Key Points
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Psychiatric disorders cause enormous morbidity, mortality and personal and societal costs.
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Despite considerable investigation, little is known for certain about aetiologies. Genetic approaches are a major avenue of investigation.
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In the past 5 years, a considerable number of new findings have been discovered that meet community standards for robustness and replication.
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Where sample sizes are sufficiently large, genome-wide association has yielded several dozen findings that suggest novel biological mechanisms.
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Studies of rare variation (generally using genome-wide association study chips) have yielded over ten copy number variants that confer markedly increased risk. However, these tend to be nonspecific and increase risk for multiple different neuropsychiatric conditions.
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Studies of exonic variation have yielded new findings for autism. However, for autism and schizophrenia, these findings are not abundant, and their genetic architectures do not appear to consist of a series of Mendelian traits, making the 'many Mendelian model' very unlikely.
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Looking at the psychiatric disorders for which there are sufficient genetics data, it seems that these disorders are fairly typical complex traits with genetic variation scattered across the allelic spectrum.
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For the first time, a fairly complete enumeration of the 'parts list' for these disorders is attainable using established methods. Further study using a balanced portfolio of methods to assess multiple forms of genetic variation is likely to yield many additional new findings.
Abstract
Psychiatric disorders are among the most intractable enigmas in medicine. In the past 5 years, there has been unprecedented progress on the genetics of many of these conditions. In this Review, we discuss the genetics of nine cardinal psychiatric disorders (namely, Alzheimer's disease, attention-deficit hyperactivity disorder, alcohol dependence, anorexia nervosa, autism spectrum disorder, bipolar disorder, major depressive disorder, nicotine dependence and schizophrenia). Empirical approaches have yielded new hypotheses about aetiology and now provide data on the often debated genetic architectures of these conditions, which have implications for future research strategies. Further study using a balanced portfolio of methods to assess multiple forms of genetic variation is likely to yield many additional new findings.
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Acknowledgements
We remain indebted to the tens of thousand of individuals with psychiatric disorders for their participation in genetic studies of these disorders. We thank many colleagues for helpful critiques, plus a wealth of conversations with colleagues in the Psychiatric Genomics Consortium. We thank the US National Institutes of Health (NIH) for funding (MH077139 and MH085520), T. Lehner of the US National Institute of Mental Health (NIMH) for his continued support, B. Voight and J. Hirschhorn for data relevant to power estimation, S. Ripke for help with figures, J. Szatkiewicz for assistance in reviewing the structural variation literature, and C. Bulik and J. Crowley for helpful comments. M.O. is supported for schizophrenia research by grants from the UK Medical Research Council (MRC) (G0800509, G0801418), the European Community's Seventh Framework Programme (HEALTH-F2-2010-241909 (Project EU-GEI)) and by NIMH (5P50MH066392-09). This study makes use of data generated by DECIPHER. A full list of centres that contributed to the generation of the data is available from http://decipher.sanger.ac.uk. Funding for DECIPHER was provided by the Wellcome Trust. The authors jointly conceived and wrote this paper and take responsibility for its content.
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Supplementary information
Supplementary information S1 (table)
Data for Figure 1a (PDF 149 kb)
Supplementary information S2 (table)
Genetic findings for psychiatric disorders before 2005 (PDF 150 kb)
Supplementary information S3 (figure)
Variants of strong effect on psychiatric disorders (PDF 1094 kb)
Supplementary information S4 (figure)
Psychiatric GWAS authorship network graph (PDF 285 kb)
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FURTHER INFORMATION
Patrick F. Sullivan's homepage
Michael O'Donovan's homepage (at University of Cardiff)
Michael O'Donovan's profile at the National Centre for Mental Health
Nature Reviews Genetics Series on Disease mechanisms
Psychiatric Genomics Consortium
Ricopili (a tool for visualizing regions of interest in select GWAS data sets)
Glossary
- Pellagra
-
A disease caused by niacin (vitamin B3) deficiency that has prominent neuropsychiatric symptoms.
- Neurosyphilis
-
Infection of the central nervous system by Treponema pallidum (which is the spirochete that causes syphilis) and often causes prominent neuropsychiatric symptoms.
- Genome-wide association studies
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(GWASs). Unbiased genome screens of unrelated cases and appropriately matched controls or parent-affected child trios. The dominant technology has been individual genotyping using highly multiplexed SNP arrays.
- Structural variation
-
A genomic alteration that changes the number of copies or the arrangement of the genome. Copy number variants are one type of structural variation.
- Genome-wide linkage
-
A type of unbiased genome screen based on multiplex pedigrees. Genotyping approaches have included restriction fragment length polymorphisms, microsatellites and SNP arrays. After adjustment for multiple comparisons, the signal is the co-segregation of a genotype with a disease phenotype within the pedigrees.
- Karyotyping
-
Determination of the microscopic appearance and gross changes in chromosomal content and structure of a cell.
- Meta-analyses
-
These are methods for summarizing and combining results across multiple studies and are widely used in complex trait genetics. Meta-analyses combine the summary results from each study.
- Lowess smoother
-
Locally weighted scatterplot smoothing, which is one technique to fit a curve to a scatterplot.
- β-amyloid
-
Neuronal accumulation of this peptide contributes to the aetiology of Alzheimer's disease.
- Multiplex pedigrees
-
Family constellations containing more than one affected individual.
- Simplex pedigrees
-
Family constellations containing one affected individual.
- Genotypic relative risk
-
(GRR). A measure of the effect size of a genetic variant ranging from zero to infinity. A GRR of 1 means no change in risk, GRR < 1 is protective and GRR > 1 is predisposing.
- Odds ratio
-
Similar to genotypic relative risk: a measure of the change in risk associated with a genetic variant.
- Mega-analyses
-
These are methods (that are less widely used than meta-analyses) for summarizing and combining results across multiple studies. Mega-analysis combines individual-level genotype and phenotype data from all subjects in each study.
- Major histocompatibility complex region
-
(MHC). A region of approximately 3 Mb on human chromosome 6p22.1 that is exceptionally complex and has considerable importance to disease. It contains genes encoding cell surface molecules that are important to immunity and disease susceptibility and many other functions.
- Expression quantitative trait locus
-
(eQTL). DNA variation that is strongly associated with the expression of a particular mRNA transcript.
- Polygenic
-
Meaning 'many genes'. As a description of genetic architecture, polygenic gives no indications about the frequencies, modes of action or effect sizes of any relevant genetic variation.
- Prodrome
-
Premonitory symptoms. In this case, a collection of psychotic symptoms that sometimes evolves into schizophrenia or a mood disorder or that resolves without further sequella.
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Sullivan, P., Daly, M. & O'Donovan, M. Genetic architectures of psychiatric disorders: the emerging picture and its implications. Nat Rev Genet 13, 537–551 (2012). https://doi.org/10.1038/nrg3240
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DOI: https://doi.org/10.1038/nrg3240
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