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Meta-Analysis
, 10 (1), 4957

Associations of Autozygosity With a Broad Range of Human Phenotypes

David W Clark  1 Yukinori Okada  2   3   4 Kristjan H S Moore  5 Dan Mason  6 Nicola Pirastu  1 Ilaria Gandin  7   8 Hannele Mattsson  9   10 Catriona L K Barnes  1 Kuang Lin  11 Jing Hua Zhao  12   13 Patrick Deelen  14 Rebecca Rohde  15 Claudia Schurmann  16 Xiuqing Guo  17 Franco Giulianini  18 Weihua Zhang  19   20 Carolina Medina-Gomez  21   22   23 Robert Karlsson  24 Yanchun Bao  25 Traci M Bartz  26 Clemens Baumbach  27 Ginevra Biino  28 Matthew J Bixley  29 Marco Brumat  8 Jin-Fang Chai  30 Tanguy Corre  31   32   33 Diana L Cousminer  34   35 Annelot M Dekker  36 David A Eccles  37   38 Kristel R van Eijk  36 Christian Fuchsberger  39 He Gao  19   40 Marine Germain  41   42 Scott D Gordon  43 Hugoline G de Haan  44 Sarah E Harris  45   46 Edith Hofer  47   48 Alicia Huerta-Chagoya  49 Catherine Igartua  50 Iris E Jansen  51   52 Yucheng Jia  17 Tim Kacprowski  53   54 Torgny Karlsson  55 Marcus E Kleber  56 Shengchao Alfred Li  57 Ruifang Li-Gao  44 Anubha Mahajan  58 Koichi Matsuda  59 Karina Meidtner  60   61 Weihua Meng  62 May E Montasser  63   64 Peter J van der Most  65 Matthias Munz  66   67   68   69 Teresa Nutile  70 Teemu Palviainen  71 Gauri Prasad  72 Rashmi B Prasad  73 Tallapragada Divya Sri Priyanka  74 Federica Rizzi  75   76 Erika Salvi  76   77 Bishwa R Sapkota  78 Daniel Shriner  79 Line Skotte  80 Melissa C Smart  25 Albert Vernon Smith  81   82 Ashley van der Spek  22 Cassandra N Spracklen  83 Rona J Strawbridge  84   85 Salman M Tajuddin  86 Stella Trompet  87   88 Constance Turman  89   90 Niek Verweij  91 Clara Viberti  92 Lihua Wang  93 Helen R Warren  94   95 Robyn E Wootton  96   97 Lisa R Yanek  98 Jie Yao  17 Noha A Yousri  99   100 Wei Zhao  101 Adebowale A Adeyemo  79 Saima Afaq  19 Carlos Alberto Aguilar-Salinas  102   103 Masato Akiyama  3   104 Matthew L Albert  105   106   107   108 Matthew A Allison  109 Maris Alver  110 Tin Aung  111   112   113 Fereidoun Azizi  114 Amy R Bentley  79 Heiner Boeing  115 Eric Boerwinkle  116 Judith B Borja  117 Gert J de Borst  118 Erwin P Bottinger  16   119 Linda Broer  21 Harry Campbell  1 Stephen Chanock  120 Miao-Li Chee  111 Guanjie Chen  79 Yii-Der I Chen  17 Zhengming Chen  11 Yen-Feng Chiu  121 Massimiliano Cocca  122 Francis S Collins  123 Maria Pina Concas  122 Janie Corley  45   124 Giovanni Cugliari  92 Rob M van Dam  30   125   126 Anna Damulina  47 Maryam S Daneshpour  127 Felix R Day  12 Graciela E Delgado  56 Klodian Dhana  22   126   128 Alexander S F Doney  129 Marcus Dörr  130   131 Ayo P Doumatey  79 Nduna Dzimiri  132 S Sunna Ebenesersdóttir  5   133 Joshua Elliott  19 Paul Elliott  19   40   134   135   136 Ralf Ewert  130 Janine F Felix  22   23   137 Krista Fischer  110 Barry I Freedman  138 Giorgia Girotto  8   139 Anuj Goel  58   140 Martin Gögele  39 Mark O Goodarzi  141 Mariaelisa Graff  15 Einat Granot-Hershkovitz  142 Francine Grodstein  89 Simonetta Guarrera  92 Daniel F Gudbjartsson  5   143 Kamran Guity  127 Bjarni Gunnarsson  5 Yu Guo  144 Saskia P Hagenaars  45   124   145 Christopher A Haiman  146 Avner Halevy  142 Tamara B Harris  86 Mehdi Hedayati  127 David A van Heel  147 Makoto Hirata  148 Imo Höfer  149 Chao Agnes Hsiung  121 Jinyan Huang  150 