%0 Journal Article %J Nature Genetics %D 2018 %T Genome-wide association meta-analysis in 269,867 individuals identifies new genetic and functional links to intelligence %A Savage, Jeanne E. %A Philip R Jansen %A Stringer, Sven %A Watanabe, Kyoko %A Bryois, Julien %A Christiaan de Leeuw %A Nagel, Mats %A Awasthi, Swapnil %A Barr, Peter B. %A Coleman, Jonathan R. I. %A Grasby, Katrina L. %A Anke R Hammerschlag %A Kaminski, Jakob A. %A Karlsson, Robert %A Krapohl, Eva %A Lam, Max %A Nygaard, Marianne %A Chandra A Reynolds %A Joey W Trampush %A Young, Hannah %A Zabaneh, Delilah %A Hägg, Sara %A Narelle K Hansell %A Ida Karlsson %A Linnarsson, Sten %A Grant W Montgomery %A Muñoz-Manchado, Ana B. %A Quinlan, Erin B. %A Schumann, Gunter %A Skene, Nathan G. %A Webb, Bradley T. %A White, Tonya %A Dan E Arking %A Avramopoulos, Dimitrios %A Robert M Bilder %A Bitsios, Panos %A Katherine E Burdick %A Tyrone D. Cannon %A Chiba-Falek, Ornit %A Christoforou, Andrea %A Elizabeth T. Cirulli %A Congdon, Eliza %A Corvin, Aiden %A Gail Davies %A Ian J Deary %A DeRosse, Pamela %A Dickinson, Dwight %A Djurovic, Srdjan %A Donohoe, Gary %A Conley, Emily Drabant %A Johan G Eriksson %A Espeseth, Thomas %A Nelson A. Freimer %A Giakoumaki, Stella %A Giegling, Ina %A Gill, Michael %A David C. Glahn %A Ahmad R Hariri %A Hatzimanolis, Alex %A Matthew C Keller %A Knowles, Emma %A Koltai, Deborah %A Konte, Bettina %A Lahti, Jari %A Stephanie Le Hellard %A Lencz, Todd %A David C Liewald %A London, Edythe %A Astri J Lundervold %A Anil K. Malhotra %A Melle, Ingrid %A Morris, Derek %A Anna C Need %A William E R Ollier %A Aarno Palotie %A Payton, Antony %A Pendleton, Neil %A Russell A Poldrack %A Katri Räikkönen %A Reinvang, Ivar %A Roussos, Panos %A Rujescu, Dan %A Fred W Sabb %A Matthew A Scult %A Smeland, Olav B. %A Smyrnis, Nikolaos %A John M Starr %A Vidar M Steen %A Nikos C Stefanis %A Richard E Straub %A Sundet, Kjetil %A Henning Tiemeier %A Aristotle N Voineskos %A Daniel R Weinberger %A Elisabeth Widen %A Yu, Jin %A Gonçalo R Abecasis %A Andreassen, Ole A. %A Breen, Gerome %A Christiansen, Lene %A Debrabant, Birgit %A Danielle M. Dick %A Heinz, Andreas %A Hjerling-Leffler, Jens %A Mohammed Arfan Ikram %A Kendler, Kenneth S. %A Nicholas G Martin %A Sarah E Medland %A Nancy L Pedersen %A Plomin, Robert %A Tinca J Polderman %A Ripke, Stephan %A van der Sluis, Sophie %A Patrick F. Sullivan %A Scott Vrieze %A Margaret J Wright %A Posthuma, Danielle %K Genome-Wide Association Study %K Intelligence %K Meta-analyses %X Intelligence is highly heritable1 and a major determinant of human health and well-being2. Recent genome-wide meta-analyses have identified 24 genomic loci linked to variation in intelligence3-7, but much about its genetic underpinnings remains to be discovered. Here, we present a large-scale genetic association study of intelligence (n = 269,867), identifying 205 associated genomic loci (190 new) and 1,016 genes (939 new) via positional mapping, expression quantitative trait locus (eQTL) mapping, chromatin interaction mapping, and gene-based association analysis. We find enrichment of genetic effects in conserved and coding regions and associations with 146 nonsynonymous exonic variants. Associated genes are strongly expressed in the brain, specifically in striatal medium spiny neurons and hippocampal pyramidal neurons. Gene set analyses implicate pathways related to nervous system development and synaptic structure. We confirm previous strong genetic correlations with multiple health-related outcomes, and Mendelian randomization analysis results suggest protective effects of intelligence for Alzheimer's disease and ADHD and bidirectional causation with pleiotropic effects for schizophrenia. These results are a major step forward in understanding the neurobiology of cognitive function as well as genetically related neurological and psychiatric disorders. %B Nature Genetics %V 50 %P 912 - 919 %8 Jan-07-2018 %G eng %U http://www.nature.com/articles/s41588-018-0152-6http://www.nature.com/articles/s41588-018-0152-6.pdfhttp://www.nature.com/articles/s41588-018-0152-6http://www.nature.com/articles/s41588-018-0152-6.pdf %N 7 %! Nat Genet %R 10.1038/s41588-018-0152-6 %0 Journal Article %J Nat Genet %D 2018 %T Protein-altering variants associated with body mass index implicate pathways that control energy intake and expenditure in obesity. %A Turcot, Valérie %A Lu, Yingchang %A Highland, Heather M %A Schurmann, Claudia %A Justice, Anne E %A Fine, Rebecca S %A Bradfield, Jonathan P %A Tõnu Esko %A Giri, Ayush %A Graff, Mariaelisa %A Guo, Xiuqing %A Hendricks, Audrey E %A Karaderi, Tugce %A Lempradl, Adelheid %A Locke, Adam E %A Mahajan, Anubha %A Marouli, Eirini %A Sivapalaratnam, Suthesh %A Young, Kristin L %A Alfred, Tamuno %A Feitosa, Mary F %A Masca, Nicholas G D %A Alisa Manning %A Medina-Gomez, Carolina %A Mudgal, Poorva %A Ng, Maggie C Y %A Reiner, Alex P %A Vedantam, Sailaja %A Willems, Sara M %A Thomas W Winkler %A Gonçalo R Abecasis %A Aben, Katja K %A Alam, Dewan S %A Alharthi, Sameer E %A Matthew A. Allison %A Amouyel, Philippe %A Asselbergs, Folkert W %A Auer, Paul L %A Balkau, Beverley %A Bang, Lia E %A Barroso, Inês %A Bastarache, Lisa %A Benn, Marianne %A Bergmann, Sven %A Bielak, Lawrence F %A Blüher, Matthias %A Boehnke, Michael %A Boeing, Heiner %A Boerwinkle, Eric %A Böger, Carsten A %A Bork-Jensen, Jette %A Bots, Michiel L %A Erwin P Bottinger %A Bowden, Donald W %A Brandslund, Ivan %A Breen, Gerome %A Brilliant, Murray H %A Broer, Linda %A Brumat, Marco %A Burt, Amber A %A Adam S Butterworth %A Campbell, Peter T %A Cappellani, Stefania %A Carey, David J %A Catamo, Eulalia %A Caulfield, Mark J %A Chambers, John C %A Daniel I Chasman %A Yii-Der I Chen %A Chowdhury, Rajiv %A Cramer Christensen %A Chu, Audrey Y %A Cocca, Massimiliano %A Collins, Francis S %A Cook, James P %A Corley, Janie %A Jordi Corominas Galbany %A Cox, Amanda J %A Crosslin, David S %A Cuellar-Partida, Gabriel %A D'Eustacchio, Angela %A Danesh, John %A Gail Davies %A Bakker, Paul I W %A Groot, Mark C H %A Mutsert, Renée %A Ian J Deary %A George Dedoussis %A Ellen W Demerath %A Heijer, Martin %A Anneke I den Hollander %A Hester M den Ruijter %A Joe G Dennis %A Denny, Josh C %A Angelantonio, Emanuele %A Drenos, Fotios %A Du, Mengmeng %A Dubé, Marie-Pierre %A Dunning, Alison M %A Easton, Douglas F %A Edwards, Todd L %A Ellinghaus, David %A Ellinor, Patrick T %A Elliott, Paul %A Evangelou, Evangelos %A Farmaki, Aliki-Eleni %A Farooqi, I Sadaf %A Jessica Faul %A Fauser, Sascha %A Feng, Shuang %A Ferrannini, Ele %A Ferrières, Jean %A Florez, Jose C %A Ford, Ian %A Myriam Fornage %A Franco, Oscar H %A Franke, Andre %A Franks, Paul W %A Friedrich, Nele %A Frikke-Schmidt, Ruth %A Galesloot, Tessel E %A Gan, Wei %A Gandin, Ilaria %A Paolo P. Gasparini %A Gibson, Jane %A Giedraitis, Vilmantas %A Gjesing, Anette P %A Gordon-Larsen, Penny %A Gorski, Mathias %A Hans-Jörgen Grabe %A Grant, Struan F A %A Grarup, Niels %A Griffiths, Helen L %A Grove, Megan L %A Gudnason, Vilmundur %A Gustafsson, Stefan %A Jeffrey Haessler %A Hakonarson, Hakon %A Anke R Hammerschlag %A Hansen, Torben %A Tamara B Harris %A Andrew T Hattersley %A Have, Christian T %A Caroline Hayward %A He, Liang %A Heard-Costa, Nancy L %A Andrew C Heath %A Iris M Heid %A Helgeland, Øyvind %A Hernesniemi, Jussi %A Hewitt, Alex W %A Oddgeir L Holmen %A Hovingh, G Kees %A Howson, Joanna M M %A Hu, Yao %A Huang, Paul L %A Huffman, Jennifer E %A Mohammed Arfan Ikram %A Ingelsson, Erik %A Jackson, Anne U %A Jansson, Jan-Håkan %A Jarvik, Gail P %A Jensen, Gorm B %A Jia, Yucheng %A Johansson, Stefan %A Jørgensen, Marit E %A Jørgensen, Torben %A Jukema, J Wouter %A Kahali, Bratati %A Kahn, René S %A Kähönen, Mika %A Kamstrup, Pia R %A Kanoni, Stavroula %A Kaprio, Jaakko %A Karaleftheri, Maria %A Sharon L R Kardia %A Karpe, Fredrik %A Kathiresan, Sekar %A Kee, Frank %A Lambertus A Kiemeney %A Eric S Kim %A Kitajima, Hidetoshi %A Komulainen, Pirjo %A Kooner, Jaspal S %A Charles Kooperberg %A Korhonen, Tellervo %A Kovacs, Peter %A Kuivaniemi, Helena %A Kutalik, Zoltán %A Kuulasmaa, Kari %A Kuusisto, Johanna %A Laakso, Markku %A Lakka, Timo A %A Lamparter, David %A Lange, Ethan M %A Leslie A Lange %A Langenberg, Claudia %A Eric B Larson %A Lee, Nanette R %A Lehtimäki, Terho %A Lewis, Cora E %A Li, Huaixing %A Li, Jin %A Li-Gao, Ruifang %A Lin, Honghuang %A Lin, Keng-Hung %A Lin, Li-An %A Lin, Xu %A Lars Lind %A Lindström, Jaana %A Linneberg, Allan %A Liu, Ching-Ti %A Liu, Dajiang J %A Yongmei Liu %A Ken Sin Lo %A Lophatananon, Artitaya %A Lotery, Andrew J %A Loukola, Anu %A Luan, Jian'an %A Lubitz, Steven A %A Lyytikäinen, Leo-Pekka %A Männistö, Satu %A Marenne, Gaëlle %A Mazul, Angela L %A McCarthy, Mark I %A McKean-Cowdin, Roberta %A Sarah E Medland %A Meidtner, Karina %A Lili Milani %A Mistry, Vanisha %A Mitchell, Paul %A Mohlke, Karen L %A Moilanen, Leena %A Moitry, Marie %A Grant W Montgomery %A Dennis O Mook-Kanamori %A Moore, Carmel %A Mori, Trevor A %A Morris, Andrew D %A Morris, Andrew P %A Müller-Nurasyid, Martina %A Munroe, Patricia B %A Michael A Nalls %A Narisu, Narisu %A Nelson, Christopher P %A Neville, Matt %A Sune Fallgaard Nielsen %A Nikus, Kjell %A Njølstad, Pål R %A Børge G Nordestgaard %A Nyholt, Dale R %A Jeff O'Connell %A O'Donoghue, Michelle L %A Ophoff, Roel A %A Owen, Katharine R %A Packard, Chris J %A Padmanabhan, Sandosh %A Palmer, Colin N A %A Palmer, Nicholette D %A Pasterkamp, Gerard %A Patel, Aniruddh P %A Pattie, Alison %A Pedersen, Oluf %A Peissig, Peggy L %A Peloso, Gina M %A Pennell, Craig E %A Markus Perola %A Perry, James A %A Perry, John R B %A Pers, Tune H %A Person, Thomas N %A Peters, Annette %A Petersen, Eva R B %A Peyser, Patricia A %A Pirie, Ailith %A Polasek, Ozren %A Tinca J Polderman %A Puolijoki, Hannu %A Olli T Raitakari %A Rasheed, Asif %A Rauramaa, Rainer %A Reilly, Dermot F %A Renstrom, Frida %A Rheinberger, Myriam %A Ridker, Paul M %A Rioux, John D %A Rivas, Manuel A %A Roberts, David J %A Neil R Robertson %A Robino, Antonietta %A Rolandsson, Olov %A Rudan, Igor %A Ruth, Katherine S %A Saleheen, Danish %A Veikko Salomaa %A Nilesh J Samani %A Sapkota, Yadav %A Sattar, Naveed %A Schoen, Robert E %A Schreiner, Pamela J %A Schulze, Matthias B %A Scott, Robert A %A Segura-Lepe, Marcelo P %A Svati H Shah %A Sheu, Wayne H-H %A Sim, Xueling %A Slater, Andrew J %A Small, Kerrin S %A Albert Vernon Smith %A Southam, Lorraine %A Timothy Spector %A Elizabeth K Speliotes %A John M Starr %A Stefansson, Kari %A Steinthorsdottir, Valgerdur %A Kathleen E Stirrups %A Strauch, Konstantin %A Heather M Stringham %A Stumvoll, Michael %A Sun, Liang %A Surendran, Praveen %A Swift, Amy J %A Tada, Hayato %A Tansey, Katherine E %A Tardif, Jean-Claude %A Kent D Taylor %A Teumer, Alexander %A Thompson, Deborah J %A Thorleifsson, Gudmar %A Thorsteinsdottir, Unnur %A Thuesen, Betina H %A Tönjes, Anke %A Tromp, Gerard %A Trompet, Stella %A Tsafantakis, Emmanouil %A Tuomilehto, Jaakko %A Tybjaerg-Hansen, Anne %A Tyrer, Jonathan P %A Uher, Rudolf %A André G Uitterlinden %A Uusitupa, Matti %A Laan, Sander W %A Duijn, Cornelia M %A Leeuwen, Nienke %A van Setten, Jessica %A Vanhala, Mauno %A Varbo, Anette %A Varga, Tibor V %A Varma, Rohit %A Digna R Velez Edwards %A Vermeulen, Sita H %A Veronesi, Giovanni %A Vestergaard, Henrik %A Vitart, Veronique %A Vogt, Thomas F %A Völker, Uwe %A Vuckovic, Dragana %A Wagenknecht, Lynne E %A Walker, Mark %A Wallentin, Lars %A Wang, Feijie %A Wang, Carol A %A Wang, Shuai %A Wang, Yiqin %A Erin B Ware %A Wareham, Nicholas J %A Warren, Helen R %A Dawn M Waterworth %A Wessel, Jennifer %A White, Harvey D %A Willer, Cristen J %A Wilson, James G %A Daniel Witte %A Andrew R Wood %A Wu, Ying %A Yaghootkar, Hanieh %A Yao, Jie %A Yao, Pang %A Laura M Yerges-Armstrong %A Young, Robin %A Zeggini, Eleftheria %A Zhan, Xiaowei %A Zhang, Weihua %A Wei Zhao %A Zhou, Wei %A Krina T Zondervan %A Rotter, Jerome I %A Pospisilik, John A %A Fernando Rivadeneira %A Ingrid B Borecki %A Deloukas, Panos %A Timothy M Frayling %A Lettre, Guillaume %A Kari E North %A Lindgren, Cecilia M %A Joel N Hirschhron %A Ruth J F Loos %X

