Identification of genetic variants influencing methylation in brain with pleiotropic effects on psychiatric disorders

Psychiatric disorders affect 29% of the global population at least once in the lifespan, and genetic studies have proved a shared genetic basis among them, although the underlying molecular mechanisms remain largely unknown. DNA methylation plays an important role in complex disorders and, remarkably, enrichment of common genetic variants influencing allele-specific methylation (ASM) has been reported among variants associated with specific psychiatric disorders. In the present study we assessed the contribution of ASM to a set of eight psychiatric disorders by combining genetic, epigenetic and expression data. We interrogated a list of 3896 ASM tagSNPs in the brain in the summary statistics of a cross-disorder GWAS meta-analysis of eight psychiatric disorders from the Psychiatric Genomics Consortium, including more than 162,000 cases and 276,000 controls. We identified 80 SNPs with pleiotropic effects on psychiatric disorders that show an opposite directional effect on methylation and gene expression. These SNPs converge on eight candidate genes: ZSCAN29, ZSCAN31, BTN3A2, DDAH2, HAPLN4, ARTN, FAM109B and NAGA. ZSCAN29 shows the broadest pleiotropic effects, showing associations with five out of eight psychiatric disorders considered, followed by ZSCAN31 and BTN3A2, associated with three disorders. All these genes overlap with CNVs related to cognitive phenotypes and psychiatric traits, they are expressed in the brain, and seven of them have previously been associated with specific psychiatric disorders, supporting our results. To sum up, our integrative functional genomics analysis identified eight psychiatric disease risk genes that impact a broad list of disorders and highlight an etiologic role of SNPs that influence DNA methylation and gene expression in the brain.