Rare variant associations with plasma protein levels in the UK Biobank

蛋白质基因组学 现象 生物 生命银行 全基因组关联研究 外显子组 蛋白质组学 遗传学 基因 蛋白质组 计算生物学 遗传关联 疾病 定量蛋白质组学 外显子组测序 生物信息学 基因组 基因型 表型 基因组学 医学 单核苷酸多态性 内科学
作者
Ryan S. Dhindsa,Oliver S. Burren,Benjamin B. Sun,Bram P. Prins,Dorota Matelska,Eleanor Wheeler,Jonathan Mitchell,Erin Oerton,Ventzislava A. Hristova,Katherine R. Smith,Keren Carss,Sebastian Wasilewski,Andrew R. Harper,Dirk S. Paul,Margarete A. Fabre,Heiko Runz,Coralie Viollet,Benjamin Challis,Adam Platt,Rasmus Ågren,Lauren Anderson-Dring,Santosh S. Atanur,David H. Baker,Carl Barrett,Maria G. Belvisi,Mohammad Bohlooly‐Y,Lisa Buvall,Niedzica Camacho,Lisa H. Cazares,Sophia Cameron‐Christie,Morris Chen,E. Suzanne Cohen,Regina Fritsche Danielson,Shikta Das,Andrew Davis,Sri Vishnu Vardhan Deevi,Wei Ding,Brian Dougherty,Zammy Fairhurst-Hunter,Manik Garg,Benjamin Georgi,Carmen Guerrero Rangel,Carolina Haefliger,Mårten Hammar,Richard N. Hanna,Pernille Hansen,Jennifer Harrow,Ian Henry,Sonja Hess,Ben Hollis,Fengyuan Hu,Xiao Jiang,Kousik Kundu,Zhongwu Lai,Mark Lal,Glenda Lassi,Yupu Liang,Margarida Lopes,Kieren Lythgow,Stewart MacArthur,Meeta Maisuria-Armer,Ruth March,Carla Martins,Karyn Mégy,Robert Menzies,Erik Michaëlsson,Fiona K. Middleton,Bill Mowrey,Daniel Muthas,Abhishek Nag,Sean M. O’Dell,Yoichiro Ohne,Henric Olsson,Amanda O’Neill,Kristoffer Ostridge,Benjamin Pullman,William Rae,Arwa Bin Raies,Anna Reznichenko,Xavier Romero Ros,Maria Ryaboshapkina,Hitesh J. Sanganee,Ben S. Sidders,Mike Snowden,Stasa Stankovic,Helen Stevens,Ioanna Tachmazidou,Haeyam Taiy,Lifeng Tian,Christina Underwood,Anna Walentinsson,Qing‐Dong Wang,Ahmet Zehir,Zoe Zou,Dimitrios Vitsios,Euan A. Ashley,Christopher D. Whelan,Menelas N. Pangalos,Quanli Wang,Slavé Petrovski
出处
期刊:Nature [Nature Portfolio]
卷期号:622 (7982): 339-347 被引量:66
标识
DOI:10.1038/s41586-023-06547-x
摘要

Integrating human genomics and proteomics can help elucidate disease mechanisms, identify clinical biomarkers and discover drug targets1-4. Because previous proteogenomic studies have focused on common variation via genome-wide association studies, the contribution of rare variants to the plasma proteome remains largely unknown. Here we identify associations between rare protein-coding variants and 2,923 plasma protein abundances measured in 49,736 UK Biobank individuals. Our variant-level exome-wide association study identified 5,433 rare genotype-protein associations, of which 81% were undetected in a previous genome-wide association study of the same cohort5. We then looked at aggregate signals using gene-level collapsing analysis, which revealed 1,962 gene-protein associations. Of the 691 gene-level signals from protein-truncating variants, 99.4% were associated with decreased protein levels. STAB1 and STAB2, encoding scavenger receptors involved in plasma protein clearance, emerged as pleiotropic loci, with 77 and 41 protein associations, respectively. We demonstrate the utility of our publicly accessible resource through several applications. These include detailing an allelic series in NLRC4, identifying potential biomarkers for a fatty liver disease-associated variant in HSD17B13 and bolstering phenome-wide association studies by integrating protein quantitative trait loci with protein-truncating variants in collapsing analyses. Finally, we uncover distinct proteomic consequences of clonal haematopoiesis (CH), including an association between TET2-CH and increased FLT3 levels. Our results highlight a considerable role for rare variation in plasma protein abundance and the value of proteogenomics in therapeutic discovery.
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