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

Abstract

Psychiatric disorders are among the most intractable enigmas in medicine. In the past five 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 (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 etiology, 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.

Assessment of first and second degree relatives of individuals with bipolar disorder shows increased genetic risk scores in both affected relatives and young At‐Risk Individuals

“…It remains to be seen as to whether polygenic risk scores alone [Patel et al, 2010], or in conjunction with early clinical signs, exposure to psychosocial risk factors, and other potential biomarkers [Brietzke et al, 2012] may provide a more robust predictor of future illness. The predictive power of polygenic risk scores is likely to improve with increased discovery sample sizes and the assessment of a larger number of both common and rare genetic variants within the prediction models [Sullivan et al, 2012; Chatterjee et al, 2013; Craddock and Sklar, 2013; Dudbridge, 2013]. …”

“…Individually, each of those genes/loci contributes only a small fraction toward overall disease risk, typically <1% of the phenotypic variance [Ferreira et al, 2008]. It is now understood that multiple genes containing both common and rare variants contribute to the genetic architecture of BP [Sullivan et al, 2012], and there are significant overlaps in the single nucleotide polymorphism (SNP)‐based heritabilities of BP with both schizophrenia and major depression [Lee et al, 2013]. Indeed, variation across many thousands of common risk variants together (termed polygenic risk [Purcell et al, 2009]) contributes a substantial proportion (i.e., 25–40%) of the percentage of phenotypic variance at a population level [Lee et al, 2011; 2013]—although most of those loci do not individually reach genome‐wide significance thresholds for disease association with current sample sizes [Craddock and Sklar, 2013; Dudbridge, 2013].…”

Genetic studies of schizophrenia: an update

“…(see Table 2 for more details). For the involved genes, the effect is more pronounced [34,[57][58][59] . The large 22q11.21 locus (3 Mb), also known as DiGeorge and velo-cardio-facial syndrome critical region, was first reported to be associated with SCZ in the 1990s [60] , and this was verified in many later studies [38,39,44,46,47,[51][52][53][54][55] .…”

Les « gènes » de la schizophrénie

“…Contrairement à une impression assez répandue, les travaux sur les déterminants génétiques de maladies psychiatriques ont largement progressé depuis quelques années -le tournant se situant vers 2007 [7]. Les études GWAS, menées avec des effectifs importants et interprétées avec la rigueur statistique requise, ont identifié de nombreux variants fréquents (common variants) dont l'implication a été confirmée par la suite ; par ailleurs, des variants de structure rares (souvent des délétions) ont aussi été identifiés par l'emploi de puces à ADN et parfois par le séquençage.…”