Bipex 2.0: large-scale exome sequencing of over 75,000 individuals identifies novel genetic insights into bipolar disorder

Bipolar disorder (BD) is a complex psychiatric disorder characterized by recurrent mood disturbances with significant variations in disease severity and treatment response. Despite its substantial impact on individuals, the genetic factors contributing to BD remain incompletely understood. Exome sequencing has emerged as a powerful tool for elucidating the genetic architecture of various diseases. Here, we provide updates from the Bipolar Exome (BipEx) consortia, where we leverage large-scale exome sequencing to investigate the role of protein-truncating variants (PTVs), copy number variants (CNVs), and damaging missense variants in the pathogenesis of BD. Our study cohort comprised of over 75,000 individuals of bipolar disorder and controls, with highly diverse populations from Europe, Central and South America, Asia, Australia and Africa. Whole exome sequencing was conducted to capture protein-coding regions, followed by robust variant calling and stringent filtering. We filtered to ultra-rare genetic variants with a minor allele count less than 5 for PTVs and damaging missense variants. Additionally, we used GATK-gCNV to call rare exonic duplications and deletions (>3 exons). Previous benchmarking of exome sequencing against whole-genome sequencing for CNVs was done to identify optimal filtering of CNVs. The initial PTV analyses revealed that the top significant associations were for AKAP11, DOP1A, KDM5B and SP4. There are additionally significant enrichments in highly constrained loss-of-function genes (pLI > 0.9) across PTVs (OR: 1.20, P = 3.18 × 10^-29), missense (OR: 1.07, P = 5.95 × 10^-11), deletions (OR: 1.94, P = 2.47 × 10^-24) and duplications (OR: 1.09, P = 0.01). Furthermore, we see significant enrichment of schizophrenia, autism, and neurodevelopmental disorder associated genes across these genetic variant types. By leveraging a large cohort of over 75,000 individuals, BipEx 2.0 provides comprehensive insights into the genetic landscape of BD. We demonstrate the importance of PTVs, CNVs and damaging missense variants in the genetic architecture of BD, shedding light on the biological mechanisms underlying this complex disorder. Overall, these findings begin to unravel the complexities of BD biology and point towards potential convergence across genetic variant classes.