Dataset Information

Directional dominance on stature and cognition in diverse human populations.

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.

SUBMITTER: Joshi PK

PROVIDER: S-EPMC4516141 | biostudies-literature | 2015 Jul

REPOSITORIES: biostudies-literature

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Directional dominance on stature and cognition in diverse human populations.

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

Nature 20150701 7561

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 inferr ...[more]

PMID: 26131930

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Project description:The genetic basis of gene expression variation has long been studied with the aim to understand the landscape of regulatory variants, but also more recently to assist in the interpretation and elucidation of disease signals. To date, many studies have looked in specific tissues and population-based samples, but there has been limited assessment of the degree of inter-population variability in regulatory variation. We analyzed genome-wide gene expression in lymphoblastoid cell lines from a total of 726 individuals from 8 global populations from the HapMap3 project and correlated gene expression levels with HapMap3 SNPs located in cis to the genes. We describe the influence of ancestry on gene expression levels within and between these diverse human populations and uncover a non-negligible impact on global patterns of gene expression. We further dissect the specific functional pathways differentiated between populations. We also identify 5,691 expression quantitative trait loci (eQTLs) after controlling for both non-genetic factors and population admixture and observe that half of the cis-eQTLs are replicated in one or more of the populations. We highlight patterns of eQTL-sharing between populations, which are partially determined by population genetic relatedness, and discover significant sharing of eQTL effects between Asians, European-admixed, and African subpopulations. Specifically, we observe that both the effect size and the direction of effect for eQTLs are highly conserved across populations. We observe an increasing proximity of eQTLs toward the transcription start site as sharing of eQTLs among populations increases, highlighting that variants close to TSS have stronger effects and therefore are more likely to be detected across a wider panel of populations. Together these results offer a unique picture and resource of the degree of differentiation among human populations in functional regulatory variation and provide an estimate for the transferability of complex trait variants across populations.

Project description:BackgroundThe quantitative genetics theory argues that inbreeding depression and heterosis are founded on the existence of directional dominance. However, most procedures for genomic selection that have included dominance effects assumed prior symmetrical distributions. To address this, two alternatives can be considered: (1) assume the mean of dominance effects different from zero, and (2) use skewed distributions for the regularization of dominance effects. The aim of this study was to compare these approaches using two pig datasets and to confirm the presence of directional dominance.ResultsFour alternative models were implemented in two datasets of pig litter size that consisted of 13,449 and 11,581 records from 3631 and 2612 sows genotyped with the Illumina PorcineSNP60 BeadChip. The models evaluated included (1) a model that does not consider directional dominance (Model SN), (2) a model with a covariate b for the average individual homozygosity (Model SC), (3) a model with a parameter ? that reflects asymmetry in the context of skewed Gaussian distributions (Model AN), and (4) a model that includes both b and ? (Model Full). The results of the analysis showed that posterior probabilities of a negative b or a positive ? under Models SC and AN were higher than 0.99, which indicate positive directional dominance. This was confirmed with the predictions of inbreeding depression under Models Full, SC and AN, that were higher than in the SN Model. In spite of differences in posterior estimates of variance components between models, comparison of models based on LogCPO and DIC indicated that Model SC provided the best fit for the two datasets analyzed.ConclusionsOur results confirmed the presence of positive directional dominance for pig litter size and suggested that it should be taken into account when dominance effects are included in genomic evaluation procedures. The consequences of ignoring directional dominance may affect predictions of breeding values and can lead to biased prediction of inbreeding depression and performance of potential mates. A model that assumes Gaussian dominance effects that are centered on a non-zero mean is recommended, at least for datasets with similar features to those analyzed here.

Dataset Information

Directional dominance on stature and cognition in diverse human populations.

Publications

Directional dominance on stature and cognition in diverse human populations.

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