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

Abstract

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.