Calcium signaling pathway implicates a shared genetic basis between psychiatric and cardiovascular diseases

Psychiatric and cardiovascular diseases (CVDs) are frequently comorbid and are interconnected through the brain-heart axis. However, the underlying shared genetic etiology remains unknown in East Asians. To address this critical gap, we conducted a genome-wide pairwise trait pleiotropy study by leveraging genome-wide association studies of three major psychiatric disorders (schizophrenia [SCZ], bipolar disorder [BIP], major depressive disorder [MDD]) and ten cardiovascular traits (including eight CVDs) in East Asians. We identified genetic overlaps across seven disease pairs, such as SCZ with coronary artery disease. Through this pairwise approach, six of a total of 18 pleiotropic loci demonstrated tissue-specific expression in brain and cardiovascular systems. In the cross-ancestry replication, nine of the pleiotropic loci were validated. Among the novel pleiotropic genes, TPCN1, CACNA2D2, CACNA1D, and ATP2B1 are involved in voltage-dependent calcium channel activity, regulation of calcium influx, enriched in calcium-related pathway. We validated association with calcium signal pathway in an independent cohort. Calcium pathway-specific polygenic risk score for SCZ was associated with prolonged corrected QT (QTc) interval, which remained robust among individuals free from QTc-affecting drugs. Given that calcium-channel blockers are commonly prescribed for heart and blood vessel conditions, we performed drug target analysis by integrating gene expression profiles from the brain and cardiovascular tissues. Our findings implicated that calcium-channel blockers and peripheral vasodilators elevated SCZ risk, diuretics reduced the risks of SCZ, BIP, and MDD. Our study reveals extensive shared genetic architectures underlying psychiatric and CVDs, which warrant prudence in the use of calcium channel blockers among patients with concurrent psychiatric and CVDs.