Directional dominance on stature and cognition in diverse human populations

Peter K. Joshi, Tonu Esko, Hannele Mattsson, Niina Eklund, Ilaria Gandin, Teresa Nutile, Anne U. Jackson, Claudia Schurmann, Albert V. Smith, Weihua Zhang, Yukinori Okada, Alena Stančáková, Jessica D. Faul, Wei Zhao, Traci M. Bartz, Maria Pina Concas, Nora Franceschini, Stefan Enroth, Veronique Vitart, Stella TrompetXiuqing Guo, Daniel I. Chasman, Jeffrey R. O'Connel, Tanguy Corre, Suraj S. Nongmaithem, Yuning Chen, Massimo Mangino, Daniela Ruggiero, Michela Traglia, Aliki Eleni Farmaki, Tim Kacprowski, Andrew Bjonnes, Ashley Van Der Spek, Ying Wu, Anil K. Giri, Lisa R. Yanek, Lihua Wang, Edith Hofer, Cornelius A. Rietveld, Olga McLeod, Marilyn C. Cornelis, Cristian Pattaro, Niek Verweij, Clemens Baumbach, Abdel Abdellaoui, Helen R. Warren, Dragana Vuckovic, Hao Mei, Claude Bouchard, John R B Perry, Stefania Cappellani, Saira S. Mirza, Miles C. Benton, Ulrich Broeckel, Sarah E. Medland, Penelope A. Lind, Giovanni Malerba, Alexander Drong, Loic Yengo, Lawrence F. Bielak, Degui Zhi, Peter J. Van Der Most, Daniel Shriner, Reedik Mägi, Gibran Hemani, Tugce Karaderi, Zhaoming Wang, Tian Liu, Ilja Demuth, Jing Hua Zhao, Weihua Meng, Lazaros Lataniotis, Sander W. Van Der Laan, Jonathan P. Bradfield, Andrew R. Wood, Amelie Bonnefond, Tarunveer S. Ahluwalia, Leanne M. Hall, Erika Salvi, Seyhan Yazar, Lisbeth Carstensen, Hugoline G. De Haan, Mark Abney, Uzma Afzal, Matthew A. Allison, Najaf Amin, Folkert W. Asselbergs, Stephan J L Bakker, R. Graham Barr, Sebastian E. Baumeister, Daniel J. Benjamin, Sven Bergmann, Eric Boerwinkle, Erwin P. Bottinger, Archie Campbell, Aravinda Chakravarti, Yingleong Chan, Stephen J. Chanock, Constance Chen, Y. D Ida Chen, Francis S. Collins, John Connell, Adolfo Correa, L. Adrienne Cupples, George Davey Smith, Gail Davies, Marcus Dörr, Georg Ehret, Stephen B. Ellis, Bjarke Feenstra, Mary F. Feitosa, Ian Ford, Caroline S. Fox, Timothy M. Frayling, Nele Friedrich, Frank Geller, Generation Scotland, Irina Gillham-Nasenya, Omri Gottesman, Misa Graff, Francine Grodstein, Charles Gu, Chris Haley, Christopher J. Hammond, Sarah E. Harris, Tamara B. Harris, Nicholas D. Hastie, Nancy L. Heard-Costa, Kauko Heikkilä, Lynne J. Hocking, Georg Homuth, Jouke Jan Hottenga, Jinyan Huang, Jennifer E. Huffman, Pirro G. Hysi, M. Arfan Ikram, Erik Ingelsson, Anni Joensuu, Åsa Johansson, Pekka Jousilahti, J. Wouter Jukema, Mika Kähönen, Yoichiro Kamatani, Stavroula Kanoni, Shona M. Kerr, Nazir M. Khan, Philipp Koellinger, Heikki A. Koistinen, Manraj K. Kooner, Michiaki Kubo, Johanna Kuusisto, Jari Lahti, Lenore J. Launer, Rodney A. Lea, Benjamin Lehne, Terho Lehtimäki, David C M Liewald, Lars Lind, Marie Loh, Marja Liisa Lokki, Stephanie J. London, Stephanie J. Loomis, Anu Loukola, Yingchang Lu, Thomas Lumley, Annamari Lundqvist, Satu Männistö, Pedro Marques-Vidal, Corrado Masciullo, Angela Matchan, Rasika A. Mathias, Koichi Matsuda, James B. Meigs, Christa Meisinger, Thomas Meitinger, Cristina Menni, Frank D. Mentch, Evelin Mihailov, Lili Milani, May E. Montasser, Grant W. Montgomery, Alanna Morrison, Richard H. Myers, Rajiv Nadukuru, Pau Navarro, Mari Nalis, Markku S. Nieminen, Ilja M. Nolte, George T. O'Connor, Adesola