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Nature. 2015 Jul 23;523(7561):459-462. doi: 10.1038/nature14618. Epub 2015 Jul 1.

Directional dominance on stature and cognition in diverse human populations.

Joshi PK#1, Esko T#2,3,4,5, Mattsson H6,7, Eklund N6, Gandin I8, Nutile T9, Jackson AU10, Schurmann C11,12, Smith AV13,14, Zhang W15,16, Okada Y17,18, Stančáková A19, Faul JD20, Zhao W21, Bartz TM22, Concas MP23, Franceschini N24, Enroth S25, Vitart V26, Trompet S27, Guo X28,29, Chasman DI30, O'Connel JR31, Corre T32,33, Nongmaithem SS34, Chen Y35, Mangino M36,37, Ruggiero D9, Traglia M38, Farmaki AE39, Kacprowski T40, Bjonnes A41, van der Spek A42, Wu Y43, Giri AK44, Yanek LR45, Wang L46, Hofer E47,48, Rietveld CA49, McLeod O50, Cornelis MC51,52, Pattaro C53, Verweij N54, Baumbach C55,56,57, Abdellaoui A58, Warren HR59,60, Vuckovic D8, Mei H61, Bouchard C62, Perry JRB63, Cappellani S64, Mirza SS42, Benton MC65, Broeckel U66, Medland SE67, Lind PA67, Malerba G68, Drong A69, Yengo L70, Bielak LF21, Zhi D71, van der Most PJ72, Shriner D73, Mägi R2, Hemani G74, Karaderi T69, Wang Z75,76, Liu T77,78, Demuth I79,80, Zhao JH63, Meng W81, Lataniotis L82, van der Laan SW83, Bradfield JP84, Wood AR85, Bonnefond A70, Ahluwalia TS86,87,88, Hall LM89, Salvi E90, Yazar S91, Carstensen L92, de Haan HG93, Abney M94, Afzal U15,16, Allison MA95, Amin N42, Asselbergs FW96,97,98, Bakker SJL99, Barr RG100, Baumeister SE101, Benjamin DJ102,103, Bergmann S32,33, Boerwinkle E104, Bottinger EP11, Campbell A105, Chakravarti A106, Chan Y3,4,5, Chanock SJ75, Chen C107, Chen YI28,29, Collins FS108, Connell J109, Correa A61, Cupples LA35,110, Smith GD74, Davies G111,112, Dörr M113, Ehret G106,114, Ellis SB11, Feenstra B92, Feitosa MF46, Ford I115, Fox CS110,116, Frayling TM85, Friedrich N117, Geller F92, Scotland G105, Gillham-Nasenya I36, Gottesman O11, Graff M118, Grodstein F52, Gu C119, Haley C26,120, Hammond CJ36, Harris SE105,112, Harris TB121, Hastie ND26, Heard-Costa NL110,122, Heikkilä K123, Hocking LJ124, Homuth G40, Hottenga JJ58, Huang J125, Huffman JE26, Hysi PG36, Ikram MA42,126, Ingelsson E69,127, Joensuu A6,7, Johansson Å25,128, Jousilahti P129, Jukema JW130, Kähönen M131, Kamatani Y18, Kanoni S82, Kerr SM26, Khan NM44, Koellinger P49, Koistinen HA132,133,134, Kooner MK16, Kubo M135, Kuusisto J136, Lahti J137,138, Launer LJ121, Lea RA65, Lehne B15, Lehtimäki T139, Liewald DCM112, Lind L140, Loh M15, Lokki ML141, London SJ142, Loomis SJ143, Loukola A123, Lu Y11,12, Lumley T144, Lundqvist A145, Männistö S129, Marques-Vidal P146, Masciullo C38, Matchan A147, Mathias RA45,148, Matsuda K149, Meigs JB150, Meisinger C56, Meitinger T151,152, Menni C36, Mentch FD84, Mihailov E2, Milani L2, Montasser ME31, Montgomery GW153, Morrison A104, Myers RH154, Nadukuru R11, Navarro P26, Nelis M2, Nieminen MS155, Nolte IM72, O'Connor GT110,156, Ogunniyi A157, Padmanabhan S158, Palmas WR100, Pankow JS159, Patarcic I160, Pavani F53, Peyser PA21, Pietilainen K7,133,161, Poulter N162, Prokopenko I163, Ralhan S164, Redmond P111, Rich SS165, Rissanen H145, Robino A64, Rose LM30, Rose R166, Sala C38, Salako B157, Salomaa V129, Sarin AP6,7, Saxena R41, Schmidt H167, Scott LJ10, Scott WR15,16, Sennblad B50,168, Seshadri S110,122, Sever P162, Shrestha S34, Smith BH169, Smith JA21, Soranzo N147, Sotoodehnia N170, Southam L69,147, Stanton AV171, Stathopoulou MG172, Strauch K57,173, Strawbridge RJ50, Suderman MJ74, Tandon N174, Tang ST175, Taylor KD28,29, Tayo