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; 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

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, 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'ConnellHilary C. Martin^*

^*Corresponding author for this work

Computer Science

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

6 Scopus citations

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.

Original language	English (US)
Pages (from-to)	4514-4527.e14
Journal	Cell
Volume	186
Issue number	21
DOIs	https://doi.org/10.1016/j.cell.2023.08.028
State	Published - Oct 12 2023

Bibliographical note

Publisher Copyright:
© 2023 The Author(s)

Keywords

autozygosity
common diseases
consanguinity
diverse cohorts
medical genetics
recessive

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.cell.2023.08.028

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Malawsky, D. S., van Walree, E., Jacobs, B. M., Heng, T. H., Huang, Q. Q., Sabir, A. H., Rahman, S., Sharif, S. M., Khan, A., Mirkov, M. U., Kuwahara, H., Gao, X., Alkuraya, F. S., Posthuma, D., Newman, W. G., Griffiths, C. J., Mathur, R., van Heel, D. A., Finer, S., ... Martin, H. C. (2023). Influence of autozygosity on common disease risk across the phenotypic spectrum. Cell, 186(21), 4514-4527.e14. https://doi.org/10.1016/j.cell.2023.08.028

@article{dc5cdd38386049acb37a5896283db790,

title = "Influence of autozygosity on common disease risk across the phenotypic spectrum",

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 (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.",

keywords = "autozygosity, common diseases, consanguinity, diverse cohorts, medical genetics, recessive",

author = "Malawsky, {Daniel S.} and {van Walree}, Eva and Jacobs, {Benjamin M.} and Heng, {Teng Hiang} and Huang, {Qin Qin} and Sabir, {Ataf H.} and Saadia Rahman and Sharif, {Saghira Malik} and Ahsan Khan and Mirkov, {Ma{\v s}a Umi{\'c}evi{\'c}} and Hiroyuki Kuwahara and Xin Gao and Alkuraya, {Fowzan S.} and Danielle Posthuma and Newman, {William G.} and Griffiths, {Christopher J.} and Rohini Mathur and {van Heel}, {David A.} and Sarah Finer and Jared O'Connell and Martin, {Hilary C.}",

note = "Publisher Copyright: {\textcopyright} 2023 The Author(s)",

year = "2023",

month = oct,

day = "12",

doi = "10.1016/j.cell.2023.08.028",

language = "English (US)",

volume = "186",

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Malawsky, DS, van Walree, E, Jacobs, BM, Heng, TH, Huang, QQ, Sabir, AH, Rahman, S, Sharif, SM, Khan, A, Mirkov, MU, Kuwahara, H , Gao, X, Alkuraya, FS, Posthuma, D, Newman, WG, Griffiths, CJ, Mathur, R, van Heel, DA, Finer, S, O'Connell, J & Martin, HC 2023, 'Influence of autozygosity on common disease risk across the phenotypic spectrum', Cell, vol. 186, no. 21, pp. 4514-4527.e14. https://doi.org/10.1016/j.cell.2023.08.028

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 - 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.

PY - 2023/10/12

Y1 - 2023/10/12

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.

KW - autozygosity

KW - common diseases

KW - consanguinity

KW - diverse cohorts

KW - medical genetics

KW - recessive

UR - http://www.scopus.com/inward/record.url?scp=85173460108&partnerID=8YFLogxK

U2 - 10.1016/j.cell.2023.08.028

DO - 10.1016/j.cell.2023.08.028

M3 - Article

C2 - 37757828

AN - SCOPUS:85173460108

SN - 0092-8674

VL - 186

SP - 4514-4527.e14

JO - Cell

JF - Cell

IS - 21

ER -

Influence of autozygosity on common disease risk across the phenotypic spectrum

Abstract

Bibliographical note

Keywords

ASJC Scopus subject areas

UN SDGs

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