TY - JOUR
T1 - Influence of autozygosity on common disease risk across the phenotypic spectrum.
AU - Malawsky, Daniel S
AU - van Walree, Eva
AU - Jacobs, Benjamin M
AU - Heng, Teng Hiang
AU - Huang, Qin Qin
AU - Sabir, Ataf H
AU - Rahman, Saadia
AU - Sharif, Saghira Malik
AU - Khan, Ahsan
AU - Mirkov, Maša Umićević
AU - Team, 23andMe Research
AU - Kuwahara, Hiroyuki
AU - Gao, Xin
AU - Alkuraya, Fowzan S
AU - Posthuma, Danielle
AU - Newman, William G
AU - Griffiths, Christopher J
AU - Mathur, Rohini
AU - van Heel, David A
AU - Finer, Sarah
AU - O'Connell, Jared
AU - Martin, Hilary C
N1 - KAUST Repository Item: Exported on 2023-10-03
Acknowledgements: We thank Richard Durbin, Loic Yengo, Peter Visscher, John Perry, Nicole Soranzo, and Matt Hurles for useful discussions, and Muhammad Forhad and Naheed Choudhry from the G&H Community Advisory Board for their help on the Frequently Asked Questions document. This research was funded in whole or in part by the Wellcome Trust grant 220540/Z/20/A, “Wellcome Sanger Institute Quinquennial Review 2021–2026.” For the purpose of Open Access, the author has applied a CC BY public copyright license to any Author Accepted Manuscript version arising from this submission. D.S.M. is supported by a Gates Cambridge Scholarship (OPP1144). G&H is/has recently been core-funded by Wellcome (WT102627 and WT210561), the Medical Research Council (UK) (M009017 and MR/X009777/1), the Higher Education Funding Council for England Catalyst, Barts Charity (845/1796), Health Data Research UK (for the London substantive site), and research delivery support from the NHS National Institute for Health Research Clinical Research Network (North Thames). G&H is/has recently been funded by Alnylam Pharmaceuticals, Genomics PLC, and Life Sciences Industry Consortium of Astra Zeneca PLC, Bristol-Myers Squibb Company, GlaxoSmithKline Research and Development Limited, Maze Therapeutics Inc., Merck Sharp & Dohme LLC, Novo Nordisk A/S, Pfizer Inc., and Takeda Development Centre Americas Inc. Additional funding for this work was awarded by the Medical Research Council (MR/S027297/1) and to S.F. by the Diabetes Research and Wellness Foundation (SCA/PP/12/19). We thank Social Action for Health Centre of The Cell, members of our Community Advisory Group, and staff who have recruited and collected data from volunteers. We thank the NIHR National Biosample Centre (UK Biocentre), the Social Genetic & Developmental Psychiatry Centre (King's College London), the Wellcome Sanger Institute, and the Broad Institute for sample processing, genotyping, sequencing, and variant annotation. We thank Barts Health NHS Trust, NHS Clinical Commissioning Groups (City and Hackney, Waltham Forest, Tower Hamlets, Newham, Redbridge, Havering, Barking, and Dagenham), East London NHS Foundation Trust, Bradford Teaching Hospitals NHS Foundation Trust, Public Health England (especially David Wyllie), Discovery Data Service/Endeavour Health Charitable Trust (especially David Stables), and NHS Digital—for GDPR-compliant data sharing backed by individual written informed consent. Most of all, we thank all of the volunteers participating in G&H and UKB. This research has been conducted using the UK Biobank Resource, a major biomedical database, under application number 44165. We would like to thank the research participants and employees of 23andMe for making this work possible.
PY - 2023/9/26
Y1 - 2023/9/26
N2 - Autozygosity is associated with rare Mendelian disorders and clinically relevant quantitative traits. We investigated associations between the fraction of the genome in runs of homozygosity (FROH) and common diseases in Genes & Health (n = 23,978 British South Asians), UK Biobank (n = 397,184), and 23andMe. We show that restricting analysis to offspring of first cousins is an effective way of reducing confounding due to social/environmental correlates of FROH. Within this group in G&H+UK Biobank, we found experiment-wide significant associations between FROH and twelve common diseases. We replicated associations with type 2 diabetes (T2D) and post-traumatic stress disorder via within-sibling analysis in 23andMe (median n = 480,282). We estimated that autozygosity due to consanguinity accounts for 5%–18% of T2D cases among British Pakistanis. Our work highlights the possibility of widespread non-additive genetic effects on common diseases and has important implications for global populations with high rates of consanguinity.
AB - Autozygosity is associated with rare Mendelian disorders and clinically relevant quantitative traits. We investigated associations between the fraction of the genome in runs of homozygosity (FROH) and common diseases in Genes & Health (n = 23,978 British South Asians), UK Biobank (n = 397,184), and 23andMe. We show that restricting analysis to offspring of first cousins is an effective way of reducing confounding due to social/environmental correlates of FROH. Within this group in G&H+UK Biobank, we found experiment-wide significant associations between FROH and twelve common diseases. We replicated associations with type 2 diabetes (T2D) and post-traumatic stress disorder via within-sibling analysis in 23andMe (median n = 480,282). We estimated that autozygosity due to consanguinity accounts for 5%–18% of T2D cases among British Pakistanis. Our work highlights the possibility of widespread non-additive genetic effects on common diseases and has important implications for global populations with high rates of consanguinity.
UR - http://hdl.handle.net/10754/694820
UR - https://linkinghub.elsevier.com/retrieve/pii/S0092867423009182
U2 - 10.1016/j.cell.2023.08.028
DO - 10.1016/j.cell.2023.08.028
M3 - Article
C2 - 37757828
SN - 0092-8674
JO - Cell
JF - Cell
ER -
