schizophrenia" (PDF). Lancet 374 (9690): 63545.
doi:10.1016/S0140-6736(09)60995-8. PMID 19700006.
3. Yellowlees, P. MRI Changes in Schizophrenia. January 25, 2012 Medscape Psychiatry &
Mental Health retrieved September 27, 2015 from http://www.medscape.com/viewarticle/757151
4. Kety SS. Schizophrenic illness in the families of schizophrenic adoptees: findings from the
Danish national sample. Schizophr Bull 1998; 14: 217-222
5. Salleh, M. R. The genetics of schizophrenia. Malaysian Journal of Medical Sciences, Vol. 11,
No. 2, July 2004 (3-11).
6. The Schizophrenia Psychiatric Genome-Wide Association Study (GWAS) Consortium (PGC):
Genome-wide association study identifies five new schizophrenia loci Nat Genet. ; 43(10): 969
976. doi:10.1038/ng.940.
7. Schizophrenia Working Group of the Psychiatric Genomics Consortium Biological insights
from 108 schizophrenia-associated genetic loci. Nature, July 24, 2014. doi:10.1038/nature13595
8. Leask, S.J. Environmental influences in schizophrenia: the known and the unknown Advances
in Psychiatric Treatment (2004), vol. 10, 3233. DOI: 10.1192/apt.10.5.323.
9. Adam, G. 2012. What is Heritability? Science 2.0. September 6th 2012 08:01 AM retrieved
October 4, 2015 from http://www.science20.com/gerhard_adam/what_heritability-93424 .
10. Light, G. Comparison of the Heritability of Schizophrenia and
Endophenotypes in the COGS-1 Family Study. Schizophr Bull (2014) 40
(6): 1404-1411. doi: 10.1093/schbul/sbu064
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