BO176, Töglhofer AM167, Tomaszewski M89,177, Tšernikova N2,178, Tuomilehto J132,179,180, Uitterlinden AG42,181, Vaidya D45,182, van Hylckama Vlieg A93, van Setten J83, Vasankari T183, Vedantam S3,4,5, Vlachopoulou E141, Vozzi D64, Vuoksimaa E123, Waldenberger M55,56, Ware EB21, Wentworth-Shields W94, Whitfield JB184, Wild S1, Willemsen G58, Yajnik CS185, Yao J28, Zaza G186, Zhu X187, Project TBJ18, Salem RM3,4,5, Melbye M92,188, Bisgaard H86,87, Samani NJ89,177, Cusi D90, Mackey DA91, Cooper RS176, Froguel P70,163, Pasterkamp G83, Grant SFA84,189, Hakonarson H84,189, Ferrucci L190, Scott RA63, Morris AD191, Palmer CNA192, Dedoussis G39, Deloukas P82,193, Bertram L78,194, Lindenberger U77, Berndt SI75, Lindgren CM4,69, Timpson NJ74, Tönjes A195, Munroe PB59,60, Sørensen TIA88,196, Rotimi CN73, Arnett DK197, Oldehinkel AJ198, Kardia SLR21, Balkau B199, Gambaro G200, Morris AP2,69,201, Eriksson JG129,202,203,204,205, Wright MJ206, Martin NG184, Hunt SC207, Starr JM112,208, Deary IJ111,112, Griffiths LR65, Tiemeier H42,209, Pirastu N8,64, Kaprio J7,123,210, Wareham NJ63, Pérusse L211, Wilson JG212, Girotto G8, Caulfield MJ59,60, Raitakari O213,214, Boomsma DI58, Gieger C55,56,57, van der Harst P54,97,215, Hicks AA53, Kraft P107, Sinisalo J155, Knekt P145, Johannesson M216, Magnusson PKE217, Hamsten A50, Schmidt R47, Borecki IB218, Vartiainen E129, Becker DM45,219, Bharadwaj D44, Mohlke KL43, Boehnke M10, van Duijn CM42, Sanghera DK220,221, Teumer A101, Zeggini E147, Metspalu A2,178, Gasparini P64, Ulivi S64, Ober C94, Toniolo D38, Rudan I1, Porteous DJ105,112, Ciullo M9, Spector TD36, Hayward C26, Dupuis J35,110, Loos RJF11,12,222, Wright AF26, Chandak GR34,223, Vollenweider P146, Shuldiner A31,224,225, Ridker PM30, Rotter JI28,29, Sattar N226, Gyllensten U25, North KE118,227, Pirastu M23, Psaty BM228,229, Weir DR20, Laakso M136, Gudnason V13,14, Takahashi A18, Chambers JC15,16,230, Kooner JS16,175,230, Strachan DP231, Campbell H1, Hirschhorn JN3,4,5, Perola M2,6, Polašek O#1,160, Wilson JF#1,26.

Author information

1
Usher Institute for Population Health Sciences and Informatics, University of Edinburgh, Teviot Place, Edinburgh, EH8 9AG, Scotland.
2
Estonian Genome Center, University of Tartu, Riia 23b, 51010, Tartu, Estonia.
3
Division of Endocrinology and Center for Basic and Translational Obesity Research, Boston Children's Hospital, Cambridge, 02141, MA, USA.
4
Program in Medical and Population Genetics, Broad Institute, Cambridge Center 7, Cambridge, 02242, MA, USA.
5
Department of Genetics, Harvard Medical School, 25 Shattuck St, Boston, 02115, MA, USA.
6
Unit of Public Health Genomics, National Institute for Health and Welfare, P.O. Box 104, Helsinki, FI-00251, Finland.
7
Institute for Molecular Medicine Finland (FIMM), University of Helsinki, P.O. Box 20, Helsinki, FI-00014, Finland.
8
Department of Medical Sciences, University of Trieste, Strada di Fiume 447 - Osp. di Cattinara, Trieste, 34149, Italy.
9
Institute of Genetics and Biophysics "A. Buzzati-Traverso" CNR, via Pietro Castellino, 111, Naples, 80131, Italy.
10
Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, 48109, MI, USA.
11
The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, 10029, USA.
12
The Genetics of Obesity and Related Metabolic Traits Program, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, 10029, USA.
13
Icelandic Heart Association, Holtasmari 1, 201, Kopavogur, Iceland.
14
Faculty of Medicine, University of Iceland, Reykjavik, 101, Iceland.
