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Ninety-nine independent genetic loci influencing general cognitive function include genes associated with brain health and structure (N = 280,360)

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

Posted 17 Aug 2017
bioRxiv DOI: 10.1101/176511 (published DOI: 10.1038/s41467-018-04362-x)

General cognitive function is a prominent human trait associated with many important life outcomes including longevity. The substantial heritability of general cognitive function is known to be polygenic, but it has had little explication in terms of the contributing genetic variants. Here, we combined cognitive and genetic data from the CHARGE and COGENT consortia, and UK Biobank (total N=280,360; age range = 16 to 102). We found 9,714 genome-wide significant SNPs (P<5 x 10-8) in 99 independent loci. Most showed clear evidence of functional importance. Among many novel genes associated with general cognitive function were SGCZ, ATXN1, MAPT, AUTS2, and P2RY6. Within the novel genetic loci were variants associated with neurodegenerative disorders, neurodevelopmental disorders, physical and psychiatric illnesses, brain structure, and BMI. Gene-based analyses found 536 genes significantly associated with general cognitive function; many were highly expressed in the brain, and associated with neurogenesis and dendrite gene sets. Genetic association results predicted up to 4% of general cognitive function variance in independent samples. There was significant genetic overlap between general cognitive function and information processing speed, as well as many health variables including longevity.

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