Genome-wide association meta-analysis in 269,867 individuals identifies new genetic and functional links to intelligence

Jeanne E. Savage; Philip R. Jansen; Sven Stringer; Kyoko Watanabe; Julien Bryois; Christiaan A. De Leeuw; Mats Nagel; Swapnil Awasthi; Peter B. Barr; Jonathan R.I. Coleman; Katrina L. Grasby; Anke R. Hammerschlag; Jakob A. Kaminski; Robert Karlsson; Eva Krapohl; Max Lam; Marianne Nygaard; Chandra A. Reynolds; Joey W. Trampush; Hannah Young; Delilah Zabaneh; Sara Hägg; Narelle K. Hansell; Ida K. Karlsson; Sten Linnarsson; Grant W. Montgomery; Ana B. Muñoz-Manchado; Erin B. Quinlan; Gunter Schumann; Nathan G. Skene; Bradley T. Webb; Tonya White; Dan E. Arking; Dimitrios Avramopoulos; Robert M. Bilder; Panos Bitsios; Katherine E. Burdick; Tyrone D. Cannon; Ornit Chiba-Falek; Andrea Christoforou; Elizabeth T. Cirulli; Eliza Congdon; Aiden Corvin; Gail Davies; Ian J. Deary; Pamela Derosse; Dwight Dickinson; Srdjan Djurovic; Gary Donohoe; Emily Drabant Conley; Johan G. Eriksson; Thomas Espeseth; Nelson A. Freimer; Stella Giakoumaki; Ina Giegling; Michael Gill; David C. Glahn; Ahmad R. Hariri; Alex Hatzimanolis; Matthew C. Keller; Emma Knowles; Deborah Koltai; Bettina Konte; Jari Lahti; Stephanie Le Hellard; Todd Lencz; David C. Liewald; Edythe London; Astri J. Lundervold; Anil K. Malhotra; Ingrid Melle; Derek Morris; Anna C. Need; William Ollier; Aarno Palotie; Antony Payton; Neil Pendleton; Russell A. Poldrack; Katri Räikkönen; Ivar Reinvang; Panos Roussos; Dan Rujescu; Fred W. Sabb; Matthew A. Scult; Olav B. Smeland; Nikolaos Smyrnis; John M. Starr; Vidar M. Steen; Nikos C. Stefanis; Richard E. Straub; Kjetil Sundet; Henning Tiemeier; Aristotle N. Voineskos; Daniel R. Weinberger; Elisabeth Widen; Jin Yu; Goncalo Abecasis; Ole A. Andreassen; Gerome Breen; Lene Christiansen; Birgit Debrabant; Danielle M. Dick; Andreas Heinz; Jens Hjerling-Leffler; M. Arfan Ikram; Kenneth S. Kendler; Nicholas G. Martin; Sarah E. Medland; Nancy L. Pedersen; Robert Plomin; Tinca J.C. Polderman; Stephan Ripke; Sophie Van Der Sluis; Patrick F. Sullivan; Scott I. Vrieze; Margaret J. Wright; Danielle Posthuma

doi:10.1038/s41588-018-0152-6

Genome-wide association meta-analysis in 269,867 individuals identifies new genetic and functional links to intelligence

Jeanne E. Savage
, Philip R. Jansen
, Sven Stringer
, Kyoko Watanabe
, Julien Bryois
, Christiaan A. De Leeuw
, Mats Nagel
, Swapnil Awasthi
, Peter B. Barr
, Jonathan R.I. Coleman
, Katrina L. Grasby
, Anke R. Hammerschlag
, Jakob A. Kaminski
, Robert Karlsson
, Eva Krapohl
, Max Lam
, Marianne Nygaard
, Chandra A. Reynolds
, Joey W. Trampush
, Hannah Young

