• Meng-Yuan Shang, Yong Wu, Chu-Yi Zhang, Hao-Xiang Qi, Qing Zhang, Jin-Hua Huo, Lu Wang, Chuang Wang, and Ming Li.
• Zhejiang Key Laboratory of Pathophysiology, School of Medicine, Ningbo University, Ningbo, Zhejiang, China.
• Bmc Med. 2022 Nov 30; 20 (1): 464464.

BackgroundBipolar disorder (BD) is a highly heritable psychiatric illness exhibiting substantial correlation with intelligence.MethodsTo investigate the shared genetic signatures between BD and intelligence, we utilized the summary statistics from genome-wide association studies (GWAS) to conduct the bivariate causal mixture model (MiXeR) and conjunctional false discovery rate (conjFDR) analyses. Subsequent expression quantitative trait loci (eQTL) mapping in human brain and enrichment analyses were also performed.ResultsAnalysis with MiXeR suggested that approximately 10.3K variants could influence intelligence, among which 7.6K variants were correlated with the risk of BD (Dice: 0.80), and 47% of these variants predicted BD risk and intelligence in consistent allelic directions. The conjFDR analysis identified 37 distinct genomic loci that were jointly associated with BD and intelligence with a conjFDR < 0.01, and 16 loci (43%) had the same directions of allelic effects in both phenotypes. Brain eQTL analyses found that genes affected by the "concordant loci" were distinct from those modulated by the "discordant loci". Enrichment analyses suggested that genes related to the "concordant loci" were significantly enriched in pathways/phenotypes related with synapses and sleep quality, whereas genes associated with the "discordant loci" were enriched in pathways related to cell adhesion, calcium ion binding, and abnormal emotional phenotypes.ConclusionsWe confirmed the polygenic overlap with mixed directions of allelic effects between BD and intelligence and identified multiple genomic loci and risk genes. This study provides hints for the mesoscopic phenotypes of BD and relevant biological mechanisms, promoting the knowledge of the genetic and phenotypic heterogeneity of BD. The essential value of leveraging intelligence in BD investigations is also highlighted.© 2022. The Author(s).

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