TY - JOUR AB - In many species, the offspring of related parents suffer reduced vigor, survival and reproductive success, a phenomenon known as inbreeding depression1. In humans, the importance of this effect has remained unclear2, partly because reproduction between close relatives is both rare in many cultures and frequently associated with confounding social factors3. Here, using genomic inbreeding coefficients4 (FROH) for >1.3 million individuals, we show that FROH is significantly associated (P < 0.0005) with apparently deleterious changes in 32 out of 100 traits analysed. Increased FROH is associated with reduced reproductive success (decreased number and likelihood of having children, older age at first sex and first birth, decreased number of sexual partners), as well as reduced risk-taking behaviour (alcohol intake, ever-smoked, self-reported risk taking) and increased disease risk (self-reported overall health, and risk factors including grip strength and heart rate). 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. These effects are associated with runs of homozygosity (ROH), but not with common variant homozygosity, suggesting that genetic variants causing inbreeding depression are predominantly rare. For a subset of traits, the effect of FROH differs significantly between men and women. Indeed, an increased FROH is associated with decreased total and LDL cholesterol in men, raising the possibility that increases in these traits may have benefited evolutionary fitness, despite being known coronary risk factors. Finally, the effects of FROH are confirmed within full-sibling pairs, where the variation in FROH is independent of environmental confounding. We conclude that inbreeding depression influences a broad range of human phenotypes through the action of rare, recessive variants. AU - Clark,DW AU - Zhang,W AU - Gao,H AU - Afaq,S AU - Elliott,P AU - Elliott,J AU - Poulter,N AU - Scott,W AU - Sever,P AU - Tzoulaki,I AU - Lehne,B AU - Chambers,J AU - Evangelou,E AU - Kooner,J AU - Walters,R AU - Wilson,J DO - 10.1038/s41467-019-12283-6 PY - 2019/// SN - 2041-1723 TI - Associations of autozygosity with a broad range of human phenotypes T2 - Nature Communications UR - http://dx.doi.org/10.1038/s41467-019-12283-6 UR - http://hdl.handle.net/10044/1/74028 VL - 10 ER -