Yi-Jen Hung  151   152 M Arfan Ikram  22 Anuradha Jagadeesan  5   133 Pekka Jousilahti  153 Yoichiro Kamatani  3   154 Masahiro Kanai  2   3   155 Nicola D Kerrison  12 Thorsten Kessler  156 Kay-Tee Khaw  157 Chiea Chuen Khor  111   158 Dominique P V de Kleijn  118 Woon-Puay Koh  30   159 Ivana Kolcic  160 Peter Kraft  126 Bernhard K Krämer  56 Zoltán Kutalik  32   33 Johanna Kuusisto  161   162 Claudia Langenberg  12 Lenore J Launer  86 Deborah A Lawlor  96   163   164 I-Te Lee  165   166   167 Wen-Jane Lee  168 Markus M Lerch  169 Liming Li  170 Jianjun Liu  125   158 Marie Loh  19   171   172 Stephanie J London  173 Stephanie Loomis  174 Yingchang Lu  16 Jian'an Luan  12 Reedik Mägi  110 Ani W Manichaikul  175 Paolo Manunta  176 Gísli Másson  5 Nana Matoba  3 Xue W Mei  11 Christa Meisinger  177 Thomas Meitinger  178   179   180 Massimo Mezzavilla  139 Lili Milani  181 Iona Y Millwood  11 Yukihide Momozawa  182 Amy Moore  120 Pierre-Emmanuel Morange  183   184 Hortensia Moreno-Macías  185 Trevor A Mori  186 Alanna C Morrison  187 Taulant Muka  22   188 Yoshinori Murakami  189 Alison D Murray  190 Renée de Mutsert  44 Josyf C Mychaleckyj  175 Mike A Nalls  191   192 Matthias Nauck  131   193 Matt J Neville  194   195 Ilja M Nolte  65 Ken K Ong  12   196 Lorena Orozco  197 Sandosh Padmanabhan  198 Gunnar Pálsson  5 James S Pankow  199 Cristian Pattaro  39 Alison Pattie  124 Ozren Polasek  160   200 Neil Poulter  201   202 Peter P Pramstaller  39 Lluis Quintana-Murci  203   204   205 Katri Räikkönen  206 Sarju Ralhan  207 Dabeeru C Rao  208 Wouter van Rheenen  36 Stephen S Rich  175 Paul M Ridker  18   209 Cornelius A Rietveld  210   211 Antonietta Robino  122 Frank J A van Rooij  22 Daniela Ruggiero  70   212 Yasaman Saba  213 Charumathi Sabanayagam  111   112   113 Maria Sabater-Lleal  85   214 Cinzia Felicita Sala  215 Veikko Salomaa  216 Kevin Sandow  17 Helena Schmidt  213 Laura J Scott  217 William R Scott  19 Bahareh Sedaghati-Khayat  127 Bengt Sennblad  85   218 Jessica van Setten  219 Peter J Sever  201 Wayne H-H Sheu  152   165   220   221 Yuan Shi  111 Smeeta Shrestha  74   222 Sharvari Rahul Shukla  223   224 Jon K Sigurdsson  5 Timo Tonis Sikka  110 Jai Rup Singh  225 Blair H Smith  226 Alena Stančáková  161 Alice Stanton  227 John M Starr  45   228 Lilja Stefansdottir  5 Leon Straker  229 Patrick Sulem  5 Gardar Sveinbjornsson  5 Morris A Swertz  14 Adele M Taylor  124 Kent D Taylor  17 Natalie Terzikhan  22   230 Yih-Chung Tham  111   112 Gudmar Thorleifsson  5 Unnur Thorsteinsdottir  5   82 Annika Tillander  24 Russell P Tracy  231 Teresa Tusié-Luna  232   233 Ioanna Tzoulaki  19   40   234 Simona Vaccargiu  235 Jagadish Vangipurapu  161 Jan H Veldink  36 Veronique Vitart  236 Uwe Völker  53   131 Eero Vuoksimaa  237 Salma M Wakil  132 Melanie Waldenberger  27 Gurpreet S Wander  238 Ya Xing Wang  239 Nicholas J Wareham  12 Sarah Wild  240 Chittaranjan S Yajnik  241 Jian-Min Yuan  242 Lingyao Zeng  156 Liang Zhang  111 Jie Zhou  79 Najaf Amin  22 Folkert W Asselbergs  243   244   245   246 Stephan J L Bakker  247 Diane M Becker  98 Benjamin Lehne  19 David A Bennett  248   249 Leonard H van den Berg  36 Sonja I Berndt  120 Dwaipayan Bharadwaj  250 Lawrence F Bielak  101 Murielle Bochud  32 Mike Boehnke  217 Claude Bouchard  251 Jonathan P Bradfield  252   253 Jennifer A Brody  254 Archie Campbell  46 