Ogunniyi, Sandosh Padmanabhan, Walter R. Palmas, James S. Pankow, Inga Patarcic, Francesca Pavani, Patricia A. Peyser, Kirsi Pietilainen, Neil Poulter, Inga Prokopenko, Sarju Ralhan, Paul Redmond, Stephen S. Rich, Harri Rissanen, Antonietta Robino, Lynda M. Rose, Richard Rose, Cinzia Sala, Babatunde Salako, Veikko Salomaa, Antti Pekka Sarin, Richa Saxena, Helena Schmidt, Laura J. Scott, William R. Scott, Bengt Sennblad, Sudha Seshadri, Peter Sever, Smeeta Shrestha, Blair H. Smith, Jennifer A. Smith, Nicole Soranzo, Nona Sotoodehnia, Lorraine Southam, Alice V. Stanton, Maria G. Stathopoulou, Konstantin Strauch, Rona J. Strawbridge, Matthew J. Suderman, Nikhil Tandon, Sian Tsun Tang, Kent D. Taylor, Bamidele O. Tayo, Anna Maria Töglhofer, Maciej Tomaszewski, Natalia Tšernikova, Jaakko Tuomilehto, Andre G. Uitterlinden, Dhananjay Vaidya, Astrid Van Hylckama Vlieg, Jessica Van Setten, Tuula Vasankari, Sailaja Vedantam, Efthymia Vlachopoulou, Diego Vozzi, Eero Vuoksimaa, Melanie Waldenberger, Erin B. Ware, William Wentworth-Shields, John B. Whitfield, Sarah Wild, Gonneke Willemsen, Chittaranjan S. Yajnik, Jie Yao, Gianluigi Zaza, Xiaofeng Zhu, Rany M. Salem, Mads Melbye, Hans Bisgaard, Nilesh J. Samani, Daniele Cusi, David A. Mackey, Richard S. Cooper, Philippe Froguel, Gerard Pasterkamp, Struan F A Grant, Hakon Hakonarson, Luigi Ferrucci, Robert A. Scott, Andrew D. Morris, Colin N A Palmer, George Dedoussis, Panos Deloukas, Lars Bertram, Ulman Lindenberger, Sonja I. Berndt, Cecilia M. Lindgren, Nicholas J. Timpson, Anke Tönjes, Patricia B. Munroe, Thorkild I A Sørensen, Charles N. Rotimi, Donna K. Arnett, Albertine J. Oldehinkel, Sharon L R Kardia, Beverley Balkau, Giovanni Gambaro, Andrew P. Morris, Johan G. Eriksson, Margie J. Wright, Nicholas G. Martin, Steven C. Hunt, John M. Starr, Ian J. Deary, Lyn R. Griffiths, Henning Tiemeier, Nicola Pirastu, Jaakko Kaprio, Nicholas J. Wareham, Louis Pérusse, James G. Wilson, Giorgia Girotto, Mark J. Caulfield, Olli Raitakari, Dorret I. Boomsma, Christian Gieger, Pim Van Der Harst, Andrew A. Hicks, Peter Kraft, Juha Sinisalo, Paul Knekt, Magnus Johannesson, Patrik K E Magnusson, Anders Hamsten, Reinhold Schmidt, Ingrid B. Borecki, Erkki Vartiainen, Diane M. Becker, Dwaipayan Bharadwaj, Karen L. Mohlke, Michael Boehnke, Cornelia M. Van Duijn, Dharambir K. Sanghera, Alexander Teumer, Eleftheria Zeggini, Andres Metspalu, Paolo Gasparini, Sheila Ulivi, Carole Ober, Daniela Toniolo, Igor Rudan, David J. Porteous, Marina Ciullo, Tim D. Spector, Caroline Hayward, Josée Dupuis, Ruth J F Loos, Alan F. Wright, Giriraj R. Chandak, Peter Vollenweider, Alan R. Shuldiner, Paul M. Ridker, Jerome I. Rotter, Naveed Sattar, Ulf Gyllensten, Kari E. North, Mario Pirastu, Bruce M. Psaty, David R. Weir, Markku Laakso, Vilmundur Gudnason, Atsushi Takahashi, John C. Chambers, Jaspal S. Kooner, David P. Strachan, Harry Campbell, Joel N. Hirschhorn, Markus Perola, Ozren Polašek, James F. Wilson

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish
Pages (from-to)459-462
Number of pages4
JournalNature
Volume523
Issue number7561
DOIs
Publication statusPublished - Jul 23 2015

ASJC Scopus subject areas

  • General

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