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Meta-Analysis
, 523 (7561), 459-462

Directional Dominance on Stature and Cognition in Diverse Human Populations

Peter K Joshi #  1 Tonu Esko #  2   3   4   5 Hannele Mattsson  6   7 Niina Eklund  6 Ilaria Gandin  8 Teresa Nutile  9 Anne U Jackson  10 Claudia Schurmann  11   12 Albert V Smith  13   14 Weihua Zhang  15   16 Yukinori Okada  17   18 Alena Stančáková  19 Jessica D Faul  20 Wei Zhao  21 Traci M Bartz  22 Maria Pina Concas  23 Nora Franceschini  24 Stefan Enroth  25 Veronique Vitart  26 Stella Trompet  27 Xiuqing Guo  28   29 Daniel I Chasman  30 Jeffery R O'Connel  31 Tanguy Corre  32   33 Suraj S Nongmaithem  34 Yuning Chen  35 Massimo Mangino  36   37 Daniela Ruggiero  9 Michela Traglia  38 Aliki-Eleni Farmaki  39 Tim Kacprowski  40 Andrew Bjonnes  41 Ashley van der Spek  42 Ying Wu  43 Anil K Giri  44 Lisa R Yanek  45 Lihua Wang  46 Edith Hofer  47   48 Cornelius A Rietveld  49 Olga McLeod  50 Marilyn C Cornelis  51   52 Cristian Pattaro  53 Niek Verweij  54 Clemens Baumbach  55   56   57 Abdel Abdellaoui  58 Helen R Warren  59   60 Dragana Vuckovic  8 Hao Mei  61 Claude Bouchard  62 John R B Perry  63 Stefania Cappellani  64 Saira S Mirza  42 Miles C Benton  65 Ulrich Broeckel  66 Sarah E Medland  67 Penelope A Lind  67 Giovanni Malerba  68 Alexander Drong  69 Loic Yengo  70 Lawrence F Bielak  21 Degui Zhi  71 Peter J van der Most  72 Daniel Shriner  73 Reedik Mägi  2 Gibran Hemani  74 Tugce Karaderi  69 Zhaoming Wang  75   76 Tian Liu  77   78 Ilja Demuth  79   80 Jing Hua Zhao  63 Weihua Meng  81 Lazaros Lataniotis  82 Sander W van der Laan  83 Jonathan P Bradfield  84 Andrew R Wood  85 Amelie Bonnefond  70 Tarunveer S Ahluwalia  86   87   88 Leanne M Hall  89 Erika Salvi  90 Seyhan Yazar  91 Lisbeth Carstensen  92 Hugoline G de Haan  93 Mark Abney  94 Uzma Afzal  15   16 Matthew A Allison  95 Najaf Amin  42 Folkert W Asselbergs  96   97   98 Stephan J L Bakker  99 R Graham Barr  100 Sebastian E Baumeister  101 Daniel J Benjamin  102   103 Sven Bergmann  32   33 Eric Boerwinkle  104 Erwin P Bottinger  11 Archie Campbell  105 Aravinda Chakravarti  106 Yingleong Chan  3   4   5 Stephen J Chanock  75 Constance Chen  107 Y-D Ida Chen  28   29 Francis S Collins  108 John Connell  109 Adolfo Correa  61 L Adrienne Cupples  35   110 George Davey Smith  74 Gail Davies  111   112 Marcus Dörr  113 Georg Ehret  106   114 Stephen B Ellis  11 Bjarke Feenstra  92 Mary F Feitosa  46 Ian Ford  115 Caroline S Fox  110   116 Timothy M Frayling  85 Nele Friedrich  117 Frank Geller  92 Generation Scotland  105 Irina Gillham-Nasenya  36 Omri Gottesman  11 Misa Graff  118 Francine Grodstein  52 Charles Gu  119 Chris Haley  26   120 Christopher