Rare variant associations with plasma protein levels in the UK Biobank
Authors: Dhindsa Ryan S. , Burren Oliver S. , Sun Benjamin B. , Prins Bram P. , Matelska Dorota , Wheeler Eleanor , Mitchell Jonathan , Oerton Erin , Hristova Ventzislava A. , Smith Katherine R. , Carss Keren , Wasilewski Sebastian , Harper Andrew R. , Paul Dirk S. , Fabre Margarete A. , Runz Heiko , Viollet Coralie , Challis Benjamin , Platt Adam ,   AstraZeneca Genomics Initiative, Ågren Rasmus , Anderson-Dring Lauren , Atanur Santosh , Baker David , Barrett Carl , Belvisi Maria , Bohlooly-Y Mohammad , Buvall Lisa , Camacho Niedzica , Cazares Lisa , Cameron-Christie Sophia , Chen Morris , Cohen Suzanne , Danielson Regina F. , Das Shikta , Davis Andrew , Deevi Sri Vishnu Vardhan , Ding Wei , Dougherty Brian , Fairhurst-Hunter Zammy , Garg Manik , Georgi Benjamin , Rangel Carmen Guerrero , Haefliger Carolina , Hammar Mårten , Hanna Richard N. , Hansen Pernille B. L. , Harrow Jennifer , Henry Ian , Hess Sonja , Hollis Ben , Hu Fengyuan , Jiang Xiao , Kundu Kousik , Lai Zhongwu , Lal Mark , Lassi Glenda , Liang Yupu , Lopes Margarida , Lythgow Kieren , MacArthur Stewart , Maisuria-Armer Meeta , March Ruth , Martins Carla , Megy Karine , Menzies Rob , Michaëlsson Erik , Middleton Fiona , Mowrey Bill , Muthas Daniel , Nag Abhishek , O’Dell Sean , Ohne Yoichiro , Olsson Henric , O’Neill Amanda , Ostridge Kristoffer , Pullman Benjamin , Rae William , Raies Arwa , Reznichenko Anna , Ros Xavier Romero , Ryaboshapkina Maria , Sanganee Hitesh , Sidders Ben , Snowden Mike , Stankovic Stasa , Stevens Helen , Tachmazidou Ioanna , Taiy Haeyam , Tian Lifeng , Underwood Christina , Walentinsson Anna , Wang Qing-Dong , Zehir Ahmet , Zou Zoe , Vitsios Dimitrios , Ashley Euan A. , Whelan Christopher D. , Pangalos Menelas N. , Wang Quanli , Petrovski Slavé 
Published: October 2023

AbstractIntegrating 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.