Psychiatric genetics - Does diagnosis matter?

Since its beginnings, psychiatric genetics has stimulated the field of psychiatry and led to crucial questions about the nature of psychiatric disorders. An example of the early debates is the nature–nurture controversy. More recently, we have been witnessing discussions about the association between the genetic architecture of psychiatric disorders and their clinical manifestations — in other words, how are genetic mechanisms linked to behaviour, cognitive functions, and emotional regulation. Most psychiatric disorders are heritable; many, including schizophrenia, autism and bipolar disorder, are in fact highly heritable, with heritability estimates exceeding 50%. The heritability data are derived mainly from twin studies, with added support from adoption studies, showing that family resemblance is primarily due to shared genes rather than shared environment. These findings have led to an expectation that clarifying the gen etic mechanisms and discoveries of specific genetic variants would lead to deeper understanding of the pathophysiology of psychiatric disorders and provide clinically useful guidance for differential diagnosis, treatment selection and/or novel treatments based on genetic mechanisms. Until recently, specific genetic variants predisposing individuals to these disorders have been hard to pinpoint. However, modern genetic methods and largescale collaborations have led to a continuously increasing number of replicated findings. Needless to say, genetic studies are finding what their methods are supposed to find. There are a handful of loci of major effect, including copy number variations, playing a role in a minute fraction of cases (families) as well as a number of loci that are relatively common and have small effects. The latter have been identified through genome-wide association studies, and their effect sizes (relative risk values) are typically around 1.1 or less. Discoveries of such associations will, no doubt, continue with increasing sample sizes. For instance, there have been 155 reported loci associated with the risk of schizophrenia in combined samples totaling 60 995 and 19 reported loci for bipolar disorder in samples of 20 352 cases (unpublished data, Sullivan and colleagues, 2017). The search for nongenetic, environmental risk factors is also relevant, but arguably even more difficult as their potential number is almost infinite. Inferring from quantitative gen etic analyses, the overall nongenetic contribution to most severe psychiatric disorders is relatively small and may depend on gene × environment interactions, possibly necessitating even larger sample sizes than purely genetic studies. The complex nature of the genetic architecture of behavioural disorders is hardly surprising. Many other traits that ori ginally seemed genetically simple show much complexity characterized by heterogeneity, multiple mutation of varying biological impact, and gene × gene or gene × environment interactions. On the other hand, many less complex and more uncommon conditions can lead to behavioural phenotypes presenting, for instance, as schizophrenia.1 The large case–control samples available also permit tests of shared predisposition to disorders traditionally considered to be distinct diagnostic entities.2,3 These studies show considerable overlap in polygenic susceptibility, with reported correlations between liabilities for major psychiatric disorders in the range of 0.3 to 0.7.3 Taken together, genetic findings in psychiatry seem to indicate that the genetic predisposition to most disorders is polygenic, pleiotropic and, to a large extent, nonspecific. An intuitive generalization of this concept is the “omnigenic” model proposed by Boyle and colleagues.4 The model postulates that many complex traits are associated with variants in “most genes expressed in diseaserelevant cells.” The susceptibility to a disorder is conferred by a dysfunction in gene regulatory networks rather than changes in a single or a few coding variants. The support for the model comes from several observations that include only modest enrichment of positive