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 - Christiansen, Lene
AU - Debrabant, Birgit
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.
KW - Adolescent
KW - Brain/physiology
KW - Female
KW - Genetic Predisposition to Disease
KW - Genome-Wide Association Study/methods
KW - Humans
KW - Intelligence/genetics
KW - Male
KW - Middle Aged
KW - Polymorphism, Single Nucleotide
KW - Quantitative Trait Loci
U2 - 10.1038/s41588-018-0152-6
DO - 10.1038/s41588-018-0152-6
M3 - Journal article
C2 - 29942086
AN - SCOPUS:85048943479
SN - 1061-4036
VL - 50
SP - 912
EP - 919
JO - Nature Genetics
JF - Nature Genetics
IS - 7
ER -