J Hammond  36 Sarah E Harris  105   112 Tamara B Harris  121 Nicholas D Hastie  26 Nancy L Heard-Costa  110   122 Kauko Heikkilä  123 Lynne J Hocking  124 Georg Homuth  40 Jouke-Jan Hottenga  58 Jinyan Huang  125 Jennifer E Huffman  26 Pirro G Hysi  36 M Arfan Ikram  42   126 Erik Ingelsson  69   127 Anni Joensuu  6   7 Åsa Johansson  25   128 Pekka Jousilahti  129 J Wouter Jukema  130 Mika Kähönen  131 Yoichiro Kamatani  18 Stavroula Kanoni  82 Shona M Kerr  26 Nazir M Khan  44 Philipp Koellinger  49 Heikki A Koistinen  132   133   134 Manraj K Kooner  16 Michiaki Kubo  135 Johanna Kuusisto  136 Jari Lahti  137   138 Lenore J Launer  121 Rodney A Lea  65 Benjamin Lehne  15 Terho Lehtimäki  139 David C M Liewald  112 Lars Lind  140 Marie Loh  15 Marja-Liisa Lokki  141 Stephanie J London  142 Stephanie J Loomis  143 Anu Loukola  123 Yingchang Lu  11   12 Thomas Lumley  144 Annamari Lundqvist  145 Satu Männistö  129 Pedro Marques-Vidal  146 Corrado Masciullo  38 Angela Matchan  147 Rasika A Mathias  45   148 Koichi Matsuda  149 James B Meigs  150 Christa Meisinger  56 Thomas Meitinger  151   152 Cristina Menni  36 Frank D Mentch  84 Evelin Mihailov  2 Lili Milani  2 May E Montasser  31 Grant W Montgomery  153 Alanna Morrison  104 Richard H Myers  154 Rajiv Nadukuru  11 Pau Navarro  26 Mari Nelis  2 Markku S Nieminen  155 Ilja M Nolte  72 George T O'Connor  110   156 Adesola Ogunniyi  157 Sandosh Padmanabhan  158 Walter R Palmas  100 James S Pankow  159 Inga Patarcic  160 Francesca Pavani  53 Patricia A Peyser  21 Kirsi Pietilainen  7   133   161 Neil Poulter  162 Inga Prokopenko  163 Sarju Ralhan  164 Paul Redmond  111 Stephen S Rich  165 Harri Rissanen  145 Antonietta Robino  64 Lynda M Rose  30 Richard Rose  166 Cinzia Sala  38 Babatunde Salako  157 Veikko Salomaa  129 Antti-Pekka Sarin  6   7 Richa Saxena  41 Helena Schmidt  167 Laura J Scott  10 William R Scott  15   16 Bengt Sennblad  50   168 Sudha Seshadri  110   122 Peter Sever  162 Smeeta Shrestha  34 Blair H Smith  169 Jennifer A Smith  21 Nicole Soranzo  147 Nona Sotoodehnia  170 Lorraine Southam  69   147 Alice V Stanton  171 Maria G Stathopoulou  172 Konstantin Strauch  57   173 Rona J Strawbridge  50 Matthew J Suderman  74 Nikhil Tandon  174 Sian-Tsun Tang  175 Kent D Taylor  28   29 Bamidele O Tayo  176 Anna Maria Töglhofer  167 Maciej Tomaszewski  89   177 Natalia Tšernikova  2   178 Jaakko Tuomilehto  132   179   180 Andre G Uitterlinden  42   181 Dhananjay Vaidya  45   182 Astrid van Hylckama Vlieg  93 Jessica van Setten  83 Tuula Vasankari  183 Sailaja Vedantam  3   4   5 Efthymia Vlachopoulou  141 Diego Vozzi  64 Eero Vuoksimaa  123 Melanie Waldenberger  55   56 Erin B Ware  21 William Wentworth-Shields  94 John B