Abstract
Variation in the klotho gene is linked to differences in health outcomes: klotho allele KL-VS heterozygosity is associated with longevity, better cognition and greater right frontal grey matter volume in late life. Contradicting reports, however, suggest that KL-VS’s effect on health might be age-dependent. Here we examine the relationship between KL-VS genotype, cognition and brain structure in childhood and adolescence. We hypothesized that KL-VS has early influences on cognitive and brain development. We investigated the associations of KL-VS carrier status with cognition and brain morphology in a cohort of 1387 children and adolescents aged 3–21 years, examining main effects and interactions between age, sex and socioeconomic circumstance. KL-VS had no main effect on either cognition or brain structure, though there was a significant KL-VS × age interaction for cognition (specifically executive function, attention, episodic memory, and general cognition), total grey matter and total brain volume. KL-VS heterozygotes had better cognition than non-carriers before age 11, but lower cognition after age 11. Heterozygotes had smaller brains than non-carriers did in early childhood. Sex moderated the association between KL-VS and white matter volume. Among girls, KL-VS heterozygotes had smaller white matter volumes than non-carriers. Among boys, heterozygotes had greater white matter volumes than non-carriers. However, a replication in a cohort of 2306 children aged 6–12 years showed no significant associations. In contrast to findings in late life, these results show that KL-VS does not have a main effect on cognition and brain structure. Furthermore, KL-VS’s influence may depend on age and sex.
Highlights
Children’s cognitive developmental trajectories and outcomes are highly variable, which leads to both societal and personal disparities
We investigated the associations between KL-VS carrier status, cognition and brain structure in 1387 children and adolescents in the Pediatric Imaging, Neurocognition and Genetics (PING) sample (Jernigan et al 2016)
The interaction terms KL-VS × sex and KL-VS × age were not significant. In both the PING sample of 1387 children and adolescents, and the Generation R sample of 2306 children studied here, we found that klotho allele KL-VS has no main effect on cognition or brain structure
Summary
Children’s cognitive developmental trajectories and outcomes are highly variable, which leads to both societal and personal disparities. The klotho (KL) gene, which codes for the klotho protein, is associated with health and survival. Higher klotho protein levels are associated with various positive physical health outcomes, which include increased survival in lung cancer patients (Usuda et al 2011a; Usuda et al 2011b), and decreased risk of cardiovascular disease (Navarro-Gonzalez et al 2014; Semba et al 2011) and kidney function decline (Drew et al 2017). Variation in the KL allele KL-VS is associated with differences in cognition (Dubal et al 2014; Yokoyama et al 2015; Mengel-From et al 2016), brain volumes (Yokoyama et al 2015) and survival (Arking et al 2002; Arking et al 2005; Invidia et al 2010)
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