15
Department of Epidemiology and Biostatistics, Imperial College London, Norfolk Place, London, W2 1PG, UK.
16
Department of Cardiology, Ealing Hospital NHS Trust, Uxbridge Road, Southall, Middlesex, UB1 3HW, UK.
17
Department of Human Genetics and Disease Diversity, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyoku, Tokyo, 113-8510, Japan.
18
Laboratory for Statistical Analysis, RIKEN Center for Integrative Medical Sciences, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa, 230-0045, Japan.
19
Department of Medicine, University of Eastern Finland, 70210 Kuopio, Finland.
20
Institute for Social Research, University of Michigan, 426 Thompson Street, 48104, Ann Arbor, MI, USA.
21
Department of Epidemiology, University of Michigan, 1415 Washington Heights, 48109, Ann Arbor, MI, USA.
22
Cardiovascular Health Research Unit, Departments of Biostatistics and Medicine, University of Washington, 1730 Minor Ave, Suite 1360, Seattle, 98101, WA, USA.
23
Institute of Population Genetics, National Research Council, Trav. La Crucca n. 3 - Reg. Baldinca, Sassari, 07100, Italy.
24
Epidemiology, University of North Carolina, 137 E. Franklin St., Suite 306, 27599-8050, Chapel Hill, USA.
25
Immunology, Genetics & Pathology, Uppsala University, Husargatan 3, Box 815, Uppsala, SE-751 08, Sweden.
26
MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Crewe Road, EH4 2XU, Edinburgh, UK.
27
Department of Gerontology and Geriatrics, Leiden University Medical Center , PO Box 9600, Leiden, Netherlands.
28
Institute for Translational Genomics and Population Sciences , Los Angeles Biomedical Research Institute, 1124 W. Carson Street, Torrance, 90502, USA.
29
Department of Pediatrics, Harbor-UCLA Medical Center, Torrance, 90502, USA.
30
Division of Preventive Medicine, Brigham and Women's Hospital, 900 Commonwealth Avenue, East, Harvard Medical School, Boston, Boston, MA 02215, USA.
31
Division of Endocrinology, Diabetes, and Nutrition and Program for Personalised and Genomic Medicine, Department of Medicine, University of Maryland School of Medicine, 685 Baltimore St. MSTF, Baltimore, 21201, USA.
32
Department of Medical Genetics, University of Lausanne, Rue du Bugnon 27, Lausanne, 1005, Switzerland.
33
Swiss Institute of Bioinformatics, Quartier Sorge - batiment génopode, Lausanne, 1015, Switzerland.
34
Genomic Research on Complex Diseases (GRC) Group, CSIR-Centre for Cellular and Molecular Biology, Habshiguda, Uppal Road, Hyderabad, 500007, India.
35
Department of Biostatistics, Boston University School of Public Health, 801 Massachusetts Avenue, Boston, 02118, MA, USA.
36
Department of Twin Research & Genetic Epidemiology, King's College London, South Wing, Block D, 3rd Floor, Westminster Bridge Road, London, SE1 7EH, UK.
37
NIHR Biomedical Research Centre , Guy's and St. Thomas' Foundation Trust, Westminster Bridge Road, London, SE1 7EH, UK.
38
Division of Genetics and Cell Biology, San Raffaele Scientific Institute, Via Olgettina 58, Milano, 20132, Italy.
39
Department of Nutrition and Dietetics, Harokopio University of Athens, 70, El. Venizelou Ave, Athens, 17671, Greece.
40
Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, Friedrich-Ludwig-Jahn-Str. 15A, Greifswald, 17475, Germany.
41
Center for Human Genetic Research , 55 Fruit Street, Massachusetts General Hospital, 2114, USA.
42
Department of Epidemiology, Erasmus Medical Center, PO Box 2040, Rotterdam, 3000 CA, The Netherlands.
43
Department of Genetics, University of North Carolina, Chapel Hill, 27599, NC, USA.
44
Genomics and Molecular Medicine, CSIR-Institute of Genomics & Integrative Biology, Mathura Road, New Delhi, 110025, India.
45
The GeneSTAR Research Program, Division of General Internal Medicine, Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, 21287, Maryland, USA.
46
Department of Genetics, Washington University School of Medicine, 4444 Forest Park Boulevard, Saint Louis, 63108, MO, USA.
47
Department of Neurology, Clinical Division of Neurogeriatrics, Medical University Graz, Auenbruggerplatz 22, Graz, A-8036, Austria.
48
Institute for Medical Informatics, Statistics and Documentation, Medical University Graz, Auenbruggerplatz2, Graz, A-8036, Austria.
49
Erasmus School of Economics, Erasmus University Rotterdam, Burgemeester Oudlaan 50, Rotterdam, 3000 DR, The Netherlands.
