%0 Journal Article %J Nature %D 2015 %T Directional dominance on stature and cognition in diverse human populations. %A Joshi, Peter K %A Esko, Tõnu %A Mattsson, Hannele %A Eklund, Niina %A Gandin, Ilaria %A Nutile, Teresa %A Jackson, Anne U %A Schurmann, Claudia %A Smith, Albert V %A Zhang, Weihua %A Okada, Yukinori %A Stančáková, Alena %A Faul, Jessica D %A Zhao, Wei %A Bartz, Traci M %A Concas, Maria Pina %A Franceschini, Nora %A Enroth, Stefan %A Vitart, Veronique %A Trompet, Stella %A Guo, Xiuqing %A Chasman, Daniel I %A O'Connel, Jeffrey R %A Corre, Tanguy %A Nongmaithem, Suraj S %A Chen, Yuning %A Mangino, Massimo %A Ruggiero, Daniela %A Traglia, Michela %A Farmaki, Aliki-Eleni %A Kacprowski, Tim %A Bjonnes, Andrew %A van der Spek, Ashley %A Wu, Ying %A Giri, Anil K %A Yanek, Lisa R %A Wang, Lihua %A Hofer, Edith %A Rietveld, Cornelius A %A McLeod, Olga %A Cornelis, Marilyn C %A Pattaro, Cristian %A Verweij, Niek %A Baumbach, Clemens %A Abdellaoui, Abdel %A Warren, Helen R %A Vuckovic, Dragana %A Mei, Hao %A Bouchard, Claude %A Perry, John R B %A Cappellani, Stefania %A Mirza, Saira S %A Benton, Miles C %A Broeckel, Ulrich %A Medland, Sarah E %A Lind, Penelope A %A Malerba, Giovanni %A Drong, Alexander %A Yengo, Loic %A Bielak, Lawrence F %A Zhi, Degui %A van der Most, Peter J %A Shriner, Daniel %A Mägi, Reedik %A Hemani, Gibran %A Karaderi, Tugce %A Wang, Zhaoming %A Liu, Tian %A Demuth, Ilja %A Zhao, Jing Hua %A Meng, Weihua %A Lataniotis, Lazaros %A van der Laan, Sander W %A Bradfield, Jonathan P %A Wood, Andrew R %A Bonnefond, Amelie %A Ahluwalia, Tarunveer S %A Hall, Leanne M %A Salvi, Erika %A Yazar, Seyhan %A Carstensen, Lisbeth %A de Haan, Hugoline G %A Abney, Mark %A Afzal, Uzma %A Allison, Matthew A %A Amin, Najaf %A Asselbergs, Folkert W %A Bakker, Stephan J L %A Barr, R Graham %A Baumeister, Sebastian E %A Benjamin, Daniel J %A Bergmann, Sven %A Boerwinkle, Eric %A Bottinger, Erwin P %A Campbell, Archie %A Chakravarti, Aravinda %A Chan, Yingleong %A Chanock, Stephen J %A Chen, Constance %A Chen, Y-D Ida %A Collins, Francis S %A Connell, John %A Correa, Adolfo %A Cupples, L Adrienne %A Smith, George Davey %A Davies, Gail %A Dörr, Marcus %A Ehret, Georg %A Ellis, Stephen B %A Feenstra, Bjarke %A Feitosa, Mary F %A Ford, Ian %A Fox, Caroline S %A Frayling, Timothy M %A Friedrich, Nele %A Geller, Frank %A Scotland, Generation %A Gillham-Nasenya, Irina %A Gottesman, Omri %A Graff, Misa %A Grodstein, Francine %A Gu, Charles %A Haley, Chris %A Hammond, Christopher J %A Harris, Sarah E %A Harris, Tamara B %A Hastie, Nicholas D %A Heard-Costa, Nancy L %A Heikkilä, Kauko %A Hocking, Lynne J %A Homuth, Georg %A Hottenga, Jouke-Jan %A Huang, Jinyan %A Huffman, Jennifer E %A Hysi, Pirro G %A Ikram, M Arfan %A Ingelsson, Erik %A Joensuu, Anni %A Johansson, Åsa %A Jousilahti, Pekka %A Jukema, J Wouter %A Kähönen, Mika %A Kamatani, Yoichiro %A Kanoni, Stavroula %A Kerr, Shona M %A Khan, Nazir M %A