Influence of autozygosity on common disease risk across the phenotypic spectrum

Daniel S Malawsky; Eva van Walree; Benjamin M Jacobs; Teng Hiang Heng; Qin Qin Huang; Ataf H Sabir; Saadia Rahman; Saghira Malik Sharif; Ahsan Khan; Maša Umićević Mirkov; 23andMe Research Team; Genes & Health Research Team; Hiroyuki Kuwahara; Xin Gao; Fowzan S Alkuraya; Danielle Posthuma; William G Newman; Christopher J Griffiths; Rohini Mathur; David A van Heel; Sarah Finer; Jared O'Connell; Hilary C Martin

doi:10.1016/j.cell.2023.08.028

Influence of autozygosity on common disease risk across the phenotypic spectrum

Cell. 2023 Oct 12;186(21):4514-4527.e14. doi: 10.1016/j.cell.2023.08.028. Epub 2023 Sep 26.

Authors

Daniel S Malawsky¹, Eva van Walree², Benjamin M Jacobs³, Teng Hiang Heng⁴, Qin Qin Huang⁴, Ataf H Sabir⁵, Saadia Rahman⁶, Saghira Malik Sharif⁷, Ahsan Khan⁸, Maša Umićević Mirkov⁹; 23andMe Research Team; Genes & Health Research Team; Hiroyuki Kuwahara¹⁰, Xin Gao¹⁰, Fowzan S Alkuraya¹¹, Danielle Posthuma¹², William G Newman¹³, Christopher J Griffiths¹⁴, Rohini Mathur¹⁵, David A van Heel¹⁶, Sarah Finer³, Jared O'Connell¹⁷, Hilary C Martin¹⁸

Affiliations

¹ Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, UK. Electronic address: dm22@sanger.ac.uk.
² Department of Clinical Genetics, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands; Department of Complex Trait Genetics Center for Neurogenomics and Cognitive Research, Amsterdam Neuroscience, VU Amsterdam, Amsterdam, the Netherlands.
³ Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK; Wolfson Institute of Population Health, Queen Mary University of London, London, UK.
⁴ Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, UK.
⁵ West Midlands Regional Clinical Genetics Unit, Birmingham Women's and Children's NHS FT, Birmingham, UK; Institute of Cancer and Genomics, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK.
⁶ Queen Square Institute of Neurology, University College London, London, UK.
⁷ Yorkshire Regional Genetics Service, Leeds Teaching Hospitals NHS Trust, Leeds, UK.
⁸ Waltham Forest Council, Waltham Forest Town Hall, Forest Road, Walthamstow E17 4JF, UK.
⁹ Congenica Limited, BioData Innovation Centre, Wellcome Genome Campus, Hinxton, UK.
¹⁰ King Abdullah University of Science and Technology (KAUST), Computational Bioscience Research Center (CBRC), Thuwal 23955, Saudi Arabia.
¹¹ Department of Translational Genomics, Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
¹² Department of Complex Trait Genetics Center for Neurogenomics and Cognitive Research, Amsterdam Neuroscience, VU Amsterdam, Amsterdam, the Netherlands.
¹³ Division of Evolution, Infection and Genomics, Faculty of Biology, Medicine and Human Sciences, University of Manchester, Manchester M13 9PL, UK; Manchester Centre for Genomic Medicine, Manchester University NHS Foundation Trust, Manchester M13 9WL, UK.
¹⁴ Wolfson Institute of Population Health, Queen Mary University of London, London, UK; MRC and Asthma UK Centre in Allergic Mechanisms of Asthma, King's College London, London, UK.
¹⁵ Wolfson Institute of Population Health, Queen Mary University of London, London, UK.
¹⁶ Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
¹⁷ 23andMe, Inc., Sunnyvale, CA, USA.
¹⁸ Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, UK. Electronic address: hcm@sanger.ac.uk.

Abstract

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 (F_ROH) 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 F_ROH. Within this group in G&H+UK Biobank, we found experiment-wide significant associations between F_ROH 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.

Keywords: autozygosity; common diseases; consanguinity; diverse cohorts; medical genetics; recessive.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Biological Specimen Banks
Consanguinity*
Diabetes Mellitus, Type 2* / genetics
Genetic Predisposition to Disease
Genome, Human
Homozygote
Humans
Phenotype
Polymorphism, Single Nucleotide
United Kingdom

Abstract

Publication types

MeSH terms

Grants and funding