Genome-wide association meta-analysis of 78,308 individuals identifies new loci and genes influencing human intelligence

Intelligence is associated with important economic and health-related life outcomes. Despite intelligence having substantial heritability (0.54) and a confirmed polygenic nature, initial genetic studies were mostly underpowered. Here we report a meta-analysis for intelligence of 78,308 individuals. We identify 336 associated SNPs (METAL P < 5 × 10−8) in 18 genomic loci, of which 15 are new. Around half of the SNPs are located inside a gene, implicating 22 genes, of which 11 are new findings. Gene-based analyses identified an additional 30 genes (MAGMA P < 2.73 × 10−6), of which all but one had not been implicated previously. We show that the identified genes are predominantly expressed in brain tissue, and pathway analysis indicates the involvement of genes regulating cell development (MAGMA competitive P = 3.5 × 10−6). Despite the well-known difference in twin-based heritability for intelligence in childhood (0.45) and adulthood (0.80), we show substantial genetic correlation (rg = 0.89, LD score regression P = 5.4 × 10−29). These findings provide new insight into the genetic architecture of intelligence.

[1]  A. Hofman,et al.  Disease variants alter transcription factor levels and methylation of their binding sites , 2016, Nature Genetics.

[2]  M. Ashburner,et al.  Gene Ontology: tool for the unification of biology , 2000, Nature Genetics.

[3]  M. Peters,et al.  Systematic identification of trans eQTLs as putative drivers of known disease associations , 2013, Nature Genetics.

[4]  Richard A. Gibbs,et al.  Novel Genetic Loci Identified for the Pathophysiology of Childhood Obesity in the Hispanic Population , 2012, PloS one.

[5]  U. Brinkmann,et al.  CSE1L/CAS: Its role in proliferation and apoptosis , 2004, Apoptosis.

[6]  P. Donnelly,et al.  A new multipoint method for genome-wide association studies by imputation of genotypes , 2007, Nature Genetics.

[7]  M. Daly,et al.  LD Score regression distinguishes confounding from polygenicity in genome-wide association studies , 2014, Nature Genetics.

[8]  Jonathan P. Beauchamp,et al.  Most Reported Genetic Associations With General Intelligence Are Probably False Positives , 2012, Psychological science.

[9]  I. Deary,et al.  The neuroscience of human intelligence differences , 2010, Nature Reviews Neuroscience.

[10]  Christian Gieger,et al.  Six new loci associated with body mass index highlight a neuronal influence on body weight regulation , 2009, Nature Genetics.

[11]  Ross M. Fraser,et al.  Genetic studies of body mass index yield new insights for obesity biology , 2015, Nature.

[12]  Pablo Tamayo,et al.  Gene set enrichment analysis: A knowledge-based approach for interpreting genome-wide expression profiles , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[13]  Mark I McCarthy,et al.  Genomic inflation factors under polygenic inheritance , 2011, European Journal of Human Genetics.

[14]  Thomas J. Bouchard,et al.  Just one g: consistent results from three test batteries , 2004 .

[15]  A Hofman,et al.  Genetic contributions to variation in general cognitive function: a meta-analysis of genome-wide association studies in the CHARGE consortium (N=53 949) , 2015, Molecular Psychiatry.

[16]  P. Elliott,et al.  UK Biobank: An Open Access Resource for Identifying the Causes of a Wide Range of Complex Diseases of Middle and Old Age , 2015, PLoS medicine.

[17]  Malcolm James Ree,et al.  The stability of g across different methods of estimation , 1991 .

[18]  Stefan Schreiber,et al.  Association of FOXO3A variation with human longevity confirmed in German centenarians , 2009, Proceedings of the National Academy of Sciences.

[19]  Henning Hermjakob,et al.  The Reactome pathway Knowledgebase , 2015, Nucleic acids research.

[20]  JoAnn E. Manson,et al.  Gene-environment interactions and obesity traits among postmenopausal African-American and Hispanic women in the Women’s Health Initiative SHARe Study , 2012, Human Genetics.

[21]  Katsuhiko Yano,et al.  FOXO3A genotype is strongly associated with human longevity , 2008, Proceedings of the National Academy of Sciences.

[22]  Inês Barroso,et al.  Genome-wide SNP and CNV analysis identifies common and low-frequency variants associated with severe early-onset obesity , 2013, Nature Genetics.

[23]  Eurie L. Hong,et al.  Annotation of functional variation in personal genomes using RegulomeDB , 2012, Genome research.

[24]  Jun S. Liu,et al.  The Genotype-Tissue Expression (GTEx) pilot analysis: Multitissue gene regulation in humans , 2015, Science.

[25]  Yun Li,et al.  METAL: fast and efficient meta-analysis of genomewide association scans , 2010, Bioinform..

[26]  P. Visscher,et al.  Childhood intelligence is heritable, highly polygenic and associated with FNBP1L , 2014, Molecular Psychiatry.

[27]  Ian J. Deary,et al.  Common genetic variants associated with cognitive performance identified using the proxy-phenotype method , 2014, Proceedings of the National Academy of Sciences.

[28]  P. Visscher,et al.  Nature Genetics Advance Online Publication , 2022 .

[29]  Joris M. Mooij,et al.  MAGMA: Generalized Gene-Set Analysis of GWAS Data , 2015, PLoS Comput. Biol..

[30]  C. Sudlow,et al.  UK Biobank Data: Come and Get It , 2014, Science Translational Medicine.

[31]  Lorna M. Lopez,et al.  Genome-wide association studies establish that human intelligence is highly heritable and polygenic , 2011, Molecular Psychiatry.

[32]  C. Spencer,et al.  Biological Insights From 108 Schizophrenia-Associated Genetic Loci , 2014, Nature.

[33]  Marcel J. T. Reinders,et al.  2D Representation of Transcriptomes by t-SNE Exposes Relatedness between Human Tissues , 2016, PloS one.

[34]  J. Murabito,et al.  The epidemiology of longevity and exceptional survival. , 2013, Epidemiologic reviews.

[35]  Stuart J. Ritchie,et al.  Genome-wide association study of cognitive functions and educational attainment in UK Biobank (N=112 151) , 2016, Molecular Psychiatry.

[36]  Christian Gieger,et al.  Genome-wide meta-analysis identifies 11 new loci for anthropometric traits and provides insights into genetic architecture , 2013, Nature Genetics.

[37]  Jonathan P. Beauchamp,et al.  Genome-wide association study identifies 74 loci associated with educational attainment , 2016, Nature.

[38]  Michael Q. Zhang,et al.  Integrative analysis of 111 reference human epigenomes , 2015, Nature.

[39]  Michael Boehnke,et al.  LocusZoom: regional visualization of genome-wide association scan results , 2010, Bioinform..

[40]  Henrik,et al.  Association analyses of 249,796 individuals reveal eighteen new loci associated with body mass index , 2012 .

[41]  J. Shendure,et al.  A general framework for estimating the relative pathogenicity of human genetic variants , 2014, Nature Genetics.

[42]  O. Andreassen,et al.  Beyond SNP Heritability: Polygenicity and Discoverability of Phenotypes Estimated with a Univariate Gaussian Mixture Model , 2018 .

[43]  P. Visscher,et al.  Modeling Linkage Disequilibrium Increases Accuracy of Polygenic Risk Scores , 2015, bioRxiv.

[44]  Manolis Kellis,et al.  ChromHMM: automating chromatin-state discovery and characterization , 2012, Nature Methods.