50
Atherosclerosis Research Unit, Department of Medicine Solna, Karolinska Institutet, CMM L8:03, Karolinska University Hospital, Solna, Stockholm, 171 76, Sweden.
51
Channing Division of Network Medicine, Brigham & Women's Hospital, 181 Longwood, Boston, 02115, USA.
52
Nutrition, Harvard School of Public Health, 401 Park Drive, Boston, 02215, USA.
53
Center for Biomedicine, European Academy Bozen/Bolzano (EURAC), Bolzano, Italy - Affiliated Institute of the University of Lübeck, Lübeck, Germany.
54
University of Groningen, University Medical Center Groningen, Department of Cardiology, Hanzeplein 1, Groningen, 9700RB, The Netherlands.
55
Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Ingolstädter Landstr. 1, Neuherberg, 85764, Germany.
56
Institute of Epidemiology II, Helmholtz Zentrum München, German Research Center for Environmental Health, Ingolstädter Landstr. 1, Neuherberg, 85764, Germany.
57
Institute of Genetic Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Ingolstädter Landstr. 1, Neuherberg, 85764, Germany.
58
Department of Biological Psychology, VU University Amsterdam, Van der Boechorststraat 1, 1081 BT, Amsterdam, Netherlands.
59
Clinical Pharmacology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, Charterhouse Square, London, EC1M 6BQ, UK.
60
NIHR Barts Cardiovascular Biomedical Research Unit, Queen Mary University of London, Charterhouse Square, London, EC1M 6BQ, UK.
61
Department of Medicine, University of Mississippi Medical Center, 2500 N. State St., Jackson, 39216, MS, USA.
62
Pennington Biomedical Research Center, 6400 Perkins Rd, Baton Rouge, LA 70808, USA.
63
MRC Epidemiology Unit, University of Cambridge School of Clinical Medicine, Cambridge Biomedical Campus, Cambridge, CB2 0QQ, UK.
64
Institute for Maternal and Child Health - IRCCS "Burlo Garofolo", via dell'Istria 65, Trieste, 34137, Italy.
65
Institute of Health and Biomedical Innovation, Queensland University of Technology, 60 Musk Avenue, Kelvin Grove, GPO Box 2434, Brisbane Qld 4001, Brisbane, Australia.
66
Department of Pediatrics, Medical College of Wisconsin, 8701 Watertown Plank Rd, Milwaukee, 53226, WI, USA.
67
Quantitative Genetics, QIMR Berghofer Medical Research Institute, 300 Herston Rd, Herston, Brisbane, 4006, Australia.
68
Dipartimento di Scienze della Vita e della Riproduzione, University of Verona, Strada Le Grazie 15, Verona, 37134, Italy.
69
Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford, OX3 7BN, UK.
70
CNRS UMR 8199, European Genomic Institute for Diabetes (EGID), Lille 2 University, 1 Rue du Professeur Calmette, 59000, Lille, France.
71
Department of Biostatistics, University of Alabama at Birmingham, 1665 University Blvd, Birmingham, 35294, AL, USA.
72
Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, P.O. box 30.001, 9700 RB, Groningen, The Netherlands.
73
Center for Research on Genomics and Global Health, National Human Genome Research Institute, Building 12A/Room 4047, 12 South Dr., Bethesda, 20892, Maryland, USA.
74
MRC Integrative Epidemiology Unit, University of Bristol, Oakfield House, Oakfield Grove, Bristol, BS8 2BN, UK.
75
Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, 9609 Medical Center Drive, Rockville, 20850, MD, USA.
76
Cancer Genomics Research Laboratory, National Cancer Institute, SAIC-Frederick, Inc., Frederick National Laboratory for Cancer Research, Frederick,MD, USA.
77
Center for Lifespan Psychology, Max Planck Institute for Human Development, Lentzeallee 94, Berlin, 14195, Germany.
78
Vertebrate Genomics, Max Planck Institute for Molecular Genetics, Ihnestr. 72, Berlin, 14195, Germany.
79
Charité Research Group on Geriatrics, Charité - Universitätsmedizin Berlin, Reinickendorferstr. 61, 13347, Berlin, Germany.
80
Institute of Medical and Human Genetics, Charité - Universitätsmedizin Berlin, Augustenburger Platz 1, Berlin, 13353, Germany.
81
Division of Population Health Sciences, Medical Research Institute, University of Dundee, Ninewells hospital and School of Medicine, Dundee, DD2 4BF, Scotland.
82
William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, Charterhouse Square, London, EC1M 6BQ, UK.
83
Experimental Cardiology, Division Heart and Lungs, University Medical Center Utrecht, Heidelberglaan 100, Utrecht, 3584 CX, The Netherlands.
84
Center for Applied Genomics, Children's Hospital of Philadelphia, 3615 Civic Center Boulevard, Philadelphia, PA 19104, USA.