Koellinger, Philipp %A Koistinen, Heikki A %A Kooner, Manraj K %A Kubo, Michiaki %A Kuusisto, Johanna %A Lahti, Jari %A Launer, Lenore J %A Lea, Rodney A %A Lehne, Benjamin %A Lehtimäki, Terho %A Liewald, David C M %A Lind, Lars %A Loh, Marie %A Lokki, Marja-Liisa %A London, Stephanie J %A Loomis, Stephanie J %A Loukola, Anu %A Lu, Yingchang %A Lumley, Thomas %A Lundqvist, Annamari %A Männistö, Satu %A Marques-Vidal, Pedro %A Masciullo, Corrado %A Matchan, Angela %A Mathias, Rasika A %A Matsuda, Koichi %A Meigs, James B %A Meisinger, Christa %A Meitinger, Thomas %A Menni, Cristina %A Mentch, Frank D %A Mihailov, Evelin %A Milani, Lili %A Montasser, May E %A Montgomery, Grant W %A Morrison, Alanna %A Myers, Richard H %A Nadukuru, Rajiv %A Navarro, Pau %A Nelis, Mari %A Nieminen, Markku S %A Nolte, Ilja M %A O'Connor, George T %A Ogunniyi, Adesola %A Padmanabhan, Sandosh %A Palmas, Walter R %A Pankow, James S %A Patarcic, Inga %A Pavani, Francesca %A Peyser, Patricia A %A Pietilainen, Kirsi %A Poulter, Neil %A Prokopenko, Inga %A Ralhan, Sarju %A Redmond, Paul %A Rich, Stephen S %A Rissanen, Harri %A Robino, Antonietta %A Rose, Lynda M %A Rose, Richard %A Sala, Cinzia %A Salako, Babatunde %A Salomaa, Veikko %A Sarin, Antti-Pekka %A Saxena, Richa %A Schmidt, Helena %A Scott, Laura J %A Scott, William R %A Sennblad, Bengt %A Seshadri, Sudha %A Sever, Peter %A Shrestha, Smeeta %A Smith, Blair H %A Smith, Jennifer A %A Soranzo, Nicole %A Sotoodehnia, Nona %A Southam, Lorraine %A Stanton, Alice V %A Stathopoulou, Maria G %A Strauch, Konstantin %A Strawbridge, Rona J %A Suderman, Matthew J %A Tandon, Nikhil %A Tang, Sian-Tsun %A Taylor, Kent D %A Tayo, Bamidele O %A Töglhofer, Anna Maria %A Tomaszewski, Maciej %A Tšernikova, Natalia %A Tuomilehto, Jaakko %A Uitterlinden, André G %A Vaidya, Dhananjay %A van Hylckama Vlieg, Astrid %A van Setten, Jessica %A Vasankari, Tuula %A Vedantam, Sailaja %A Vlachopoulou, Efthymia %A Vozzi, Diego %A Vuoksimaa, Eero %A Waldenberger, Melanie %A Ware, Erin B %A Wentworth-Shields, William %A Whitfield, John B %A Wild, Sarah %A Willemsen, Gonneke %A Yajnik, Chittaranjan S %A Yao, Jie %A Zaza, Gianluigi %A Zhu, Xiaofeng %A Salem, Rany M %A Melbye, Mads %A Bisgaard, Hans %A Samani, Nilesh J %A Cusi, Daniele %A Mackey, David A %A Cooper, Richard S %A Froguel, Philippe %A Pasterkamp, Gerard %A Grant, Struan F A %A Hakonarson, Hakon %A Ferrucci, Luigi %A Scott, Robert A %A Morris, Andrew D %A Palmer, Colin N A %A Dedoussis, George %A Deloukas, Panos %A Bertram, Lars %A Lindenberger, Ulman %A Berndt, Sonja I %A Lindgren, Cecilia M %A Timpson, Nicholas J %A Tönjes, Anke %A Munroe, Patricia B %A Sørensen, Thorkild I A %A Rotimi, Charles N %A Arnett, Donna K %A Oldehinkel, Albertine J %A Kardia, Sharon L R %A Balkau, Beverley %A Gambaro, Giovanni %A Morris, Andrew P %A Eriksson, Johan G %A Wright, Margie J %A Martin, Nicholas G %A Hunt, Steven C %A Starr, John M %A Deary, Ian J %A