Genome-wide association studies (GWAS) have identified >250 loci for body mass index (BMI), implicating pathways related to neuronal biology. Most GWAS loci represent clusters of common, noncoding variants from which pinpointing causal genes remains challenging. Here we combined data from 718,734 individuals to discover rare and low-frequency (minor allele frequency (MAF) < 5%) coding variants associated with BMI. We identified 14 coding variants in 13 genes, of which 8 variants were in genes (ZBTB7B, ACHE, RAPGEF3, RAB21, ZFHX3, ENTPD6, ZFR2 and ZNF169) newly implicated in human obesity, 2 variants were in genes (MC4R and KSR2) previously observed to be mutated in extreme obesity and 2 variants were in GIPR. The effect sizes of rare variants are ~10 times larger than those of common variants, with the largest effect observed in carriers of an MC4R mutation introducing a stop codon (p.Tyr35Ter, MAF = 0.01%), who weighed ~7 kg more than non-carriers. Pathway analyses based on the variants associated with BMI confirm enrichment of neuronal genes and provide new evidence for adipocyte and energy expenditure biology, widening the potential of genetically supported therapeutic targets in obesity.

%B Nat Genet %V 50 %P 26-41 %8 2018 Jan %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29273807?dopt=Abstract %R 10.1038/s41588-017-0011-x %0 Journal Article %J Nature Communications %D 2018 %T Study of 300,486 individuals identifies 148 independent genetic loci influencing general cognitive function. %A Gail Davies %A Lam, Max %A Sarah E Harris %A Joey W Trampush %A Luciano, Michelle %A W David Hill %A Hagenaars, Saskia P %A Ritchie, Stuart J %A Riccardo E Marioni %A Fawns-Ritchie, Chloe %A David C Liewald %A Okely, Judith A %A Ahola-Olli, Ari V %A Barnes, Catriona L K %A Bertram, Lars %A Joshua C. Bis %A Katherine E Burdick %A Christoforou, Andrea %A DeRosse, Pamela %A Djurovic, Srdjan %A Espeseth, Thomas %A Giakoumaki, Stella %A Giddaluru, Sudheer %A Gustavson, Daniel E %A Caroline Hayward %A Edith Hofer %A Ikram, M Arfan %A Karlsson, Robert %A Knowles, Emma %A Lahti, Jari %A Leber, Markus %A Li, Shuo %A Mather, Karen A %A Melle, Ingrid %A Morris, Derek %A Christopher J Oldmeadow %A Palviainen, Teemu %A Payton, Antony %A Pazoki, Raha %A Katja E Petrovic %A Chandra A Reynolds %A Sargurupremraj, Muralidharan %A Scholz, Markus %A Smith, Jennifer A %A Smith, Albert V %A Terzikhan, Natalie %A Thalamuthu, Anbupalam %A Trompet, Stella %A Sven J van der Lee %A Erin B Ware %A Windham, B Gwen %A Margaret J Wright %A Yang, Jingyun %A Yu, Jin %A Ames, David %A Amin, Najaf %A Amouyel, Philippe %A Andreassen, Ole A %A Armstrong, Nicola J %A Assareh, Amelia A %A John R. Attia %A Attix, Deborah %A Avramopoulos, Dimitrios %A David A Bennett %A Böhmer, Anne C %A Patricia A. Boyle %A Brodaty, Henry %A Campbell, Harry %A Tyrone D. Cannon %A Elizabeth T. Cirulli %A Congdon, Eliza %A Conley, Emily Drabant %A Corley, Janie %A Cox, Simon R %A Dale, Anders M %A Dehghan, Abbas %A Danielle M. Dick %A Dickinson, Dwight %A Johan G Eriksson %A Evangelou, Evangelos %A Jessica Faul %A Ford, Ian %A Nelson A. Freimer %A Gao, He %A Giegling, Ina %A Gillespie, Nathan A %A Gordon, Scott D %A Gottesman, Rebecca F %A Michael E Griswold %A Gudnason, Vilmundur %A Tamara B Harris %A Hartmann, Annette M %A Hatzimanolis, Alex %A Gerardo Heiss %A Holliday, Elizabeth G %A Joshi, Peter K %A Kähönen, Mika %A Sharon L R Kardia %A Ida Karlsson %A Kleineidam, Luca %A David S Knopman %A Kochan, Nicole A %A Konte, Bettina %A Kwok, John B %A Stephanie Le Hellard %A Lee, Teresa %A Lehtimäki, Terho %A Li, Shu-Chen %A Lill, Christina M %A Liu, Tian %A Koini, Marisa %A London, Edythe %A Longstreth, Will T %A Lopez, Oscar L %A Loukola, Anu %A Luck, Tobias %A Astri J Lundervold %A Lundquist, Anders %A Lyytikäinen, Leo-Pekka %A Nicholas G Martin %A Grant W Montgomery %A Murray, Alison D %A Anna C Need %A Noordam, Raymond %A Nyberg, Lars %A William E R Ollier %A Papenberg, Goran %A Pattie, Alison %A Polasek, Ozren %A Russell A Poldrack %A Psaty, Bruce M %A Reppermund, Simone %A Steffi G Riedel-Heller %A Rose, Richard J %A Rotter, Jerome I %A Roussos, Panos %A Rovio, Suvi P %A Saba, Yasaman %A Fred W Sabb %A Sachdev, Perminder S %A Satizabal, Claudia L %A Schmid, Matthias %A Rodney J Scott %A Matthew A Scult %A Simino, Jeannette %A Slagboom, P Eline %A Smyrnis, Nikolaos %A Soumaré, Aïcha %A Nikos C Stefanis %A Stott, David J %A Richard E Straub %A Sundet, Kjetil %A Taylor, Adele M %A Kent D Taylor %A Tzoulaki, Ioanna %A Tzourio, Christophe %A André G Uitterlinden %A Vitart, Veronique %A Aristotle N Voineskos %A Kaprio, Jaakko %A Wagner, Michael %A Wagner, Holger %A Weinhold, Leonie %A Wen, K Hoyan %A Elisabeth Widen %A Yang, Qiong %A Zhao, Wei %A Hieab H Adams %A Dan E Arking %A Robert M Bilder %A Bitsios, Panos %A Boerwinkle, Eric %A Chiba-Falek, Ornit %A Corvin, Aiden %A Philip L de Jager %A Debette, Stéphanie %A Donohoe, Gary %A Elliott, Paul %A Fitzpatrick, Annette L %A Gill, Michael %A David C. Glahn %A Hägg, Sara %A Narelle K Hansell %A Ahmad R Hariri %A Ikram, M Kamran %A Jukema, J Wouter %A Vuoksimaa, Eero %A Matthew C Keller %A Kremen, William S %A Lenore J Launer %A Lindenberger, Ulman %A Aarno Palotie %A Nancy L Pedersen %A Pendleton, Neil %A David J Porteous %A Katri Räikkönen %A Olli T Raitakari %A Ramirez, Alfredo %A Reinvang, Ivar %A Rudan, Igor %A Schmidt, Reinhold %A Schmidt, Helena %A Peter W Schofield %A Peter R Schofield %A John M Starr %A Vidar M Steen %A Trollor, Julian N %A Turner, Steven T %A Cornelia M van Duijn %A Villringer, Arno %A Daniel R Weinberger %A David R Weir %A James F Wilson %A Anil K. Malhotra %A McIntosh, Andrew M %A Gale, Catharine R %A Seshadri, Sudha %A Thomas H Mosley %A Bressler, Jan %A Lencz, Todd %A Ian J Deary %K Adolescent %K Adult %K Aged %K Aged, 80 and over %K Cognition %K Genetic Loci %K Genetic Predisposition to Disease %K Humans %K Mental Disorders %K Middle Aged %K Multifactorial Inheritance %K Neurodegenerative Diseases %K Neurodevelopmental Disorders %K Polymorphism, Single Nucleotide %K Reaction Time %K Young Adult %X

