Genetic relationship between five psychiatric disorders estimated from genome-wide SNPs

Abstract

Most psychiatric disorders are moderately to highly heritable. The degree to which genetic variation is unique to individual disorders or shared across disorders is unclear. To examine shared genetic etiology, we use genome-wide genotype data from the Psychiatric Genomics Consortium (PGC) for cases and controls in schizophrenia, bipolar disorder, major depressive disorder, autism spectrum disorders (ASD) and attention-deficit/hyperactivity disorder (ADHD). We apply univariate and bivariate methods for the estimation of genetic variation within and covariation between disorders. SNPs explained 17-29% of the variance in liability. The genetic correlation calculated using common SNPs was high between schizophrenia and bipolar disorder (0.68 ± 0.04 s.e.), moderate between schizophrenia and major depressive disorder (0.43 ± 0.06 s.e.), bipolar disorder and major depressive disorder (0.47 ± 0.06 s.e.), and ADHD and major depressive disorder (0.32 ± 0.07 s.e.), low between schizophrenia and ASD (0.16 ± 0.06 s.e.) and non-significant for other pairs of disorders as well as between psychiatric disorders and the negative control of Crohn's disease. This empirical evidence of shared genetic etiology for psychiatric disorders can inform nosology and encourages the investigation of common pathophysiologies for related disorders.

Figure 1

Evidence for genome-wide pleiotropy between psychiatric disorders. Proportion of variance in liability (SNP-based heritability) and proportion of covariance in liability between disorder (SNP-based coheritability) for five major psychiatric disorders. The 95% error bars represent the estimates ± 1.96 s.e. SCZ, schizophrenia; MDD, major depressive disorder; BPD, bipolar disorder.

Figure 2

Genomic partitioning of SNP-based heritability and SNP-based coheritability by annotation. Shown is the proportion of SNPs attributable to genes in the CNS+ set (red), the proportion of SNP-based heritability attributable to SNPs in the CNS+ set (dark green), the proportion of SNP-based coheritability attributable to SNPs in the CNS+ set (light green) and the proportion of SNP-based heritability for Crohn’s disease attributed to SNPs in the CNS+ set (orange). The 95% error bars represent the estimates ± 1.96 s.e. ***P < 1 × 10⁻⁵ in a test of whether the proportion of heritability explained by SNPs was equal to the proportion of SNP for the CNS+ set.

Figure 3

SNP-based heritabilities and coheritabilities. (a) For each disorder, SNP-based heritabilities are estimated from univariate analyses of the full data set (dark green) or of sample subsets (red and pink bars). These heritabilities are also estimated from bivariate analyses in which different subsets of the same disorder comprise the two traits (blue). Test of the heterogeneity of estimates, P value for Cochran’s Q: schizophrenia, 0.3; bipolar disorder, 1 × 10⁻⁶; major depressive disorder, 4 × 10⁻³; ADHD, 9 × 10⁻⁶; ASD, 0.99; Higgins’ I²: schizophrenia, 21%; bipolar disorder, 86%; major depressive disorder, 71%; ADHD, 91%; ASD, 0%). (b) For comparison, the coheritabilities using the full data sets reported in Figure 1 are shown. (c) As a negative control, estimates of coheritabilities with Crohn’s disease, a disease not expected to be genetically related to psychiatric disorders, are shown. We estimated 95% error bars using ± 1.96 s.e.