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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.

SUBMITTER: Savage JE

PROVIDER: S-EPMC6411041 | biostudies-literature | 2018 Jul

REPOSITORIES: biostudies-literature

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

Savage Jeanne E JE Jansen Philip R PR Stringer Sven S Watanabe Kyoko K Bryois Julien J de Leeuw Christiaan A CA Nagel Mats M Awasthi Swapnil S Barr Peter B PB Coleman Jonathan R I JRI Grasby Katrina L KL Hammerschlag Anke R AR Kaminski Jakob A JA Karlsson Robert R Krapohl Eva E Lam Max M Nygaard Marianne M Reynolds Chandra A CA Trampush Joey W JW Young Hannah H Zabaneh Delilah D Hägg Sara S Hansell Narelle K NK Karlsson Ida K IK Linnarsson Sten S Montgomery Grant W GW Muñoz-Manchado Ana B AB Quinlan Erin B EB Schumann Gunter G Skene Nathan G NG Webb Bradley T BT White Tonya T Arking Dan E DE Avramopoulos Dimitrios D Bilder Robert M RM Bitsios Panos P Burdick Katherine E KE Cannon Tyrone D TD Chiba-Falek Ornit O Christoforou Andrea A Cirulli Elizabeth T ET Congdon Eliza E Corvin Aiden A Davies Gail G Deary Ian J IJ DeRosse Pamela P Dickinson Dwight D Djurovic Srdjan S Donohoe Gary G Conley Emily Drabant ED Eriksson Johan G JG Espeseth Thomas T Freimer Nelson A NA Giakoumaki Stella S Giegling Ina I Gill Michael M Glahn David C DC Hariri Ahmad R AR Hatzimanolis Alex A Keller Matthew C MC Knowles Emma E Koltai Deborah D Konte Bettina B Lahti Jari J Le Hellard Stephanie S Lencz Todd T Liewald David C DC London Edythe E Lundervold Astri J AJ Malhotra Anil K AK Melle Ingrid I Morris Derek D Need Anna C AC Ollier William W Palotie Aarno A Payton Antony A Pendleton Neil N Poldrack Russell A RA Räikkönen Katri K Reinvang Ivar I Roussos Panos P Rujescu Dan D Sabb Fred W FW Scult Matthew A MA Smeland Olav B OB Smyrnis Nikolaos N Starr John M JM Steen Vidar M VM Stefanis Nikos C NC Straub Richard E RE Sundet Kjetil K Tiemeier Henning H Voineskos Aristotle N AN Weinberger Daniel R DR Widen Elisabeth E Yu Jin J Abecasis Goncalo G Andreassen Ole A OA Breen Gerome G Christiansen Lene L Debrabant Birgit B Dick Danielle M DM Heinz Andreas A Hjerling-Leffler Jens J Ikram M Arfan MA Kendler Kenneth S KS Martin Nicholas G NG Medland Sarah E SE Pedersen Nancy L NL Plomin Robert R Polderman Tinca J C TJC Ripke Stephan S van der Sluis Sophie S Sullivan Patrick F PF Vrieze Scott I SI Wright Margaret J MJ Posthuma Danielle D

Nature genetics 20180625 7

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 quant ...[more]

PMID: 29942086

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Project description:Disrupted circadian rhythms and reduced sleep duration are associated with several human diseases, particularly obesity and type 2 diabetes, but until recently, little was known about the genetic factors influencing these heritable traits. We performed genome-wide association studies of self-reported chronotype (morning/evening person) and self-reported sleep duration in 128,266 white British individuals from the UK Biobank study. Sixteen variants were associated with chronotype (P<5x10-8), including variants near the known circadian rhythm genes RGS16 (1.21 odds of morningness, 95% CI [1.15, 1.27], P = 3x10-12) and PER2 (1.09 odds of morningness, 95% CI [1.06, 1.12], P = 4x10-10). The PER2 signal has previously been associated with iris function. We sought replication using self-reported data from 89,283 23andMe participants; thirteen of the chronotype signals remained associated at P<5x10-8 on meta-analysis and eleven of these reached P<0.05 in the same direction in the 23andMe study. We also replicated 9 additional variants identified when the 23andMe study was used as a discovery GWAS of chronotype (all P<0.05 and meta-analysis P<5x10-8). For sleep duration, we replicated one known signal in PAX8 (2.6 minutes per allele, 95% CI [1.9, 3.2], P = 5.7x10-16) and identified and replicated two novel associations at VRK2 (2.0 minutes per allele, 95% CI [1.3, 2.7], P = 1.2x10-9; and 1.6 minutes per allele, 95% CI [1.1, 2.2], P = 7.6x10-9). Although we found genetic correlation between chronotype and BMI (rG = 0.056, P = 0.05); undersleeping and BMI (rG = 0.147, P = 1x10-5) and oversleeping and BMI (rG = 0.097, P = 0.04), Mendelian Randomisation analyses, with limited power, provided no consistent evidence of causal associations between BMI or type 2 diabetes and chronotype or sleep duration. Our study brings the total number of loci associated with chronotype to 22 and with sleep duration to three, and provides new insights into the biology of sleep and circadian rhythms in humans.

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

Publications

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

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