Shai Carmi  142 Mark J Caulfield  94   95 David Cesarini  255   256 John C Chambers  19   20   40   257   258 Giriraj Ratan Chandak  74 Ching-Yu Cheng  111   112   113 Marina Ciullo  70   212 Marilyn Cornelis  259 Daniele Cusi  76   260   261 George Davey Smith  96   164 Ian J Deary  45   124 Rajkumar Dorajoo  158 Cornelia M van Duijn  11   22 David Ellinghaus  262 Jeanette Erdmann  66 Johan G Eriksson  263   264   265   266   267 Evangelos Evangelou  19   234 Michele K Evans  86 Jessica D Faul  268 Bjarke Feenstra  80 Mary Feitosa  93 Sylvain Foisy  269 Andre Franke  262 Yechiel Friedlander  142 Paolo Gasparini  8   139 Christian Gieger  27   61 Clicerio Gonzalez  270 Philippe Goyette  269 Struan F A Grant  35   252   271 Lyn R Griffiths  37 Leif Groop  71   73 Vilmundur Gudnason  81   82 Ulf Gyllensten  55 Hakon Hakonarson  252   271 Anders Hamsten  272 Pim van der Harst  91 Chew-Kiat Heng  273   274 Andrew A Hicks  39 Hagit Hochner  142 Heikki Huikuri  275 Steven C Hunt  99   276 Vincent W V Jaddoe  22   23   137 Philip L De Jager  277   278 Magnus Johannesson  279 Åsa Johansson  55 Jost B Jonas  239   280 J Wouter Jukema  87 Juhani Junttila  275 Jaakko Kaprio  71   281 Sharon L R Kardia  101 Fredrik Karpe  194   282 Meena Kumari  25 Markku Laakso  161   162 Sander W van der Laan  283 Jari Lahti  206   284 Matthias Laudes  285 Rodney A Lea  37 Wolfgang Lieb  286 Thomas Lumley  287 Nicholas G Martin  43 Winfried März  56   288   289 Giuseppe Matullo  92 Mark I McCarthy  58   194   282 Sarah E Medland  43 Tony R Merriman  29 Andres Metspalu  110 Brian F Meyer  290 Karen L Mohlke  83 Grant W Montgomery  43   291 Dennis Mook-Kanamori  44   292 Patricia B Munroe  94   95 Kari E North  15 Dale R Nyholt  43   293 Jeffery R O'connell  63   64 Carole Ober  50 Albertine J Oldehinkel  294 Walter Palmas  295 Colin Palmer  296 Gerard G Pasterkamp  149 Etienne Patin  203   204   205 Craig E Pennell  297   298 Louis Perusse  299   300 Patricia A Peyser  101 Mario Pirastu  301 Tinca J C Polderman  51 David J Porteous  45   46 Danielle Posthuma  51   302 Bruce M Psaty  303   304 John D Rioux  269   305 Fernando Rivadeneira  21   22   23 Charles Rotimi  79 Jerome I Rotter  17 Igor Rudan  1 Hester M Den Ruijter  306 Dharambir K Sanghera  78   307 Naveed Sattar  198 Reinhold Schmidt  47 Matthias B Schulze  60   61   308 Heribert Schunkert  156   309 Robert A Scott  12 Alan R Shuldiner  63   64   310 Xueling Sim  30 Neil Small  311 Jennifer A Smith  101   268 Nona Sotoodehnia  312 E-Shyong Tai  30   125   313 Alexander Teumer  131   314 Nicholas J Timpson  96   315   316 Daniela Toniolo  215 David-Alexandre Tregouet  41 Tiinamaija Tuomi  10   317   318   319 Peter Vollenweider  320 Carol A Wang  297   298 David R Weir  268 John B Whitfield  43 Cisca Wijmenga  14 Tien-Yin Wong  111   112 John Wright  6 Jingyun Yang  248   249 Lei Yu  248   249 Babette S Zemel  271   321 Alan B Zonderman  86 Markus Perola  322 Patrik K E Magnusson  24 André G Uitterlinden  21   22   23 Jaspal S Kooner  20   40   258   323 Daniel I Chasman  18   209 Ruth J F Loos  16   324 Nora Franceschini  15 Lude Franke  14 Chris S Haley  236   325 Caroline Hayward  236 Robin G Walters  11 John R B Perry  12 Tōnu Esko  110   326 Agnar Helgason  5   133 Kari Stefansson  5   82 Peter K Joshi  1 Michiaki Kubo  182 James F Wilson  327   328
Affiliations
Meta-Analysis

