Associations of autozygosity with a broad range of human phenotypes
Files
Publication date
2019-12-01
Authors
Clark, David W
Okada, Yukinori
Moore, Kristjan H S
Mason, Dan
Pirastu, Nicola
Gandin, Ilaria
Mattsson, Hannele
Barnes, Catriona L K
Lin, Kuang
Zhao, Jing Hua
Editors
Advisors
Supervisors
Document Type
Article
Metadata
Show full item recordCollections
License
Abstract
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 (F ROH) for >1.4 million individuals, we show that F ROH 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: F ROH 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 F ROH are confirmed within full-sibling pairs, where the variation in F ROH is independent of all environmental confounding.
Keywords
General Physics and Astronomy, General Chemistry, General Biochemistry,Genetics and Molecular Biology, Journal Article
Citation
Clark, D W, Okada, Y, Moore, K H S, Mason, D, Pirastu, N, Gandin, I, Mattsson, H, Barnes, C L K, Lin, K, Zhao, J H, Deelen, P, Rohde, R, Schurmann, C, Guo, X, Giulianini, F, Zhang, W, Medina-Gomez, C, Karlsson, R, Bao, Y, Bartz, T M, Baumbach, C, Biino, G, Bixley, M J, Brumat, M, Chai, J-F, Corre, T, Cousminer, D L, Dekker, A M, Eccles, D A, van Eijk, K R, Fuchsberger, C, Gao, H, Germain, M, Gordon, S D, de Haan, H G, Harris, S E, Hofer, E, Huerta-Chagoya, A, Igartua, C, Jansen, I E, Jia, Y, Kacprowski, T, Karlsson, T, Kleber, M E, Li, S A, Li-Gao, R, Mahajan, A, Matsuda, K, Meidtner, K, Meng, W, Montasser, M E, van der Most, P J, Munz, M, Nutile, T, Palviainen, T, Prasad, G, Prasad, R B, Priyanka, T D S, Rizzi, F, Salvi, E, Sapkota, B R, Shriner, D, Skotte, L, Smart, M C, Smith, A V, van der Spek, A, Spracklen, C N, Strawbridge, R J, Tajuddin, S M, Trompet, S, Turman, C, Verweij, N, Viberti, C, Wang, L, Warren, H R, Wootton, R E, Yanek, L R, Yao, J, Yousri, N A, Zhao, W, Adeyemo, A A, Afaq, S, Aguilar-Salinas, C A, Akiyama, M, Albert, M L, Allison, M A, Alver, M, Aung, T, Azizi, F, Bentley, A R, Boeing, H, Boerwinkle, E, Borja, J B, de Borst, G J, Bottinger, E P, Broer, L, Campbell, H, Chanock, S, Chee, M-L, Chen, G, Chen, Y-D I, Chen, Z, Chiu, Y-F, Cocca, M, Collins, F S, Concas, M P, Corley, J, Cugliari, G, van Dam, R M, Damulina, A, Daneshpour, M S, Day, F R, Delgado, G E, Dhana, K, Doney, A S F, Dörr, M, Doumatey, A P, Dzimiri, N, Ebenesersdóttir, S S, Elliott, J, Elliott, P, Ewert, R, Felix, J F, Fischer, K, Freedman, B I, Girotto, G, Goel, A, Gögele, M, Goodarzi, M O, Graff, M, Granot-Hershkovitz, E, Grodstein, F, Guarrera, S, Gudbjartsson, D F, Guity, K, Gunnarsson, B, Guo, Y, Hagenaars, S P, Haiman, C A, Halevy, A, Harris, T B, Hedayati, M, van Heel, D A, Hirata, M, Höfer, I, Hsiung, C A, Huang, J, Hung, Y-J, Ikram, M A, Jagadeesan, A, Jousilahti, P, Kamatani, Y, Kanai, M, Kerrison, N D, Kessler, T, Khaw, K-T, Khor, C C, de Kleijn, D P V, Koh, W-P, Kolcic, I, Kraft, P, Krämer, B K, Kutalik, Z, Kuusisto, J, Langenberg, C, Launer, L J, Lawlor, D A, Lee, I-T, Lee, W-J, Lerch, M M, Li, L, Liu, J, Loh, M, London, S J, Loomis, S, Lu, Y, Luan, J, Mägi, R, Manichaikul, A W, Manunta, P, Másson, G, Matoba, N, Mei, X W, Meisinger, C, Meitinger, T, Mezzavilla, M, Milani, L, Millwood, I Y, Momozawa, Y, Moore, A, Morange, P-E, Moreno-Macías, H, Mori, T A, Morrison, A C, Muka, T, Murakami, Y, Murray, A