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 & 97 others 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 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 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

Research output: Contribution to journalArticle

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 languageEnglish (US)
Pages (from-to)912-919
Number of pages8
JournalNature Genetics
Volume50
Issue number7
DOIs
StatePublished - Jul 1 2018

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Genome-Wide Association Study
Intelligence
Meta-Analysis
Mendelian Randomization Analysis
Genes
Corpus Striatum
Neurobiology
Pyramidal Cells
Chromosome Mapping
Quantitative Trait Loci
Health
Genetic Association Studies
Nervous System Diseases
Causality
Cognition
Nervous System
Chromatin
Psychiatry
Schizophrenia
Alzheimer Disease

ASJC Scopus subject areas

  • Genetics

Cite this

Savage, J. E., Jansen, P. R., Stringer, S., Watanabe, K., Bryois, J., De Leeuw, C. A., ... 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

Genome-wide association meta-analysis in 269,867 individuals identifies new genetic and functional links to intelligence. / Savage, Jeanne E.; Jansen, Philip R.; Stringer, Sven; Watanabe, Kyoko; Bryois, Julien; De Leeuw, Christiaan A.; Nagel, Mats; Awasthi, Swapnil; Barr, Peter B.; Coleman, Jonathan R.I.; Grasby, Katrina L.; Hammerschlag, Anke R.; Kaminski, Jakob A.; Karlsson, Robert; Krapohl, Eva; Lam, Max; Nygaard, Marianne; Reynolds, Chandra A.; Trampush, Joey W.; Young, Hannah; Zabaneh, Delilah; Hägg, Sara; Hansell, Narelle K.; Karlsson, Ida K.; Linnarsson, Sten; Montgomery, Grant W.; Muñoz-Manchado, Ana B.; Quinlan, Erin B.; Schumann, Gunter; Skene, Nathan G.; Webb, Bradley T.; White, Tonya; Arking, Dan; Avramopoulos, Dimitrios; Bilder, Robert M.; Bitsios, Panos; Burdick, Katherine E.; Cannon, Tyrone D.; Chiba-Falek, Ornit; Christoforou, Andrea; Cirulli, Elizabeth T.; Congdon, Eliza; Corvin, Aiden; Davies, Gail; Deary, Ian J.; Derosse, Pamela; Dickinson, Dwight; Djurovic, Srdjan; Donohoe, Gary; Conley, Emily Drabant; Eriksson, Johan G.; Espeseth, Thomas; Freimer, Nelson A.; Giakoumaki, Stella; Giegling, Ina; Gill, Michael; Glahn, David C.; Hariri, Ahmad R.; Hatzimanolis, Alex; Keller, Matthew C.; Knowles, Emma; Koltai, Deborah; Konte, Bettina; Lahti, Jari; Le Hellard, Stephanie; Lencz, Todd; Liewald, David C.; London, Edythe; Lundervold, Astri J.; Malhotra, Anil K.; Melle, Ingrid; Morris, Derek; Need, Anna C.; Ollier, William; Palotie, Aarno; Payton, Antony; Pendleton, Neil; Poldrack, Russell A.; Räikkönen, Katri; Reinvang, Ivar; Roussos, Panos; Rujescu, Dan; Sabb, Fred W.; Scult, Matthew A.; Smeland, Olav B.; Smyrnis, Nikolaos; Starr, John M.; Steen, Vidar M.; Stefanis, Nikos C.; Straub, Richard E.; Sundet, Kjetil; Tiemeier, Henning; Voineskos, Aristotle N.; Weinberger, Daniel; Widen, Elisabeth; Yu, Jin; Abecasis, Goncalo; Andreassen, Ole A.; Breen, Gerome; Christiansen, Lene; Debrabant, Birgit; Dick, Danielle M.; Heinz, Andreas; Hjerling-Leffler, Jens; Ikram, M. Arfan; Kendler, Kenneth S.; Martin, Nicholas G.; Medland, Sarah E.; Pedersen, Nancy L.; Plomin, Robert; Polderman, Tinca J.C.; Ripke, Stephan; Van Der Sluis, Sophie; Sullivan, Patrick F.; Vrieze, Scott I.; Wright, Margaret J.; Posthuma, Danielle.

