TY - JOUR T1 - Genome-wide association meta-analysis in 269,867 individuals identifies new genetic and functional links to intelligence JF - Nature Genetics Y1 - 2018 A1 - Savage, Jeanne E. A1 - Philip R Jansen A1 - Stringer, Sven A1 - Watanabe, Kyoko A1 - Bryois, Julien A1 - Christiaan de Leeuw A1 - Nagel, Mats A1 - Awasthi, Swapnil A1 - Barr, Peter B. A1 - Coleman, Jonathan R. I. A1 - Grasby, Katrina L. A1 - Anke R Hammerschlag A1 - Kaminski, Jakob A. A1 - Karlsson, Robert A1 - Krapohl, Eva A1 - Lam, Max A1 - Nygaard, Marianne A1 - Chandra A Reynolds A1 - Joey W Trampush A1 - Young, Hannah A1 - Zabaneh, Delilah A1 - Hägg, Sara A1 - Narelle K Hansell A1 - Ida Karlsson A1 - Linnarsson, Sten A1 - Grant W Montgomery A1 - Muñoz-Manchado, Ana B. A1 - Quinlan, Erin B. A1 - Schumann, Gunter A1 - Skene, Nathan G. A1 - Webb, Bradley T. A1 - White, Tonya A1 - Dan E Arking A1 - Avramopoulos, Dimitrios A1 - Robert M Bilder A1 - Bitsios, Panos A1 - Katherine E Burdick A1 - Tyrone D. Cannon A1 - Chiba-Falek, Ornit A1 - Christoforou, Andrea A1 - Elizabeth T. Cirulli A1 - Congdon, Eliza A1 - Corvin, Aiden A1 - Gail Davies A1 - Ian J Deary A1 - DeRosse, Pamela A1 - Dickinson, Dwight A1 - Djurovic, Srdjan A1 - Donohoe, Gary A1 - Conley, Emily Drabant A1 - Johan G Eriksson A1 - Espeseth, Thomas A1 - Nelson A. Freimer A1 - Giakoumaki, Stella A1 - Giegling, Ina A1 - Gill, Michael A1 - David C. Glahn A1 - Ahmad R Hariri A1 - Hatzimanolis, Alex A1 - Matthew C Keller A1 - Knowles, Emma A1 - Koltai, Deborah A1 - Konte, Bettina A1 - Lahti, Jari A1 - Stephanie Le Hellard A1 - Lencz, Todd A1 - David C Liewald A1 - London, Edythe A1 - Astri J Lundervold A1 - Anil K. Malhotra A1 - Melle, Ingrid A1 - Morris, Derek A1 - Anna C Need A1 - William E R Ollier A1 - Aarno Palotie A1 - Payton, Antony A1 - Pendleton, Neil A1 - Russell A Poldrack A1 - Katri Räikkönen A1 - Reinvang, Ivar A1 - Roussos, Panos A1 - Rujescu, Dan A1 - Fred W Sabb A1 - Matthew A Scult A1 - Smeland, Olav B. A1 - Smyrnis, Nikolaos A1 - John M Starr A1 - Vidar M Steen A1 - Nikos C Stefanis A1 - Richard E Straub A1 - Sundet, Kjetil A1 - Henning Tiemeier A1 - Aristotle N Voineskos A1 - Daniel R Weinberger A1 - Elisabeth Widen A1 - Yu, Jin A1 - Gonçalo R Abecasis A1 - Andreassen, Ole A. A1 - Breen, Gerome A1 - Christiansen, Lene A1 - Debrabant, Birgit A1 - Danielle M. Dick A1 - Heinz, Andreas A1 - Hjerling-Leffler, Jens A1 - Mohammed Arfan Ikram A1 - Kendler, Kenneth S. A1 - Nicholas G Martin A1 - Sarah E Medland A1 - Nancy L Pedersen A1 - Plomin, Robert A1 - Tinca J Polderman A1 - Ripke, Stephan A1 - van der Sluis, Sophie A1 - Patrick F. Sullivan A1 - Scott Vrieze A1 - Margaret J Wright A1 - Posthuma, Danielle KW - Genome-Wide Association Study KW - Intelligence