Delilah Zabaneh, Sara Hägg, Narelle K. Hansell, Ida K. Karlsson, Sten Linnarsson, Grant W. Montgomery, Ana B. Muñoz-Manchado, Erin B. Quinlan, Gunter Schumann, Nathan G. Skene, Bradley T. Webb, Tonya White, Dan E. Arking, Dimitrios Avramopoulos, Robert M. Bilder, Panos Bitsios, Katherine E. Burdick, Tyrone D. Cannon, Ornit Chiba-Falek, Andrea Christoforou, Elizabeth T. Cirulli, Eliza Congdon, Aiden Corvin, Gail Davies, Ian J. Deary, Pamela Derosse, Dwight Dickinson, Srdjan Djurovic, Gary Donohoe, Emily Drabant Conley, Johan G. Eriksson, Thomas Espeseth, Nelson A. Freimer, Stella Giakoumaki, Ina Giegling, Michael Gill, David C. Glahn, Ahmad R. Hariri, Alex Hatzimanolis, Matthew C. Keller, Emma Knowles, Deborah Koltai, Bettina Konte, Jari Lahti, Stephanie Le Hellard, Todd Lencz, David C. Liewald, Edythe London, Astri J. Lundervold, Anil K. Malhotra, Ingrid Melle, Derek Morris, Anna C. Need, William Ollier, Aarno Palotie, Antony Payton, Neil Pendleton, Russell A. Poldrack, Katri Räikkönen, Ivar Reinvang, Panos Roussos, Dan Rujescu, Fred W. Sabb, Matthew A. Scult, Olav B. Smeland, Nikolaos Smyrnis, John M. Starr, Vidar M. Steen, Nikos C. Stefanis, Richard E. Straub, Kjetil Sundet, Henning Tiemeier, Aristotle N. Voineskos, Daniel R. Weinberger, Elisabeth Widen, Jin Yu, Goncalo Abecasis, Ole A. Andreassen, Gerome Breen, Lene Christiansen, Birgit Debrabant, Danielle M. Dick, Andreas Heinz, Jens Hjerling-Leffler, M. Arfan Ikram, Kenneth S. Kendler, Nicholas G. Martin, Sarah E. Medland, Nancy L. Pedersen, Robert Plomin, Tinca J.C. Polderman, Stephan Ripke, Sophie Van Der Sluis, Patrick F. Sullivan, Scott I. Vrieze, Margaret J. Wright, Danielle Posthuma

Psychology

Amsterdam UMC
Erasmus University Rotterdam
Karolinska Institutet
Section of Complex Trait Genetics
Charité – Universitätsmedizin Berlin
Virginia Commonwealth University
SocialGenetic Developmental Psychiatry Centre
South London and Maudsley NHS Foundation Trust
Queensland Institute of Medical Research
Charité-Universitätsmedizin Berlin
Singapore Institute of Mental Health
University of Southern Denmark
University of California at Riverside
BrainWorkup, LLC
University of Southern California
University of Minnesota Twin Cities
University of Queensland
King's College London
University College London
Johns Hopkins University
University of California at Los Angeles
University of Crete
Icahn School of Medicine at Mount Sinai
VA Medical Center
Brigham and Women’s Hospital
Yale University
Duke University
University of Bergen
Human Longevity, Inc.
Trinity College Dublin
University of Edinburgh
National Institutes of Health
University of Oslo
University of Galway
23andMe Inc.
Helsinki University Central Hospital
Martin Luther University Halle-Wittenberg
National and Kapodistrian University of Athens
University Mental Health Research Institute
Theodor-Theohari Cozzika Foundation
University of Colorado Boulder
University of Helsinki
Zucker Hillside Hospital
Hofstra North Shore-Long Island Jewish School of Medicine
Northwell Health System
Imperial College London
University of Manchester
Wellcome Trust
Massachusetts General Hospital
Stanford University
University of Oregon
University of Toronto
University of Michigan, Ann Arbor
Broad Institute
University of North Carolina at Chapel Hill

Research output: Contribution to journal › Article › peer-review

883 Scopus citations

Abstract

Intelligence is highly heritable ¹ and a major determinant of human health and well-being ² . Recent genome-wide meta-analyses have identified 24 genomic loci linked to variation in intelligence ^3-7 , 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.

