Associations of autozygosity with a broad range of human phenotypes

被引：77

作者：

Clark, David W. ^{[1
]}

Okada, Yukinori ^{[2
,3
,4
]}

Moore, Kristjan H. S. ^{[5
]}

Mason, Dan ^{[6
]}

Pirastu, Nicola ^{[1
]}

Gandin, Ilaria ^{[7
,8
]}

Mattsson, Hannele ^{[9
,10
]}

Barnes, Catriona L. K. ^{[1
]}

Lin, Kuang ^{[11
]}

Zhao, Jing Hua ^{[12
,13
]}

Deelen, Patrick ^{[14
]}

Rohde, Rebecca ^{[15
]}

Schurmann, Claudia ^{[16
]}

Guo, Xiuqing ^{[17
]}

Giulianini, Franco ^{[18
]}

Zhang, Weihua ^{[19
,20
]}

Medina-Gomez, Carolina ^{[21
,22
,23
]}

Karlsson, Robert ^{[24
]}

Bao, Yanchun ^{[25
]}

Bartz, Traci M. ^{[26
]}

Baumbach, Clemens ^{[27
]}

Biino, Ginevra ^{[28
]}

Bixley, Matthew J. ^{[29
]}

Brumat, Marco ^{[8
]}

Chai, Jin-Fang ^{[30
]}

Corre, Tanguy ^{[31
,32
,33
]}

Cousminer, Diana L. ^{[34
,35
]}

Dekker, Annelot M. ^{[36
]}

Eccles, David A. ^{[37
,38
]}

Van Eijk, Kristel R. ^{[36
]}

Fuchsberger, Christian ^{[39
]}

Gao, He ^{[19
,40
]}

Germain, Marine ^{[41
,42
]}

Gordon, Scott D. ^{[43
]}

de Haan, Hugoline G. ^{[44
]}

Harris, Sarah E. ^{[45
,46
]}

Hofer, Edith ^{[47
,48
]}

Huerta-Chagoya, Alicia ^{[49
]}

Igartua, Catherine ^{[50
]}

Jansen, Iris E. ^{[51
,52
]}

Jia, Yucheng ^{[17
]}

Kacprowski, Tim ^{[53
,54
]}

Karlsson, Torgny ^{[55
]}

Kleber, Marcus E. ^{[56
]}

Li, Shengchao Alfred ^{[57
]}

Li-Gao, Ruifang ^{[44
]}

Mahajan, Anubha ^{[58
]}

Matsuda, Koichi ^{[59
]}

Meidtner, Karina ^{[60
,61
]}

Meng, Weihua ^{[62
,63
]}

机构：

[1] Univ Edinburgh, Usher Inst, Ctr Global Hlth Res, Edinburgh EH8 9AG, Midlothian, Scotland

[2] Osaka Univ, Dept Stat Genet, Grad Sch Med, Suita, Osaka 5650871, Japan

[3] RIKEN, Lab Stat Anal, Ctr Integrat Med Sci, Yokohama, Kanagawa 2300045, Japan

[4] Osaka Univ, Immunol Frontier Res Ctr WPI IFReC, Lab Stat Immunol, Suita, Osaka 5650871, Japan

[5] Amgen Inc, DeCODE Genet, IS-101 Reykjavik, Iceland

[6] Bradford Teaching Hosp NHS Trust, Bradford Inst Hlth Res, Bradford BD9 6RJ, W Yorkshire, England

[7] Area Sci Pk, Res Unit, I-34149 Trieste, Italy

[8] Univ Trieste, Dept Med Surg & Hlth Sci, Trieste, Italy

[9] Natl Inst Hlth & Welf, Unit Publ Hlth Solut, Helsinki, Finland

[10] Univ Helsinki, Inst Mol Med Finland, Helsinki, Finland

[11] Univ Oxford, Nuffield Dept Populat Hlth, Oxford OX3 7LF, England

[12] Univ Cambridge, Sch Clin Med, MRC Epidemiol Unit, Cambridge CB2 0QQ, England

[13] Univ Cambridge, Dept Publ Hlth & Primary Care, Cardiovasc Epidemiol Unit, Cambridge CB1 8RN, England

[14] Univ Groningen, Univ Med Ctr Groningen, Dept Genet, NL-9700 RB Groningen, Netherlands

[15] Univ N Carolina, Gillings Sch Global Publ Hlth, Dept Epidemiol, Chapel Hill, NC 27514 USA