General cognitive function is a prominent and relatively stable human trait that is associated with many important life outcomes. We combine cognitive and genetic data from the CHARGE and COGENT consortia, and UK Biobank (total N = 300,486; age 16-102) and find 148 genome-wide significant independent loci (P < 5 × 10) associated with general cognitive function. Within the novel genetic loci are variants associated with neurodegenerative and neurodevelopmental disorders, physical and psychiatric illnesses, and brain structure. Gene-based analyses find 709 genes associated with general cognitive function. Expression levels across the cortex are associated with general cognitive function. Using polygenic scores, up to 4.3% of variance in general cognitive function is predicted in independent samples. We detect significant genetic overlap between general cognitive function, reaction time, and many health variables including eyesight, hypertension, and longevity. In conclusion we identify novel genetic loci and pathways contributing to the heritability of general cognitive function.

%B Nature Communications %V 9 %P 2098 %G eng %N 1 %R 10.1038/s41467-018-04362-x %0 Journal Article %J Aging (Albany NY) %D 2017 %T The complex genetics of gait speed: genome-wide meta-analysis approach. %A Ben-Avraham, Dan %A Karasik, David %A Joe Verghese %A Kathryn L Lunetta %A John D Eicher %A Vered, Rotem %A Deelen, Joris %A Alice M. Arnold %A Aron S Buchman %A Toshiko Tanaka %A Jessica Faul %A Nethander, Maria %A Myriam Fornage %A Hieab H Adams %A Amy M Matteini %A Michele L Callisaya %A Albert Vernon Smith %A Lei Yu %A Philip L de Jager %A Denis A Evans %A Gudnason, Vilmundur %A Hofman, Albert %A Pattie, Alison %A Corley, Janie %A Lenore J Launer %A David S Knopman %A Parimi, Neeta %A Stephen T Turner %A Bandinelli, Stefania %A Beekman, Marian %A Gutman, Danielle %A Sharvit, Lital %A Simon P Mooijaart %A David C Liewald %A Jeanine J Houwing-Duistermaat %A Ohlsson, Claes %A Moed, Matthijs %A Vincent J Verlinden %A Mellström, Dan %A Jos N van der Geest %A Karlsson, Magnus %A Dena G Hernandez %A McWhirter, Rebekah %A Yongmei Liu %A Thomson, Russell %A Tranah, Gregory J %A André G Uitterlinden %A David R Weir %A Wei Zhao %A John M Starr %A Mohammed Arfan Ikram %A David A Bennett %A Steven R Cummings %A Ian J Deary %A Tamara B Harris %A Sharon L R Kardia %A Thomas H Mosley %A Velandai K Srikanth %A Beverly G Windham %A Anne B Newman %A Jeremy D Walston %A Gail Davies %A Daniel S Evans %A Eline P Slagboom %A Luigi Ferrucci %A Douglas P Kiel %A Joanne M Murabito %A Atzmon, Gil %K Genetics %K GWAS %X Emerging evidence suggests that the basis for variation in late-life mobility is attributable, in part, to genetic factors, which may become increasingly important with age. Our objective was to systematically assess the contribution of genetic variation to gait speed in older individuals. We conducted a meta-analysis of gait speed GWASs in 31,478 older adults from 17 cohorts of the CHARGE consortium, and validated our results in 2,588 older adults from 4 independent studies. We followed our initial discoveries with network and eQTL analysis of candidate signals in tissues. The meta-analysis resulted in a list of 536 suggestive genome wide significant SNPs in or near 69 genes. Further interrogation with Pathway Analysis placed gait speed as a polygenic complex trait in five major networks. Subsequent eQTL analysis revealed several SNPs significantly associated with the expression of PRSS16, WDSUB1 and PTPRT, which in addition to the meta-analysis and pathway suggested that genetic effects on gait speed may occur through synaptic function and neuronal development pathways. No genome-wide significant signals for gait speed were identified from this moderately large sample of older adults, suggesting that more refined physical function phenotypes will be needed to identify the genetic basis of gait speed in aging. %B Aging (Albany NY) %V 9 %P 209-246 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/28077804?dopt=Abstract %R 10.18632/aging.101151 %0 Journal Article %J Nature %D 2017 %T Rare and low-frequency coding variants alter human adult height. %A Marouli, Eirini %A Graff, Mariaelisa %A Medina-Gomez, Carolina %A Ken Sin Lo %A Andrew R Wood %A Kjaer, Troels R %A Fine, Rebecca S %A Lu, Yingchang %A Schurmann, Claudia %A Highland, Heather M %A Rüeger, Sina %A Thorleifsson, Gudmar %A Justice, Anne E %A Lamparter, David %A Kathleen E Stirrups %A Turcot, Valérie %A Young, Kristin L %A Thomas W Winkler %A Tõnu Esko %A Karaderi, Tugce %A Locke, Adam E %A Masca, Nicholas G D %A Ng, Maggie C Y %A Mudgal, Poorva %A Rivas, Manuel A %A Vedantam, Sailaja %A Mahajan, Anubha %A Guo, Xiuqing %A Gonçalo R Abecasis %A Aben, Katja K %A Adair, Linda S %A Alam, Dewan S %A Albrecht, Eva %A Allin, Kristine H %A Matthew A. Allison %A Amouyel, Philippe %A Appel, Emil V %A Arveiler, Dominique %A Asselbergs, Folkert W %A Auer, Paul L %A Balkau, Beverley %A Banas, Bernhard %A Bang, Lia E %A Benn, Marianne %A Bergmann, Sven %A Bielak, Lawrence F %A Blüher, Matthias %A Boeing, Heiner %A Boerwinkle, Eric %A Böger, Carsten A %A Bonnycastle, Lori L %A Bork-Jensen, Jette %A Bots, Michiel L %A Erwin P Bottinger %A Bowden, Donald W %A Brandslund, Ivan %A Breen, Gerome %A Brilliant, Murray H %A Broer, Linda %A Burt, Amber A %A Adam S Butterworth %A Carey, David J %A Caulfield, Mark J %A Chambers, John C %A Daniel I Chasman %A Yii-Der I Chen %A Chowdhury, Rajiv %A Cramer Christensen %A Chu, Audrey Y %A Cocca, Massimiliano %A Collins, Francis S %A Cook, James P %A Corley, Janie %A Jordi Corominas Galbany %A Cox, Amanda J %A Cuellar-Partida, Gabriel %A Danesh, John %A Gail Davies %A de Bakker, Paul I W %A de Borst, Gert J %A de Denus, Simon %A de Groot, Mark C H %A de Mutsert, Renée %A Ian J Deary %A George Dedoussis %A Ellen W Demerath %A Anneke I den Hollander %A Joe G Dennis %A Di Angelantonio, Emanuele %A Drenos, Fotios %A Du, Mengmeng %A Dunning, Alison M %A Easton, Douglas F %A Ebeling, Tapani %A Edwards, Todd L %A Ellinor, Patrick T %A Elliott, Paul %A Evangelou, Evangelos %A Farmaki, Aliki-Eleni %A Jessica Faul %A Feitosa, Mary F %A Feng, Shuang %A Ferrannini, Ele %A Marco M Ferrario %A Ferrières, Jean %A Florez, Jose C %A Ford, Ian %A Myriam Fornage %A Franks, Paul W %A Frikke-Schmidt, Ruth %A Galesloot, Tessel E %A Gan, Wei %A Gandin, Ilaria %A Paolo P. Gasparini %A Giedraitis, Vilmantas %A Giri, Ayush %A Giorgia G Girotto %A Gordon, Scott D %A Gordon-Larsen, Penny %A Gorski, Mathias %A Grarup, Niels %A Grove, Megan L %A Gudnason, Vilmundur %A Gustafsson, Stefan %A Hansen, Torben %A Kathleen Mullan Harris %A Tamara B Harris %A Andrew T Hattersley %A Caroline Hayward %A He, Liang %A Iris M Heid %A Heikkilä, Kauko %A Helgeland, Øyvind %A Hernesniemi, Jussi %A Hewitt, Alex W %A Lynne J Hocking %A Hollensted, Mette %A Oddgeir L Holmen %A Hovingh, G Kees %A Howson, Joanna M M %A Hoyng, Carel B %A Huang, Paul L %A Hveem, Kristian %A Mohammed Arfan Ikram %A Ingelsson, Erik %A Jackson, Anne U %A Jansson, Jan-Håkan %A Jarvik, Gail P %A Jensen, Gorm B %A Jhun, Min A %A Jia, Yucheng %A Jiang, Xuejuan %A Johansson, Stefan %A Jørgensen, Marit E %A Jørgensen, Torben %A Jousilahti, Pekka %A Jukema, J Wouter %A Kahali, Bratati %A Kahn, René S %A Kähönen, Mika %A Kamstrup, Pia R %A Kanoni, Stavroula %A Kaprio, Jaakko %A Karaleftheri, Maria %A Sharon L R Kardia %A Karpe, Fredrik %A Kee, Frank %A Keeman, Renske %A Lambertus A Kiemeney %A Kitajima, Hidetoshi %A Kluivers, Kirsten B %A Kocher, Thomas %A Komulainen, Pirjo %A Kontto, Jukka %A Kooner, Jaspal S %A Charles Kooperberg %A Kovacs, Peter %A Kriebel, Jennifer %A Kuivaniemi, Helena %A Küry, Sébastien %A Kuusisto, Johanna %A La Bianca, Martina %A Laakso, Markku %A Lakka, Timo A %A Lange, Ethan M %A Leslie A Lange %A Langefeld, Carl D %A Langenberg, Claudia %A Eric B Larson %A Lee, I-Te %A Lehtimäki, Terho %A Lewis, Cora E %A Li, Huaixing %A Li, Jin %A Li-Gao, Ruifang %A Lin, Honghuang %A Lin, Li-An %A Lin, Xu %A Lars Lind %A Lindström, Jaana %A Linneberg, Allan %A Liu, Yeheng %A Yongmei Liu %A Lophatananon, Artitaya %A Luan, Jian'an %A Lubitz, Steven A %A Lyytikäinen, Leo-Pekka %A Mackey, David A %A Pamela A F Madden %A Alisa Manning %A Männistö, Satu %A Marenne, Gaëlle %A Marten, Jonathan %A Nicholas G Martin %A Mazul, Angela L %A Meidtner, Karina %A Andres Metspalu %A Mitchell, Paul %A Mohlke, Karen L %A Dennis O Mook-Kanamori %A Morgan, Anna %A Morris, Andrew D %A Morris, Andrew P %A Müller-Nurasyid, Martina %A Munroe, Patricia B %A Michael A Nalls %A Nauck, Matthias %A Nelson, Christopher P %A Neville, Matt %A Sune Fallgaard Nielsen %A Nikus, Kjell %A Njølstad, Pål R %A Børge G Nordestgaard %A Ntalla, Ioanna %A Jeff O'Connell %A Oksa, Heikki %A Loes M Olde Loohuis %A Ophoff, Roel A %A Owen, Katharine R %A Packard, Chris J %A Padmanabhan, Sandosh %A Palmer, Colin N A %A Pasterkamp, Gerard %A Patel, Aniruddh P %A Pattie, Alison %A Pedersen, Oluf %A Peissig, Peggy L %A Peloso, Gina M %A Pennell, Craig E %A Markus Perola %A Perry, James A %A Perry, John R B %A Person, Thomas N %A Pirie, Ailith %A Polasek, Ozren %A Posthuma, Danielle %A Olli T Raitakari %A Rasheed, Asif %A Rauramaa, Rainer %A Reilly, Dermot F %A Reiner, Alex P %A Renstrom, Frida %A Ridker, Paul M %A Rioux, John D %A Neil R Robertson %A Robino, Antonietta %A Rolandsson, Olov %A Rudan, Igor %A Ruth, Katherine S %A Saleheen, Danish %A Veikko Salomaa %A Nilesh J Samani %A Sandow, Kevin %A Sapkota, Yadav %A Sattar, Naveed %A Schmidt, Marjanka K %A Schreiner, Pamela J %A Schulze, Matthias B %A Scott, Robert A %A Segura-Lepe, Marcelo P %A Svati H Shah %A Sim, Xueling %A Sivapalaratnam, Suthesh %A Small, Kerrin S %A Albert Vernon Smith %A Jennifer A Smith %A Southam, Lorraine %A Timothy Spector %A Elizabeth K Speliotes %A John M Starr %A Steinthorsdottir, Valgerdur %A Heather M Stringham %A Stumvoll, Michael %A Surendran, Praveen %A 't Hart, Leen M %A Tansey, Katherine E %A Tardif, Jean-Claude %A Kent D Taylor %A Teumer, Alexander %A Thompson, Deborah J %A Thorsteinsdottir, Unnur %A Thuesen, Betina H %A Tönjes, Anke %A Tromp, Gerard %A Trompet, Stella %A Tsafantakis, Emmanouil %A Tuomilehto, Jaakko %A Tybjaerg-Hansen, Anne %A Tyrer, Jonathan P %A Uher, Rudolf %A André G Uitterlinden %A Ulivi, Sheila %A van der Laan, Sander W %A Van Der Leij, Andries R %A Cornelia M van Duijn %A van Schoor, Natasja M %A van Setten, Jessica %A Varbo, Anette %A Varga, Tibor V %A Varma, Rohit %A Digna R Velez Edwards %A Vermeulen, Sita H %A Vestergaard, Henrik %A Vitart, Veronique %A Vogt, Thomas F %A Vozzi, Diego %A Walker, Mark %A Wang, Feijie %A Wang, Carol A %A Wang, Shuai %A Wang, Yiqin %A Wareham, Nicholas J %A Warren, Helen R %A Wessel, Jennifer %A Willems, Sara M %A Wilson, James G %A Daniel Witte %A Woods, Michael O %A Wu, Ying %A Yaghootkar, Hanieh %A Yao, Jie %A Yao, Pang %A Laura M Yerges-Armstrong %A Young, Robin %A Zeggini, Eleftheria %A Zhan, Xiaowei %A Zhang, Weihua %A Jing Hua Zhao %A Wei Zhao %A Wei Zhao %A Zheng, He %A Zhou, Wei %A Rotter, Jerome I %A Boehnke, Michael %A Kathiresan, Sekar %A McCarthy, Mark I %A Willer, Cristen J %A Stefansson, Kari %A Ingrid B Borecki %A Liu, Dajiang J %A Kari E North %A Heard-Costa, Nancy L %A Pers, Tune H %A Lindgren, Cecilia M %A Oxvig, Claus %A Kutalik, Zoltán %A Fernando Rivadeneira %A Ruth J F Loos %A Timothy M Frayling %A Joel N Hirschhron %A Deloukas, Panos %A Lettre, Guillaume %X