Original language	English
Pages (from-to)	912-919
Number of pages	8
Journal	Nature Genetics
Volume	50
Issue number	7
DOIs	https://doi.org/10.1038/s41588-018-0152-6
State	Published - Jul 1 2018

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10.1038/s41588-018-0152-6

Cite this

Savage, J. E., Jansen, P. R., Stringer, S., Watanabe, K., Bryois, J., De Leeuw, C. A., Nagel, M., Awasthi, S., Barr, P. B., Coleman, J. R. I., Grasby, K. L., Hammerschlag, A. R., Kaminski, J. A., Karlsson, R., Krapohl, E., Lam, M., Nygaard, M., Reynolds, C. A., Trampush, J. W., ... Posthuma, D. (2018). Genome-wide association meta-analysis in 269,867 individuals identifies new genetic and functional links to intelligence. Nature Genetics, 50(7), 912-919. https://doi.org/10.1038/s41588-018-0152-6

@article{1206ab4790474ab087f0f1e4ac11646c,

title = "Genome-wide association meta-analysis in 269,867 individuals identifies new genetic and functional links to intelligence",

abstract = " Intelligence is highly heritable 1 and a major determinant of human health and well-being 2 . Recent genome-wide meta-analyses have identified 24 genomic loci linked to variation in intelligence 3-7 , 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.",

author = "Savage, \{Jeanne E.\} and Jansen, \{Philip R.\} and Sven Stringer and Kyoko Watanabe and Julien Bryois and \{De Leeuw\}, \{Christiaan A.\} and Mats Nagel and Swapnil Awasthi and Barr, \{Peter B.\} and Coleman, \{Jonathan R.I.\} and Grasby, \{Katrina L.\} and Hammerschlag, \{Anke R.\} and Kaminski, \{Jakob A.\} and Robert Karlsson and Eva Krapohl and Max Lam and Marianne Nygaard and Reynolds, \{Chandra A.\} and Trampush, \{Joey W.\} and Hannah Young and Delilah Zabaneh and Sara H{\"a}gg and Hansell, \{Narelle K.\} and Karlsson, \{Ida K.\} and Sten Linnarsson and Montgomery, \{Grant W.\} and Mu{\~n}oz-Manchado, \{Ana B.\} and Quinlan, \{Erin B.\} and Gunter Schumann and Skene, \{Nathan G.\} and Webb, \{Bradley T.\} and Tonya White and Arking, \{Dan E.\} and Dimitrios Avramopoulos and Bilder, \{Robert M.\} and Panos Bitsios and Burdick, \{Katherine E.\} and Cannon, \{Tyrone D.\} and Ornit Chiba-Falek and Andrea Christoforou and Cirulli, \{Elizabeth T.\} and Eliza Congdon and Aiden Corvin and Gail Davies and Deary, \{Ian J.\} and Pamela Derosse and Dwight Dickinson and Srdjan Djurovic and Gary Donohoe and Conley, \{Emily Drabant\} and Eriksson, \{Johan G.\} and Thomas Espeseth and Freimer, \{Nelson A.\} and Stella Giakoumaki and Ina Giegling and Michael Gill and Glahn, \{David C.\} and Hariri, \{Ahmad R.\} and Alex Hatzimanolis and Keller, \{Matthew C.\} and Emma Knowles and Deborah Koltai and Bettina Konte and Jari Lahti and \{Le Hellard\}, Stephanie and Todd Lencz and Liewald, \{David C.\} and Edythe London and Lundervold, \{Astri J.\} and Malhotra, \{Anil K.\} and Ingrid Melle and Derek Morris and Need, \{Anna C.\} and William Ollier and Aarno Palotie and Antony Payton and Neil Pendleton and Poldrack, \{Russell A.\} and Katri R{\"a}ikk{\"o}nen and Ivar Reinvang and Panos Roussos and Dan Rujescu and Sabb, \{Fred W.\} and Scult, \{Matthew A.\} and Smeland, \{Olav B.\} and Nikolaos Smyrnis and Starr, \{John M.\} and Steen, \{Vidar M.\} and Stefanis, \{Nikos C.\} and Straub, \{Richard E.\} and Kjetil Sundet and Henning Tiemeier and Voineskos, \{Aristotle N.\} and Weinberger, \{Daniel R.\} and Elisabeth Widen and Jin Yu and Goncalo Abecasis and Andreassen, \{Ole A.\} and Gerome Breen and Lene Christiansen and Birgit Debrabant and Dick, \{Danielle M.\} and Andreas Heinz and Jens Hjerling-Leffler and Ikram, \{M. Arfan\} and Kendler, \{Kenneth S.\} and Martin, \{Nicholas G.\} and Medland, \{Sarah E.\} and Pedersen, \{Nancy L.\} and Robert Plomin and Polderman, \{Tinca J.C.\} and Stephan Ripke and \{Van Der Sluis\}, Sophie and Sullivan, \{Patrick F.\} and Vrieze, \{Scott I.\} and Wright, \{Margaret J.\} and Danielle Posthuma",

