Associations of autozygosity with a broad range of human phenotypes

Alison D. Murray; David W.  Clark; Okada  Yukinori; Moore Kristjan H S; Dan Mason; Nicola N Pirastu; ROHgen  consortium

doi:10.1038/s41467-019-12283-6

Associations of autozygosity with a broad range of human phenotypes

Alison D. Murray, David W. Clark (Corresponding Author), Okada Yukinori, Moore Kristjan H S, Dan Mason, Nicola N Pirastu, ROHgen consortium

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Abstract

In many species, the offspring of related parents suffer reduced reproductive success, a phenomenon known as inbreeding depression. In humans, the importance of this effect has remained unclear, partly because reproduction between close relatives is both rare and frequently associated with confounding social factors. Here, using genomic inbreeding coefficients (FROH) for >1.4 million individuals, we show that FROH is significantly associated (p < 0.0005) with apparently deleterious changes in 32 out of 100 traits analysed. These changes are associated with runs of homozygosity (ROH), but not with common variant homozygosity, suggesting that genetic variants associated with inbreeding depression are predominantly rare. The effect on fertility is striking: FROH equivalent to the offspring of first cousins is associated with a 55% decrease [95% CI 44–66%] in the odds of having children. Finally, the effects of FROH are confirmed within full-sibling pairs, where the variation in FROH is independent of all environmental confounding.

Original language	English
Article number	4957
Journal	Nature Communications
Volume	10
DOIs	https://doi.org/10.1038/s41467-019-12283-6
Publication status	Published - 31 Oct 2019

Bibliographical note

This paper is the work of the ROHgen consortium. We thank the Sigma T2D Consortium, whose members are detailed in Supplementary Note 3. We thank the UK Biobank Resource, approved under application 19655; we acknowledge funding from the UK Medical Research Council Human Genetics Unit and MRC Doctoral Training Programme in Precision Medicine. We also thank Neil Robertson, Wellcome Trust Centre for Human Genetics, Oxford, for use of his author details management software, Authorial. Finally, we thank all the participants, researchers and funders of ROHgen cohorts. Cohort-specific acknowledgements are in Supplementary Data 2; personal acknowledgements and disclosures are in Supplementary Note 2. We thank Rachel Edwards for administrative assistance.

Keywords

Breeding Success
Reproduction
genetic variance
Homozygosity
Social Factors
Phenotypes
Fertility
Inbreeding
Inbreeding depression
Progeny
Offspring
Children
QUANTIFICATION
LOCI
RUNS
FERTILITY
HOMOZYGOSITY
INBREEDING DEPRESSION

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Cite this

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title = "Associations of autozygosity with a broad range of human phenotypes",

abstract = "In many species, the offspring of related parents suffer reduced reproductive success, a phenomenon known as inbreeding depression. In humans, the importance of this effect has remained unclear, partly because reproduction between close relatives is both rare and frequently associated with confounding social factors. Here, using genomic inbreeding coefficients (FROH) for >1.4 million individuals, we show that FROH is significantly associated (p < 0.0005) with apparently deleterious changes in 32 out of 100 traits analysed. These changes are associated with runs of homozygosity (ROH), but not with common variant homozygosity, suggesting that genetic variants associated with inbreeding depression are predominantly rare. The effect on fertility is striking: FROH equivalent to the offspring of first cousins is associated with a 55% decrease [95% CI 44–66%] in the odds of having children. Finally, the effects of FROH are confirmed within full-sibling pairs, where the variation in FROH is independent of all environmental confounding.",

keywords = "Breeding Success, Reproduction, genetic variance, Homozygosity, Social Factors, Phenotypes, Fertility, Inbreeding, Inbreeding depression, Progeny, Offspring, Children, QUANTIFICATION, LOCI, RUNS, FERTILITY, HOMOZYGOSITY, INBREEDING DEPRESSION",

author = "Murray, {Alison D.} and Clark, {David W.} and Okada Yukinori and {Kristjan H S}, Moore and Dan Mason and Pirastu, {Nicola N} and ROHgen consortium",

note = "This paper is the work of the ROHgen consortium. We thank the Sigma T2D Consortium, whose members are detailed in Supplementary Note 3. We thank the UK Biobank Resource, approved under application 19655; we acknowledge funding from the UK Medical Research Council Human Genetics Unit and MRC Doctoral Training Programme in Precision Medicine. We also thank Neil Robertson, Wellcome Trust Centre for Human Genetics, Oxford, for use of his author details management software, Authorial. Finally, we thank all the participants, researchers and funders of ROHgen cohorts. Cohort-specific acknowledgements are in Supplementary Data 2; personal acknowledgements and disclosures are in Supplementary Note 2. We thank Rachel Edwards for administrative assistance.",

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N2 - In many species, the offspring of related parents suffer reduced reproductive success, a phenomenon known as inbreeding depression. In humans, the importance of this effect has remained unclear, partly because reproduction between close relatives is both rare and frequently associated with confounding social factors. Here, using genomic inbreeding coefficients (FROH) for >1.4 million individuals, we show that FROH is significantly associated (p < 0.0005) with apparently deleterious changes in 32 out of 100 traits analysed. These changes are associated with runs of homozygosity (ROH), but not with common variant homozygosity, suggesting that genetic variants associated with inbreeding depression are predominantly rare. The effect on fertility is striking: FROH equivalent to the offspring of first cousins is associated with a 55% decrease [95% CI 44–66%] in the odds of having children. Finally, the effects of FROH are confirmed within full-sibling pairs, where the variation in FROH is independent of all environmental confounding.

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KW - Offspring

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JO - Nature Communications

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Associations of autozygosity with a broad range of human phenotypes

Abstract

Bibliographical note

Keywords

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