KW - Meta-analyses AB - 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. VL - 50 UR - 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 IS - 7 JO - Nat Genet ER - TY - JOUR T1 - Study of 300,486 individuals identifies 148 independent genetic loci influencing general cognitive function. JF - Nature Communications Y1 - 2018 A1 - Gail Davies A1 - Lam, Max A1 - Sarah E Harris A1 - Joey W Trampush A1 - Luciano, Michelle A1 - W David Hill A1 - Hagenaars, Saskia P A1 - Ritchie, Stuart J A1 - Riccardo E Marioni A1 - Fawns-Ritchie, Chloe A1 - David C Liewald A1 - Okely, Judith A A1 - Ahola-Olli, Ari V A1 - Barnes, Catriona L K A1 - Bertram, Lars A1 - Joshua C. Bis A1 - Katherine E Burdick A1 - Christoforou, Andrea A1 - DeRosse, Pamela A1 - Djurovic, Srdjan A1 - Espeseth, Thomas A1 - Giakoumaki, Stella A1 - Giddaluru, Sudheer A1 - Gustavson, Daniel E A1 - Caroline Hayward A1 - Edith Hofer A1 - Ikram, M Arfan A1 - Karlsson, Robert A1 - Knowles, Emma A1 - Lahti, Jari A1 - Leber, Markus A1 - Li, Shuo A1 - Mather, Karen A A1 - Melle, Ingrid A1 - Morris, Derek A1 - Christopher J Oldmeadow A1 - Palviainen, Teemu A1 - Payton, Antony A1 - Pazoki, Raha A1 - Katja E Petrovic A1 - Chandra A Reynolds A1 - Sargurupremraj, Muralidharan A1 - Scholz, Markus A1 - Smith, Jennifer A A1 - Smith, Albert V A1 - Terzikhan, Natalie A1 - Thalamuthu, Anbupalam A1 - Trompet, Stella A1 - Sven J van der Lee A1 - Erin B Ware A1 - Windham, B Gwen A1 - Margaret J Wright A1 - Yang, Jingyun A1 - Yu, Jin A1 - Ames, David A1 - Amin, Najaf A1 - Amouyel, Philippe A1 - Andreassen, Ole A A1 - Armstrong, Nicola J A1 - Assareh, Amelia A A1 - John R. Attia A1 - Attix, Deborah A1 - Avramopoulos, Dimitrios A1 - David A Bennett A1 - Böhmer, Anne C A1 - Patricia A. Boyle A1 - Brodaty, Henry A1 - Campbell, Harry A1 - Tyrone D. Cannon A1 - Elizabeth T. Cirulli A1 - Congdon, Eliza A1 - Conley, Emily Drabant A1 - Corley, Janie A1 - Cox, Simon R A1 - Dale, Anders M A1 - Dehghan, Abbas A1 - Danielle M. Dick A1 - Dickinson, Dwight A1 - Johan G Eriksson A1 - Evangelou, Evangelos A1 - Jessica Faul A1 - Ford, Ian A1 - Nelson A. Freimer A1 - Gao, He A1 - Giegling, Ina A1 - Gillespie, Nathan A A1 - Gordon, Scott D A1 - Gottesman, Rebecca F A1 - Michael E Griswold A1 - Gudnason, Vilmundur A1 - Tamara B Harris A1 - Hartmann, Annette M A1 - Hatzimanolis, Alex A1 - Gerardo Heiss A1 - Holliday, Elizabeth G A1 - Joshi, Peter K A1 - Kähönen, Mika A1 - Sharon L R Kardia A1 - Ida Karlsson A1 - Kleineidam, Luca A1 - David S Knopman A1 - Kochan, Nicole A A1 - Konte, Bettina A1 - Kwok, John B A1 - Stephanie Le Hellard A1 - Lee, Teresa A1 - Lehtimäki, Terho A1 - Li, Shu-Chen A1 - Lill, Christina M A1 - Liu, Tian A1 - Koini, Marisa A1 - London, Edythe A1 - Longstreth, Will