Epidemiological studies have identified multimorbidities for psychiatric disorders and cognitive functioning and suggest that common biological mechanisms may underlie these phenotypes. Single nucleotide polymorphisms (SNPs) represent common predisposing genetic factors. These can occur at regulatory sites and contribute to multimorbidities via their impact on gene expression and biological pathways. Genome-wide association studies (GWAS) have identified thousands of SNPs associated with psychiatric disorders and cognition. However, the regulatory contributions that these SNPs make to multimorbidity are largely unknown.
Here, we integrate 3D genome organization and expression quantitative trait (eQTL) analyses to identify genes and pathways that are functionally impacted by 2,893 GWAS SNPs (p < 1×10−6) associated with cognition and five psychiatric disorders (i.e. ADHD, anxiety, bipolar disorder, unipolar depression and schizophrenia). The analysis revealed 33 genes and 62 biological pathways that were commonly affected by the gene regulatory interactions associated with all six phenotypes despite there being no common SNPs and eQTLs. 16% of the ADHD-risk, 16.7% of the anxiety-risk, 20.5% of the BD-risk, 15.4% of the UD-risk, 17.1% of the SCZ-risk and 15.8% of the cognition-associated genes we identified represent known drug targets. Four druggable genes (i.e. AS3MT, FLOT1, HLA-A and PBRM1) were affected by eQTLs from all six phenotypes.
Collectively, our analyses inform the extent of genetic impacts on regulatory mechanisms and pathways that contribute to multimorbidities among psychiatric and cognitive phenotypes. Our results represent the foundation for a shift from a gene-targeted towards a pathway-based approach to the treatment and enhancement of multimorbid psychiatric and cognitive conditions.