Jones Angela G, Connelly Guinevere G, Dalapati Trisha, Wang Liuyang, Schott Benjamin H, San Roman Adrianna K, Ko Dennis C
Department of Molecular Genetics and Microbiology, School of Medicine, Duke University; Durham, NC, USA.
Duke University Program in Genetics and Genomics, Duke University; Durham, NC, USA.
medRxiv. 2024 Sep 5:2024.09.03.24313025. doi: 10.1101/2024.09.03.24313025.
Humans display sexual dimorphism across many traits, but little is known about underlying genetic mechanisms and impacts on disease. We utilized single-cell RNA-seq of 480 lymphoblastoid cell lines to reveal that the vast majority (79%) of sex-biased genes are targets of transcription factors that display sex-biased expression. Further, we developed a two-step regression method that identified sex-biased expression quantitative trait loci (sb-eQTL) across the genome. In contrast to previous work, these sb-eQTL are abundant (n=10,754; FDR 5%) and reproducible (replication up to π=0.56). These sb-eQTL are enriched in over 600 GWAS phenotypes, including 120 sb-eQTL associated with the female-biased autoimmune disease multiple sclerosis. Our results demonstrate widespread genetic impacts on sexual dimorphism and identify possible mechanisms and clinical targets for sex differences in diverse diseases.
人类在许多性状上表现出性别二态性，但对于其潜在的遗传机制以及对疾病的影响却知之甚少。我们利用480个淋巴母细胞系的单细胞RNA测序来揭示，绝大多数（79%）的性别偏向基因是那些表现出性别偏向表达的转录因子的靶标。此外，我们开发了一种两步回归方法，该方法在全基因组范围内鉴定出了性别偏向的表达数量性状位点（sb-eQTL）。与之前的研究不同，这些sb-eQTL数量丰富（n = 10,754；FDR < 5%）且具有可重复性（复制率高达π = 0.56）。这些sb-eQTL在600多种全基因组关联研究（GWAS）表型中富集，其中包括120个与女性偏向的自身免疫性疾病多发性硬化症相关的sb-eQTL。我们的研究结果证明了遗传因素对性别二态性具有广泛影响，并确定了多种疾病中性别差异的可能机制和临床靶点。