Associations of Autozygosity With a Broad Range of Human Phenotypes

David W Clark et al. Nat Commun.

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 (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.

Conflict of interest statement

M.L.A. is an employee of Genentech, a member of The Roche Group. D.A.L. has received support from several national and international government and charity funders, as well as Roche Diagnostics and Medtronic for work unrelated to this publication. M.I.M.: The views expressed in this article are those of the author(s) and not necessarily those of the NHS, the NIHR, or the Department of Health. He has served on advisory panels for Pfizer, NovoNordisk, Zoe Global; has received honoraria from Merck, Pfizer, NovoNordisk and Eli Lilly; has stock options in Zoe Global; has received research funding from Abbvie, Astra Zeneca, Boehringer Ingelheim, Eli Lilly, Janssen, Merck, NovoNordisk, Pfizer, Roche, Sanofi Aventis, Servier & Takeda. As of June 2019, M.Mc.C. is an employee of Genentech, and holds stock in Roche. T. Muka is now working as medical specialist at Novo Nordisk. O.P. is owner of Gen-info Ltd. Gen‐info Ltd provided support in the form of salaries and financial gains for author O.P., but did not have any additional role in selection of the journal or preparation of this manuscript. N. Poulter received financial support from several pharmaceutical companies which manufacture either blood pressure lowering or lipid lowering agents, or both, and consultancy fees. V.S. has participated in a congress trip sponsored By Novo Nordisk. P.J.S. has received research awards from Pfizer Inc. M.J.C. is Chief Scientist for Genomics England, a UK government company. B.M.P. serves on the DSMB of a clinical trial funded by Zoll LifeCor and on the Steering Committee of the Yale Open Data Access Project funded by Johnson & Johnson. A.R.S. is an employee of Regeneron Pharmaceutical Inc. The remaining authors declare no competing interests.

