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

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 (χ(2) = 83.89, df = 1; p = 5.2 × 10(-20)). 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.