Whitfield  184 Sarah Wild  1 Gonneke Willemsen  58 Chittaranjan S Yajnik  185 Jie Yao  28 Gianluigi Zaza  186 Xiaofeng Zhu  187 The BioBank Japan Project  18 Rany M Salem  3   4   5 Mads Melbye  92   188 Hans Bisgaard  86   87 Nilesh J Samani  89   177 Daniele Cusi  90 David A Mackey  91 Richard S Cooper  176 Philippe Froguel  70   163 Gerard Pasterkamp  83 Struan F A Grant  84   189 Hakon Hakonarson  84   189 Luigi Ferrucci  190 Robert A Scott  63 Andrew D Morris  191 Colin N A Palmer  192 George Dedoussis  39 Panos Deloukas  82   193 Lars Bertram  78   194 Ulman Lindenberger  77 Sonja I Berndt  75 Cecilia M Lindgren  4   69 Nicholas J Timpson  74 Anke Tönjes  195 Patricia B Munroe  59   60 Thorkild I A Sørensen  88   196 Charles N Rotimi  73 Donna K Arnett  197 Albertine J Oldehinkel  198 Sharon L R Kardia  21 Beverley Balkau  199 Giovanni Gambaro  200 Andrew P Morris  2   69   201 Johan G Eriksson  129   202   203   204   205 Margie J Wright  206 Nicholas G Martin  184 Steven C Hunt  207 John M Starr  112   208 Ian J Deary  111   112 Lyn R Griffiths  65 Henning Tiemeier  42   209 Nicola Pirastu  8   64 Jaakko Kaprio  7   123   210 Nicholas J Wareham  63 Louis Pérusse  211 James G Wilson  212 Giorgia Girotto  8 Mark J Caulfield  59   60 Olli Raitakari  213   214 Dorret I Boomsma  58 Christian Gieger  55   56   57 Pim van der Harst  54   97   215 Andrew A Hicks  53 Peter Kraft  107 Juha Sinisalo  155 Paul Knekt  145 Magnus Johannesson  216 Patrik K E Magnusson  217 Anders Hamsten  50 Reinhold Schmidt  47 Ingrid B Borecki  218 Erkki Vartiainen  129 Diane M Becker  45   219 Dwaipayan Bharadwaj  44 Karen L Mohlke  43 Michael Boehnke  10 Cornelia M van Duijn  42 Dharambir K Sanghera  220   221 Alexander Teumer  101 Eleftheria Zeggini  147 Andres Metspalu  2   178 Paolo Gasparini  64 Sheila Ulivi  64 Carole Ober  94 Daniela Toniolo  38 Igor Rudan  1 David J Porteous  105   112 Marina Ciullo  9 Tim D Spector  36 Caroline Hayward  26 Josée Dupuis  35   110 Ruth J F Loos  11   12   222 Alan F Wright  26 Giriraj R Chandak  34   223 Peter Vollenweider  146 Alan Shuldiner  31   224   225 Paul M Ridker  30 Jerome I Rotter  28   29 Naveed Sattar  226 Ulf Gyllensten  25 Kari E North  118   227 Mario Pirastu  23 Bruce M Psaty  228   229 David R Weir  20 Markku Laakso  136 Vilmundur Gudnason  13   14 Atsushi Takahashi  18 John C Chambers  15   16   230 Jaspal S Kooner  16   175   230 David P Strachan  231 Harry Campbell  1 Joel N Hirschhorn  3   4   5 Markus Perola  2   6 Ozren Polašek #  1   160 James F Wilson #  1   26
Affiliations
Meta-Analysis

Directional Dominance on Stature and Cognition in Diverse Human Populations

Peter K Joshi et al. Nature.

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.