85
Genetics of Complex Traits, University of Exeter Medical School, University of Exeter, Royal Devon and Exeter Hospital, Barrack Road, Exeter, EX2 5DW, UK.
86
Copenhagen Prospective Studies on Asthma in Childhood, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
87
The Danish Pediatric Asthma Center, Gentofte Hospital, The Capital Region, Copenhagen, Denmark.
88
Novo Nordisk Centre for Basic Metabolic Research, Section of Metabolic Genetics, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 1, Copenhagen, 2100, Denmark.
89
Department of Cardiovascular Sciences, University of Leicester, BHF Cardiovascular Research Centre, Glenfield Hospital, Groby Road, Leicester, LE3 9QP, UK.
90
Department of Health Sciences, University of Milan, via A. di Rudinì 8, 20142 Milan, Italy.
91
Centre for Ophthalmology and Visual Science, University of Western Australia, Lions Eye Institute, 2 Verdun St, Perth, 6009, Australia.
92
Department of Epidemiology Research, Statens Serum Institut, Artillerivej 5, Copenhagen, 2300, Denmark.
93
Clinical Epidemiology, Leiden University Medical Center, PO Box 9600, Leiden, 2300RC, The Netherlands.
94
Department of Human Genetics, University of Chicago, 920 E. 58th Street, Chicago, IL, USA.
95
Department of Family and Preventive Medicine, University of California San Diego, 9500 Gilman Drive, La Jolla, 92093, USA.
96
Department of Cardiology, Division Heart and Lungs, University Medical Center Utrecht, Heidelberglaan 100, Utrecht, 3584 CX, The Netherlands.
97
Durrer Center for Cardiogenetic Research, ICIN-Netherlands Heart Institute, Catharijnesingel 52, Utrecht, 3501 DG, The Netherlands.
98
Institute of Cardiovascular Science, faculty of Population Health Sciences, University College London, Gower Street, London, WC1E 6BT, UK.
99
University of Groningen, University Medical Center Groningen, Department of Internal Medicine, Hanzeplein 1, Groningen, 9700RB, The Netherlands.
100
Department of Medicine, Columbia University, 622 W. 168th Street, New York, 10032, NY, USA.
101
Institute for Community Medicine, University Medicine Greifswald, W.-Rathenau-Str. 48, Greifswald, 17475, Germany.
102
Department of Economics, Cornell University, 480 Uris Hall, Ithaca, NY, 14853, USA.
103
Department of Economics and Center for Economic and Social Research, University of Southern California, 314C Dauterive Hall, 635 Downey Way, Los Angeles, CA, 90089, USA.
104
Human Genetics Center, School of Public Health, University of Texas Health Science Center at Houston, 1200 Pressler St., Suite 453E, Houston, Texas, 77030, USA.
105
Centre for Genomic and Experimental Medicine, University of Edinburgh, Western General Hospital, Edinburgh, EH4 2XU, UK.
106
McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, 21205, MD, USA.
107
Program in Genetic Epidemiology and Statistical Genetics, Harvard School of Public Health, 665 Huntington Ave, Boston, 02115, USA.
108
Genome Technology Branch, National Human Genome Research Institute, NIH, Bethesda, 20892, MD, USA.
109
College of Medicine, Dentistry and Nursing, Ninewells Hospital and Medical School, College Office, Level 10, Dundee, DD1 9SY, UK.
110
National Heart, Lung, and Blood Institute's Framingham Heart Study, 73 Mt. Wayte Ave, Framingham, 01702, MA, USA.
111
Psychology, University of Edinburgh, 7 George Square, Edinburgh, EH8 9JZ, UK.
112
Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, 7 George Square, Edinburgh, EH8 9JZ, UK.
113
Department of Internal Medicine B, University Medicine Greifswald, Ferdinand-Sauerbruch-Str. NK, Greifswald, 17475, Germany.
114
Cardiology, Geneva University Hospitals, Rue Gabrielle-Perret-Gentil, 4, Genève 14, 1211, Switzerland.
115
Robertson Centre, University of Glasgow, Boyd Orr Building, Glasgow, G12 8QQ, Scotland.
116
Division of Endocrinology, Brigham and Women's Hospital and Harvard Medical School , 75 Francis St, Boston, 02115, MA, USA.
117
Institute of Clinical Chemistry and Laboratory Medicine, University Medicine Greifswald, Ferdinand-Sauerbruch-Str. NK, 17475, Greifswald, Germany.
118
Epidemiology, University of North Carolina, 137 E Franklin St., Suite 306, USA.
119
Division of Biostatistics, Washington University, 660 S Euclid, St Louis, 63110, MO, USA.
120
Roslin Institute, University of Edinburgh, Easter Bush, Midlothian, EH25 9RG, Scotland.
