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 (US) |
|---|---|
| Pages (from-to) | 912-919 |
| Number of pages | 8 |
| Journal | Nature Genetics |
| Volume | 50 |
| Issue number | 7 |
| DOIs | |
| State | Published - Jul 1 2018 |
ASJC Scopus subject areas
- Genetics
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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 E.; 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 R.; 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 journal › Article › peer-review
}
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
N1 - Funding Information: 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. Funding Information: 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.
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 - http://www.scopus.com/inward/record.url?scp=85048943479&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85048943479&partnerID=8YFLogxK
U2 - 10.1038/s41588-018-0152-6
DO - 10.1038/s41588-018-0152-6
M3 - Article
C2 - 29942086
AN - SCOPUS:85048943479
VL - 50
SP - 912
EP - 919
JO - Nature Genetics
JF - Nature Genetics
SN - 1061-4036
IS - 7
ER -