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Bipolar disorder (BD) is a heritable mental illness with complex etiology. While the largest published genome-wide association study identified 64 BD risk loci, the causal SNPs and genes within these loci remain unknown. We applied a suite of statistical and functional fine-mapping methods to these loci, and prioritized 22 likely causal SNPs for BD. We mapped these SNPs to genes, and investigated their likely functional consequences by integrating variant annotations, brain cell-type epigenomic annotations, brain quantitative trait loci, and results from rare variant exome sequencing in BD. Convergent lines of evidence supported the roles of SCN2A, TRANK1, DCLK3, INSYN2B, SYNE1, THSD7A, CACNA1B, TUBBP5, PLCB3, PRDX5, KCNK4, AP001453.3, TRPT1, FKBP2, DNAJC4, RASGRP1, FURIN, FES, YWHAE, DPH1, GSDMB, MED24, THRA, EEF1A2, and KCNQ2 in BD. These represent promising candidates for functional experiments to understand biological mechanisms and therapeutic potential. Additionally, we demonstrated that fine-mapping effect sizes can improve performance and transferability of BD polygenic risk scores across ancestrally diverse populations, and present a high-throughput fine-mapping pipeline (https://github.com/mkoromina/SAFFARI).
Men and women differ substantially regarding height, weight, and body fat. Interestingly, previous work detecting genetic effects for waist-to-hip ratio, to assess body fat distribution, has found that many of these showed sex-differences. However, systematic searches for sex-differences in genetic effects have not yet been conducted. Therefore, we undertook a genome-wide search for sexually dimorphic genetic effects for anthropometric traits including 133,723 individuals in a large meta-analysis and followed promising variants in further 137,052 individuals, including a total of 94 studies. We identified seven loci with significant sex-difference including four previously established (near GRB14/COBLL1, LYPLAL1/SLC30A10, VEGFA, ADAMTS9) and three novel anthropometric trait loci (near MAP3K1, HSD17B4, PPARG), all of which were significant in women, but not in men. Of interest is that sex-difference was only observed for waist phenotypes, but not for height or body-mass-index. We found no evidence for sex-differences with opposite effect direction for men and women. The PPARG locus is of specific interest due to its link to diabetes genetics and therapy. Our findings demonstrate the importance of investigating sex differences, which may lead to a better understanding of disease mechanisms with a potential relevance to treatment options.