<p>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 (F<sub>ROH</sub>) for >1.4 million individuals, we show that F<sub>ROH</sub> 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: F<sub>ROH</sub> 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 F<sub>ROH</sub> are confirmed within full-sibling pairs, where the variation in F<sub>ROH</sub> is independent of all environmental confounding.</p>
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M.L.A. is an employee of Genentech, a member of The Roche Group. D.A.L. has received support from several national and international government and charity funders, as well as Roche Diagnostics and Medtronic for work unrelated to this publication. M.I.M.: The views expressed in this article are those of the author(s) and not necessarily those of the NHS, the NIHR, or the Department of Health. He has served on advisory panels for Pfizer, NovoNordisk, Zoe Global; has received honoraria from Merck, Pfizer, Novo-Nordisk and Eli Lilly; has stock options in Zoe Global; has received research funding from Abbvie, Astra Zeneca, Boehringer Ingelheim, Eli Lilly, Janssen, Merck, Novo-Nordisk, Pfizer, Roche, Sanofi Aventis, Servier & Takeda. As of June 2019, M.Mc.C. is an employee of Genentech, and holds stock in Roche. T. Muka is now working as medical specialist at Novo Nordisk. O.P. is owner of Gen-info Ltd. Gen‐info Ltd provided support in the form of salaries and financial gains for author O.P., but did not have any additional role in selection of the journal or preparation of this manuscript. N. Poulter received financial support from several pharmaceutical companies which manufacture either blood pressure lowering or lipid lowering agents, or both, and consultancy fees. V.S. has participated in a congress trip sponsored By Novo Nordisk. P.J.S. has received research awards from Pfizer Inc. M.J.C. is Chief Scientist for Genomics England, a UK government company. B.M.P. serves on the DSMB of a clinical trial funded by Zoll LifeCor and on the Steering Committee of the Yale Open Data Access Project funded by Johnson & Johnson. A.R.S. is an employee of Regeneron Pharmaceutical Inc. The remaining authors declare no competing interests.
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