note = "Publisher Copyright: {\textcopyright} 2018 The Author(s).",

year = "2018",

month = jul,

day = "1",

doi = "10.1038/s41588-018-0152-6",

language = "English",

volume = "50",

pages = "912--919",

journal = "Nature Genetics",

issn = "1061-4036",

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Savage, JE, Jansen, PR, Stringer, S, Watanabe, K, Bryois, J, De Leeuw, CA, Nagel, M, Awasthi, S, Barr, PB, Coleman, JRI, Grasby, KL, Hammerschlag, AR, Kaminski, JA, Karlsson, R, Krapohl, E, Lam, M, Nygaard, M, Reynolds, CA, Trampush, JW, Young, H, Zabaneh, D, Hägg, S, Hansell, NK, Karlsson, IK, Linnarsson, S, Montgomery, GW, Muñoz-Manchado, AB, Quinlan, EB, Schumann, G, Skene, NG, Webb, BT, White, T, Arking, DE, Avramopoulos, D, Bilder, RM, Bitsios, P, Burdick, KE, Cannon, TD, Chiba-Falek, O, Christoforou, A, Cirulli, ET, Congdon, E, Corvin, A, Davies, G, Deary, IJ, Derosse, P, Dickinson, D, Djurovic, S, Donohoe, G, Conley, ED, Eriksson, JG, Espeseth, T, Freimer, NA, Giakoumaki, S, Giegling, I, Gill, M, Glahn, DC, Hariri, AR, Hatzimanolis, A, Keller, MC, Knowles, E, Koltai, D, Konte, B, Lahti, J, Le Hellard, S, Lencz, T, Liewald, DC, London, E, Lundervold, AJ, Malhotra, AK, Melle, I, Morris, D, Need, AC, Ollier, W, Palotie, A, Payton, A, Pendleton, N, Poldrack, RA, Räikkönen, K, Reinvang, I, Roussos, P, Rujescu, D, Sabb, FW, Scult, MA, Smeland, OB, Smyrnis, N, Starr, JM, Steen, VM, Stefanis, NC, Straub, RE, Sundet, K, Tiemeier, H, Voineskos, AN, Weinberger, DR, Widen, E, Yu, J, Abecasis, G, Andreassen, OA, Breen, G, Christiansen, L, Debrabant, B, Dick, DM, Heinz, A, Hjerling-Leffler, J, Ikram, MA, Kendler, KS, Martin, NG, Medland, SE, Pedersen, NL, Plomin, R, Polderman, TJC, Ripke, S, Van Der Sluis, S, Sullivan, PF, Vrieze, SI, Wright, MJ & Posthuma, D 2018, 'Genome-wide association meta-analysis in 269,867 individuals identifies new genetic and functional links to intelligence', Nature Genetics, vol. 50, no. 7, pp. 912-919. https://doi.org/10.1038/s41588-018-0152-6

TY - JOUR

T1 - Genome-wide association meta-analysis in 269,867 individuals identifies new genetic and functional links to intelligence

AU - Savage, Jeanne E.

AU - Jansen, Philip R.

AU - Stringer, Sven

AU - Watanabe, Kyoko

AU - Bryois, Julien

AU - De Leeuw, Christiaan A.

AU - Nagel, Mats

AU - Awasthi, Swapnil

AU - Barr, Peter B.

AU - Coleman, Jonathan R.I.

AU - Grasby, Katrina L.

AU - Hammerschlag, Anke R.

AU - Kaminski, Jakob A.

AU - Karlsson, Robert

AU - Krapohl, Eva

AU - Lam, Max

AU - Nygaard, Marianne

AU - Reynolds, Chandra A.

AU - Trampush, Joey W.

AU - Young, Hannah

AU - Zabaneh, Delilah

AU - Hägg, Sara

AU - Hansell, Narelle K.

AU - Karlsson, Ida K.