Height is a highly heritable, classic polygenic trait with approximately 700 common associated variants identified through genome-wide association studies so far. Here, we report 83 height-associated coding variants with lower minor-allele frequencies (in the range of 0.1-4.8%) and effects of up to 2 centimetres per allele (such as those in IHH, STC2, AR and CRISPLD2), greater than ten times the average effect of common variants. In functional follow-up studies, rare height-increasing alleles of STC2 (giving an increase of 1-2 centimetres per allele) compromised proteolytic inhibition of PAPP-A and increased cleavage of IGFBP-4 in vitro, resulting in higher bioavailability of insulin-like growth factors. These 83 height-associated variants overlap genes that are mutated in monogenic growth disorders and highlight new biological candidates (such as ADAMTS3, IL11RA and NOX4) and pathways (such as proteoglycan and glycosaminoglycan synthesis) involved in growth. Our results demonstrate that sufficiently large sample sizes can uncover rare and low-frequency variants of moderate-to-large effect associated with polygenic human phenotypes, and that these variants implicate relevant genes and pathways.

%B Nature %V 542 %P 186-190 %8 2017 Feb 09 %G eng %N 7640 %1 http://www.ncbi.nlm.nih.gov/pubmed/28146470?dopt=Abstract %R 10.1038/nature21039 %0 Journal Article %J Nat Genet %D 2016 %T Genetic variants associated with subjective well-being, depressive symptoms, and neuroticism identified through genome-wide analyses. %A Okbay, Aysu %A Baselmans, Bart M L %A De Neve, Jan-Emmanuel %A Turley, Patrick %A Nivard, Michel G %A Mark Alan Fontana %A Meddens, S Fleur W %A Richard Karlsson Linnér %A Cornelius A Rietveld %A Derringer, Jaime %A Gratten, Jacob %A Lee, James J %A Liu, Jimmy Z %A de Vlaming, Ronald %A Ahluwalia, Tarunveer S %A Buchwald, Jadwiga %A Cavadino, Alana %A Frazier-Wood, Alexis C %A Furlotte, Nicholas A %A Garfield, Victoria %A Geisel, Marie Henrike %A Gonzalez, Juan R %A Haitjema, Saskia %A Karlsson, Robert %A van der Laan, Sander W %A Ladwig, Karl-Heinz %A J. Lahti %A Sven J van der Lee %A Penelope A Lind %A Tian Liu %A Lindsay K Matteson %A Mihailov, Evelin %A Michael B Miller %A Minica, Camelia C %A Ilja M Nolte %A Dennis O Mook-Kanamori %A van der Most, Peter J %A Christopher J Oldmeadow %A Qian, Yong %A Olli T Raitakari %A Rawal, Rajesh %A Realo, Anu %A Rueedi, Rico %A Schmidt, Börge %A Albert Vernon Smith %A Stergiakouli, Evie %A Toshiko Tanaka %A Kent D Taylor %A Wedenoja, Juho %A Jürgen Wellmann %A Westra, Harm-Jan %A Willems, Sara M %A Wei Zhao %A Amin, Najaf %A Bakshi, Andrew %A Patricia A. Boyle %A Cherney, Samantha %A Cox, Simon R %A Gail Davies %A Davis, Oliver S P %A Ding, Jun %A Nese Direk %A Eibich, Peter %A Emeny, Rebecca T %A Fatemifar, Ghazaleh %A Jessica Faul %A Luigi Ferrucci %A Andreas J Forstner %A Gieger, Christian %A Gupta, Richa %A Tamara B Harris %A Harris, Juliette M %A Holliday, Elizabeth G %A Jouke-Jan Hottenga %A Philip L de Jager %A Marika A Kaakinen %A Kajantie, Eero %A Karhunen, Ville %A Kolcic, Ivana %A Kumari, Meena %A Lenore J Launer %A Lude L Franke %A Li-Gao, Ruifang %A Koini, Marisa %A Loukola, Anu %A Marques-Vidal, Pedro %A Grant W Montgomery %A Mosing, Miriam A %A Paternoster, Lavinia %A Pattie, Alison %A Katja E Petrovic %A Pulkki-Raback, Laura %A Quaye, Lydia %A Katri Räikkönen %A Rudan, Igor %A Rodney J Scott %A Jennifer A Smith %A Angelina R Sutin %A Trzaskowski, Maciej %A Anna A E Vinkhuyzen %A Lei Yu %A Zabaneh, Delilah %A John R. Attia %A David A Bennett %A Klaus Berger %A Bertram, Lars %A Dorret I Boomsma %A Snieder, Harold %A Chang, Shun-Chiao %A Francesco Cucca %A Ian J Deary %A Cornelia M van Duijn %A Johan G Eriksson %A Bültmann, Ute %A Eco J. C. de Geus %A Groenen, Patrick J F %A Gudnason, Vilmundur %A Hansen, Torben %A Catharina A Hartman %A Haworth, Claire M A %A Caroline Hayward %A Andrew C Heath %A Hinds, David A %A Hyppönen, Elina %A Iacono, William G %A Järvelin, Marjo-Riitta %A Jöckel, Karl-Heinz %A Kaprio, Jaakko %A Sharon L R Kardia %A Keltikangas-Järvinen, Liisa %A Kraft, Peter %A Laura D Kubzansky %A Lehtimäki, Terho %A Patrik K E Magnusson %A Nicholas G Martin %A McGue, Matt %A Andres Metspalu %A Melinda C Mills %A de Mutsert, Renée %A Oldehinkel, Albertine J %A Pasterkamp, Gerard %A Nancy L Pedersen %A Plomin, Robert %A Polasek, Ozren %A Power, Christine %A Rich, Stephen S %A Rosendaal, Frits R %A Hester M. den Ruijter %A Schlessinger, David %A Schmidt, Helena %A Svento, Rauli %A Schmidt, Reinhold %A Alizadeh, Behrooz Z %A Thorkild I. A. Sørensen %A Timothy Spector %A Andrew Steptoe %A Antonio Terracciano %A A. Roy Thurik %A Nicholas J Timpson %A Henning Tiemeier %A André G Uitterlinden %A Vollenweider, Peter %A Wagner, Gert G %A David R Weir %A Yang, Jian %A Dalton C Conley %A Hofman, Albert %A Johannesson, Magnus %A David I Laibson %A Sarah E Medland %A Meyer, Michelle N %A Pickrell, Joseph K %A Tõnu Esko %A Krueger, Robert F %A Jonathan P. Beauchamp %A Philipp D Koellinger %A Daniel J. Benjamin %A Bartels, Meike %A Cesarini, David %K Anxiety Disorders %K Bayes Theorem %K depression %K Genome-Wide Association Study %K Humans %K Neuroticism %K Phenotype %K Polymorphism, Single Nucleotide %X

Very few genetic variants have been associated with depression and neuroticism, likely because of limitations on sample size in previous studies. Subjective well-being, a phenotype that is genetically correlated with both of these traits, has not yet been studied with genome-wide data. We conducted genome-wide association studies of three phenotypes: subjective well-being (n = 298,420), depressive symptoms (n = 161,460), and neuroticism (n = 170,911). We identify 3 variants associated with subjective well-being, 2 variants associated with depressive symptoms, and 11 variants associated with neuroticism, including 2 inversion polymorphisms. The two loci associated with depressive symptoms replicate in an independent depression sample. Joint analyses that exploit the high genetic correlations between the phenotypes (|ρ^| ≈ 0.8) strengthen the overall credibility of the findings and allow us to identify additional variants. Across our phenotypes, loci regulating expression in central nervous system and adrenal or pancreas tissues are strongly enriched for association.

