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Jennifer AJennifer ASmithSotoodehnia, NonaNonaSotoodehniaTai, E-ShyongE-ShyongTaiTeumer, AlexanderAlexanderTeumerTimpson, Nicholas JNicholas JTimpsonToniolo, DanielaDanielaTonioloTregouet, David-AlexandreDavid-AlexandreTregouetTuomi, TiinamaijaTiinamaijaTuomiVollenweider, PeterPeterVollenweiderWang, Carol ACarol AWangWeir, David RDavid RWeirWhitfield, John BJohn BWhitfieldWijmenga, CiscaCiscaWijmengaWong, Tien-YinTien-YinWongWright, JohnJohnWrightYang, JingyunJingyunYangYu, LeiLeiYuZemel, Babette SBabette SZemelZonderman, Alan BAlan BZondermanPerola, MarkusMarkusPerolaMagnusson, Patrik K EPatrik K EMagnussonUitterlinden, André GAndré GUitterlindenKooner, Jaspal SJaspal SKoonerChasman, Daniel IDaniel IChasmanLoos, Ruth J FRuth J FLoosFranceschini, NoraNoraFranceschiniFranke, LudeLudeFrankeHaley, Chris SChris SHaleyHayward, CarolineCarolineHaywardWalters, Robin GRobin GWaltersPerry, John R BJohn R BPerryEsko, TōnuTōnuEskoHelgason, AgnarAgnarHelgasonStefansson, KariKariStefanssonJoshi, Peter KPeter KJoshiKubo, MichiakiMichiakiKuboWilson, James FJames FWilson2024-10-282024-10-282019-10-31https://boris-portal.unibe.ch/handle/20.500.12422/182958In 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.en600 - Technology::610 - Medicine & health300 - Social sciences, sociology & anthropology::360 - Social problems & social servicesarticle10.7892/boris.1345743167308210.1038/s41467-019-12283-6