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.
Highlights
IntroductionIntelligence is a normally distributed quantitative trait with a positive end of high performance as well as a problematic end of intellectual disability.[6] Unlike other normally distributed behavioural traits, such as personality that assess average behaviour across situations, intelligence indexes maximal performance on a battery of tests, analogous to musical ability and athletic ability.[7] These features of intelligence make it especially well suited phenotypically as a target for positive genetics—that is, considering the positive end of the normal distribution of genetic effects rather than focusing on the negative effects of genetic mutations.[8] The investigation of high intelligence could be of particular utility for finding DNA variants responsible for the heritability of the entire distribution of intelligence
General cognitive ability, usually called intelligence, indexes the covariance among diverse cognitive tests and is one of the best predictors of important life outcomes such as education, occupation, and mental and physical health and illness.[1,2,3]Extensive quantitative genetic research consistently indicates that about half of the total variance of intelligence can be accounted for by genetic factors.[4,5]Unlike psychiatric disorders, intelligence is a normally distributed quantitative trait with a positive end of high performance as well as a problematic end of intellectual disability.[6]
The quantitative genetics model proposes that quantitative traits are influenced by multiple genes distributed as a bell-shaped curve, which implies that extremely high intelligence can be achieved only if an individual has many of the positive alleles and few of the negative alleles that affect intelligence
Summary
Intelligence is a normally distributed quantitative trait with a positive end of high performance as well as a problematic end of intellectual disability.[6] Unlike other normally distributed behavioural traits, such as personality that assess average behaviour across situations, intelligence indexes maximal performance on a battery of tests, analogous to musical ability and athletic ability.[7] These features of intelligence make it especially well suited phenotypically as a target for positive genetics—that is, considering the positive end of the normal distribution of genetic effects rather than focusing on the negative effects of genetic mutations.[8] The investigation of high intelligence could be of particular utility for finding DNA variants responsible for the heritability of the entire distribution of intelligence. A large group of individuals of extremely high intelligence should be enriched for alleles associated with intelligence and yield increased power to detect associations.[9]
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