Gibson, Greg and McQuillan, Ruth and Eklund, Niina and Pirastu, Nicola and Kuningas, Maris and McEvoy, Brian P. and Esko, Tõnu and Corre, Tanguy and Davies, Gail and Kaakinen, Marika and Lyytikäinen, Leo-Pekka and Kristiansson, Kati and Havulinna, Aki S. and Gögele, Martin and Vitart, Veronique and Tenesa, Albert and Aulchenko, Yurii and Hayward, Caroline and Johansson, Åsa and Boban, Mladen and Ulivi, Sheila and Robino, Antonietta and Boraska, Vesna and Igl, Wilmar and Wild, Sarah H. and Zgaga, Lina and Amin, Najaf and Theodoratou, Evropi and Polašek, Ozren and Girotto, Giorgia and Lopez, Lorna M. and Sala, Cinzia and Lahti, Jari and Laatikainen, Tiina and Prokopenko, Inga and Kals, Mart and Viikari, Jorma and Yang, Jian and Pouta, Anneli and Estrada, Karol and Hofman, Albert and Freimer, Nelson and Martin, Nicholas G. and Kähönen, Mika and Milani, Lili and Heliövaara, Markku and Vartiainen, Erkki and Räikkönen, Katri and Masciullo, Corrado and Starr, John M. and Hicks, Andrew A. and Esposito, Laura and Kolčić, Ivana and Farrington, Susan M. and Oostra, Ben and Zemunik, Tatijana and Campbell, Harry and Kirin, Mirna and Pehlic, Marina and Faletra, Flavio and Porteous, David and Pistis, Giorgio and Widén, Elisabeth and Salomaa, Veikko and Koskinen, Seppo and Fischer, Krista and Lehtimäki, Terho and Heath, Andrew and McCarthy, Mark I. and Rivadeneira, Fernando and Montgomery, Grant W. and Tiemeier, Henning and Hartikainen, Anna-Liisa and Madden, Pamela A. F. and d'Adamo, Pio and Hastie, Nicholas D. and Gyllensten, Ulf and Wright, Alan F. and van Duijn, Cornelia M. and Dunlop, Malcolm and Rudan, Igor and Gasparini, Paolo and Pramstaller, Peter P. and Deary, Ian J. and Toniolo, Daniela and Eriksson, Johan G. and Jula, Antti and Raitakari, Olli T. and Metspalu, Andres and Perola, Markus and Järvelin, Marjo-Riitta and Uitterlinden, André and Visscher, Peter M. and Wilson, James F. (2012) Evidence of Inbreeding Depression on Human Height. PLoS Genetics, 8 (7). pp. 1-15. ISSN 1553-7404

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Abstract

Stature is a classical and highly heritable complex trait, with 80%–90% of variation explained by genetic factors. In recent years, genome-wide association studies (GWAS) have successfully identified many common additive variants influencing human height; however, little attention has been given to the potential role of recessive genetic effects. Here, we investigated genome-wide recessive effects by an analysis of inbreeding depression on adult height in over 35,000 people from 21 different population samples. We found a highly significant inverse association between height and genome-wide homozygosity, equivalent to a height reduction of up to 3 cm in the offspring of first cousins compared with the offspring of unrelated individuals, an effect which remained after controlling for the effects of socio-economic status, an important confounder (x2 = 83.89, df = 1; p = 5.2610220). There was, however, a high degree of heterogeneity among populations: whereas the direction of the effect was consistent across most population samples, the effect size differed significantly among populations. It is likely that this reflects true biological heterogeneity: whether or not an effect can be observed will depend on both the variance in homozygosity in the population and the chance inheritance of individual recessive genotypes. These results predict that multiple, rare, recessive variants influence human height. Although this exploratory work focuses on height alone, the methodology developed is generally applicable to heritable quantitative traits (QT), paving the way for an investigation into inbreeding effects, and therefore genetic architecture, on a range of QT of biomedical importance.

Item Type:	Article
Keywords:	evidence; inbreeding; depression; human height;
Academic Unit:	Faculty of Science and Engineering > Biology Faculty of Science and Engineering > Research Institutes > Human Health Institute
Item ID:	17394
Identification Number:	https://doi.org/10.1371/journal.pgen.1002655
Depositing User:	Lorna Lopez
Date Deposited:	10 Jul 2023 13:52
Journal or Publication Title:	PLoS Genetics
Publisher:	Elsevier
Refereed:	Yes
URI:	Publisher
Use Licence:	This item is available under a Creative Commons Attribution Non Commercial Share Alike Licence (CC BY-NC-SA). Details of this licence are available here

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