Schizophrenia is a complex and debilitating chronic mental illness, and genetic factors play a major role in its etiology and development. Traditional genetic studies estimated the heritability of schizophrenia to be 70% to 90%.1 With the rapid advance of genomic technologies, the past decade has seen an explosion of genetic studies in schizophrenia, which opened new doors for our understanding of the molecular mechanisms in this brain disease. Some experts consider these developments to signal the advent of personalized medicine.2 With our newfound knowledge of the human genome, treatment may be increasingly tailored to the individual.
This article reviews some of the most recent findings in genetics and pharmacogenetics of schizophrenia—especially those with clinical implications.
Risk genes of schizophrenia
Researchers initially hoped to find just one or a few genes predominantly responsible for schizophrenia. However, recent studies have demonstrated that many genes may be involved in susceptibility to schizophrenia (polygenic), such as the MHC (major histocompatibility complex) region on chromosome 6, MIR137 (microRNA 137), ZNF804A (zinc finger protein 804A), DISC1 (disrupted in schizophrenia 1), and DTNBP1 (dystrobrevin binding protein 1).
Most recent reports from the Psychiatric Genomics Consortium suggest that the number of genetic loci that attain genome-wide significance in association with schizophrenia is between 50 and 100 and that these loci are distributed across many genes or genomic regions.3 In addition, any one particular gene may contribute to the risk of not only schizophrenia but also other psychiatric disorders, such as bipolar disorder (a phenomenon also known as “pleiotropy”).
A recent study found that 4 genomic loci reached genome-wide significance in a sample of 33,000 patients who had 5 psychiatric disorders (autism, schizophrenia, bipolar disorder, MDD, and ADHD) and 27,000 controls, which suggests overlaps in the genetic architecture of different mental illnesses.4 Two of these loci are voltage-gated calcium channel genes—CACNA1C and CACNB2—which supports the idea that calcium channel signaling may be a common pathway for all major mental disorders.
Our understanding of how some genes influence the risks of schizophrenia has evolved in the past decade. An example is the discovery of the DISC1 gene. Originally found in a linkage study in a Scottish family cohort, a translocation on chromosome 1 was found to be highly correlated with schizophrenia.5 This translocation directly disrupts the
DISC1 gene. The protein encoded by DISC1 appears to provide a scaffold to other proteins involved in multiple cellular functions, particularly regulation of brain development and maturation. It is involved in neuronal proliferation, differentiation, and migration via various signaling pathways by interacting with many other proteins.6
Naturally, the disruption of DISC1 results in dysfunction in multiple neurodevelopmental processes and significantly increases susceptibility not only for schizophrenia but also for bipolar disorder and depression. Despite advances in our understanding of the biology of DISC1, however, large case-control studies have not found a consistent association between DISC1 and schizophrenia.7 One possibility is that DISC1 pathology is representative of a subtype of schizophrenia that is not prevalent among the general population, therefore preventing large-scale epidemiological studies from find-ing evidence to support the role of DISC1 in schizophrenia.
Dr Zhang is Attending Psychiatrist in the division of psychiatry research at the Zucker Hillside Hospital; Assistant Investigator at the Feinstein Institute of Medical Research, North Shore-Long Island Jewish Health System in Glen Oaks, NY; and Assistant Professor of Psychiatry at the Hofstra North Shore-LIJ School of Medicine in Hempstead, NY. Dr Malhotra is Director, division of psychiatry research at the Zucker Hillside Hospital; Investigator, Center for Psychiatric Neuroscience at the Feinstein Institute for Medical Research in Manhasset, NY; and Professor of Psychiatry and Molecular Medicine at the Hofstra North Shore-LIJ School of Medicine. The authors report no conflicts of interest concerning the subject matter of this article.
1. Sullivan PF, Kendler KS, Neale MC. Schizophrenia as a complex trait: evidence from a meta-analysis of twin studies. Arch Gen Psychiatry. 2003;60:1187-1192.
2. de Leon J. AmpliChip CYP450 test: personalized medicine has arrived in psychiatry. Expert Rev Mol Diagn. 2006;6:277-286.