%B Nat Genet %V 48 %P 624-33 %8 2016 06 %G eng %N 6 %1 http://www.ncbi.nlm.nih.gov/pubmed/27089181?dopt=Abstract %R 10.1038/ng.3552 %0 Journal Article %J Nat Genet %D 2016 %T Genome-wide analysis identifies 12 loci influencing human reproductive behavior. %A Nicola Barban %A Jansen, Rick %A de Vlaming, Ronald %A Vaez, Ahmad %A Mandemakers, Jornt J %A Felix C Tropf %A Shen, Xia %A James F Wilson %A Daniel I Chasman %A Ilja M Nolte %A Tragante, Vinicius %A van der Laan, Sander W %A Perry, John R B %A Kong, Augustine %A Ahluwalia, Tarunveer S %A Albrecht, Eva %A Laura M Yerges-Armstrong %A Atzmon, Gil %A Auro, Kirsi %A Kristin L. Ayers %A Bakshi, Andrew %A Ben-Avraham, Danny %A Klaus Berger %A Bergman, Aviv %A Bertram, Lars %A Bielak, Lawrence F %A Bjornsdottir, Gyda %A Bonder, Marc Jan %A Broer, Linda %A Bui, Minh %A Barbieri, Caterina %A Cavadino, Alana %A Chavarro, Jorge E %A Turman, Constance %A Maria Pina Concas %A Cordell, Heather J %A Gail Davies %A Eibich, Peter %A Eriksson, Nicholas %A Tõnu Esko %A Eriksson, Joel %A Falahi, Fahimeh %A Felix, Janine F %A Mark Alan Fontana %A Lude L Franke %A Gandin, Ilaria %A Gaskins, Audrey J %A Gieger, Christian %A Gunderson, Erica P %A Guo, Xiuqing %A Caroline Hayward %A He, Chunyan %A Edith Hofer %A Huang, Hongyan %A Joshi, Peter K %A Kanoni, Stavroula %A Karlsson, Robert %A Kiechl, Stefan %A Kifley, Annette %A Kluttig, Alexander %A Kraft, Peter %A Lagou, Vasiliki %A Lecoeur, Cecile %A Lahti, Jari %A Li-Gao, Ruifang %A Penelope A Lind %A Tian Liu %A Makalic, Enes %A Mamasoula, Crysovalanto %A Lindsay K Matteson %A Mbarek, Hamdi %A McArdle, Patrick F %A McMahon, George %A Meddens, S Fleur W %A Mihailov, Evelin %A Michael B Miller %A Missmer, Stacey A %A Monnereau, Claire %A van der Most, Peter J %A Myhre, Ronny %A Michael A Nalls %A Nutile, Teresa %A Ioanna Panagiota Kalafati %A Porcu, Eleonora %A Prokopenko, Inga %A Rajan, Kumar B %A Rich-Edwards, Janet %A Cornelius A Rietveld %A Robino, Antonietta %A Rose, Lynda M %A Rueedi, Rico %A Ryan, Kathleen A %A Saba, Yasaman %A Schmidt, Daniel %A Jennifer A Smith %A Stolk, Lisette %A Streeten, Elizabeth %A Tönjes, Anke %A Thorleifsson, Gudmar %A Ulivi, Sheila %A Wedenoja, Juho %A Jürgen Wellmann %A Willeit, Peter %A Yao, Jie %A Yengo, Loic %A Jing Hua Zhao %A Wei Zhao %A Zhernakova, Daria V %A Amin, Najaf %A Andrews, Howard %A Balkau, Beverley %A Barzilai, Nir %A Bergmann, Sven %A Biino, Ginevra %A Bisgaard, Hans %A Bønnelykke, Klaus %A Dorret I Boomsma %A Buring, Julie E %A Campbell, Harry %A Cappellani, Stefania %A Ciullo, Marina %A Cox, Simon R %A Francesco Cucca %A Toniolo, Daniela %A Davey-Smith, George %A Ian J Deary %A George Dedoussis %A Deloukas, Panos %A Cornelia M van Duijn %A Eco J. C. de Geus %A Johan G Eriksson %A Jessica Faul %A Cinzia Felicita Sala %A Froguel, Philippe %A Paolo P. Gasparini %A Giorgia G Girotto %A Hans-Jörgen Grabe %A Greiser, Karin Halina %A Groenen, Patrick J F %A de Haan, Hugoline G %A Haerting, Johannes %A Tamara B Harris %A Andrew C Heath %A Heikkilä, Kauko %A Hofman, Albert %A Homuth, Georg %A Holliday, Elizabeth G %A John L Hopper %A Hyppönen, Elina %A Jacobsson, Bo %A Vincent Jaddoe %A Johannesson, Magnus %A Jugessur, Astanand %A Kähönen, Mika %A Kajantie, Eero %A Sharon L R Kardia %A Keavney, Bernard %A Kolcic, Ivana %A Koponen, Päivikki %A Kovacs, Peter %A Kronenberg, Florian %A Kutalik, Zoltán %A La Bianca, Martina %A Lachance, Genevieve %A Iacono, William G %A Lai, Sandra %A Lehtimäki, Terho %A David C Liewald %A Lindgren, Cecilia M %A Yongmei Liu %A Luben, Robert %A Lucht, Michael %A Luoto, Riitta %A Magnus, Per %A Patrik K E Magnusson %A Nicholas G Martin %A McGue, Matt %A McQuillan, Ruth %A Sarah E Medland %A Meisinger, Christa %A Mellström, Dan %A Andres Metspalu %A Traglia, Michela %A Lili Milani %A Mitchell, Paul %A Grant W Montgomery %A Dennis O Mook-Kanamori %A de Mutsert, Renée %A Nohr, Ellen A %A Ohlsson, Claes %A Olsen, Jørn %A Ong, Ken K %A Paternoster, Lavinia %A Pattie, Alison %A Brenda W J H Penninx %A Markus Perola %A Peyser, Patricia A %A Pirastu, Mario %A Polasek, Ozren %A Power, Chris %A Kaprio, Jaakko %A Raffel, Leslie J %A Katri Räikkönen %A Olli T Raitakari %A Ridker, Paul M %A Ring, Susan M %A Roll, Kathryn %A Rudan, Igor %A Ruggiero, Daniela %A Rujescu, Dan %A Veikko Salomaa %A Schlessinger, David %A Schmidt, Helena %A Schmidt, Reinhold %A Schupf, Nicole %A Johannes H Smit %A Sorice, Rossella %A Timothy Spector %A John M Starr %A Stöckl, Doris %A Strauch, Konstantin %A Stumvoll, Michael %A Swertz, Morris A %A Thorsteinsdottir, Unnur %A A. Roy Thurik %A Nicholas J Timpson %A Tung, Joyce Y %A André G Uitterlinden %A Vaccargiu, Simona %A Viikari, Jorma %A Vitart, Veronique %A Völzke, Henry %A Vollenweider, Peter %A Vuckovic, Dragana %A Waage, Johannes %A Wagner, Gert G %A Wang, Jie Jin %A Wareham, Nicholas J %A David R Weir %A Gonneke Willemsen %A Willeit, Johann %A Alan F Wright %A Krina T Zondervan %A Stefansson, Kari %A Krueger, Robert F %A Lee, James J %A Daniel J. Benjamin %A Cesarini, David %A Philipp D Koellinger %A den Hoed, Marcel %A Snieder, Harold %A Melinda C Mills %X

The genetic architecture of human reproductive behavior-age at first birth (AFB) and number of children ever born (NEB)-has a strong relationship with fitness, human development, infertility and risk of neuropsychiatric disorders. However, very few genetic loci have been identified, and the underlying mechanisms of AFB and NEB are poorly understood. We report a large genome-wide association study of both sexes including 251,151 individuals for AFB and 343,072 individuals for NEB. We identified 12 independent loci that are significantly associated with AFB and/or NEB in a SNP-based genome-wide association study and 4 additional loci associated in a gene-based effort. These loci harbor genes that are likely to have a role, either directly or by affecting non-local gene expression, in human reproduction and infertility, thereby increasing understanding of these complex traits.

