Homozygosity has long been associated with rare, often devastating, Mendelian disorders, and Darwin was one of the first to recognize that inbreeding reduces evolutionary fitness. However, the effect of the more distant parental relatedness that is common in modern human populations is less well understood. Genomic data now allow us to investigate the effects of homozygosity on traits of public health importance by observing contiguous homozygous segments (runs of homozygosity), which are inferred to be homozygous along their complete length. Given the low levels of genome-wide homozygosity prevalent in most human populations, information is required on very large numbers of people to provide sufficient power. Here we use runs of homozygosity to study 16 health-related quantitative traits in 354,224 individuals from 102 cohorts, and find statistically significant associations between summed runs of homozygosity and four complex traits: height, forced expiratory lung volume in one second, general cognitive ability and educational attainment (P < 1 × 10(-300), 2.1 × 10(-6), 2.5 × 10(-10) and 1.8 × 10(-10), respectively). In each case, increased homozygosity was associated with decreased trait value, equivalent to the offspring of first cousins being 1.2 cm shorter and having 10 months' less education. Similar effect sizes were found across four continental groups and populations with different degrees of genome-wide homozygosity, providing evidence that homozygosity, rather than confounding, directly contributes to phenotypic variance. Contrary to earlier reports in substantially smaller samples, no evidence was seen of an influence of genome-wide homozygosity on blood pressure and low density lipoprotein cholesterol, or ten other cardio-metabolic traits. Since directional dominance is predicted for traits under directional evolutionary selection, this study provides evidence that increased stature and cognitive function have been positively selected in human evolution, whereas many important risk factors for late-onset complex diseases may not have been.
Relationships between estimated autozygosity and complex traits in the UK Biobank.Johnson EC, Evans LM, Keller MC. Johnson EC, et al. PLoS Genet. 2018 Jul 27;14(7):e1007556. doi: 10.1371/journal.pgen.1007556. eCollection 2018 Jul. PLoS Genet. 2018. PMID: 30052639 Free PMC article.
Evidence of inbreeding depression on human height.McQuillan R, Eklund N, Pirastu N, Kuningas M, McEvoy BP, Esko T, Corre T, Davies G, Kaakinen M, Lyytikäinen LP, Kristiansson K, Havulinna AS, Gögele M, Vitart V, Tenesa A, Aulchenko Y, Hayward C, Johansson A, Boban M, Ulivi S, Robino A, Boraska V, Igl W, Wild SH, Zgaga L, Amin N, Theodoratou E, Polašek O, Girotto G, Lopez LM, Sala C, Lahti J, Laatikainen T, Prokopenko I, Kals M, Viikari J, Yang J, Pouta A, Estrada K, Hofman A, Freimer N, Martin NG, Kähönen M, Milani L, Heliövaara M, Vartiainen E, Räikkönen K, Masciullo C, Starr JM, Hicks AA, Esposito L, Kolčić I, Farrington SM, Oostra B, Zemunik T, Campbell H, Kirin M, Pehlic M, Faletra F, Porteous D, Pistis G, Widén E, Salomaa V, Koskinen S, Fischer K, Lehtimäki T, Heath A, McCarthy MI, Rivadeneira F, Montgomery GW, Tiemeier H, Hartikainen AL, Madden PA, d'Adamo P, Hastie ND, Gyllensten U, Wright AF, van Duijn CM, Dunlop M, Rudan I, Gasparini P, Pramstaller PP, Deary IJ, Toniolo D, Eriksson JG, Jula A, Raitakari OT, Metspalu A, Perola M, Järvelin MR, Uitterlinden A, Visscher PM, Wilson JF; ROHgen Consortium. McQuillan R, et al. PLoS Genet. 2012;8(7):e1002655. doi: 10.1371/journal.pgen.1002655. Epub 2012 Jul 19. PLoS Genet. 2012. PMID: 22829771 Free PMC article.
The association of genotype-based inbreeding coefficient with a range of physical and psychological human traits.Verweij KJ, Abdellaoui A, Veijola J, Sebert S, Koiranen M, Keller MC, Järvelin MR, Zietsch BP. Verweij KJ, et al. PLoS One. 2014 Jul 25;9(7):e103102. doi: 10.1371/journal.pone.0103102. eCollection 2014. PLoS One. 2014. PMID: 25062308 Free PMC article.
Runs of homozygosity: current knowledge and applications in livestock.Peripolli E, Munari DP, Silva MVGB, Lima ALF, Irgang R, Baldi F. Peripolli E, et al. Anim Genet. 2017 Jun;48(3):255-271. doi: 10.1111/age.12526. Epub 2016 Dec 1. Anim Genet. 2017. PMID: 27910110 Review.
Runs of homozygosity: windows into population history and trait architecture.Ceballos FC, Joshi PK, Clark DW, Ramsay M, Wilson JF. Ceballos FC, et al. Nat Rev Genet. 2018 Apr;19(4):220-234. doi: 10.1038/nrg.2017.109. Epub 2018 Jan 15. Nat Rev Genet. 2018. PMID: 29335644 Review.
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