AU - Linnarsson, Sten

AU - Montgomery, Grant W.

AU - Muñoz-Manchado, Ana B.

AU - Quinlan, Erin B.

AU - Schumann, Gunter

AU - Skene, Nathan G.

AU - Webb, Bradley T.

AU - White, Tonya

AU - Arking, Dan E.

AU - Avramopoulos, Dimitrios

AU - Bilder, Robert M.

AU - Bitsios, Panos

AU - Burdick, Katherine E.

AU - Cannon, Tyrone D.

AU - Chiba-Falek, Ornit

AU - Christoforou, Andrea

AU - Cirulli, Elizabeth T.

AU - Congdon, Eliza

AU - Corvin, Aiden

AU - Davies, Gail

AU - Deary, Ian J.

AU - Derosse, Pamela

AU - Dickinson, Dwight

AU - Djurovic, Srdjan

AU - Donohoe, Gary

AU - Conley, Emily Drabant

AU - Eriksson, Johan G.

AU - Espeseth, Thomas

AU - Freimer, Nelson A.

AU - Giakoumaki, Stella

AU - Giegling, Ina

AU - Gill, Michael

AU - Glahn, David C.

AU - Hariri, Ahmad R.

AU - Hatzimanolis, Alex

AU - Keller, Matthew C.

AU - Knowles, Emma

AU - Koltai, Deborah

AU - Konte, Bettina

AU - Lahti, Jari

AU - Le Hellard, Stephanie

AU - Lencz, Todd

AU - Liewald, David C.

AU - London, Edythe

AU - Lundervold, Astri J.

AU - Malhotra, Anil K.

AU - Melle, Ingrid

AU - Morris, Derek

AU - Need, Anna C.

AU - Ollier, William

AU - Palotie, Aarno

AU - Payton, Antony

AU - Pendleton, Neil

AU - Poldrack, Russell A.

AU - Räikkönen, Katri

AU - Reinvang, Ivar

AU - Roussos, Panos

AU - Rujescu, Dan

AU - Sabb, Fred W.

AU - Scult, Matthew A.

AU - Smeland, Olav B.

AU - Smyrnis, Nikolaos

AU - Starr, John M.

AU - Steen, Vidar M.

AU - Stefanis, Nikos C.

AU - Straub, Richard E.

AU - Sundet, Kjetil

AU - Tiemeier, Henning

AU - Voineskos, Aristotle N.

AU - Weinberger, Daniel R.

AU - Widen, Elisabeth

AU - Yu, Jin

AU - Abecasis, Goncalo

AU - Andreassen, Ole A.

AU - Breen, Gerome

AU - Christiansen, Lene

AU - Debrabant, Birgit

AU - Dick, Danielle M.

AU - Heinz, Andreas

AU - Hjerling-Leffler, Jens

AU - Ikram, M. Arfan

AU - Kendler, Kenneth S.

AU - Martin, Nicholas G.

AU - Medland, Sarah E.

AU - Pedersen, Nancy L.

AU - Plomin, Robert

AU - Polderman, Tinca J.C.

AU - Ripke, Stephan

AU - Van Der Sluis, Sophie

AU - Sullivan, Patrick F.

AU - Vrieze, Scott I.

AU - Wright, Margaret J.

AU - Posthuma, Danielle

PY - 2018/7/1

Y1 - 2018/7/1

N2 - Intelligence is highly heritable 1 and a major determinant of human health and well-being 2 . Recent genome-wide meta-analyses have identified 24 genomic loci linked to variation in intelligence 3-7 , 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.

AB - Intelligence is highly heritable 1 and a major determinant of human health and well-being 2 . Recent genome-wide meta-analyses have identified 24 genomic loci linked to variation in intelligence 3-7 , 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.

UR - https://www.scopus.com/pages/publications/85048943479

U2 - 10.1038/s41588-018-0152-6

DO - 10.1038/s41588-018-0152-6

M3 - Article

C2 - 29942086

AN - SCOPUS:85048943479

SN - 1061-4036

VL - 50

SP - 912

EP - 919

JO - Nature Genetics

JF - Nature Genetics

IS - 7

ER -

Genome-wide association meta-analysis in 269,867 individuals identifies new genetic and functional links to intelligence

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