%B Nat Genet %V 48 %P 1462-1472 %8 2016 Dec %G eng %N 12 %1 http://www.ncbi.nlm.nih.gov/pubmed/27798627?dopt=Abstract %R 10.1038/ng.3698 %0 Journal Article %J Nature %D 2016 %T Genome-wide association study identifies 74 loci associated with educational attainment. %A Okbay, Aysu %A Jonathan P. Beauchamp %A Mark Alan Fontana %A Lee, James J %A Pers, Tune H %A Cornelius A Rietveld %A Turley, Patrick %A Chen, Guo-Bo %A Emilsson, Valur %A Meddens, S Fleur W %A Oskarsson, Sven %A Pickrell, Joseph K %A Thom, Kevin %A Pascal N Timshel %A de Vlaming, Ronald %A Abdel Abdellaoui %A Ahluwalia, Tarunveer S %A Bacelis, Jonas %A Baumbach, Clemens %A Bjornsdottir, Gyda %A Brandsma, Johannes H %A Maria Pina Concas %A Derringer, Jaime %A Furlotte, Nicholas A %A Galesloot, Tessel E %A Giorgia G Girotto %A Gupta, Richa %A Hall, Leanne M %A Sarah E Harris %A Edith Hofer %A Horikoshi, Momoko %A Huffman, Jennifer E %A Kaasik, Kadri %A Ioanna Panagiota Kalafati %A Karlsson, Robert %A Kong, Augustine %A Lahti, Jari %A Sven J van der Lee %A Christiaan de Leeuw %A Penelope A Lind %A Lindgren, Karl-Oskar %A Tian Liu %A Mangino, Massimo %A Marten, Jonathan %A Mihailov, Evelin %A Michael B Miller %A van der Most, Peter J %A Christopher J Oldmeadow %A Payton, Antony %A Pervjakova, Natalia %A Wouter J Peyrot %A Qian, Yong %A Olli T Raitakari %A Rueedi, Rico %A Salvi, Erika %A Schmidt, Börge %A Schraut, Katharina E %A Jianxin Shi %A Albert Vernon Smith %A Poot, Raymond A %A St Pourcain, Beate %A Teumer, Alexander %A Thorleifsson, Gudmar %A Verweij, Niek %A Vuckovic, Dragana %A Jürgen Wellmann %A Westra, Harm-Jan %A Yang, Jingyun %A Wei Zhao %A Zhihong Zhu %A Alizadeh, Behrooz Z %A Amin, Najaf %A Bakshi, Andrew %A Baumeister, Sebastian E %A Biino, Ginevra %A Bønnelykke, Klaus %A Patricia A. Boyle %A Campbell, Harry %A Cappuccio, Francesco P %A Gail Davies %A De Neve, Jan-Emmanuel %A Deloukas, Panos %A Demuth, Ilja %A Ding, Jun %A Eibich, Peter %A Eisele, Lewin %A Eklund, Niina %A Jessica Faul %A Feitosa, Mary F %A Andreas J Forstner %A Gandin, Ilaria %A Gunnarsson, Bjarni %A Halldórsson, Bjarni V %A Tamara B Harris %A Andrew C Heath %A Lynne J Hocking %A Holliday, Elizabeth G %A Homuth, Georg %A Horan, Michael A %A Jouke-Jan Hottenga %A Philip L de Jager %A Joshi, Peter K %A Jugessur, Astanand %A Marika A Kaakinen %A Kähönen, Mika %A Kanoni, Stavroula %A Keltigangas-Järvinen, Liisa %A Lambertus A Kiemeney %A Kolcic, Ivana %A Koskinen, Seppo %A Kraja, Aldi T %A Kroh, Martin %A Kutalik, Zoltán %A Latvala, Antti %A Lenore J Launer %A Lebreton, Maël P %A Douglas F Levinson %A Paul Lichtenstein %A Lichtner, Peter %A David C Liewald %A Loukola, Anu %A Pamela A F Madden %A Mägi, Reedik %A Mäki-Opas, Tomi %A Riccardo E Marioni %A Marques-Vidal, Pedro %A Meddens, Gerardus A %A McMahon, George %A Meisinger, Christa %A Meitinger, Thomas %A Milaneschi, Yusplitri %A Lili Milani %A Grant W Montgomery %A Myhre, Ronny %A Nelson, Christopher P %A Nyholt, Dale R %A William E R Ollier %A Aarno Palotie %A Paternoster, Lavinia %A Nancy L Pedersen %A Katja E Petrovic %A David J Porteous %A Katri Räikkönen %A Ring, Susan M %A Robino, Antonietta %A Rostapshova, Olga %A Rudan, Igor %A Rustichini, Aldo %A Veikko Salomaa %A Sanders, Alan R %A Sarin, Antti-Pekka %A Schmidt, Helena %A Rodney J Scott %A Smith, Blair H %A Jennifer A Smith %A Staessen, Jan A %A Steinhagen-Thiessen, Elisabeth %A Strauch, Konstantin %A Antonio Terracciano %A Tobin, Martin D %A Ulivi, Sheila %A Vaccargiu, Simona %A Quaye, Lydia %A van Rooij, Frank J A %A Venturini, Cristina %A Anna A E Vinkhuyzen %A Völker, Uwe %A Völzke, Henry %A Vonk, Judith M %A Vozzi, Diego %A Waage, Johannes %A Erin B Ware %A Gonneke Willemsen %A John R. Attia %A David A Bennett %A Klaus Berger %A Bertram, Lars %A Bisgaard, Hans %A Dorret I Boomsma %A Ingrid B Borecki %A Bültmann, Ute %A Chabris, Christopher F %A Francesco Cucca %A Cusi, Daniele %A Ian J Deary %A George Dedoussis %A Cornelia M van Duijn %A Johan G Eriksson %A Franke, Barbara %A Lude L Franke %A Paolo P. Gasparini %A Gejman, Pablo V %A Gieger, Christian %A Hans-Jörgen Grabe %A Gratten, Jacob %A Groenen, Patrick J F %A Gudnason, Vilmundur %A van der Harst, Pim %A Caroline Hayward %A Hinds, David A %A Hoffmann, Wolfgang %A Hyppönen, Elina %A Iacono, William G %A Jacobsson, Bo %A Järvelin, Marjo-Riitta %A Jöckel, Karl-Heinz %A Kaprio, Jaakko %A Sharon L R Kardia %A Lehtimäki, Terho %A Lehrer, Steven F %A Patrik K E Magnusson %A Nicholas G Martin %A McGue, Matt %A Andres Metspalu %A Pendleton, Neil %A Brenda W J H Penninx %A Markus Perola %A Nicola Pirastu %A Pirastu, Mario %A Polasek, Ozren %A Posthuma, Danielle %A Power, Christine %A Province, Michael A %A Nilesh J Samani %A Schlessinger, David %A Schmidt, Reinhold %A Thorkild I. A. Sørensen %A Timothy Spector %A Stefansson, Kari %A Thorsteinsdottir, Unnur %A A. Roy Thurik %A Nicholas J Timpson %A Henning Tiemeier %A Tung, Joyce Y %A André G Uitterlinden %A Vitart, Veronique %A Vollenweider, Peter %A David R Weir %A James F Wilson %A Alan F Wright %A Dalton C Conley %A Krueger, Robert F %A George Davey Smith %A Hofman, Albert %A David I Laibson %A Sarah E Medland %A Meyer, Michelle N %A Yang, Jian %A Johannesson, Magnus %A Peter M Visscher %A Tõnu Esko %A Philipp D Koellinger %A Cesarini, David %A Daniel J. Benjamin %K Alzheimer's disease %K Bipolar Disorder %K Cognitive Ability %K Education %K Fetus %K Genome-Wide Association Study %K Humans %K Molecular Sequence Annotation %K Polymorphism, Single Nucleotide %K Schizophrenia %K United Kingdom %X

Educational attainment is strongly influenced by social and other environmental factors, but genetic factors are estimated to account for at least 20% of the variation across individuals. Here we report the results of a genome-wide association study (GWAS) for educational attainment that extends our earlier discovery sample of 101,069 individuals to 293,723 individuals, and a replication study in an independent sample of 111,349 individuals from the UK Biobank. We identify 74 genome-wide significant loci associated with the number of years of schooling completed. Single-nucleotide polymorphisms associated with educational attainment are disproportionately found in genomic regions regulating gene expression in the fetal brain. Candidate genes are preferentially expressed in neural tissue, especially during the prenatal period, and enriched for biological pathways involved in neural development. Our findings demonstrate that, even for a behavioural phenotype that is mostly environmentally determined, a well-powered GWAS identifies replicable associated genetic variants that suggest biologically relevant pathways. Because educational attainment is measured in large numbers of individuals, it will continue to be useful as a proxy phenotype in efforts to characterize the genetic influences of related phenotypes, including cognition and neuropsychiatric diseases.

%B Nature %V 533 %P 539-42 %8 2016 05 26 %G eng %N 7604 %1 http://www.ncbi.nlm.nih.gov/pubmed/27225129?dopt=Abstract %R 10.1038/nature17671 %0 Journal Article %J Aging Cell %D 2016 %T GWAS analysis of handgrip and lower body strength in older adults in the CHARGE consortium. %A Amy M Matteini %A Toshiko Tanaka %A Karasik, David %A Atzmon, Gil %A Chou, Wen-Chi %A John D Eicher %A Andrew D Johnson %A Alice M. Arnold %A Michele L Callisaya %A Gail Davies %A Daniel S Evans %A Holtfreter, Birte %A Kurt Lohman %A Kathryn L Lunetta %A Mangino, Massimo %A Albert Vernon Smith %A Jennifer A Smith %A Teumer, Alexander %A Lei Yu %A Dan E Arking %A Aron S Buchman %A Chibinik, Lori B %A Philip L de Jager %A Jessica Faul %A Melissa E Garcia %A Gillham-Nasenya, Irina %A Gudnason, Vilmundur %A Hofman, Albert %A Hsu, Yi-Hsiang %A Ittermann, Till %A Lahousse, Lies %A David C Liewald %A Yongmei Liu %A Lopez, Lorna %A Fernando Rivadeneira %A Rotter, Jerome I %A Siggeirsdottir, Kristin %A John M Starr %A Thomson, Russell %A Tranah, Gregory J %A André G Uitterlinden %A Völker, Uwe %A Völzke, Henry %A David R Weir %A Kristine Yaffe %A Wei Zhao %A Wei Vivian Zhuang %A Zmuda, Joseph M %A David A Bennett %A Steven R Cummings %A Ian J Deary %A Luigi Ferrucci %A Tamara B Harris %A Sharon L R Kardia %A Kocher, Thomas %A Stephen B Kritchevsky %A Psaty, Bruce M %A Seshadri, Sudha %A Timothy Spector %A Velandai K Srikanth %A Beverly G Windham %A Zillikens, M Carola %A Anne B Newman %A Jeremy D Walston %A Douglas P Kiel %A Joanne M Murabito %K Adult %K Aged %K Chromatin Immunoprecipitation %K Cohort Studies %K Epigenesis, Genetic %K Genome-Wide Association Study %K Hand Strength %K Humans %K Molecular Sequence Annotation %K Muscle Strength %K Polymorphism, Single Nucleotide %K Quantitative Trait Loci %K Reproducibility of Results %X

Decline in muscle strength with aging is an important predictor of health trajectory in the elderly. Several factors, including genetics, are proposed contributors to variability in muscle strength. To identify genetic contributors to muscle strength, a meta-analysis of genomewide association studies of handgrip was conducted. Grip strength was measured using a handheld dynamometer in 27 581 individuals of European descent over 65 years of age from 14 cohort studies. Genomewide association analysis was conducted on ~2.7 million imputed and genotyped variants (SNPs). Replication of the most significant findings was conducted using data from 6393 individuals from three cohorts. GWAS of lower body strength was also characterized in a subset of cohorts. Two genomewide significant (P-value< 5 × 10(-8) ) and 39 suggestive (P-value< 5 × 10(-5) ) associations were observed from meta-analysis of the discovery cohorts. After meta-analysis with replication cohorts, genomewide significant association was observed for rs752045 on chromosome 8 (β = 0.47, SE = 0.08, P-value = 5.20 × 10(-10) ). This SNP is mapped to an intergenic region and is located within an accessible chromatin region (DNase hypersensitivity site) in skeletal muscle myotubes differentiated from the human skeletal muscle myoblasts cell line. This locus alters a binding motif of the CCAAT/enhancer-binding protein-β (CEBPB) that is implicated in muscle repair mechanisms. GWAS of lower body strength did not yield significant results. A common genetic variant in a chromosomal region that regulates myotube differentiation and muscle repair may contribute to variability in grip strength in the elderly. Further studies are needed to uncover the mechanisms that link this genetic variant with muscle strength.

