Exome sequencing and analysis of 44,028 British South Asians enriched for high autozygosity

Genes & Health (G&H) is a biomedical study of adult British Pakistani and Bangladeshi research volunteers enriched for autozygosity. Here we performed whole-exome sequencing in 44,028 G&H participants, establishing a large publicly available South Asian exome resource linked to longitudinal electronic health records. We performed exome-wide association analyses for 645 electronic health record-derived traits under additive and recessive models, and meta-analyses of 33 cardiometabolic traits with UK Biobank, finding more than 100 novel gene-phenotype associations. We identified 2,991 genes with rare biallelic predicted loss-of-function ('knockout') genotypes, 546 of which had not been previously reported. We show that drugs targeting genes with knockouts in adults are associated with a 2.2-fold higher likelihood of progressing beyond phase 1 clinical trials. We further illustrate how phenotypic profiles associated with knockout genotypes can enhance efficacy and safety assessment of drug targets and aid in the interpretation of variants with ambiguous clinical significance in autosomal recessive disease genes.

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Journal
Nature Genetics
Published
2026-03-27
DOI
https://doi.org/10.1038/s41588-026-02553-7
Primary Topic
Genetic Associations and Epidemiology
Type
article
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article

Exome sequencing and analysis of 44,028 British South Asians enriched for high autozygosity

Karol Estrada, Daniel G. MacArthur, Stephen O’Rahilly, Sahar V. Mozaffari et al.
Nature Genetics
Genetic Associations and Epidemiology
article

Exome sequencing and analysis of 44,028 British South Asians enriched for high autozygosity

Karol Estrada, Daniel G. MacArthur, Stephen O’Rahilly, Sahar V. Mozaffari, Laura Addis, Anthony M. Musolf, Dorothée Diogo, Melissa Miller, Adem Y. Dawed, Cyrielle Maroteau, Emily Holzinger, Moneeza K. Siddiqui, Guillermo del Angel, Jonathan Davitte, Frederik H. Lassen, Richard M. Turner, Katrina A. Catalano, Christopher DeBoever, Teng Hiang Heng, Neha Gupta, Joseph Gafton, Eric B. Fauman, Chen Li, Hye In Kim, Slavé Petrovski, Wright, Joanna M. M. Howson, V Iyer, Karen A. Hunt, Simone Longerich, Yalda Jamshidi, Sarah Finer, C Langenberg, David A. van Heel, Richard C. Trembath, Melis A. Aksit, Robert R. Graham, Benjamin M. Jacobs, Kousik Kundu, Joseph C. Maranville, Eamonn R. Maher, Iaroslav Popov, Michael A. Simpson, Bin Guo, Duncan S. Palmer, Marie Spreckley, Georgios Kalantzis, Hilary C. Martin, Pedrum Mohammadi-Shemirani, William G. Newman, Klaudia Walter
article en

Abstract

Genes & Health (G&H) is a biomedical study of adult British Pakistani and Bangladeshi research volunteers enriched for autozygosity. Here we performed whole-exome sequencing in 44,028 G&H participants, establishing a large publicly available South Asian exome resource linked to longitudinal electronic health records. We performed exome-wide association analyses for 645 electronic health record-derived traits under additive and recessive models, and meta-analyses of 33 cardiometabolic traits with UK Biobank, finding more than 100 novel gene-phenotype associations. We identified 2,991 genes with rare biallelic predicted loss-of-function ('knockout') genotypes, 546 of which had not been previously reported. We show that drugs targeting genes with knockouts in adults are associated with a 2.2-fold higher likelihood of progressing beyond phase 1 clinical trials. We further illustrate how phenotypic profiles associated with knockout genotypes can enhance efficacy and safety assessment of drug targets and aid in the interpretation of variants with ambiguous clinical significance in autosomal recessive disease genes.

Nature Genetics
Broad Institute (US), National Health Service (GB), Merck & Co., Inc., Rahway, NJ, USA (United States) (US), Centre for Human Genetics (GB), Garvan Institute of Medical Research (AU), Bristol-Myers Squibb (Germany) (DE), Queen Mary University of London (GB), Aston University (GB), Pfizer (United States) (US), King's College London (GB), Age UK (GB), Discovery Centre (CA), Wellcome Sanger Institute (GB), University of Manchester (GB), University of Oxford (GB), Bristol-Myers Squibb (United States) (US), Novo Nordisk (Finland) (FI), GlaxoSmithKline (United States) (US), Wellcome/MRC Institute of Metabolic Science (GB), AstraZeneca (Brazil) (BR), Maze (United States) (US), AstraZeneca (Japan) (JP), Berlin Institute of Health at Charité - Universitätsmedizin Berlin (DE), Takeda (United States) (US), AstraZeneca (Spain) (ES), Murdoch Children's Research Institute (AU), Genomics (United Kingdom) (GB), MRC Epidemiology Unit (GB), NIHR Manchester Biomedical Research Centre (GB), Bradford Teaching Hospitals NHS Foundation Trust (GB)
Openalex Percentile: Top 4%
Genetic Associations and Epidemiology
DOIOpen Access PDFOpenAlex
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