D, de Mutsert, R, Mychaleckyj, J C, Nalls, M A, Nauck, M, Neville, M J, Nolte, I M, Ong, K K, Orozco, L, Padmanabhan, S, Pálsson, G, Pankow, J S, Pattaro, C, Pattie, A, Polasek, O, Poulter, N, Pramstaller, P P, Quintana-Murci, L, Räikkönen, K, Ralhan, S, Rao, D C, van Rheenen, W, Rich, S S, Ridker, P M, Rietveld, C A, Robino, A, van Rooij, F J A, Ruggiero, D, Saba, Y, Sabanayagam, C, Sabater-Lleal, M, Sala, C F, Salomaa, V, Sandow, K, Schmidt, H, Scott, L J, Scott, W R, Sedaghati-Khayat, B, Sennblad, B, van Setten, J, Sever, P J, Sheu, W H-H, Shi, Y, Shrestha, S, Shukla, S R, Sigurdsson, J K, Sikka, T T, Singh, J R, Smith, B H, Stančáková, A, Stanton, A, Starr, J M, Stefansdottir, L, Straker, L, Sulem, P, Sveinbjornsson, G, Swertz, M A, Taylor, A M, Taylor, K D, Terzikhan, N, Tham, Y-C, Thorleifsson, G, Thorsteinsdottir, U, Tillander, A, Tracy, R P, Tusié-Luna, T, Tzoulaki, I, Vaccargiu, S, Vangipurapu, J, Veldink, J H, Vitart, V, Völker, U, Vuoksimaa, E, Wakil, S M, Waldenberger, M, Wander, G S, Wang, Y X, Wareham, N J, Wild, S, Yajnik, C S, Yuan, J-M, Zeng, L, Zhang, L, Zhou, J, Amin, N, Asselbergs, F W, Bakker, S J L, Becker, D M, Lehne, B, Bennett, D A, van den Berg, L H, Berndt, S I, Bharadwaj, D, Bielak, L F, Bochud, M, Boehnke, M, Bouchard, C, Bradfield, J P, Brody, J A, Campbell, A, Carmi, S, Caulfield, M J, Cesarini, D, Chambers, J C, Chandak, G R, Cheng, C-Y, Ciullo, M, Cornelis, M, Cusi, D, Smith, G D, Deary, I J, Dorajoo, R, van Duijn, C M, Ellinghaus, D, Erdmann, J, Eriksson, J G, Evangelou, E, Evans, M K, Faul, J D, Feenstra, B, Feitosa, M, Foisy, S, Franke, A, Friedlander, Y, Gasparini, P, Gieger, C, Gonzalez, C, Goyette, P, Grant, S F A, Griffiths, L R, Groop, L, Gudnason, V, Gyllensten, U, Hakonarson, H, Hamsten, A, van der Harst, P, Heng, C-K, Hicks, A A, Hochner, H, Huikuri, H, Hunt, S C, Jaddoe, V W V, De Jager, P L, Johannesson, M, Johansson, Å, Jonas, J B, Jukema, J W, Junttila, J, Kaprio, J, Kardia, S L R, Karpe, F, Kumari, M, Laakso, M, van der Laan, S W, Lahti, J, Laudes, M, Lea, R A, Lieb, W, Lumley, T, Martin, N G, März, W, Matullo, G, McCarthy, M I, Medland, S E, Merriman, T R, Metspalu, A, Meyer, B F, Mohlke, K L, Montgomery, G W, Mook-Kanamori, D, Munroe, P B, North, K E, Nyholt, D R, O'connell, J R, Ober, C, Oldehinkel, A J, Palmas, W, Palmer, C, Pasterkamp, G G, Patin, E, Pennell, C E, Perusse, L, Peyser, P A, Pirastu, M, Polderman, T J C, Porteous, D J, Posthuma, D, Psaty, B M, Rioux, J D, Rivadeneira, F, Rotimi, C, Rotter, J I, Rudan, I, Den Ruijter, H M, Sanghera, D K, Sattar, N, Schmidt, R, Schulze, M B, Schunkert, H, Scott, R A, Shuldiner, A R, Sim, X, Small, N, Smith, J A, Sotoodehnia, N, Tai, E-S, Teumer, A, Timpson, N J, Toniolo, D, Tregouet, D-A, Tuomi, T, Vollenweider, P, Wang, C A, Weir, D R, Whitfield, J B, Wijmenga, C, Wong, T-Y, Wright, J, Yang, J, Yu, L, Zemel, B S, Zonderman, A B, Perola, M, Magnusson, P K E, Uitterlinden, A G, Kooner, J S, Chasman, D I, Loos, R J F, Franceschini, N, Franke, L, Haley, C S, Hayward, C, Walters, R G, Perry, J R B, Esko, T, Helgason, A, Stefansson, K, Joshi, P K, Kubo, M & Wilson, J F 2019, 'Associations of autozygosity with a broad range of human phenotypes', Nature Communications, vol. 10, no. 1, 4957. https://doi.org/10.1038/s41467-019-12283-6