Journal Article

Genetic architectures of psychiatric disorders: the emerging picture and its implications

Daly, Mark J., O'Donovan, Michael, Sullivan, Patrick F.

2012

Overview

Key Points Psychiatric disorders cause enormous morbidity, mortality and personal and societal costs. Despite considerable investigation, little is known for certain about aetiologies. Genetic approaches are a major avenue of investigation. In the past 5 years, a considerable number of new findings have been discovered that meet community standards for robustness and replication. Where sample sizes are sufficiently large, genome-wide association has yielded several dozen findings that suggest novel biological mechanisms. 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. 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. 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. 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. This Review considers recent findings — from genome-wide association studies, structural variant studies and exome sequencing — about the genetics of nine psychiatric disorders. The authors evaluate the implications of our current picture of the genetic architectures of these conditions for future research strategies. 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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 631/208/205/2138 / 631/80/304 / 692/699/476 / Agriculture / Alcoholism - genetics / Alzheimer Disease - genetics / Alzheimer's disease / Animal Genetics and Genomics / Anorexia / Anorexia Nervosa - genetics / Attention Deficit Disorder with Hyperactivity - genetics / Autism / Biological and medical sciences / Biomedical and Life Sciences / Biomedicine / Bipolar disorder / Bipolar Disorder - genetics / Cancer Research / Child / Child Development Disorders, Pervasive - genetics / Depressive Disorder, Major - genetics / Disease / Fundamental and applied biological sciences. Psychology / Gene Function / Gene mutations / Genetic aspects / Genetics / Genetics of eukaryotes. Biological and molecular evolution / Genomes / Health aspects / Human Genetics / Humans / Hyperactivity / Mental depression / Mental disorders / Mental Disorders - genetics / Mental illness / Models, Genetic / Mortality / Nicotine / review-article / Risk factors / Schizophrenia / Schizophrenia - genetics / Single nucleotide polymorphisms / Tobacco Use Disorder - genetics