Associations of autozygosity with a broad range of human phenotypes

Publication type

Journal Article

Published in

Nature Communications

Authors

David W. Clark, Yukinori Okada, Kristjan H.S. Moore, Dan Mason, Nicola Pirastu, Ilaria Gandin, Hannele Mattsson, Catriona L.K. Barnes, Kuang Lin, Jing Hua Zhao, Patrick Deelen, Rebecca Rohde, Claudia Schurmann, Xiuqing Guo, Franco Giulianini, Weihua Zhang, Carolina Medina-Gomez, Robert Karlsson, Yanchun Bao, Traci M. Bartz, Clemens Baumbach, Ginevra Biino, Matthew J. Bixley, Marco Brumat, Jin-Fang Chai, Tanguy Corre, Diana L. Cousminer, Annelot M. Dekker, David A. Eccles, Kristel R. van Eijk, Christian Fuchsberger, He Gao, Marine Germain, Scott D. Gordon, Hugoline G. de Haan, Sarah E. Harris, Edith Hofer, Alicia Huerta-Chagoya, Catherine Igartua, Iris E. Jansen, Yucheng Jia, Tim Kacprowski, Torgny Karlsson, Marcus E. Kleber, Shengchao Alfred Li, Ruifang Li-Gao, Anubha Mahajan, Koichi Matsuda, Karina Meidtner, Weihua Meng, May E. Montasser, Peter J. van der Most, Matthias Munz, Teresa Nutile, Teemu Palviainen, Gauri Prasad, Rashmi B. Prasad, Tallapragada Divya Sri Priyanka, Federica Rizzi, Erika Salvi, Bishwa R. Sapkota, Daniel Shriner, Line Skotte, Melissa Smart, Albert Vernon Smith, Ashley van der Spek, Cassandra N. Spracklen, Rona J. Strawbridge, Salman M. Tajuddin, Stella Trompet, Constance Turman, Niek Verweij, Clara Viberti, Lihua Wang, Helen R. Warren, Robyn E. Wootton, Lisa R. Yanek, Jie Yao, Noha A. Yousri, Wei Zhao, Adebowale A. Adeyemo, Saima Afaq, Carlos Alberto Aguilar-Salinas, Masato Akiyama, Matthew L. Albert, Matthew A. Allison, Maris Alver, Tin Aung, Fereidoun Azizi, Amy R. Bentley, Heiner Boeing, Eric Boerwinkle, Judith B. Borja, Gert J. de Borst, Erwin P. Bottinger, Linda Broer, Harry Campbell, Stephen Chanock, Miao-Li Chee, Guanjie Chen, Yii-Der I. Chen, Zhengming Chen, Yen-Feng Chiu, Massimiliano Cocca, Francis S. Collins, Maria Pina Concas, Janie Corley, Giovanni Cugliari, Rob M. van Dam, Anna Damulina, Maryam S. Daneshpour, Felix R. Day, Graciela E. Delgado, Klodian Dhana, Alexander S.F. Doney, Marcus Dörr, Ayo P. Doumatey, Nduna Dzimiri, S. Sunna Ebenesersdóttir, Joshua Elliott, Paul Elliott, Ralf Ewert, Janine F. Felix, Krista Fischer, Barry I. Freedman, Giorgia Girotto, Anuj Goel, Martin Gögele, Mark O. Goodarzi, Mariaelisa Graff, Einat Granot-Hershkovitz, Francine Grodstein, Simonetta Guarrera, Daniel F. Gudbjartsson, Kamran Guity, Bjarni Gunnarsson, Yu Guo, Saskia P. Hagenaars, Christopher A. Haiman, Avner Halevy, Tamara B. Harris, Mehdi Hedayati, David A. van Heel, Makoto Hirata, Imo Höfer, Chao Agnes Hsiung, Jinyan Huang, Yi-Jen Hung, M. Arfan Ikram, Anuradha Jagadeesan, Pekka Jousilahti, Yoichiro Kamatani, Masahiro Kanai, Nicola D. Kerrison, Thorsten Kessler, Kay-Tee Khaw, Chiea Chuen Khor, Dominique P.V. de Kleijn, Woon-Puay Koh, Ivana Kolcic, Peter Kraft, Bernhard K. Krämer, Zoltán Kutalik, Johanna Kuusisto, Claudia Langenberg, Lenore J. Launer, Deborah A. Lawlor, I-Te Lee, Wen-Jane Lee, Markus M. Lerch, Liming Li, Jianjun Liu, Marie Loh, Stephanie J. London, Stephanie Loomis, Yingchang Lu, Jian’an Luan, Reedik Mägi, Ani W. Manichaikul, Paolo Manunta, Gisli Masson, Nana Matoba, Xue W. Mei, Christa Meisinger, Thomas Meitinger, Massimo Mezzavilla, Lili Milani, Iona Y. Millwood, Yukihide Momozawa, Amy Moore, Pierre-Emmanuel Morange, Hortensia Moreno-Macías, Trevor A. Mori, Alanna C. Morrison, Taulant Muka, Yoshinori Murakami, Alison D. Murray, Renée de Mutsert, Josyf C. Mychaleckyj, Mike A. Nalls, Matthias Nauck, Matt J. Neville, Ilja M. Nolte, Ken K. Ong, Lorena Orozco, Sandosh Padmanabhan, Gunnar Pálsson, James S. Pankow, Cristian Pattaro, Alison Pattie, Ozren Polasek, Neil Poulter, Peter P. Pramstaller, Lluis Quintana-Murci, Katri Räikkönen, Sarju Ralhan, Dabeeru C. Rao, Wouter van Rheenen, Stephen S. Rich, Paul M. Ridker, Cornelius A. Rietveld, Antonietta Robino, Frank J.A. van Rooij, Daniela Ruggiero, Yasaman Saba, Sabanayagam Charumathi, Maria Sabater-Lleal, Cinzia Felicita Sala, Veikko Salomaa, Kevin Sandow, Helena Schmidt, Laura J. Scott, William R. Scott, Bahareh Sedaghati-Khayat, Bengt Sennblad, Jessica van Setten, Peter J. Sever, Wayne H.