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

Genes & Health Research Team

doi:10.1038/s41588-026-02553-7

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

Genes & Health Research Team

Research output: Contribution to journal › Article › peer-review

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.

Original language	English
Pages (from-to)	821-830
Number of pages	21
Journal	Nature Genetics
Volume	58
Issue number	4
Early online date	27 Mar 2026
DOIs	https://doi.org/10.1038/s41588-026-02553-7
Publication status	Published - Apr 2026

Bibliographical note

Copyright © The Author(s) 2026. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit https://creativecommons.org/licenses/by/4.0/

Funding

G&H is/has recently been core-funded by Wellcome (WT102627, WT210561), the Medical Research Council (UK) (M009017, MR/X009777/1, MR/X009920/1), Higher Education Funding Council for England Catalyst, Barts Charity (845/1796), Health Data Research UK (for London substantive site) and research delivery support from the NHS National Institute for Health Research Clinical Research Network (North Thames)x

Access to Document

10.1038/s41588-026-02553-7Licence: CC BY 4.0

Exome sequencing and analysis of 44,028 British South Asians enriched for high autozygosity
Copyright © The Author(s) 2026. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit https://creativecommons.org/licenses/by/4.0/
Final published version, 5.58 MBLicence: CC BY 4.0

Cite this

@article{7964ba3df80d48c88be37f4b1743c6bd,

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

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 ({\textquoteleft}knockout{\textquoteright}) 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.",

author = "Kim, \{Hye In\} and Christopher DeBoever and Klaudia Walter and Georgios Kalantzis and Chen Li and Mozaffari, \{Sahar V.\} and Kousik Kundu and Jacobs, \{Benjamin M.\} and Pedrum Mohammadi-Shemirani and Musolf, \{Anthony M.\} and Davitte, \{Jonathan M.\} and Aksit, \{Melis A.\} and Joseph Gafton and Catalano, \{Katrina A.\} and Dawed, \{Adem Y.\} and Graham, \{Robert R.\} and Bin Guo and Namrata Gupta and Heng, \{Teng Hiang\} and Hunt, \{Karen A.\} and Vivek Iyer and Claudia Langenberg and Lassen, \{Frederik H.\} and MacArthur, \{Daniel G.\} and Maher, \{Eamonn R.\} and Cyrielle Maroteau and Newman, \{William G.\} and Stephen O{\textquoteright}Rahilly and Palmer, \{Duncan S.\} and Iaroslav Popov and Siddiqui, \{Moneeza K.\} and Simpson, \{Michael A.\} and Marie Spreckley and John Wright and \{van Heel\}, \{David A.\} and \{Del Angel\}, Guillermo and Slav{\'e} Petrovski and Holzinger, \{Emily R.\} and Maranville, \{Joseph C.\} and Laura Addis and Turner, \{Richard M.\} and Karol Estrada and Simone Longerich and Howson, \{Joanna M. M.\} and Yalda Jamshidi and Fauman, \{Eric B.\} and Miller, \{Melissa R.\} and Doroth{\'e}e Diogo and Trembath, \{Richard C.\} and Sarah Finer and Martin, \{Hilary C.\} and \{van Heel\}, \{David A.\} and \{Genes \& Health Research Team\}",

note = "Copyright {\textcopyright} The Author(s) 2026. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article{\textquoteright}s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article{\textquoteright}s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit https://creativecommons.org/licenses/by/4.0/ ",

year = "2026",

month = apr,

doi = "10.1038/s41588-026-02553-7",

language = "English",

volume = "58",

pages = "821--830",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Research",

number = "4",

}

TY - JOUR

T1 - Exome sequencing and analysis of 44,028 British South Asians enriched for high autozygosity

AU - Kim, Hye In

AU - DeBoever, Christopher

AU - Walter, Klaudia

AU - Kalantzis, Georgios

AU - Li, Chen

AU - Mozaffari, Sahar V.

AU - Kundu, Kousik

AU - Jacobs, Benjamin M.

AU - Mohammadi-Shemirani, Pedrum

AU - Musolf, Anthony M.

AU - Davitte, Jonathan M.

AU - Aksit, Melis A.

AU - Gafton, Joseph

AU - Catalano, Katrina A.

AU - Dawed, Adem Y.

AU - Graham, Robert R.

AU - Guo, Bin

AU - Gupta, Namrata

AU - Heng, Teng Hiang

AU - Hunt, Karen A.

AU - Iyer, Vivek

AU - Langenberg, Claudia

AU - Lassen, Frederik H.

AU - MacArthur, Daniel G.

AU - Maher, Eamonn R.

AU - Maroteau, Cyrielle

AU - Newman, William G.

AU - O’Rahilly, Stephen

AU - Palmer, Duncan S.

AU - Popov, Iaroslav

AU - Siddiqui, Moneeza K.

AU - Simpson, Michael A.

AU - Spreckley, Marie

AU - Wright, John

AU - van Heel, David A.

AU - Del Angel, Guillermo

AU - Petrovski, Slavé

AU - Holzinger, Emily R.

AU - Maranville, Joseph C.

AU - Addis, Laura

AU - Turner, Richard M.

AU - Estrada, Karol

AU - Longerich, Simone

AU - Howson, Joanna M. M.

AU - Jamshidi, Yalda

AU - Fauman, Eric B.

AU - Miller, Melissa R.

AU - Diogo, Dorothée

AU - Trembath, Richard C.

AU - Finer, Sarah

AU - Martin, Hilary C.

AU - van Heel, David A.

AU - Genes & Health Research Team

N1 - Copyright © The Author(s) 2026. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit https://creativecommons.org/licenses/by/4.0/

PY - 2026/4

Y1 - 2026/4

N2 - 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.

AB - 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.

UR - https://www.nature.com/articles/s41588-026-02553-7

UR - https://www.scopus.com/pages/publications/105035363845

U2 - 10.1038/s41588-026-02553-7

DO - 10.1038/s41588-026-02553-7

M3 - Article

C2 - 41896352

SN - 1061-4036

VL - 58

SP - 821

EP - 830

JO - Nature Genetics

JF - Nature Genetics

IS - 4

ER -

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

Abstract

Bibliographical note

Funding

Access to Document

Other files and links

Fingerprint

Cite this