A Functional Polymorphism under Positive Evolutionary Selection in ADRB2 is Associated with Human Intelligence with Opposite Effects in the Young and the Elderly

Abstract

Comparative genomics offers a novel approach to unravel the genetic basis of complex traits. We performed a two stage analysis where genes ascertained for enhanced protein evolution in primates are subsequently searched for the presence of non-synonymous coding SNPs in the current human population at amino acid sites that differ between humans and chimpanzee. Positively selected genes among primates are generally presumed to determine phenotypic differences between humans and chimpanzee, such as the enhanced cognitive ability of our species. Amino acid substitutions segregating in humans at positively selected amino acid sites are expected to affect phenotypic differences among humans. Therefore we conducted an association study in two family based cohorts and one population based cohort between cognitive ability and the most likely candidate gene among the five that harbored more than one such polymorphism. The derived, human-specific allele of the beta-2 adrenergic receptor Arg16Gly polymorphism was found to be the increaser allele for performance IQ in the young, family based cohort but the decreaser allele for two different measures of cognition in the large Scottish cohort of unrelated individuals. The polymorphism is known to affect signaling activity and modulation of beta-2 adrenergic signaling has been shown to adjust memory consolidation, a trait related 123Behav Genet (2009) 39:15-23 DOI 10.1007 to cognition. The opposite effect of the polymorphism on cognition in the two age classes observed in the different cohorts resembles the effect of ADRB2 on hypertension, which also has been reported to be age dependent. This result illustrates the relevance of comparative genomics to detect genes that are involved in human behavior.

White Matter Integrity in the Splenium of the Corpus Callosum is Related to Successful Cognitive Aging and Partly Mediates the Protective Effect of an Ancestral Polymorphism in ADRB2

“…At a second follow-up at a mean age of 72 years, Matrix Reasoning, a test of non-verbal reasoning from the WAIS-III UK (Wechsler 1998), was administered. These were the two cognitive tests that showed significant associations with ADRB2 in the full LBC1936 sample at age 70 (Bochdanovits et al 2009). …”

“…These two variants modulate receptor activity (Cockcroft et al 2000;Johnson 2006). The opposing effects of ADRB2 polymorphisms on cognitive ability in younger and older samples in the article by Bochdanovits et al (2009) might imply that it is more closely related to individual differences in normal cognitive aging than to lifelong cognitive ability differences. Variability in ADRB2 has also been associated with autism (CheslackPostava et al 2007) and memory consolidation (see Bochdanovits et al 2009).…”

“…The opposing effects of ADRB2 polymorphisms on cognitive ability in younger and older samples in the article by Bochdanovits et al (2009) might imply that it is more closely related to individual differences in normal cognitive aging than to lifelong cognitive ability differences. Variability in ADRB2 has also been associated with autism (CheslackPostava et al 2007) and memory consolidation (see Bochdanovits et al 2009). Additionally, the hypoperfusion of the cerebral white matter in multiple sclerosis is proposed to act through astrocytic b2-adrenergic receptors (De Keyser et al 2008).…”

“…However, none of these studies found significant associations with variants in these two genes. More recently, Bochdanovits et al (2009) reported, in this journal, a list of 28 SNPs in 22 brain-expressed genes with signatures of positive selection. Two functional SNPs (rs1042713 and rs1042714) in the b 2 -adrenergic receptor gene ADRB2 stood out as they were significantly associated with cognitive ability test scores.…”

“…In a subsample of the LBC1936, in which Bochdanovits et al (2009) found an association between ADRB2 and cognitive ability, we used DT-MRI quantitative tractography Clayden et al 2007) to assess the integrity of three bilateral white matter tracts that connect frontal and posterior cerebral areas, as well as two parts of the corpus callosum, which is the main interhemispheric white matter connection in the brain. The LBC1936 is unusually valuable in that childhood IQ scores of its members are available from the Scottish Mental Survey of 1947 (Deary et al 2007).…”