T A1 - Lopez, Oscar L A1 - Loukola, Anu A1 - Luck, Tobias A1 - Astri J Lundervold A1 - Lundquist, Anders A1 - Lyytikäinen, Leo-Pekka A1 - Nicholas G Martin A1 - Grant W Montgomery A1 - Murray, Alison D A1 - Anna C Need A1 - Noordam, Raymond A1 - Nyberg, Lars A1 - William E R Ollier A1 - Papenberg, Goran A1 - Pattie, Alison A1 - Polasek, Ozren A1 - Russell A Poldrack A1 - Psaty, Bruce M A1 - Reppermund, Simone A1 - Steffi G Riedel-Heller A1 - Rose, Richard J A1 - Rotter, Jerome I A1 - Roussos, Panos A1 - Rovio, Suvi P A1 - Saba, Yasaman A1 - Fred W Sabb A1 - Sachdev, Perminder S A1 - Satizabal, Claudia L A1 - Schmid, Matthias A1 - Rodney J Scott A1 - Matthew A Scult A1 - Simino, Jeannette A1 - Slagboom, P Eline A1 - Smyrnis, Nikolaos A1 - Soumaré, Aïcha A1 - Nikos C Stefanis A1 - Stott, David J A1 - Richard E Straub A1 - Sundet, Kjetil A1 - Taylor, Adele M A1 - Kent D Taylor A1 - Tzoulaki, Ioanna A1 - Tzourio, Christophe A1 - André G Uitterlinden A1 - Vitart, Veronique A1 - Aristotle N Voineskos A1 - Kaprio, Jaakko A1 - Wagner, Michael A1 - Wagner, Holger A1 - Weinhold, Leonie A1 - Wen, K Hoyan A1 - Elisabeth Widen A1 - Yang, Qiong A1 - Zhao, Wei A1 - Hieab H Adams A1 - Dan E Arking A1 - Robert M Bilder A1 - Bitsios, Panos A1 - Boerwinkle, Eric A1 - Chiba-Falek, Ornit A1 - Corvin, Aiden A1 - Philip L de Jager A1 - Debette, Stéphanie A1 - Donohoe, Gary A1 - Elliott, Paul A1 - Fitzpatrick, Annette L A1 - Gill, Michael A1 - David C. Glahn A1 - Hägg, Sara A1 - Narelle K Hansell A1 - Ahmad R Hariri A1 - Ikram, M Kamran A1 - Jukema, J Wouter A1 - Vuoksimaa, Eero A1 - Matthew C Keller A1 - Kremen, William S A1 - Lenore J Launer A1 - Lindenberger, Ulman A1 - Aarno Palotie A1 - Nancy L Pedersen A1 - Pendleton, Neil A1 - David J Porteous A1 - Katri Räikkönen A1 - Olli T Raitakari A1 - Ramirez, Alfredo A1 - Reinvang, Ivar A1 - Rudan, Igor A1 - Schmidt, Reinhold A1 - Schmidt, Helena A1 - Peter W Schofield A1 - Peter R Schofield A1 - John M Starr A1 - Vidar M Steen A1 - Trollor, Julian N A1 - Turner, Steven T A1 - Cornelia M van Duijn A1 - Villringer, Arno A1 - Daniel R Weinberger A1 - David R Weir A1 - James F Wilson A1 - Anil K. Malhotra A1 - McIntosh, Andrew M A1 - Gale, Catharine R A1 - Seshadri, Sudha A1 - Thomas H Mosley A1 - Bressler, Jan A1 - Lencz, Todd A1 - Ian J Deary KW - Adolescent KW - Adult KW - Aged KW - Aged, 80 and over KW - Cognition KW - Genetic Loci KW - Genetic Predisposition to Disease KW - Humans KW - Mental Disorders KW - Middle Aged KW - Multifactorial Inheritance KW - Neurodegenerative Diseases KW - Neurodevelopmental Disorders KW - Polymorphism, Single Nucleotide KW - Reaction Time KW - Young Adult AB -

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.

VL - 9 IS - 1 ER -