Figures

Extended Data Figure 1
Extended Data Figure 1. Forest plot for cognitive g
Individual sub-cohort estimates of effect size and the standard error are plotted. Sub-cohorts are ordered from top to bottom according to their weight in the meta-analysis, so larger or more homozygous cohorts appear towards the top. The scale of beta FROH is in intra-sex standard deviations. The meta-analytical estimate is displayed at the bottom. Sub-cohort names follow the conventions detailed in Supplementary Table 6 and the Supplementary Table 11 legend. Sample sizes, effect sizes and P values for association are given in Table 1. This trait was rank transformed.
Extended Data Figure 2
Extended Data Figure 2. Forest plot for educational attainment
Individual sub-cohort estimates of effect size and the standard error are plotted. Subcohorts are ordered from top to bottom according to their weight in the meta-analysis, so larger or more homozygous cohorts appear towards the top. The scale of beta FROH is in intra-sex standard deviations. The meta-analytical estimate is displayed at the bottom. Sub-cohort names follow the conventions detailed in Supplementary Table 6 and the Supplementary Table 11 legend. Sample sizes, effect sizes and P values for association are given in Table 1.
Extended Data Figure 3
Extended Data Figure 3. Forest plot for height
Individual sub-cohort estimates of effect size and the standard error are plotted. Subcohorts are ordered from top to bottom according to their weight in the meta-analysis, so larger or more homozygous cohorts appear towards the top. The scale of beta FROH is in intra-sex standard deviations. The meta-analytical estimate is displayed at the bottom. Sub-cohort names follow the conventions detailed in Supplementary Table 6 and the Supplementary Table 11 legend. Sample sizes, effect sizes and P values for association are given in Table 1.
Extended Data Figure 4
Extended Data Figure 4. Forest plot for forced expiratory lung volume in one second
Individual sub-cohort estimates of effect size and the standard error are plotted. Subcohorts are ordered from top to bottom according to their weight in the meta-analysis, so larger or more homozygous cohorts appear towards the top. The scale of beta FROH is in intra-sex standard deviations. The meta-analytical estimate is displayed at the bottom. Sub-cohort names follow the conventions detailed in Supplementary Table 6 and the Supplementary Table 11 legend. Sample sizes, effect sizes and P values for association are given in Table 1. This trait was rank transformed.
Extended Data Figure 5
Extended Data Figure 5. Signals of directional dominance are robust to stratification by geography or demographic history or inclusion of educational attainment as covariate
(a) Cohorts are divided by continental biogeographic ancestry (African (15 sub-cohorts), East Asian (5), South & Central Asian (10), Hispanic (3)), with Europeans being divided into Finns (13), other European isolates (self-declared, 23), and (non-isolated) Europeans (90). Meta-analysis was carried out for all subsets with 2000 or more samples available. Sample numbers are as follows: cognitive g, Eur isolate 6638, European 44,153; educational attainment, African 4811, Eur isolate 8032, European 55,549, Finland 9068; height, African 21,500, E Asian 30,011, Eur isolate 23,116, European 228,813, Finland 30,427, Hispanic 5469, SC Asian 13,523; FEV1, African 6604, Eur isolate 4837, European 49,223, Finland 2340. βFROH is consistent across geography and in both isolates and more cosmopolitan populations. (b) Cohorts were divided into High and Low ROH strata of equal power and meta-analysis repeated – the effects are consistent across strata for all four traits. The mean SROH for the high and low strata are 13.4 and 4.3 Mb for cognitive g; 28.1 and 5.1 Mb for education attained; 31.9 and 10.8 Mb for height; and 41.4 and 4.5 Mb for FEV1. (c) To assess the potential for socio-economic confounding, where available, educational attainment was included in the regression model (edu) and compared to a model without educational attainment (none) in the same subset of cohorts. The signals reduce slightly when the education covariate is included; the analysis is not possible for educational attainment as a trait. For cognitive g, numbers are 36847 and 36023 for edu and none; for height 131,614 and 120,945; and for FEV1, 15717 and 15425. The numbers differ because of missing individual educational data within cohorts. + indicates phenotype was rank transformed. FEV1, forced expiratory lung volume in one second; g is the general cognitive component (first unrotated principal component of test scores across diverse tests of cognition); SC Asian is South & Central Asian, E Asian is East Asian, trait units are intra-sex standard deviations and the genomic measure is unpruned SROH.