121
National Institutes on Aging, National Institutes of Health, Bethesda, MD, USA.
122
Department of Neurology, Boston University School of Medicine, 72 E Concord St, Boston, 02118, MA, USA.
123
Department of Public Health, University of Helsinki, Hjelt Institute, P.O.Box 41, Mannerheimintie 172, Helsinki, FI-00014, Finland.
124
Musculoskeletal Research Programme, Division of Applied Medicine, University of Aberdeen, Foresterhill, Aberdeen, AB25 2ZD, UK.
125
State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Rui Jin Hospital Affiliated with Shanghai Jiao Tong University School of Medicine, 197 Rui Jin Er Road, Shanghai, 200025 China.
126
Department of Radiology, Erasmus Medical Center, PO Box 2040, Rotterdam, 3000 CA, The Netherlands.
127
Department of Medical Sciences, Molecular Epidemiology and Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
128
Uppsala Clinical Research Center, Uppsala University, Uppsala, SE-75237, Sweden.
129
Department of Chronic Disease Prevention, National Institute for Health and Welfare, P.O. Box 30, Helsinki, FI-00271, Finland.
130
Department of Cardiology C5-P , Leiden University Medical Center, PO Box 9600, Leiden, Netherlands.
131
Department of Clinical Physiology, University of Tampere and Tampere University Hospital, P.O. Box 2000, Tampere, 33521, Finland.
132
Diabetes Prevention Unit, National Institute for Health and Welfare, P.O. Box 30, FI-00271 Helsinki, Finland.
133
Department of Medicine, Division of Endocrinology, Helsinki University Central Hospital, P.O.Box 340, Haartmaninkatu 4, Helsinki, FI-00029, Finland.
134
Minerva Foundation Institute for Medical Research, Biomedicum 2U, Tukholmankatu 8, Helsinki, FI-00290, Finland.
135
Laboratory for Genotyping Development RCfIMS, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa, 230-0045, Japan.
136
Department of Medicine, University of Eastern Finland and Kuopio University Hospital, Kuopio, 70210, Finland.
137
Institute of Behavioural Sciences, University of Helsinki, P.O. Box 9, FI-00014 University of Helsinki, Helsinki, Finland.
138
Folkhälsan Reasearch Centre, PB 63, Helsinki, FI-00014 University of Helsinki, Finland.
139
Department of Clinical Chemistry, Fimlab Laboratories and School of Medicine University of Tampere, Tampere, 33520, Finland.
140
Department of Medical Sciences, University Hospital, Uppsala, 75185, Sweden.
141
Transplantation laboratory, Haartman Institute, University of Helsinki, P.O. Box 21, Helsinki, FI-00014, Finland.
142
National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, RTP, NC, USA.
143
Ophthalmology, Massachusetts Eye and Ear, 243 Charles St, Boston, 02114, USA.
144
Department of Statistics, University of Auckland, 303.325 Science Centre, Private Bag 92019, Auckland, 1142, New Zealand.
145
Department of Health, Functional Capacity and Welfare, National Institute for Health and Welfare, P.O. Box 30, Helsinki, FI-00271, Finland.
146
Department of Internal Medicine, University Hospital, Route du Bugnon 44, Lausanne, 1011, Switzerland.
147
Human Genetics, Wellcome Trust Sanger Institute, Hinxton, Cambridge, CB10 1HH, UK.
148
Division of Allergy and Clinical Immunology, Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland, 21224, USA.
149
Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo, 108-8639, Japan.
150
Division of General Internal Medicine, Massachusetts General Hospital , 50 Staniford St, Boston, 02114, MA, USA.
151
Institute of Human Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Ingolstädter Landstr. 1, Neuherberg, 85764 Germany.
152
Institute of Human Genetics, Klinikum rechts der Isar, Technische Universität München, Ismaninger Str. 22, München, 81675, Germany.
153
Molecular Epidemiology, QIMR Berghofer Medical Research Institute, 300 Herston Rd, Herston, Brisbane, 4006, Australia.
154
Genome Science Institute, Boston University School of Medicine, 72 East Concord Street, E-304, Boston, 2118, MA, USA.
155
HUCH Heart and Lung center, Helsinki University Central Hospital, P.O. Box 340, Helsinki, FI-00029, Finland.
156
Pulmonary Center and Department of Medicine, Boston University School of Medicine, 72 E Concord St, Boston, 02118, MA, USA.
157
Department of Medicine, University of Ibadan, Ibadan, Nigeria.
158
ICAMS, University of Glasgow, 126 University Way, Glasgow, G12 8TA, UK.
159
Division of Epidemiology and Community Health , University of Minnesota , 1300 S 2nd Street, Minneapolis, 55454, USA.
160
Centre for Global Health and Department of Public Health, School of Medicine, University of Split, Soltanska 2, 21000 Split, Croatia.
