Investigating Shared Genetic Bases between Psychiatric Disorders, Cardiometabolic and Sleep Traits Using K-Means Clustering and Local Genetic Correlation Analysis

Psychiatric disorders are among the top leading causes of the global health-related burden. Comorbidity with cardiometabolic and sleep disorders contribute substantially to this burden. While both genetic and environmental factors have been suggested to underlie these comorbidities, the specific molecular underpinnings are not well understood. In this study, we leveraged large datasets from genome-wide association studies (GWAS) on psychiatric disorders, cardiometabolic and sleeprelated traits. We computed genetic correlations between pairs of traits using cross-trait linkage disequilibrium (LD) score regression and identified clusters of genetically correlated traits using k-means clustering. We further investigated the identified associations using two-sample mendelian randomization (MR) and tested the local genetic correlation at the identified loci. In the 7-cluster optimal solution, we identified a cluster including insomnia and the psychiatric disorders major depressive disorder (MDD), post-traumatic stress disorder (PTSD), and attention-deficit/hyperactivity disorder (ADHD). MR analysis supported the existence of a bidirectional association between MDD and insomnia and the genetic variants driving this association were found to affect gene expression in different brain regions. Some of the identified loci were further supported by results of local genetic correlation analysis, with body mass index (BMI) and C-reactive protein (CRP) levels suggested to explain part of the observed effects. We discuss how the investigation of the genetic relationships between psychiatric disorders and comorbid conditions might help us to improve our understanding of their pathogenesis and develop improved treatment strategies.