Rare variant associations with plasma protein levels in the UK Biobank

Dhindsa, Ryan S. and Burren, Oliver S. and Sun, Benjamin B. and Prins, Bram P. and Matelska, Dorota and Wheeler, Eleanor and Mitchell, Jonathan and Oerton, Erin and Hristova, Ventzislava A. and Smith, Katherine R. and Carss, Keren and Wasilewski, Sebastian and Harper, Andrew R. and Paul, Dirk S. and Fabre, Margarete A. and Runz, Heiko and Viollet, Coralie and Challis, Benjamin and Platt, Adam and Ågren, Rasmus and Anderson-Dring, Lauren and Atanur, Santosh and Baker, David and Barrett, Carl and Belvisi, Maria and Bohlooly-Y, Mohammad and Buvall, Lisa and Camacho, Niedzica and Cazares, Lisa and Cameron-Christie, Sophia and Chen, Morris and Cohen, Suzanne and Danielson, Regina F. and Das, Shikta and Davis, Andrew and Deevi, Sri Vishnu Vardhan and Ding, Wei and Dougherty, Brian and Fairhurst-Hunter, Zammy and Garg, Manik and Georgi, Benjamin and Rangel, Carmen Guerrero and Haefliger, Carolina and Hammar, Mårten and Hanna, Richard N. and Hansen, Pernille B. L. and Harrow, Jennifer and Henry, Ian and Hess, Sonja and Hollis, Ben and Hu, Fengyuan and Jiang, Xiao and Kundu, Kousik and Lai, Zhongwu and Lal, Mark and Lassi, Glenda and Liang, Yupu and Lopes, Margarida and Lythgow, Kieren and MacArthur, Stewart and Maisuria-Armer, Meeta and March, Ruth and Martins, Carla and Megy, Karine and Menzies, Rob and Michaëlsson, Erik and Middleton, Fiona and Mowrey, Bill and Muthas, Daniel and Nag, Abhishek and O’Dell, Sean and Ohne, Yoichiro and Olsson, Henric and O’Neill, Amanda and Ostridge, Kristoffer and Pullman, Benjamin and Rae, William and Raies, Arwa and Reznichenko, Anna and Ros, Xavier Romero and Ryaboshapkina, Maria and Sanganee, Hitesh and Sidders, Ben and Snowden, Mike and Stankovic, Stasa and Stevens, Helen and Tachmazidou, Ioanna and Taiy, Haeyam and Tian, Lifeng and Underwood, Christina and Walentinsson, Anna and Wang, Qing-Dong and Zehir, Ahmet and Zou, Zoe and Vitsios, Dimitrios and Ashley, Euan A. and Whelan, Christopher D. and Pangalos, Menelas N. and Wang, Quanli and Petrovski, Slavé (2023) Rare variant associations with plasma protein levels in the UK Biobank. Nature, 622 (7982). pp. 339-347. ISSN 0028-0836

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Abstract

Integrating human genomics and proteomics can help elucidate disease mechanisms, identify clinical biomarkers and discover drug targets1,2,3,4. 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.

Item Type: Article
Subjects: Open Research Librarians > Multidisciplinary
Depositing User: Unnamed user with email support@open.researchlibrarians.com
Date Deposited: 10 Nov 2023 06:54
Last Modified: 10 Nov 2023 06:54
URI: http://stm.e4journal.com/id/eprint/2053

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