%B Aging Cell %V 15 %P 792-800 %8 2016 10 %G eng %N 5 %1 http://www.ncbi.nlm.nih.gov/pubmed/27325353?dopt=Abstract %R 10.1111/acel.12468 %0 Journal Article %J Nature %D 2015 %T Directional dominance on stature and cognition in diverse human populations. %A Joshi, Peter K %A Tõnu Esko %A Mattsson, Hannele %A Eklund, Niina %A Gandin, Ilaria %A Nutile, Teresa %A Jackson, Anne U %A Schurmann, Claudia %A Albert Vernon Smith %A Zhang, Weihua %A Okada, Yukinori %A Stančáková, Alena %A Jessica Faul %A Wei Zhao %A Traci M Bartz %A Maria Pina Concas %A Franceschini, Nora %A Enroth, Stefan %A Vitart, Veronique %A Trompet, Stella %A Guo, Xiuqing %A Daniel I Chasman %A Jeff O'Connell %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 Edith Hofer %A Cornelius A Rietveld %A McLeod, Olga %A Marilyn C Cornelis %A Pattaro, Cristian %A Verweij, Niek %A Baumbach, Clemens %A Abdel Abdellaoui %A Warren, Helen R %A Vuckovic, Dragana %A Mei, Hao %A Bouchard, Claude %A Perry, John R B %A Cappellani, Stefania %A Saira S Mirza %A Benton, Miles C %A Broeckel, Ulrich %A Sarah E Medland %A Penelope A Lind %A Malerba, Giovanni %A Alexander W Drong %A Yengo, Loic %A Bielak, Lawrence F %A Zhi, Degui %A van der Most, Peter J %A Daniel Shriner %A Mägi, Reedik %A Hemani, Gibran %A Karaderi, Tugce %A Wang, Zhaoming %A Tian Liu %A Demuth, Ilja %A Jing Hua Zhao %A Meng, Weihua %A Lataniotis, Lazaros %A van der Laan, Sander W %A Bradfield, Jonathan P %A Andrew R Wood %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 Matthew A. Allison %A Amin, Najaf %A Asselbergs, Folkert W %A Bakker, Stephan J L %A Barr, R Graham %A Baumeister, Sebastian E %A Daniel J. Benjamin %A Bergmann, Sven %A Boerwinkle, Eric %A Erwin P Bottinger %A Campbell, Archie %A Chakravarti, Aravinda %A Chan, Yingleong %A Chanock, Stephen J %A Chen, Constance %A Yii-Der I Chen %A Collins, Francis S %A Connell, John %A Correa, Adolfo %A Cupples, L Adrienne %A Gail Davies %A Dörr, Marcus %A Georg B Ehret %A Ellis, Stephen B %A Feenstra, Bjarke %A Feitosa, Mary F %A Ford, Ian %A Caroline S Fox %A Timothy M Frayling %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 Sarah E Harris %A Tamara B Harris %A Nicholas D Hastie %A Heard-Costa, Nancy L %A Heikkilä, Kauko %A Lynne J Hocking %A Homuth, Georg %A Jouke-Jan Hottenga %A Huang, Jinyan %A Huffman, Jennifer E %A Hysi, Pirro G %A Mohammed Arfan Ikram %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 Philipp D Koellinger %A Koistinen, Heikki A %A Kooner, Manraj K %A Kubo, Michiaki %A Kuusisto, Johanna %A Lahti, Jari %A Lenore J Launer %A Lea, Rodney A %A Lehne, Benjamin %A Lehtimäki, Terho %A David C Liewald %A Lars Lind %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 Lili Milani %A Montasser, May E %A Grant W Montgomery %A Alanna C Morrison %A Myers, Richard H %A Nadukuru, Rajiv %A Navarro, Pau %A Nelis, Mari %A Nieminen, Markku S %A Ilja M Nolte %A O'Connor, George T %A Ogunniyi, Adesola %A Padmanabhan, Sandosh %A Walter R Palmas %A Pankow, James S %A Patarcic, Inga %A Pavani, Francesca %A Peyser, Patricia A %A Pietilainen, Kirsi %A Neil Poulter %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 Cinzia Felicita Sala %A Babatunde Salako %A Veikko Salomaa %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 Peter Sever %A Shrestha, Smeeta %A Smith, Blair H %A Jennifer A Smith %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 Kent D Taylor %A Bamidele O Tayo %A Töglhofer, Anna Maria %A Tomaszewski, Maciej %A Tšernikova, Natalia %A Tuomilehto, Jaakko %A André G Uitterlinden %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 Erin B Ware %A Wentworth-Shields, William %A Whitfield, John B %A Sarah Wild %A Gonneke Willemsen %A Yajnik, Chittaranjan S %A Yao, Jie %A Zaza, Gianluigi %A Zhu, Xiaofeng %A Salem, Rany M %A Melbye, Mads %A Bisgaard, Hans %A Nilesh J Samani %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 Luigi Ferrucci %A Scott, Robert A %A Morris, Andrew D %A Palmer, Colin N A %A George Dedoussis %A Deloukas, Panos %A Bertram, Lars %A Lindenberger, Ulman %A Berndt, Sonja I %A Lindgren, Cecilia M %A Nicholas J Timpson %A Tönjes, Anke %A Munroe, Patricia B %A Thorkild I. A. Sørensen %A Charles N Rotimi %A Donna K Arnett %A Oldehinkel, Albertine J %A Sharon L R Kardia %A Balkau, Beverley %A Gambaro, Giovanni %A Morris, Andrew P %A Johan G Eriksson %A Margaret J Wright %A Nicholas G Martin %A Hunt, Steven C %A John M Starr %A Ian J Deary %A Griffiths, Lyn R %A Henning Tiemeier %A Nicola Pirastu %A Kaprio, Jaakko %A Wareham, Nicholas J %A Pérusse, Louis %A Wilson, James G %A Giorgia G Girotto %A Caulfield, Mark J %A Olli T Raitakari %A Dorret I Boomsma %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 Patrik K E Magnusson %A Hamsten, Anders %A Schmidt, Reinhold %A Ingrid B Borecki %A Vartiainen, Erkki %A Becker, Diane M %A Bharadwaj, Dwaipayan %A Mohlke, Karen L %A Boehnke, Michael %A Cornelia M van Duijn %A Sanghera, Dharambir K %A Teumer, Alexander %A Zeggini, Eleftheria %A Andres Metspalu %A Paolo P. Gasparini %A Ulivi, Sheila %A Ober, Carole %A Toniolo, Daniela %A Rudan, Igor %A David J Porteous %A Ciullo, Marina %A Timothy Spector %A Caroline Hayward %A Dupuis, Josée %A Ruth J F Loos %A Alan F Wright %A Chandak, Giriraj R %A Vollenweider, Peter %A Alan R Shuldiner %A Ridker, Paul M %A Rotter, Jerome I %A Sattar, Naveed %A Gyllensten, Ulf %A Kari E North %A Pirastu, Mario %A Psaty, Bruce M %A David R Weir %A Laakso, Markku %A Gudnason, Vilmundur %A Takahashi, Atsushi %A Chambers, John C %A Kooner, Jaspal S %A David P Strachan %A Campbell, Harry %A Joel N Hirschhron %A Markus Perola %A Polasek, Ozren %A James F Wilson %K Biological Evolution %K Blood pressure %K Body Height %K Cholesterol %K Cognitive Ability %K Cohort Studies %K Education %K Female %K Forced Expiratory Volume %K Genome %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 Mol Psychiatry %D 2015 %T Genetic contributions to variation in general cognitive function: a meta-analysis of genome-wide association studies in the CHARGE consortium (N=53949). %A Gail Davies %A Armstrong, N. %A Joshua C. Bis %A Bressler, J. %A Chouraki, V. %A Giddaluru, S. %A Edith Hofer %A Carla A Ibrahim-Verbaas %A Kirin, M. %A J. Lahti %A Sven J van der Lee %A Stephanie Le Hellard %A Tian Liu %A Riccardo E Marioni %A Christopher J Oldmeadow %A Postmus, I. %A Albert Vernon Smith %K Aged %K Aged, 80 and over %K Atherosclerosis %K Cognition %K Cognition Disorders %K Cohort Studies %K Female %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K HMGN1 Protein %K Humans %K Male %K Middle Aged %K Neuropsychological tests %K Phenotype %K Polymorphism, Single Nucleotide %K Scotland %X

General cognitive function is substantially heritable across the human life course from adolescence to old age. We investigated the genetic contribution to variation in this important, health- and well-being-related trait in middle-aged and older adults. We conducted a meta-analysis of genome-wide association studies of 31 cohorts (N=53,949) in which the participants had undertaken multiple, diverse cognitive tests. A general cognitive function phenotype was tested for, and created in each cohort by principal component analysis. We report 13 genome-wide significant single-nucleotide polymorphism (SNP) associations in three genomic regions, 6q16.1, 14q12 and 19q13.32 (best SNP and closest gene, respectively: rs10457441, P=3.93 × 10(-9), MIR2113; rs17522122, P=2.55 × 10(-8), AKAP6; rs10119, P=5.67 × 10(-9), APOE/TOMM40). We report one gene-based significant association with the HMGN1 gene located on chromosome 21 (P=1 × 10(-6)). These genes have previously been associated with neuropsychiatric phenotypes. Meta-analysis results are consistent with a polygenic model of inheritance. To estimate SNP-based heritability, the genome-wide complex trait analysis procedure was applied to two large cohorts, the Atherosclerosis Risk in Communities Study (N=6617) and the Health and Retirement Study (N=5976). The proportion of phenotypic variation accounted for by all genotyped common SNPs was 29% (s.e.=5%) and 28% (s.e.=7%), respectively. Using polygenic prediction analysis, ~1.2% of the variance in general cognitive function was predicted in the Generation Scotland cohort (N=5487; P=1.5 × 10(-17)). In hypothesis-driven tests, there was significant association between general cognitive function and four genes previously associated with Alzheimer's disease: TOMM40, APOE, ABCG1 and MEF2C.

%B Mol Psychiatry %I 20 %V 20 %P 183-92 %8 2015 Feb %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/25644384?dopt=Abstract %2 PMC4356746 %4 genetics/genetics/GENOME-WIDE ASSOCIATION/TOMM40/ABCG1/MEF2C/complex train anaysis/Atherosclerosis Risk in Communities Study/cross-national study %$ 999999 %R 10.1038/mp.2014.188 %0 Journal Article %J Proc Natl Acad Sci U S A %D 2014 %T Common genetic variants associated with cognitive performance identified using the proxy-phenotype method. %A Cornelius A Rietveld %A Tõnu Esko %A Gail Davies %A Pers, Tune H %A Turley, Patrick %A Benyamin, Beben %A Chabris, Christopher F %A Emilsson, Valur %A Andrew D Johnson %A Lee, James J %A Christiaan de Leeuw %A Riccardo E Marioni %A Sarah E Medland %A Michael B Miller %A Rostapshova, Olga %A Sven J van der Lee %A Anna A E Vinkhuyzen %A Amin, Najaf %A Dalton C Conley %A Derringer, Jaime %A Cornelia M van Duijn %A Fehrmann, Rudolf %A Lude L Franke %A Edward L Glaeser %A Narelle K Hansell %A Caroline Hayward %A Iacono, William G %A Carla A Ibrahim-Verbaas %A Vincent Jaddoe %A Karjalainen, Juha %A David I Laibson %A Paul Lichtenstein %A David C Liewald %A Patrik K E Magnusson %A Nicholas G Martin %A McGue, Matt %A McMahon, George %A Nancy L Pedersen %A Pinker, Steven %A David J Porteous %A Posthuma, Danielle %A Fernando Rivadeneira %A Smith, Blair H %A John M Starr %A Henning Tiemeier %A Nicholas J Timpson %A Trzaskowski, Maciej %A André G Uitterlinden %A Verhulst, Frank C %A Mary E Ward %A Margaret J Wright %A George Davey Smith %A Ian J Deary %A Johannesson, Magnus %A Plomin, Robert %A Peter M Visscher %A Daniel J. Benjamin %A Cesarini, David %A Philipp D Koellinger %K Cell Adhesion Molecules, Neuronal %K Cognition %K Female %K Humans %K Learning %K Male %K Memory %K Multifactorial Inheritance %K Nerve Tissue Proteins %K Neuronal Plasticity %K Octamer Transcription Factors %K Polymorphism, Single Nucleotide %K Synaptic Transmission %X

We identify common genetic variants associated with cognitive performance using a two-stage approach, which we call the proxy-phenotype method. First, we conduct a genome-wide association study of educational attainment in a large sample (n = 106,736), which produces a set of 69 education-associated SNPs. Second, using independent samples (n = 24,189), we measure the association of these education-associated SNPs with cognitive performance. Three SNPs (rs1487441, rs7923609, and rs2721173) are significantly associated with cognitive performance after correction for multiple hypothesis testing. In an independent sample of older Americans (n = 8,652), we also show that a polygenic score derived from the education-associated SNPs is associated with memory and absence of dementia. Convergent evidence from a set of bioinformatics analyses implicates four specific genes (KNCMA1, NRXN1, POU2F3, and SCRT). All of these genes are associated with a particular neurotransmitter pathway involved in synaptic plasticity, the main cellular mechanism for learning and memory.