In: Nature Genetics, Vol. 50, No. 7, 01.07.2018, p. 912-919.

Research output: Contribution to journalArticle

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, D, 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, D, 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
Savage, Jeanne E. ; Jansen, Philip R. ; Stringer, Sven ; Watanabe, Kyoko ; Bryois, Julien ; De Leeuw, Christiaan A. ; Nagel, Mats ; Awasthi, Swapnil ; Barr, Peter B. ; Coleman, Jonathan R.I. ; Grasby, Katrina L. ; Hammerschlag, Anke R. ; Kaminski, Jakob A. ; Karlsson, Robert ; Krapohl, Eva ; Lam, Max ; Nygaard, Marianne ; Reynolds, Chandra A. ; Trampush, Joey W. ; Young, Hannah ; Zabaneh, Delilah ; Hägg, Sara ; Hansell, Narelle K. ; Karlsson, Ida K. ; Linnarsson, Sten ; Montgomery, Grant W. ; Muñoz-Manchado, Ana B. ; Quinlan, Erin B. ; Schumann, Gunter ; Skene, Nathan G. ; Webb, Bradley T. ; White, Tonya ; Arking, Dan ; Avramopoulos, Dimitrios ; Bilder, Robert M. ; Bitsios, Panos ; Burdick, Katherine E. ; Cannon, Tyrone D. ; Chiba-Falek, Ornit ; Christoforou, Andrea ; Cirulli, Elizabeth T. ; Congdon, Eliza ; Corvin, Aiden ; Davies, Gail ; Deary, Ian J. ; Derosse, Pamela ; Dickinson, Dwight ; Djurovic, Srdjan ; Donohoe, Gary ; Conley, Emily Drabant ; Eriksson, Johan G. ; Espeseth, Thomas ; Freimer, Nelson A. ; Giakoumaki, Stella ; Giegling, Ina ; Gill, Michael ; Glahn, David C. ; Hariri, Ahmad R. ; Hatzimanolis, Alex ; Keller, Matthew C. ; Knowles, Emma ; Koltai, Deborah ; Konte, Bettina ; Lahti, Jari ; Le Hellard, Stephanie ; Lencz, Todd ; Liewald, David C. ; London, Edythe ; Lundervold, Astri J. ; Malhotra, Anil K. ; Melle, Ingrid ; Morris, Derek ; Need, Anna C. ; Ollier, William ; Palotie, Aarno ; Payton, Antony ; Pendleton, Neil ; Poldrack, Russell A. ; Räikkönen, Katri ; Reinvang, Ivar ; Roussos, Panos ; Rujescu, Dan ; Sabb, Fred W. ; Scult, Matthew A. ; Smeland, Olav B. ; Smyrnis, Nikolaos ; Starr, John M. ; Steen, Vidar M. ; Stefanis, Nikos C. ; Straub, Richard E. ; Sundet, Kjetil ; Tiemeier, Henning ; Voineskos, Aristotle N. ; Weinberger, Daniel ; Widen, Elisabeth ; Yu, Jin ; Abecasis, Goncalo ; Andreassen, Ole A. ; Breen, Gerome ; Christiansen, Lene ; Debrabant, Birgit ; Dick, Danielle M. ; Heinz, Andreas ; Hjerling-Leffler, Jens ; Ikram, M. Arfan ; Kendler, Kenneth S. ; Martin, Nicholas G. ; Medland, Sarah E. ; Pedersen, Nancy L. ; Plomin, Robert ; Polderman, Tinca J.C. ; Ripke, Stephan ; Van Der Sluis, Sophie ; Sullivan, Patrick F. ; Vrieze, Scott I. ; Wright, Margaret J. ; Posthuma, Danielle. / Genome-wide association meta-analysis in 269,867 individuals identifies new genetic and functional links to intelligence. In: Nature Genetics. 2018 ; Vol. 50, No. 7. pp. 912-919.
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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

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

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.

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