Griffiths, Lyn R %A Tiemeier, Henning %A Pirastu, Nicola %A Kaprio, Jaakko %A Wareham, Nicholas J %A Pérusse, Louis %A Wilson, James G %A Girotto, Giorgia %A Caulfield, Mark J %A Raitakari, Olli %A Boomsma, Dorret I %A Gieger, Christian %A van der Harst, Pim %A Hicks, Andrew A %A Kraft, Peter %A Sinisalo, Juha %A Knekt, Paul %A Johannesson, Magnus %A Magnusson, Patrik K E %A Hamsten, Anders %A Schmidt, Reinhold %A Borecki, Ingrid B %A Vartiainen, Erkki %A Becker, Diane M %A Bharadwaj, Dwaipayan %A Mohlke, Karen L %A Boehnke, Michael %A van Duijn, Cornelia M %A Sanghera, Dharambir K %A Teumer, Alexander %A Zeggini, Eleftheria %A Metspalu, Andres %A Gasparini, Paolo %A Ulivi, Sheila %A Ober, Carole %A Toniolo, Daniela %A Rudan, Igor %A Porteous, David J %A Ciullo, Marina %A Spector, Tim D %A Hayward, Caroline %A Dupuis, Josée %A Loos, Ruth J F %A Wright, Alan F %A Chandak, Giriraj R %A Vollenweider, Peter %A Shuldiner, Alan R %A Ridker, Paul M %A Rotter, Jerome I %A Sattar, Naveed %A Gyllensten, Ulf %A North, Kari E %A Pirastu, Mario %A Psaty, Bruce M %A Weir, David R %A Laakso, Markku %A Gudnason, Vilmundur %A Takahashi, Atsushi %A Chambers, John C %A Kooner, Jaspal S %A Strachan, David P %A Campbell, Harry %A Hirschhorn, Joel N %A Perola, Markus %A Polasek, Ozren %A Wilson, James F %K Biological Evolution %K Blood Pressure %K Body Height %K Cholesterol, LDL %K Cognition %K Cohort Studies %K Educational Status %K Female %K Forced Expiratory Volume %K Genome, Human %K Homozygote %K Humans %K Lung Volume Measurements %K Male %K Phenotype %X

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.

%B Nature %V 523 %P 459-62 %8 2015 Jul 23 %G eng %N 7561 %1 http://www.ncbi.nlm.nih.gov/pubmed/26131930?dopt=Abstract %R 10.1038/nature14618 %0 Journal Article %J PLoS One %D 2015 %T Modulation of genetic associations with serum urate levels by body-mass-index in humans. %A Huffman, Jennifer E %A Albrecht, Eva %A Teumer, Alexander %A Mangino, Massimo %A Kapur, Karen %A Johnson, Toby %A Kutalik, Zoltán %A Pirastu, Nicola %A Pistis, Giorgio %A Lopez, Lorna M %A Haller, Toomas %A Salo, Perttu %A Goel, Anuj %A Li, Man %A Tanaka, Toshiko %A Dehghan, Abbas %A Ruggiero, Daniela %A Malerba, Giovanni %A Smith, Albert V %A Nolte, Ilja M %A Portas, Laura %A Phipps-Green, Amanda %A Boteva, Lora %A Navarro, Pau %A Johansson, Åsa %A Hicks, Andrew A %A Polasek, Ozren %A Esko, Tõnu %A Peden, John F %A Harris, Sarah E %A Murgia, Federico %A Wild, Sarah H %A Tenesa, Albert %A Tin, Adrienne %A Mihailov, Evelin %A Grotevendt, Anne %A Gislason, Gauti K %A Coresh, Josef %A d'Adamo, Pio %A Ulivi, Sheila %A Vollenweider, Peter %A Waeber, Gerard %A Campbell, Susan %A Kolcic, Ivana %A Fisher, Krista %A Viigimaa, Margus %A Metter, Jeffrey E %A Masciullo, Corrado %A Trabetti, Elisabetta %A Bombieri, Cristina %A Sorice, Rossella %A Döring, Angela %A Reischl, Eva %A Strauch, Konstantin %A Hofman, Albert %A Uitterlinden, André G %A Waldenberger, Melanie %A Wichmann, H-Erich %A Davies, Gail %A Gow, Alan J %A Dalbeth, Nicola %A Stamp, Lisa %A Smit, Johannes H %A Kirin, Mirna %A Nagaraja, Ramaiah %A Nauck, Matthias %A Schurmann, Claudia %A Budde, Kathrin %A Farrington, Susan M %A Theodoratou, Evropi %A Jula, Antti %A Salomaa, Veikko %A Sala, Cinzia %A Hengstenberg, Christian %A Burnier, Michel %A Mägi, Reedik %A Klopp, Norman %A Kloiber, Stefan %A Schipf, Sabine %A Ripatti, Samuli %A Cabras, Stefano %A Soranzo, Nicole %A Homuth, Georg %A Nutile, Teresa %A Munroe, Patricia B %A Hastie, Nicholas %A Campbell, Harry %A Rudan, Igor %A Cabrera, Claudia %A Haley, Chris %A Franco, Oscar H %A Merriman, Tony R %A Gudnason, Vilmundur %A Pirastu, Mario %A Penninx, Brenda W %A Snieder, Harold %A Metspalu, Andres %A Ciullo, Marina %A Pramstaller, Peter P %A van Duijn, Cornelia M %A Ferrucci, Luigi %A Gambaro, Giovanni %A Deary, Ian J %A Dunlop, Malcolm G %A Wilson, James F %A Gasparini, Paolo %A Gyllensten, Ulf %A Spector, Tim D %A Wright, Alan F %A Hayward, Caroline %A Watkins, Hugh %A Perola, Markus %A Bochud, Murielle %A Kao, W H Linda %A Caulfield, Mark %A Toniolo, Daniela %A Völzke, Henry %A Gieger, Christian %A Köttgen, Anna %A Vitart, Veronique %X

We tested for interactions between body mass index (BMI) and common genetic variants affecting serum urate levels, genome-wide, in up to 42569 participants. Both stratified genome-wide association (GWAS) analyses, in lean, overweight and obese individuals, and regression-type analyses in a non BMI-stratified overall sample were performed. The former did not uncover any novel locus with a major main effect, but supported modulation of effects for some known and potentially new urate loci. The latter highlighted a SNP at RBFOX3 reaching genome-wide significant level (effect size 0.014, 95% CI 0.008-0.02, Pinter= 2.6 x 10-8). Two top loci in interaction term analyses, RBFOX3 and ERO1LB-EDARADD, also displayed suggestive differences in main effect size between the lean and obese strata. All top ranking loci for urate effect differences between BMI categories were novel and most had small magnitude but opposite direction effects between strata. They include the locus RBMS1-TANK (men, Pdifflean-overweight= 4.7 x 10-8), a region that has been associated with several obesity related traits, and TSPYL5 (men, Pdifflean-overweight= 9.1 x 10-8), regulating adipocytes-produced estradiol. The top-ranking known urate loci was ABCG2, the strongest known gout risk locus, with an effect halved in obese compared to lean men (Pdifflean-obese= 2 x 10-4). Finally, pathway analysis suggested a role for N-glycan biosynthesis as a prominent urate-associated pathway in the lean stratum. These results illustrate a potentially powerful way to monitor changes occurring in obesogenic environment.

%B PLoS One %V 10 %P e0119752 %8 2015 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/25811787?dopt=Abstract %R 10.1371/journal.pone.0119752