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 YoungDelilah 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

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Abstract

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.

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
Publication status	Published - 1 Jul 2018

Funding

P.F.S. reports the following potentially competing financial interests: Lundbeck (advisory committee), Pfizer (scientific advisory board member), and Roche (grant recipient, speaker reimbursement). G.B. reports consultancy and speaker fees from Eli Lilly and Illumina and grant funding from Eli Lilly. J.H.-L. reports interests from Cartana (scientific advisor) and Roche (grant recipient). T.D.C. is a consultant to Boehringer Ingelheim Pharmaceuticals and Lundbeck. All other authors declare no financial interests or potential conflicts of interest. This work was funded by the Netherlands Organization for Scientific Research through the following grants: NWO Brain and Cognition 433-09-228 (D.P.), NWO MagW VIDI 452-12-014 (S.v.d.S.), NWO VICI 453-13-005 (D.P.), and 645-000-003 (D.P.). P.R.J. was funded by the Sophia Foundation for Scientific Research (SSWO, grant S14-27 to P.R.J.). The analyses were carried out on the Genetic Cluster Computer, which is financed by the Netherlands Scientific Organization (NWO: 480-05-003 to D.P.), Vrije Universiteit, Amsterdam, The Netherlands, and the Dutch Brain Foundation, and is hosted by the Dutch National Computing and Networking Services, SurfSARA. J.H.-L. was funded by the Swedish Research Council (Vetenskapsrådet, award 20143863), StratNeuro, the Wellcome Trust (108726/Z/15/Z), and the Swedish Brain Foundation (Hjärnfonden). N.G.S. was supported by the Wellcome Trust (108726/Z/15/Z). J.B. was funded by the Swiss National Science Foundation. This research has been conducted using the UK Biobank resource under application 16406. We thank the numerous participants, researchers, and staff from many studies who collected and contributed to the data. Additional acknowledgements can be found in the Supplementary Information.

Funders	Funder number
Dutch Brain Foundation
Dutch National Computing and Networking Services
Netherlands Organization for Scientific Research
Netherlands Scientific Organization	480-05-003
SSWO	S14-27
Sophia Foundation for Scientific Research
Swedish Brain Foundation
National Institute on Aging	R01AG049789
Eli Lilly and Company
Roche
Wellcome Trust	108726/Z/15/Z
Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung
Nederlandse Organisatie voor Wetenschappelijk Onderzoek	645-000-003, VICI 453-13-005, MagW VIDI 452-12-014
Vetenskapsrådet	20143863

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10.1038/s41588-018-0152-6

Genome-wide association meta-analysis in 269,867 individuals identifies new genetic and functional links to intelligenceFinal published version, 4.46 MBLicence: Article 25fa Dutch Copyright Act

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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

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

abstract = "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.",

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",

year = "2018",

month = jul,

day = "1",

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

language = "English",

volume = "50",

pages = "912--919",

journal = "Nature Genetics",

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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 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.

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.

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U2 - 10.1038/s41588-018-0152-6

DO - 10.1038/s41588-018-0152-6

M3 - Article

C2 - 29942086

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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