[16] Ichan Sch Med Mt Sinai, Charles Bronfman Inst Personalized Med, New York, NY 10029 USA

[17] Harbor UCLA Med Ctr, Inst Translat Genom & Populat Sci, LABioMed, Div Genom Outcomes,Dept Pediat, Torrance, CA 90502 USA

[18] Brigham & Womens Hosp, Div Prevent Med, Boston, MA 02215 USA

[19] Imperial Coll London, Dept Epidemiol & Biostat, London W2 1PG, England

[20] Ealing Gen Hosp, Dept Cardiol, Middlesex UB1 3HW, England

[21] Erasmus MC, Dept Internal Med, NL-3015 CN Rotterdam, Netherlands

[22] Erasmus MC, Dept Epidemiol, NL-3015 CN Rotterdam, Netherlands

[23] Erasmus MC, Generat R Study Grp, NL-3015 CN Rotterdam, Netherlands

[24] Karolinska Inst, Dept Med Epidemiol & Biostat, S-17177 Stockholm, Sweden

[25] Univ Essex, Inst Social & Econ Res, Colchester CO4 3SQ, Essex, England

[26] Univ Washington, Dept Biostat & Med, Cardiovasc Hlth Res Unit, Seattle, WA 98101 USA

[27] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Epidemiol, Res Unit Mol Epidemiol, D-85764 Neuherberg, Germany

[28] Natl Res Council Italy, Inst Mol Genet, I-27100 Pavia, Italy

[29] Univ Otago, Dept Biochem, Dunedin 9054, New Zealand

[30] Natl Univ Singapore, Saw Swee Hock Sch Publ Hlth, Singapore 117549, Singapore

[31] Univ Lausanne, Dept Computat Biol, CH-1011 Lausanne, Switzerland

[32] Univ Lausanne, Ctr Primary Care & Publ Hlth Unisante, Lausanne, Switzerland

[33] Swiss Inst Bioinformat, CH-1015 Lausanne, Switzerland

[34] Childrens Hosp Philadelphia, Div Human Genet, Philadelphia, PA 19104 USA

[35] Univ Penn, Perelman Sch Med, Dept Genet, Philadelphia, PA 19104 USA

[36] Univ Utrecht, Univ Med Ctr Utrecht, Brain Ctr Rudolf Magnus, Dept Neurol, NL-3584 CX Utrecht, Netherlands

[37] Queensland Univ Technol, Inst Hlth & Biomed Innovat, Sch Biomed Sci, Genom Res Ctr, Brisbane, Qld 4059, Australia

[38] Malaghan Inst Med Res, Wellington 6242, New Zealand

[39] Univ Lubeck, Affiliated Inst, Inst Biomed, Eurac Res, I-39100 Bolzano, Italy

[40] Imperial Coll London, MRC PHE Ctr Environm & Hlth, London W2 1PG, England

[41] Sorbonne Univ, INSERM, UMR S 1166, F-75013 Paris, France

[42] ICAN Inst Cardiometab & Nutr, F-75013 Paris, France

[43] QIMR Berghofer Inst Med Res, Brisbane, Qld, Australia

[44] Leiden Univ, Dept Clin Epidemiol, Med Ctr, NL-2333 ZA Leiden, Netherlands

[45] Univ Edinburgh, Ctr Cognit Ageing & Cognit Epidemiol, Edinburgh EH8 9JZ, Midlothian, Scotland

[46] Univ Edinburgh, Inst Genet & Mol Med, Ctr Genom & Expt Med, Edinburgh EH4 2XU, Midlothian, Scotland

[47] Med Univ Graz, Clin Div Neurogeriatr, Dept Neurol, A-8036 Graz, Austria

[48] Med Univ Graz, Inst Med Informat Stat & Documentat, A-8036 Graz, Austria

[49] CONACyT, Inst Nacl Ciencias Med & Nutr Salvador Zubiran, Mexico City 03940, DF, Mexico

[50] Univ Chicago, Dept Human Genet, Chicago, IL 60637 USA

来源：

NATURE COMMUNICATIONS | 2019年 / 10卷 / 1期

基金：

英国医学研究理事会; 英国生物技术与生命科学研究理事会;

关键词：

INBREEDING DEPRESSION; HOMOZYGOSITY; FERTILITY; LOCI; RUNS; QUANTIFICATION;

D O I：

10.1038/s41467-019-12283-6

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

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