3. Ripke S. Psychiatric Genomics Consortium (PGC) doubles schizophrenia GWAS sample size to an estimated 40,000 individuals. Presented at: World Congress of Psychiatric Genetics; October 14-18, 2012; Hamburg, Germany.
4. Cross-Disorder Group of the Psychiatric Genomics Consortium, Smoller JW, Craddock N, Kendler K, et al. Identification of risk loci with shared effects on five major psychiatric disorders: a genome-wide analysis [published correction appears in Lancet. 2013;381:1360]. Lancet. 2013;381:1371-1379.
5. Millar JK, Wilson-Annan JC, Anderson S, et al. Disruption of two novel genes by a translocation co-segregating with schizophrenia. Hum Mol Genet. 2000;9:1415-1423.
6. Porteous DJ, Millar JK, Brandon NJ, Sawa A. DISC1 at 10: connecting psychiatric genetics and neuroscience. Trends Mol Med. 2011;17:699-706.
7. Mathieson I, Munafò MR, Flint J. Meta-analysis indicates that common variants at the DISC1 locus are not associated with schizophrenia. Mol Psychiatry. 2012;17:634-641.
8. O’Donovan MC, Craddock N, Norton N, et al; Molecular Genetics of Schizophrenia Collaboration. Identification of loci associated with schizophrenia by genome-wide association and follow-up. Nat Genet. 2008;40:1053-1055.
9. Girgenti MJ, LoTurco JJ, Maher BJ. ZNF804A regulates expression of the schizophrenia-associated genes PRSS16, COMT, PDE4B, and DRD2. PLoS One. 2012;7:e32404.
10. Lencz T, Szeszko PR, DeRosse P, et al. A schizophrenia risk gene, ZNF804A, influences neuroanatomical and neurocognitive phenotypes. Neuropsychopharmacology. 2010;35:2284-2291.
11. Esslinger C, Walter H, Kirsch P, et al. Neural mechanisms of a genome-wide supported psychosis variant. Science. 2009;324:605.
12. Handel AE, Ramagopalan SV. The potential role of major histocompatibility complex class I in schizophrenia. Biol Psychiatry. 2010;68:e29-e30; author reply e31.
13. Schizophrenia Psychiatric Genome-Wide Association Study (GWAS) Consortium. Genome-wide association study identifies five new schizophrenia loci. Nat Genet. 2011;43:969-976.
14. Athanasiou MC, Dettling M, Cascorbi I, et al. Candidate gene analysis identifies a polymorphism in HLA-DQB1 associated with clozapine-induced agranulocytosis. J Clin Psychiatry. 2011;72:458-463.
15. Malhotra AK. The state of pharmacogenetics. Psychiatr Times. 2010;27(4):38-41, 62, 63.
16. Malhotra AK, Correll CU, Chowdhury NI, et al. Association between common variants near the melanocortin 4 receptor gene and severe antipsychotic drug-induced weight gain. Arch Gen Psychiatry. 2012;69:904-912.
17. Zhang JP, Malhotra AK. Pharmacogenetics and antipsychotics: therapeutic efficacy and side effects prediction. Expert Opin Drug Metab Toxicol. 2011;7:9-37.
18. Patsopoulos NA, Ntzani EE, Zintzaras E, Ioannidis JP. CYP2D6 polymorphisms and the risk of tardive dyskinesia in schizophrenia: a meta-analysis. Pharmacogenet Genomics. 2005;15:151-158.
19. Malhotra AK, Zhang JP, Lencz T. Pharmacogenetics in psychiatry: translating research into clinical practice. Mol Psychiatry. 2012;17:760-769.
20. Mitchell PB, Meiser B, Wilde A, et al. Predictive and diagnostic genetic testing in psychiatry. Psychiatr Clin North Am. 2010;33:225-243.
21. Rundell JR, Staab JP, Shinozaki G, et al. Pharmacogenomic testing in a tertiary care outpatient psychosomatic medicine practice. Psychosomatics. 2011;52:141-146.
22. Stingl JC, Brockmöller J, Viviani R. Genetic variability of drug-metabolizing enzymes: the dual impact on psychiatric therapy and regulation of brain function. Mol Psychiatry. 2013;18:273-287.