Extended Data Figure 6
Extended Data Figure 6. Signals of directional dominance are robust to model choice
Meta-analytical estimates of effect size and standard errors are plotted for various models. Fixed indicates no mixed modelling was used, gr res indicates the GRAMMAR+ residuals were fitted and hglm indicates the full hierarchical generalised linear mixed model was used. + indicates the phenotype was rank transformed; FEV1 is forced expiratory lung volume in one second; Cognitive g is the general cognitive factor. 15,355 subjects were used for cognitive g, 36,060 for educational attainment, 89,112 for height and 15,262 for FEV1.
Extended Data Figure 7
Extended Data Figure 7. Correlation in SROH for different genotyping arrays using HapMap populations
In panels (a) – (c), X and Y axes show SROH (sum of runs of homozygosity) from 0-30 Mb (30,000 kb). ill370: Illumina CNV370, aff6: Affymetrix6, illomni: Illumina OmniExpress. The graphs are shown for the specific plink call parameters used. (d) Sample numbers per continent are presented in a bar chart. AFR: African, AMR: Mixed American, ASN: East Asian, EUR: European, SAN: South Asian. Only samples with SROH below 30 Mb are plotted, to be conservative to the effect of outliers, which have very strongly correlated estimates of SROH (r = 0.96-0.97 for comparisons including such very homozygous individuals). In these plots, the correlation between SROH called by the two arrays, r = 0.93-0.94.
Figure 1
Figure 1. Runs of Homozygosity by Cohort
The sum of runs of homozygosity (SROH) and the number of runs of homozygosity (NROH) are shown by sub-cohort. . Populations differ by an order of magnitude in their mean burden of ROH. There are clear differences by continent and population type both in the mean SROH, and the relationship between SROH and NROH.. SC.Asian is South & Central Asian, E.Asian is East Asian, Eur.Isolate is European isolates. The ten most homozygous cohorts are labelled: AMISH are the Old Order Amish from Lancaster County, Pennsylvania; HUTT, S-Leut Hutterites from South Dakota; NSPHS, North Swedish Population Health Study, 06 and 09 suffixes are different sampling years from different counties in Northern Sweden; OGP, Ogliastra Genetic Park, Sardinia, Italy; Talana is a particular village in the region; FVG, Friuli-Venezia-Giulia Genetic Park, Italy, omni and 370 suffices refer to subsets genotyped with the Illumina OmniX and 370CNV arrays; HELIC, Hellenic Isolates, Greece, from Pomak villages in Thrace, and CLHNS, Cebu Longitudinal Health and Nutrition Study in the Philippines.
Figure 2
Figure 2. Effects of genome-wide homozygosity, βFROH, on 16 traits
Four phenotypes show a significant effect of burden of ROH: height (145 sub-cohorts), FEV1 (34), educational attainment (47) and general cognitive ability, g (23). HDL and total cholesterol are not significantly different from zero after correcting for 16 tests and no effect is observed for the other traits. To account for the different numbers of males and females in cohorts and marked effect of sex on some traits, trait units are intra-sex standard deviations. βFROH is the estimated effect of FROH on the trait, where FROH is the ratio of the SROH to the total length of the genome. 95% confidence intervals (CIs) are also plotted. + indicates phenotype was rank transformed, * indicates phenotype was log transformed. BMI, body mass index; BP, blood pressure; FP fasting plasma; HbA1c, haemoglobin A1c (glycated haemoglobin); FEV1, forced expiratory volume in one second; FVC, forced vital capacity; HDL, high density lipoprotein; LDL, low density lipoprotein.

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