跨多个祖先群体的性别二态性蛋白质数量性状位点的鉴定与验证及其与疾病的关联

Identification and replication of sex-dimorphic protein quantitative trait loci across multiple ancestries and their associations with diseases.

作者信息

Bhak Youngjune, Raptis Vasilis, He Yunye, Nakanishi Tomoko, Macdonald-Dunlop Erin, Sagiya Yoji, Morisaki Takayuki, Matsuda Koichi, Kanai Akinori, Suzuki Yutaka, Oda Yoshiya, Kamatani Yoichiro, Namkoong Ho, Saiki Ryunosuke, Kimura Akinori, Koike Ryuji, Ogawa Seishi, Miyano Satoru, Imoto Seiya, Kanai Takanori, Fukunaga Koichi, Okada Yukinori, Mälarstig Anders, Tenesa Albert

机构信息

The Roslin Institute, University of Edinburgh, Easter Bush Campus, Midlothian, UK.

Advanced Care Research Centre Academy, University of Edinburgh, Edinburgh, UK.

出版信息

Sci Rep. 2025 Aug 28;15(1):31721. doi: 10.1038/s41598-025-10031-z.

DOI:10.1038/s41598-025-10031-z

PMID:40877285

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC12394655/

Abstract

Males and females exhibit differences in proteome profiles associated with disease risk. However, sex-dimorphic protein quantitative trait loci (SD-pQTL) and their effects on sex differences in health disorders have not been thoroughly investigated. We conducted a sex-stratified, genome-wide association study on 2,922 proteins using data from 30,272 individuals of Caucasian ancestry from the UK Biobank and compared the estimated effects on protein levels of these variants in the men and women to identify SD-pQTLs. The identified SD-pQTLs were replicated using data from two Japanese cohorts (comprising 2,886 and 1,394 individuals, respectively), as well as from 1,990 Finnish, 630 South Asian, and 662 Black ancestry individuals. Sex-dimorphic pleiotropy and the causal relationship between protein levels and health disorders were assessed using the identified SD-pQTLs. We identified 113 SD-pQTLs associated with 65 proteins. Of the 113 SD-pQTLs, 52 were significant in both sexes, five were not significant in either sex, and 42 and 14 were significant only in males and females, respectively. Variant rs2270416 was significantly associated with the CDH15 protein in both sexes but showed opposite effect direction in men and women. Of the 113 SD-pQTLs identified, a total of 41 were replicated in a meta-analysis encompassing Japanese, South Asian, and Black ancestry individuals. SD-pQTLs for proteins APOE (rs157581) and SNAP25 (rs4420638) exhibited sex-dimorphic associations with dementia, indicating sex dimorphic pleiotropy in both proteins and health disorders. From sex-stratified Mendelian randomization using the SD-pQTLs, proteins NCAM1 and PZP showed significant causal relationship with dementia in males and females, respectively. The present study provides evidence of sex-dimorphic genetic architecture in protein-level regulation, elucidating the proteo-genetic architecture for sex differences in human variation.

摘要

男性和女性在与疾病风险相关的蛋白质组图谱上存在差异。然而，性别二态性蛋白质数量性状位点（SD-pQTL）及其对健康疾病中性别差异的影响尚未得到充分研究。我们利用来自英国生物银行的30272名白种人血统个体的数据，对2922种蛋白质进行了性别分层的全基因组关联研究，并比较了这些变异对男性和女性蛋白质水平的估计影响，以确定SD-pQTL。使用来自两个日本队列（分别包括2886名和1394名个体）以及1990名芬兰人、630名南亚人和662名黑人血统个体的数据对鉴定出的SD-pQTL进行了重复验证。利用鉴定出的SD-pQTL评估了性别二态性多效性以及蛋白质水平与健康疾病之间的因果关系。我们鉴定出113个与65种蛋白质相关的SD-pQTL。在这113个SD-pQTL中，52个在两性中均显著，5个在两性中均不显著，42个和14个分别仅在男性和女性中显著。变异体rs2270416在两性中均与CDH15蛋白显著相关，但在男性和女性中显示出相反的效应方向。在鉴定出的113个SD-pQTL中，共有41个在一项涵盖日本、南亚和黑人血统个体的荟萃分析中得到重复验证。蛋白质APOE（rs157581）和SNAP25（rs4420638）的SD-pQTL与痴呆症表现出性别二态性关联，表明这两种蛋白质和健康疾病中均存在性别二态性多效性。通过使用SD-pQTL进行性别分层的孟德尔随机化分析，蛋白质NCAM1和PZP分别在男性和女性中与痴呆症表现出显著的因果关系。本研究提供了蛋白质水平调控中性别二态性遗传结构的证据，阐明了人类变异中性别差异的蛋白质遗传结构。