Influence of autozygosity on common disease risk across the phenotypic spectrum

Daniel Shiloh Malawsky; Eva S. van Walree; Benjamin M. Jacobs; Teng Hiang Heng; Qin Huang; Ataf Hussain Sabir; Saadia Rahman; Saghira Malik Sharif; Ahsan Khan; Maša Umićević Mirkov; Hiroyuki Kuwahara; Xin Gao; Fowzan Sami Alkuraya; Daniëlle Posthuma; William G. Newman; Chris Griffiths; Rohini Mathur; David A. van Heel; Sarah Finer; Jared O’Connell; Hilary C. Martin

doi:10.1016/j.cell.2023.08.028

Genetic & Genomic MedicineCellSep 26, 2023

Peer-reviewed journal article

Influence of autozygosity on common disease risk across the phenotypic spectrum

Daniel Shiloh Malawsky iD, Eva S. van Walree iD, Benjamin M. Jacobs iD, Teng Hiang Heng iD, Qin Huang iD, Ataf Hussain Sabir iD, Saadia Rahman, Saghira Malik Sharif iD, Ahsan Khan iD, Maša Umićević Mirkov, Hiroyuki Kuwahara iD, Xin Gao iD, Fowzan Sami Alkuraya iD, Daniëlle Posthuma iD, William G. Newman iD, Chris Griffiths iD, Rohini Mathur iD, David A. van Heel iD, Sarah Finer iD, Jared O’Connell iD, Hilary C. Martin iD

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Abstract

Autozygosity is associated with rare Mendelian disorders and clinically-relevant quantitative traits. We investigated associations between FROH (fraction of the genome in runs of homozygosity) and common diseases in Genes & Health (N=23,978 British South Asians), UK Biobank (N=397,184), and 23andMe, Inc. We show that restricting analysis to offspring of first cousins is an effective way of removing 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 the associations with type 2 diabetes (T2D) and post-traumatic stress disorder via between-sibling analysis in 23andMe (median N=480,282). We estimated that autozygosity due to consanguinity accounts for 5-18% of T2D cases amongst British Pakistanis. Our work highlights the possibility of widespread non-additive effects on common diseases and has important implications for global populations with high rates of consanguinity.