Figures

Fig. 1
Fig. 1
Census of complex traits. Sample sizes are given for analyses of 57 representative phenotypes, arranged into 16 groups covering major organ systems and disease risk factors. HDL high-density lipoprotein, LDL low-density lipoprotein, hs-CRP high-sensitivity C-reactive protein, TNF-alpha tumour necrosis factor alpha, FEV1 forced expiratory volume in one second, FVC forced vital capacity, eGFR estimated glomerular filtration rate
Fig. 2
Fig. 2
Mean FROH and FIS for 234 ROHgen sub-cohorts. Each cohort is represented by a circle whose area is proportional to the approximate statistical power (NσFROH2) contributed to estimates of βFROH. Mean FROH can be considered as an estimate of total inbreeding relative to an unknown base generation, approximately tens of generations past. FIS measures inbreeding in the current generation, with FIS = 0 indicating random mating, FIS > 0 indicating consanguinity, and FIS < 0 inbreeding avoidance. In cohorts along the y-axis, such as the Polynesians and the Anabaptist isolates, autozygosity is primarily caused by small effective population size rather than preferential consanguineous unions. In contrast, in cohorts along the dotted unity line, all excess SNP homozygosity is accounted for by ROH, as expected of consanguinity within a large effective population. A small number of cohorts along the x-axis, such as Hispanic and mixed-race groups, show excess SNP homozygosity without elevated mean FROH, indicating population genetic structuring, caused for instance by admixture and known as the Wahlund effect. A few notable cohorts are labelled. BBJ Biobank Japan, BiB Born in Bradford, UKB UK Biobank, MESA Multiethnic Study of Atherosclerosis, TCGS Tehran Cardiometabolic Genetic Study
Fig. 3
Fig. 3
Scope of inbreeding depression. a Effect of FROH on 25 quantitative traits. To facilitate comparison between traits, effect estimates are presented in units of within-sex standard deviations. Traits shown here reached Bonferroni-corrected significance of p = 0.0005 (=0.05/100 traits). Sample sizes, within-sex standard deviations, and effect estimates in measurement units are shown in Supplementary Data 9. FEV1 forced expiratory volume in one second. Traits are grouped by type. b Effect of FROH on eight binary traits with associated p values. Effect estimates are reported as ln(Odds-Ratio) for the offspring of first cousins, for which E(FROH) = 0.0625. Self-declared infertility is shown for information, although this trait does not reach Bonferroni corrected significant (OR0.0625 = 2.6 ± 1.1, p= 0.0006). Numbers of cases and controls and effect estimates for all binary traits are shown in Supplementary Data 10. c Sex-specificity of ROH effects. The effect of FROH in men versus that in women is shown for 13 traits for which there was evidence of significant differences in the effects between sexes. For 11 of these 13 traits the magnitude of effect is greater in men than in women. Traits such as liver enzymes levels (alanine transaminase, gamma-glutamyl transferase) show sex-specific effects of opposite sign (positive in women, negative in men), which cancel out in the overall analysis. BMI body mass index, LDL low-density lipoprotein. All errors bars represent 95% confidence intervals
Fig. 4
Fig. 4
Inbreeding depression caused by ROH. a Effect of different ROH lengths on height, compared with the effect of SNP homozygosity outside of ROH. The effects of shorter (<5 Mb) and longer (>5 Mb) ROH per unit length are similar and strongly negative, whereas the effect of homozygosity outside ROH is much weaker. The pattern is similar for other traits (Supplementary Fig. 11a; Supplementary Data 14). b FROH is more strongly associated than FGRM in a bivariate model of height. Meta-analysed effect estimates, and 95% confidence intervals, are shown for a bivariate model of height (Height~FROH+FGRM). The reduction in height is more strongly associated with FROH than FGRM, as predicted if the causal variants are in weak LD with the common SNPs used to calculate FGRM (Supplementary Note 5). The pattern is similar for other traits (Supplementary Fig. 15a, b; Supplementary Data 22). c FROH is a lower variance estimator of the inbreeding coefficient than FGRM. The ratio of βFGRM:βFROH is plotted against var(FROH)var(FGRM) for all traits in all cohorts. When the variation of FGRM which is independent of FROH has no effect on traits, β^FGRM is downwardly biased by a factor of var(FROH)var(FGRM) (Supplementary Note 4). A linear maximum likelihood fit, shown in red, has a gradient consistent with unity [1.01; 95% CI 0.84–1.18], as expected when the difference between FGRM and FROH is not informative about the excess homozygosity at causal variants (Supplementary Note 5). d FROH is a better predictor of rare variant homozygosity than FGRM. The excess homozygosities of SNPs, extracted from UK Biobank imputed genotypes, were calculated at seven discrete minor allele frequencies (FMAF), and regressed on two estimators of inbreeding in a bivariate statistical model (see Supplementary Note 5). The homozygosity of common SNPs is better predicted by FGRM, but rare variant homozygosity is better predicted by FROH. The results from real data (Fig. 4b, Supplementary Figs 15a, b and Supplementary Data 22) are consistent with those simulated here, if the causal variants are predominantly rare. All errors bars represent 95% confidence intervals
Fig. 5
Fig. 5
Evidence ROH effects are un-confounded. a Linear decrease in height with increasing FROH. Average heights (in metres) is plotted in bins of increasing FROH. The limits of each bin are shown by red dotted lines, and correspond to the offspring of increasing degree unions left-to-right. The overall estimate of βFROH is shown as a solid black line. Subjects with kinship equal to offspring of full-sibling or parent–child unions are significantly shorter than those of avuncular or half-sibling unions who in turn are significantly shorter than those of first-cousin unions. b Linear decrease in odds of ever having children with increasing FROH. Linear model approximations of ln(Odds-Ratio) for ever having children (1 = parous, 0 = childless) are plotted in bins of increasing FROH. A strong relationship is evident, extending beyond the offspring of first cousins. c ROH effects are consistent in adoptees. The ratios of effect estimates, βFROH, between adoptees and all individuals are presented by trait. All traits are directionally consistent and overall show a strongly significant difference from zero (average = 0.78, 95% CI 0.56–1.00, p = 2 × 10−12). FEV1 forced expiratory volume in one second. d ROH effects are consistent in full siblings. The ratios of effect estimates within full siblings to effects in all individuals (βFROH_wSibs:βFROH) are presented by trait. Twenty-three of 29 estimates are directionally consistent and overall show a significant difference from zero (average = 0.78, 95% CI 0.53–1.04, p= 7 × 10−10). BMI body mass index. All errors bars represent 95% confidence intervals

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