161
Obesity Research Unit, Research Programs Unit, Diabetes and Obesity, University of Helsinki, P.O.Box 63, Haartmaninkatu 8, FI-00014, Helsinki, Finland.
162
International Centre for Circulatory Health, Imperial College London, London, W2 1LA, UK.
163
Department of Genomics of Common Disease, School of Public Health, Imperial College London, London, SW7 2AZ, UK.
164
Department of Cardiology and Cardio thoracic Surgery Hero DMC Heart Institute, Civil Lines, 141001, Ludhiana, India.
165
Department Public Health Sciences, University of Virginia School of Medicine, 3232 West Complex, Charlottesville, 22908, USA.
166
Department of Psychological & Brain Sciences, Indiana University Bloomington, 1101 E. 10th St., Bloomington, IN 47405, USA.
167
Institute of Molecular Biology and Biochemistry, Medical University Graz, Harrachgasse 21, Graz, A-8010, Austria.
168
Science for Life Laboratory, Karolinska Institutet, Stockholm, Sweden.
169
University of Dundee, Kirsty Semple Way, Dundee, DD2 4DB, UK.
170
Cardiovascular Health Research Unit, Division of Cardiology, University of Washington, 1730 Minor Ave, Suite 1360, Seattle, 98101, WA, USA.
171
Molecular and Cellular Therapeutics, Royal College of Surgeons in Ireland, St. Stephen's Green, Dublin 2, Ireland.
172
UMR INSERM U1122; IGE-PCV "Interactions Gène-Environnement en Physiopathologie Cardio-Vasculaire", INSERM, University of Lorraine, 30 Rue Lionnois, Nancy, 54000, France.
173
Institute of Medical Informatics, Biometry and Epidemiology, Chair of Genetic Epidemiology, Ludwig-Maximilians-Universität, Munich, Germany.
174
Department of Endocrinology, All India Institute of Medical Sciences, Ansari Nagar East, New Delhi, 110029, India.
175
National Heart and Lung Institute, Imperial College London, Du Cane Road, London, W12 0NN, UK.
176
Department of Public Health Sciences, Stritch School of Medicine, Loyola University Chicago, Maywood, USA.
177
NIHR Leicester Cardiovascular Biomedical Research Unit, University of Leicester, Glenfield Hospital, Groby Road, Leicester, LE3 9QP, UK.
178
Institute of Molecular and Cell Biology, University of Tartu, Riia 23, Tartu, 51010 Estonia.
179
Centre for Vascular Prevention, Danube-University Krems, 3500 Krems, Austria.
180
Diabetes Research Group, King Abdulaziz University, 21589 Jeddah, Saudi Arabia.
181
Department of Internal Medicine, Erasmus Medical Center, PO Box 2040, Rotterdam, 3000 CA, The Netherlands.
182
Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, 21205, USA.
183
Finnish Lung Health Association, Sibeliuksenkatu 11 A 1, Helsinki, FI-00250, Finland.
184
Genetic Epidemiology, QIMR Berghofer Medical Research Institute, 300 Herston Rd, Herston, Brisbane, 4006, Australia.
185
Diabetes Unit, KEM Hospital and Research Centre, Rasta Peth, Pune, 411011, India.
186
Renal Unit, Department of Medicine, Piazzale A. Stefani 1, Verona, 37124, Italy.
187
Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, USA.
188
Department of Medicine, Stanford University, 300 Pasteur Drive, Stanford, 94305, CA, USA.
189
Department of Pediatrics, Perelman School of Medicine, The University of Pennsylvania, 3615 Civic Center Boulevard, Philadelphia, PA 19104, USA.
190
Translational Gerontology Branch, National institute on Aging, Baltimore, 21225, Maryland, USA.
191
Jacqui Wood Cancer Centre, Medical Research Insitute, University of Dundee, Ninewells hospital and School of Medicine, Dundee, DD1 9SY, Scotland.
192
Centre for Pharmacogenetics and Pharmacogenomics, Medical Research Institute, University of Dundee, Ninewells hospital and School of Medicine, Dundee, DD1 9SY, Scotland.
193
Princess Al-Jawhara Al-Brahim Centre of Excellence in Research of Hereditary Disorders (PACER-HD), King Abdulaziz University, Jeddah, 21589, Saudi Arabia.
194
Faculty of Medicine, Imperial College London, Charing Cross Campus - St Dunstan's Road, London, W6 8RP, UK.
195
Department of Medicine, University of Leipzig, Leipzig, Germany.
196
Institute of Preventive Medicine, Bispebjerg and Frederiksberg Hospital , The Capital Region, Copenhagen, 2000, Denmark.
197
Department of Epidemiology, University of Alabama at Birmingham, 1665 University Blvd, Birmingham, 35294, AL, USA.