-H. Sheu, Yuan Shi, Smeeta Shrestha, Sharvari Rahul Shukla, Jon K. Sigurdsson, Timo Tonis Sikka, Jai Rup Singh, Blair H. Smith, Alena Stančáková, Alice Stanton, John M. Starr, Lilja Stefansdottir, Leon Straker, Patrick Sulem, Gardar Sveinbjornsson, Morris A. Swertz, Adele M. Taylor, Kent D. Taylor, Natalie Terzikhan, Yih-Chung Tham, Gudmar Thorleifsson, Unnur Thorsteinsdottir, Annika Tillander, Russell P. Tracy, Teresa Tusié-Luna, Ioanna Tzoulaki, Simona Vaccargiu, Jagadish Vangipurapu, Jan H. Veldink, Veronique Vitart, Uwe Völker, Eero Vuoksimaa, Salma M. Wakil, Melanie Waldenberger, Gurpreet S. Wander, Ya Xing Wang, Nicholas J. Wareham, Sarah Wild, Chittaranjan S. Yajnik, Jian-Min Yuan, Lingyao Zeng, Liang Zhang, Jie Zhou, Najaf Amin, Folkert W. Asselbergs, Stephan J. L. Bakker, Diane M. Becker, Benjamin Lehne, David A. Bennett, Leonard H. van den Berg, Sonja I. Berndt, Dwaipayan Bharadwaj, Lawrence F. Bielak, Murielle Bochud, Mike Boehnke, Claude Bouchard, Jonathan P. Bradfield, Jennifer A. Brody, Archie Campbell, Shai Carmi, Mark J. Caulfield, David Cesarini, John C. Chambers, Giriraj Ratan Chandak, Ching-Yu Cheng, Marina Ciullo, Marilyn Cornelis, Daniele Cusi, George Davey Smith, Ian J. Deary, Rajkumar Dorajoo, Cornelia M. van Duijn, David Ellinghaus, Jeanette Erdmann, Johan G. Eriksson, Evangelos Evangelou, Michele K. Evans, Jessica D. Faul, Bjarke Feenstra, Mary Feitosa, Sylvain Foisy, Andre Franke, Yechiel Friedlander, Paolo Gasparini, Christian Gieger, Clicerio Gonzalez, Philippe Goyette, Struan F. A. Grant, Lyn R. Griffiths, Leif Groop, Vilmundur Gudnason, Ulf Gyllensten, Hakon Hakonarson, Anders Hamsten, Pim van der Harst, Chew-Kiat Heng, Andrew A. Hicks, Hagit Hochner, Heikki Huikuri, Steven C. Hunt, Vincent W. V. Jaddoe, Philip L. De Jager, Magnus Johannesson, Åsa Johansson, Jost B. Jonas, J. Wouter Jukema, Juhani Junttila, Jaakko Kaprio, Sharon L. R. Kardia, Fredrik Karpe, Meena Kumari, Markku Laakso, Sander W. van der Laan, Jari Lahti, Matthias Laudes, Rodney A. Lea, Wolfgang Lieb, Thomas Lumley, Nicholas G. Martin, Winfried März, Giuseppe Matullo, Mark I. McCarthy, Sarah E. Medland, Tony R. Merriman, Andres Metspalu, Brian F. Meyer, Karen L. Mohlke, Grant W. Montgomery, Dennis Mook-Kanamori, Patricia B. Munroe, Kari E. North, Dale R. Nyholt, Jeffrey R. O’Connell, Carole Ober, Albertine J. Oldehinkel, Walter Palmas, Colin Palmer, Gerard G. Pasterkamp, Etienne Patin, Craig E. Pennell, Louis Perusse, Patricia A. Peyser, Mario Pirastu, Tinca J.C. Polderman, David J. Porteous, Danielle Posthuma, Bruce M. Psaty, John D. Rioux, Fernando Rivadeneira, Charles Rotimi, Jerome I. Rotter, Igor Rudan, Hester M. den Ruijter, E. Shyong Tai, Alexander Teumer, Nicholas J. Timpson, Daniela Toniolo, David-Alexandre Tregouet, Tiinamaija Tuomi, Peter Vollenweider, Carol A. Wang, David R. Weir, John B. Whitfield, Cisca Wijmenga, Tien-Yin Wong, John Wright, Jingyun Yang, Lei Yu, Babette S. Zemel, Alan B. Zonderman, Markus Perola, Patrik K.E. Magnusson, André G. Uitterlinden, Jaspal S. Kooner, Daniel I. Chasman, Ruth J.F. Loos, Nora Franceschini, Lude Franke, Chris S. Haley, Caroline Hayward, Robin G. Walters, John R.B. Perry, Tõnu Esko, Agnar Helgason, Kari Stefansson, Peter K. Joshi, Michiaki Kubo and James F. Wilson

Publication date

Summary

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.

Volume

10:4957

DOI

https://doi.org/10.1038/s41467-019-12283-6

ISSN

16

Subjects

Childbearing: Fertility, Biology and Genetics

Notes

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