New findings from genetic association studies of schizophrenia

Abstract

In the past 20 years, association studies of schizophrenia have evolved from analyses in lesser than 100 subjects of one or two markers in candidate genes to systematic analyses of association at a genome-wide level in samples of thousands of subjects. During this process, much of the emergent literature has been difficult to interpret and definitive findings that have met with universal acceptance have been elusive, largely because studies have been underpowered for such conclusions to be drawn. Nevertheless, in the course of the past few years, a few promising candidate genes have been reported for which the evidence is positive across multiple studies, and more recently, genome-wide association studies have yielded findings of a compelling nature. It is clear that genetic studies in schizophrenia have borne fruit, a process that can be expected to accelerate in the next few years, and that these findings are providing new avenues for research into the pathophysiology of this poorly understood disorder. Keywords: association study; candidate gene; copy number variant; genome wide association study; schizophrenia INTRODUCTION Schizophrenia is a severe psychiatric disorder with a lifetime risk of B1%. It is characterized by psychotic symptoms (delusions and hallucinations), apathy, altered emotional reactivity and disorganized behavior. 1 Subtle cognitive and behavioral signs are often present from childhood onwards, but the characteristic features generally have their onset in the late teens and early 20s. Outcomes vary, but the typical course is one of relapses followed by only partial remission and a marked reduction in social and occupational functions.Schizophrenia has been the subject of an extensive series of family, twin and adoption studies (Figure 1), which clearly show variance in population risk is largely the result of genetic factors, with heritability being X80%. Patterns of recurrence in families do not suggest that the generality of schizophrenia can be attributed to a collection of single major genes, and are most compatible with a complex multi-locus model. 3,4 Similar to other disorders with complex inheritance, 5 it has been increasingly postulated that most of the genetic variance will be attributable to weak genetic effects as proposed many years ago, 6 a hypothesis compatible with meta-analyses of the linkage data. 7 Those hypotheses and data do not, however, preclude the existence of highly penetrant mutations in occasional families; indeed, there is now compelling evidence for several such events (St Clair et al. 8 and see below).Given the increasing emphasis by most researchers on small genetic effects, it has been proposed that pure association approaches independent of genetic linkage offer the greatest potential in schizophrenia and other complex disorders, 9 as they are better powered to detect

Evaluation of risk loci for schizophrenia derived from genome-wide association studies in a German population

“…In a model free approach GWAS allow the identification of previously unsuspected genes and pathways in disease aetiology. Implementation of GWAS has brought considerable progress in the identification and robust replication of common gene variants that confer susceptibility to common diseases and other phenotypes of interest although these genetic effect-sizes are almost invariably moderate to small in magnitude [Lango and Weedon, 2008;Mullen et al, 2009;Williams et al, 2009].…”

Two gene co-expression modules differentiate psychotics and controls

“…These disorders have been shown to be highly heritable by monozygotic and dizygotic twin studies and by adoption studies: the heritability estimates for SCZ range from 70 to 85% and, for BD, from 60 to 85% 5 . Over the past two decades, genetic studies of thousands of samples have identified hundreds of candidate genes 6-8 . Most of these findings have not been supported by genome-wide studies.…”

Atypical scanpaths in schizophrenia: Evidence of a trait- or state-dependent phenomenon?

“…Diagnosis of the disease is currently based on clinical criteria and lacks objective tests. Although there is much support for a genetic component in vulnerability to the illness, and a number of chromosome loci and candidate genes have been recognized, much about the genetic basis of schizophrenia remains unknown (for a recent review, see Williams and colleagues 1 ). Several genes are likely to contribute to susceptibility, and patterns of inheritance are intricate and irregular.…”