198
Department of Psychiatry, University Medical Center Groningen, University of Groningen, P.O. box 30.001, Groningen, 9700 RB, The Netherlands.
199
Epidemiology of diabetes, obesity and chronic kidney disease over the lifecourse, Inserm, CESP Center for Research in Epidemiology and Population Health U1018, 16 Avenue Paul Vaillant Couturier, Villejuif, 94807, France.
200
Dipartimento di Scienze Mediche, Catholic University of the Sacred Heart, Via G. Moscati 31/34, Roma, 00168, Italy.
201
Department of Biostatistics, University of Liverpool, Duncan Building, Daulby Stree, Liverpool, L69 3GA, UK.
202
Department of General Practice and Primary Health Care, University of Helsinki, P.O. Box 20, University of Helsinki, Helsinki, FI-00014, Finland.
203
Vasa Central Hospital, Sandviksgatan 2-4, Vasa, 65130, Finland.
204
Folkhälsan Reasearch Centre, PB 63, University of Helsinki, Helsinki, FI-00014, Finland.
205
Unit of General Practice, Helsinki University Central Hospital, Haartmaninkatu 4, Helsinki, FI-00290, Finland.
206
Neuro-Imaging Genetics, QIMR Berghofer Medical Research Institute, 300 Herston Rd, Herston, Brisbane, 4006 Australia.
207
Cardiovascular Genetics Division, University of Utah, 420 Chipeta Way, Room 1160, Salt Lake City, 84117, Utah, USA.
208
Alzheimer Scotland Research Centre, University of Edinburgh, 7 George Square, Edinburgh, EH8 9JZ, UK.
209
Department of Psychiatry, Erasmus Medical Center, PO Box 2040, Rotterdam, 3000 CA, The Netherlands.
210
National Institute for Health and Welfare (THL), P.O.Box 30, Mannerheimintie 166, Helsinki, FI-00271, Finland.
211
Department of kinesiology, Laval University, 2300 rue de la Terrasse, Quebec, G1V 0A6, Canada.
212
Department of Physiology and Biophysics, University of Mississippi Medical Center, 2500 N. State St., Jackson, 39216, MS, USA.
213
Department of Clinical Physiology and Nuclear Medicine, University of Turku and Turku University Hospital, Turku, 20521, Finland.
214
Research Center of Applied and Preventive Cardiovascular medicine, University of Turku, Turku, 20521, Finland.
215
University of Groningen, University Medical Center Groningen, Department of Genetics, Hanzeplein 1, Groningen, 9700RB, The Netherlands.
216
Department of Economics, Stockholm School of Economics, Box 6501, Stockholm, SE-113 83, Sweden.
217
Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Box 281, Stockholm, SE-171 77, Sweden.
218
Department of Genetics and Biostatistics, Washington University School of Medicine, 4444 Forest Park Boulevard, Saint Louis, 63108, MO, USA.
219
Department of Health Policy and Management, Johns Hopkins Bloomberg School of Public Health, Baltimore, 21205, Maryland, USA.
220
Department of Pediatrics, University of Oklahoma Health Sciences Center, 940 Stanton Young Boulevard, Oklahoma City, 73104, OK , USA.
221
Department of Pharmaceutical Sciences , University of Oklahoma Health Sceienecs Center, Oklahoma City , 73104, USA.
222
The Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, 10029, USA.
223
Genome Institute of Singapore, 60 Biopolis Street, #02-01 Genome, Singapore, 138672, Singapore.
224
Program for Personalised and Genomic Medicine, Department of Medicine, University of Maryland School of Medicine, 685 Baltimore St. MSTF, Baltimore, 21201, USA.
225
Geriatric Research and Education Clinical Center, Veterans Administration Medical Center, 685 W Baltimore MSTF, Baltimore, 21201, USA.
226
BHF centre, University of Glasgow, 126 University Avenue, Glasgow, G12 8TA, Scotland.
227
Carolina Center for Genome Sciences, University of North Carolina at Chapel Hill, 137 E. Franklin St., Suite 306, Chapel Hill, USA.
228
Cardiovascular Health Research Unit, Departments of Medicine, Epidemiology and Health Services, University of Washington, 1730 Minor Ave, Suite 1360, Seattle, 98101, WA, USA.
229
Group Health Research Institute, Group Health Cooperative, 1730 Minor Ave, Suite 1360, Seattle, 98101, WA, USA.
230
Imperial College Healthcare NHS Trust, Imperial College London, Praed Street, London, W2 1NY, UK.
231
Population Health Research Institute, St George's, University of London, Cranmer Terrace, London, SW17 0RE, UK.
#
Contributed equally

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.

PMID:
26131930
PMCID:
PMC4516141
DOI:
10.1038/nature14618
[Indexed for MEDLINE]
Free PMC Article

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