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

Savage, Jeanne E and Jansen, Philip R and Stringer, Sven and Watanabe, Kyoko and Bryois, Julien and de Leeuw, Christiaan A and Nagel, Mats and Awasthi, Swapnil and Barr, Peter B and Coleman, Jonathan RI and Grasby, Katrina L and Hammerschlag, Anke R and Kaminski, Jakob A and Karlsson, Robert and Krapohl, Eva and Lam, Max and Nygaard, Marianne and Reynolds, Chandra A and Trampush, Joey W and Young, Hannah and Zabaneh, Delilah and Hägg, Sara and Hansell, Narelle K and Karlsson, Ida K and Linnarsson, Sten and Montgomery, Grant W and Muñoz-Manchado, Ana B and Quinlan, Erin B and Schumann, Gunter and Skene, Nathan G and Webb, Bradley T and White, Tonya and Arking, Dan E and Avramopoulos, Dimitrios and Bilder, Robert M and Bitsios, Panos and Burdick, Katherine E and Cannon, Tyrone D and Chiba-Falek, Ornit and Christoforou, Andrea and Cirulli, Elizabeth T and Congdon, Eliza and Corvin, Aiden and Davies, Gail and Deary, Ian J and DeRosse, Pamela and Dickinson, Dwight and Djurovic, Srdjan and Donohoe, Gary and Conley, Emily Drabant and Eriksson, Johan G and Espeseth, Thomas and Freimer, Nelson A and Giakoumaki, Stella and Giegling, Ina and Gill, Michael and Glahn, David C and Hariri, Ahmad R and Hatzimanolis, Alex and Keller, Matthew C and Knowles, Emma and Koltai, Deborah and Konte, Bettina and Lahti, Jari and Le Hellard, Stephanie and Lencz, Todd and Liewald, David C and London, Edythe and Lundervold, Astri J and Malhotra, Anil K and Melle, Ingrid and Morris, Derek and Need, Anna C and Ollier, William and Palotie, Aarno and Payton, Antony and Pendleton, Neil and Poldrack, Russell A and Räikkönen, Katri and Reinvang, Ivar and Roussos, Panos and Rujescu, Dan and Sabb, Fred W and Scult, Matthew A and Smeland, Olav B and Smyrnis, Nikolaos and Starr, John M and Steen, Vidar M and Stefanis, Nikos C and Straub, Richard E and Sundet, Kjetil and Tiemeier, Henning and Voineskos, Aristotle N and Weinberger, Daniel R and Widen, Elisabeth and Yu, Jin and Abecasis, Goncalo and Andreassen, Ole A and Breen, Gerome and Christiansen, Lene and Debrabant, Birgit and Dick, Danielle M and Heinz, Andreas and Hjerling-Leffler, Jens and Ikram, M Arfan and Kendler, Kenneth S and Martin, Nicholas G and Medland, Sarah E and Pedersen, Nancy L and Plomin, Robert and Polderman, Tinca JC and Ripke, Stephan and van der Sluis, Sophie and Sullivan, Patrick F and Vrieze, Scott I and Wright, Margaret J and Posthuma, Danielle (2018) Genome-wide association meta-analysis in 269,867 individuals identifies new genetic and functional links to intelligence. Nature Genetics, 50 (7). pp. 912-919. ISSN 1061-4036

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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 intelligence3,4,5,6,7, 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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