%B Proc Natl Acad Sci U S A %V 111 %P 13790-4 %8 2014 Sep 23 %G eng %N 38 %1 http://www.ncbi.nlm.nih.gov/pubmed/25201988?dopt=Abstract %R 10.1073/pnas.1404623111 %0 Journal Article %J BMC Genet %D 2014 %T Genetic diversity is a predictor of mortality in humans. %A Bihlmeyer, Nathan A %A Brody, Jennifer A %A Albert Vernon Smith %A Kathryn L Lunetta %A Michael A Nalls %A Jennifer A Smith %A Toshiko Tanaka %A Gail Davies %A Lei Yu %A Saira S Mirza %A Teumer, Alexander %A Coresh, Josef %A Pankow, James S %A Franceschini, Nora %A Scaria, Anish %A Oshima, Junko %A Psaty, Bruce M %A Gudnason, Vilmundur %A Guðny Eiríksdóttir %A Tamara B Harris %A Li, Hanyue %A Karasik, David %A Douglas P Kiel %A Melissa E Garcia %A Yongmei Liu %A Jessica Faul %A Sharon L R Kardia %A Wei Zhao %A Luigi Ferrucci %A Allerhand, Michael %A David C Liewald %A Redmond, Paul %A John M Starr %A Philip L de Jager %A Nese Direk %A Mohammed Arfan Ikram %A André G Uitterlinden %A Homuth, Georg %A Lorbeer, Roberto %A Hans-Jörgen Grabe %A Lenore J Launer %A Joanne M Murabito %A Andrew B Singleton %A David R Weir %A Bandinelli, Stefania %A Ian J Deary %A David A Bennett %A Henning Tiemeier %A Kocher, Thomas %A Lumley, Thomas %A Dan E Arking %K Genome-Wide Association Study %K Heterozygote %K Humans %K Mortality %K Polymorphism, Single Nucleotide %K Proportional Hazards Models %X

BACKGROUND: It has been well-established, both by population genetics theory and direct observation in many organisms, that increased genetic diversity provides a survival advantage. However, given the limitations of both sample size and genome-wide metrics, this hypothesis has not been comprehensively tested in human populations. Moreover, the presence of numerous segregating small effect alleles that influence traits that directly impact health directly raises the question as to whether global measures of genomic variation are themselves associated with human health and disease.

RESULTS: We performed a meta-analysis of 17 cohorts followed prospectively, with a combined sample size of 46,716 individuals, including a total of 15,234 deaths. We find a significant association between increased heterozygosity and survival (P = 0.03). We estimate that within a single population, every standard deviation of heterozygosity an individual has over the mean decreases that person's risk of death by 1.57%.

CONCLUSIONS: This effect was consistent between European and African ancestry cohorts, men and women, and major causes of death (cancer and cardiovascular disease), demonstrating the broad positive impact of genomic diversity on human survival.

%B BMC Genet %V 15 %P 159 %8 2014 Dec 29 %G eng %U https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4301661/ %1 http://www.ncbi.nlm.nih.gov/pubmed/25543667?dopt=Abstract %R 10.1186/s12863-014-0159-7 %0 Journal Article %J Science %D 2013 %T GWAS of 126,559 individuals identifies genetic variants associated with educational attainment. %A Cornelius A Rietveld %A Sarah E Medland %A Derringer, Jaime %A Yang, Jian %A Tõnu Esko %A Martin, Nicolas W %A Westra, Harm-Jan %A Shakhbazov, Konstantin %A Abdel Abdellaoui %A Agrawal, Arpana %A Albrecht, Eva %A Alizadeh, Behrooz Z %A Amin, Najaf %A Barnard, John %A Baumeister, Sebastian E %A Benke, Kelly S %A Bielak, Lawrence F %A Boatman, Jeffrey A %A Patricia A. Boyle %A Gail Davies %A Christiaan de Leeuw %A Eklund, Niina %A Daniel S Evans %A Rudolf Ferhmann %A Fischer, Krista %A Gieger, Christian %A Gjessing, Håkon K %A Hägg, Sara %A Harris, Jennifer R %A Caroline Hayward %A Holzapfel, Christina %A Carla A Ibrahim-Verbaas %A Ingelsson, Erik %A Jacobsson, Bo %A Joshi, Peter K %A Jugessur, Astanand %A Marika A Kaakinen %A Kanoni, Stavroula %A Karjalainen, Juha %A Kolcic, Ivana %A Kristiansson, Kati %A Kutalik, Zoltán %A J. Lahti %A Lee, Sang H %A Lin, Peng %A Penelope A Lind %A Yongmei Liu %A Kurt Lohman %A Loitfelder, Marisa %A McMahon, George %A Vidal, Pedro Marques %A Osorio Meirelles %A Lili Milani %A Myhre, Ronny %A Nuotio, Marja-Liisa %A Christopher J Oldmeadow %A Katja E Petrovic %A Wouter J Peyrot %A Polasek, Ozren %A Quaye, Lydia %A Reinmaa, Eva %A Rice, John P %A Rizzi, Thais S %A Schmidt, Helena %A Schmidt, Reinhold %A Albert Vernon Smith %A Jennifer A Smith %A Toshiko Tanaka %A Antonio Terracciano %A van der Loos, Matthijs J H M %A Vitart, Veronique %A Völzke, Henry %A Jürgen Wellmann %A Lei Yu %A Wei Zhao %A Allik, Jüri %A John R. Attia %A Bandinelli, Stefania %A Bastardot, François %A Jonathan P. Beauchamp %A David A Bennett %A Klaus Berger %A Laura Bierut %A Dorret I Boomsma %A Bültmann, Ute %A Campbell, Harry %A Chabris, Christopher F %A Cherkas, Lynn %A Chung, Mina K %A Francesco Cucca %A de Andrade, Mariza %A Philip L de Jager %A De Neve, Jan-Emmanuel %A Ian J Deary %A George Dedoussis %A Deloukas, Panos %A Dimitriou, Maria %A Guðny Eiríksdóttir %A Elderson, Martin F %A Johan G Eriksson %A Jessica Faul %A Luigi Ferrucci %A Melissa E Garcia %A Grönberg, Henrik %A Guðnason, Vilmundur %A Hall, Per %A Harris, Juliette M %A Tamara B Harris %A Nicholas D Hastie %A Andrew C Heath %A Dena G Hernandez %A Hoffmann, Wolfgang %A Hofman, Adriaan %A Holle, Rolf %A Holliday, Elizabeth G %A Jouke-Jan Hottenga %A Iacono, William G %A Illig, Thomas %A Järvelin, Marjo-Riitta %A Kähönen, Mika %A Kaprio, Jaakko %A Kirkpatrick, Robert M %A Kowgier, Matthew %A Latvala, Antti %A Lenore J Launer %A Lawlor, Debbie A %A Lehtimäki, Terho %A Li, Jingmei %A Paul Lichtenstein %A Lichtner, Peter %A David C Liewald %A Pamela A F Madden %A Patrik K E Magnusson %A Mäkinen, Tomi E %A Masala, Marco %A McGue, Matt %A Andres Metspalu %A Mielck, Andreas %A Michael B Miller %A Grant W Montgomery %A Mukherjee, Sutapa %A Nyholt, Dale R %A Ben A Oostra %A Palmer, Lyle J %A Aarno Palotie %A Brenda W J H Penninx %A Markus Perola %A Peyser, Patricia A %A Preisig, Martin %A Katri Räikkönen %A Olli T Raitakari %A Realo, Anu %A Ring, Susan M %A Ripatti, Samuli %A Fernando Rivadeneira %A Rudan, Igor %A Rustichini, Aldo %A Veikko Salomaa %A Sarin, Antti-Pekka %A Schlessinger, David %A Rodney J Scott %A Snieder, Harold %A St Pourcain, Beate %A John M Starr %A Sul, Jae Hoon %A Surakka, Ida %A Svento, Rauli %A Teumer, Alexander %A Henning Tiemeier %A van Rooij, Frank J A %A Van Wagoner, David R %A Vartiainen, Erkki %A Viikari, Jorma %A Vollenweider, Peter %A Vonk, Judith M %A Waeber, Gérard %A David R Weir %A Wichmann, H-Erich %A Elisabeth Widen %A Gonneke Willemsen %A James F Wilson %A Alan F Wright %A Dalton C Conley %A Davey-Smith, George %A Lude L Franke %A Groenen, Patrick J F %A Hofman, Albert %A Johannesson, Magnus %A Sharon L R Kardia %A Krueger, Robert F %A David I Laibson %A Nicholas G Martin %A Meyer, Michelle N %A Posthuma, Danielle %A A. Roy Thurik %A Nicholas J Timpson %A André G Uitterlinden %A Cornelia M van Duijn %A Peter M Visscher %A Daniel J. Benjamin %A Cesarini, David %A Philipp D Koellinger %K Cognition %K Educational Status %K Endophenotypes %K Female %K Genetic Loci %K Genome-Wide Association Study %K Humans %K Male %K Multifactorial Inheritance %K Polymorphism, Single Nucleotide %X

A genome-wide association study (GWAS) of educational attainment was conducted in a discovery sample of 101,069 individuals and a replication sample of 25,490. Three independent single-nucleotide polymorphisms (SNPs) are genome-wide significant (rs9320913, rs11584700, rs4851266), and all three replicate. Estimated effects sizes are small (coefficient of determination R(2) ≈ 0.02%), approximately 1 month of schooling per allele. A linear polygenic score from all measured SNPs accounts for ≈2% of the variance in both educational attainment and cognitive function. Genes in the region of the loci have previously been associated with health, cognitive, and central nervous system phenotypes, and bioinformatics analyses suggest the involvement of the anterior caudate nucleus. These findings provide promising candidate SNPs for follow-up work, and our effect size estimates can anchor power analyses in social-science genetics.

%B Science %V 340 %P 1467-71 %8 2013 Jun 21 %G eng %N 6139 %1 http://www.ncbi.nlm.nih.gov/pubmed/23722424?dopt=Abstract %R 10.1126/science.1235488