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 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.

Figure 1. Results pertaining to genetic architecture

(a) Plot of heritability by log₁₀ lifetime prevalence for nine psychiatric disorders considered in this review plus three complex diseases for which genetic dissection has been particularly successful (Tables 1 and S1). Each disorder is plotted by as heritability by lifetime prevalence. Color indicates qualitative success in identifying etiological genetic variation (green=notably successful, khaki=some successes, red=minimal or no clear success to date). The bubble sizes are proportional to the numbers of cases studied in GWAS (the smaller circle indicating discovery N_case and the larger circle the total N_case for discovery plus replication samples). Abbreviations: ADHD=attention-deficit hyperactivity disorder, ALC=alcohol dependence, AD=Alzheimer’s disease, AN=anorexia nervosa, ASD=autism, BIP=bipolar disorder, BRCA=breast cancer, CD=Crohn’s disease, MDD=major depressive disorder, NIC=nicotine usage (maximum cigarettes per day), SCZ=schizophrenia, and T2DM=type 2 diabetes mellitus. (b) Allelic spectrum of SCZ. The inset is a conceptual schematic from a 2008 Nature Genetics review. The lower part of the figure depicts empirical results for SCZ. The x-axis is log₁₀(AF) in controls. The y-axis is the point estimate for genotypic relative risk (GRR, log₁₀). For clarity, confidence intervals are not shown. There are no known Mendelian variants for SCZ (AF ≪ 0.0001, GRR ≫ 50). There are no known common variants (AF > 0.05) with GRR > 1.5, and these can be excluded with > 99% statistical power. Nine SVs associated with SCZ are shown as light blue diamonds (Table 2, 1q21.1- is the deletion and 1q21.1+ is the duplication). If AF in controls was 0, AF was set to 0.0001. These SVs do not have a corresponding region in the inset. Seventeen common variants have been associated with SCZ (red circles, Table 3). SNPs contributing to the PGC SCZ risk profile score (21,171 autosomal SNPs with P_T < 0.1, Box 3, panel b) are shown in light blue dots with a lowess smoother in dark blue.

Figure 1. Results pertaining to genetic architecture

(a) Plot of heritability by log₁₀ lifetime prevalence for nine psychiatric disorders considered in this review plus three complex diseases for which genetic dissection has been particularly successful (Tables 1 and S1). Each disorder is plotted by as heritability by lifetime prevalence. Color indicates qualitative success in identifying etiological genetic variation (green=notably successful, khaki=some successes, red=minimal or no clear success to date). The bubble sizes are proportional to the numbers of cases studied in GWAS (the smaller circle indicating discovery N_case and the larger circle the total N_case for discovery plus replication samples). Abbreviations: ADHD=attention-deficit hyperactivity disorder, ALC=alcohol dependence, AD=Alzheimer’s disease, AN=anorexia nervosa, ASD=autism, BIP=bipolar disorder, BRCA=breast cancer, CD=Crohn’s disease, MDD=major depressive disorder, NIC=nicotine usage (maximum cigarettes per day), SCZ=schizophrenia, and T2DM=type 2 diabetes mellitus. (b) Allelic spectrum of SCZ. The inset is a conceptual schematic from a 2008 Nature Genetics review. The lower part of the figure depicts empirical results for SCZ. The x-axis is log₁₀(AF) in controls. The y-axis is the point estimate for genotypic relative risk (GRR, log₁₀). For clarity, confidence intervals are not shown. There are no known Mendelian variants for SCZ (AF ≪ 0.0001, GRR ≫ 50). There are no known common variants (AF > 0.05) with GRR > 1.5, and these can be excluded with > 99% statistical power. Nine SVs associated with SCZ are shown as light blue diamonds (Table 2, 1q21.1- is the deletion and 1q21.1+ is the duplication). If AF in controls was 0, AF was set to 0.0001. These SVs do not have a corresponding region in the inset. Seventeen common variants have been associated with SCZ (red circles, Table 3). SNPs contributing to the PGC SCZ risk profile score (21,171 autosomal SNPs with P_T < 0.1, Box 3, panel b) are shown in light blue dots with a lowess smoother in dark blue.