Associations of autozygosity with a broad range of human phenotypes
Clark DW., Okada Y., Moore KHS., Mason D., Pirastu N., Gandin I., Mattsson H., Barnes CLK., Lin K., Zhao JH., Deelen P., Rohde R., Schurmann C., Guo X., Giulianini F., Zhang W., Medina-Gomez C., Karlsson R., Bao Y., Bartz TM., Baumbach C., Biino G., Bixley MJ., Brumat M., Chai JF., Corre T., Cousminer DL., Dekker AM., Eccles DA., van Eijk KR., Fuchsberger C., Gao H., Germain M., Gordon SD., de Haan HG., Harris SE., Hofer E., Huerta-Chagoya A., Igartua C., Jansen IE., Jia Y., Kacprowski T., Karlsson T., Kleber ME., Li SA., Li-Gao R., Mahajan A., Matsuda K., Meidtner K., Meng W., Montasser ME., van der Most PJ., Munz M., Nutile T., Palviainen T., Prasad G., Prasad RB., Priyanka TDS., Rizzi F., Salvi E., Sapkota BR., Shriner D., Skotte L., Smart MC., Smith AV., van der Spek A., Spracklen CN., Strawbridge RJ., Tajuddin SM., Trompet S., Turman C., Verweij N., Viberti C., Wang L., Warren HR., Wootton RE., Yanek LR., Yao J., Yousri NA., Zhao W., Adeyemo AA., Afaq S., Aguilar-Salinas CA., Akiyama M., Albert ML., Allison MA., Alver M., Aung T., Azizi F., Bentley AR., Boeing H., Boerwinkle E., Borja JB., de Borst GJ., Bottinger EP., Broer L., Campbell H., Chanock S., Chee ML., Chen G.
© 2019, The Author(s). 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.