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

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, 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, 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 Jr., 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, 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
doi: https://doi.org/10.1101/176511
Gail Davies
The University of Edinburgh;
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Max Lam
Institute of Mental Health, Singapore;
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Sarah E. Harris
The University of Edinburgh;
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Joey Trampush
BrainWorkup, LLC, Los Angeles;
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Michelle Luciano
The University of Edinburgh;
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W. David Hill
The University of Edinburgh;
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Saskia P. Hagenaars
King's College London;
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Stuart J. Ritchie
The University of Edinburgh;
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Riccardo E. Marioni
The University of Edinburgh;
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Chloë Fawns-Ritchie
The University of Edinburgh;
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David C. Liewald
The University of Edinburgh;
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Judith Okely
The University of Edinburgh;
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Ari Ahola-Olli
University of Turku;
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Catriona L. K. Barnes
University of Edinburgh;
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Lars Bertram
Max Planck Institute for Molecular Genetics;
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Joshua C. Bis
University of Washington;
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Katherine E. Burdick
Harvard Medical School;
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Andrea Christoforou
University of Bergen;
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Pamela DeRosse
Institute of Mental Health, Singapore;
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Srdjan Djurovic
University of Bergen;
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Thomas Espeseth
Oslo University Hospital;
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Stella Giakoumaki
University of Crete;
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Sudheer Giddaluru
University of Bergen;
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Daniel E. Gustavson
University of California San Diego;
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Caroline Hayward
University of Edinburgh;
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Edith Hofer
Medical University Graz;
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M. Arfan Ikram
Erasmus University Medical Center;
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Robert Karlsson
Karolinska Institutet;
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Yale University School of Medicine;
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University of Helsinki;
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University of Cologne;
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Boston University School of Public Health;
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University of New South Wales;
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University of Bergen;
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Trinity College Dublin;
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University of Newcastle;
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University of Helsinki;
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The University of Manchester;
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Imperial College London;
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Medical University Graz;
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University of California Riverside;
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University of Bordeaux;
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University of Leipzig;
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University of Michigan;
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Icelandic Heart Association;
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Ghent University Hospital;
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University of New South Wales;
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Leiden University Medical Center;
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Erasmus University Medical Center;
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University of Michigan;
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University of Mississippi Medical Center;
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University of Queensland;
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Rush University Medical Center;
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Feinstein Institute for Medical Research;
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National Ageing Research Institute Royal Melbourne Hospital;
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Institut Pasteur de Lille;
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University of Oslo;
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Duke University Medical Center;
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Johns Hopkins University School of Medicine;
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Rush University Medical Center;
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Yale University;
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Human Longevity Inc, Durham, NC,;
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UCLA;
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Imperial College London;
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Virginia Commonwealth University;
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National Institute of Health;
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National Institute for Health and Welfare, Helsinki;
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Imperial College London;
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University of Michigan;
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UCLA;
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Imperial College London;
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Martin Luther University of Halle-Wittenberg;
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Virginia Commonwealth University;
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QIMR Berghofer Medical Research Institute, Brisbane;
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Johns Hopkins University School of Medicine;
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University of Mississippi Medical Center;
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National Institutes of Health, Bethesda;
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University of Michigan;
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Martin Luther University of Halle-Wittenberg;
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Neuroscience Research Australia;
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Max Planck Institute for Human Development, Berlin;
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Max Planck Institute for Human Development, Berlin;
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Medical University Graz;
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UCLA;
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Umea University;
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University of Tampere;
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QIMR Berghofer Medical Research Institute;
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Max Planck Institute for Human Development, Berlin;
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The University of Edinburgh;
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Stanford University;
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Indiana University;
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UCLA;
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Icahn School of Medicine at Mount Sinai;
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University of Turku;
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Medical University of Graz;
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University of Oregon;
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University of New South Wales;
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Boston University School of Medicine;
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University of Bonn;
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University of Newcastle;
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Duke University;
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University of Mississippi Medical Center;
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Leiden University Medical Center;
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National and Kapodistrian University of Athens Medical School;
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University of Bordeaux;
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National and Kapodistrian University of Athens Medical School;
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University of Glasgow;
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Johns Hopkins University Medical Campus, Baltimore;
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Oslo University Hospital;
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The University of Edinburgh;
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Los Angeles Biomedical Research Institute;
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Imperial College London;
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Abstract

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). 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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  • Posted August 17, 2017.

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Ninety-nine independent genetic loci influencing general cognitive function include genes associated with brain health and structure (N = 280,360)
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Ninety-nine independent genetic loci influencing general cognitive function include genes associated with brain health and structure (N = 280,360)
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, 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, 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 Jr., 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, 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
bioRxiv 176511; doi: https://doi.org/10.1101/176511
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Ninety-nine independent genetic loci influencing general cognitive function include genes associated with brain health and structure (N = 280,360)
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, 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, 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 Jr., 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, 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
bioRxiv 176511; doi: https://doi.org/10.1101/176511

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