title: A genome-wide analysis of putative functional and exonic variation associated with extremely high intelligence.
abstract: Although individual differences in intelligence (general cognitive ability) are highly heritable, molecular genetic analyses to date have had limited success in identifying specific loci responsible for its heritability. This study is the first to investigate exome variation in individuals of extremely high intelligence. Under the quantitative genetic model, sampling from the high extreme of the distribution should provide increased power to detect associations. We therefore performed a case-control association analysis with 1409 individuals drawn from the top 0.0003 (IQ >170) of the population distribution of intelligence and 3253 unselected population-based controls. Our analysis focused on putative functional exonic variants assayed on the Illumina HumanExome BeadChip. We did not observe any individual protein-altering variants that are reproducibly associated with extremely high intelligence and within the entire distribution of intelligence. Moreover, no significant associations were found for multiple rare alleles within individual genes. However, analyses using genome-wide similarity between unrelated individuals (genome-wide complex trait analysis) indicate that the genotyped functional protein-altering variation yields a heritability estimate of 17.4% (s.e. 1.7%) based on a liability model. In addition, investigation of nominally significant associations revealed fewer rare alleles associated with extremely high intelligence than would be expected under the null hypothesis. This observation is consistent with the hypothesis that rare functional alleles are more frequently detrimental than beneficial to intelligence.
authors.affiliation: Department of Medical and Molecular Genetics, Division of Genetics and Molecular Medicine, King's College London, London, UK.
authors.forename: S L
authors.initials: SL
authors.lastname: Spain
authors.affiliation: Department of Medical and Molecular Genetics, Division of Genetics and Molecular Medicine, King's College London, London, UK.
authors.forename: I
authors.initials: I
authors.lastname: Pedroso
authors.affiliation: Department of Medical and Molecular Genetics, Division of Genetics and Molecular Medicine, King's College London, London, UK.
authors.forename: N
authors.initials: N
authors.lastname: Kadeva
authors.affiliation: Department of Psychology, University of Minnesota, Minneapolis, MN, USA.
authors.forename: M B
authors.initials: MB
authors.lastname: Miller
authors.affiliation: Department of Psychology, University of Minnesota, Minneapolis, MN, USA.
authors.forename: W G
authors.initials: WG
authors.lastname: Iacono
authors.affiliation: Department of Psychology, University of Minnesota, Minneapolis, MN, USA.
authors.forename: M
authors.initials: M
authors.lastname: McGue
authors.affiliation: MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK.
authors.forename: E
authors.initials: E
authors.lastname: Stergiakouli
authors.affiliation: MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK.
authors.forename: G
authors.initials: G
authors.lastname: Davey Smith
authors.affiliation: Duke University Talent Identification Program, Duke University, Durham, NC, USA.
authors.forename: M
authors.initials: M
authors.lastname: Putallaz
authors.affiliation: Department of Psychology and Human Development, Vanderbilt University, Nashville, TN, USA.
authors.forename: D
authors.initials: D
authors.lastname: Lubinski
authors.affiliation: Department of Psychological Sciences, Birkbeck, University of London, London, UK.
authors.forename: E L
authors.initials: EL
authors.lastname: Meaburn
authors.affiliation: MRC Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
authors.forename: R
authors.initials: R
authors.lastname: Plomin
authors.affiliation: Department of Medical and Molecular Genetics, Division of Genetics and Molecular Medicine, King's College London, London, UK.
authors.forename: M A
authors.initials: MA
authors.lastname: Simpson
mesh_terms: D000328:Adult; D000483:Alleles; D003071:Cognition; D059472:Exome / Q000235:genetics; D005091:Exons / Q000235:genetics; D005260:Female; D005787:Gene Frequency / Q000235:genetics; D014644:Genetic Variation / Q000235:genetics; D055106:Genome-Wide Association Study / Q000379:methods; D005838:Genotype; D006801:Humans; D007360:Intelligence / Q000235:genetics*; D008297:Male; D020412:Multifactorial Inheritance / Q000235:genetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D019655:Quantitative Trait, Heritable