A Meta-analysis of Heritability of Cognitive Aging: Minding the “Missing Heritability” Gap

Abstract

The etiologies underlying variation in adult cognitive performance and cognitive aging have enjoyed much attention in the literature, but much of that attention has focused on broad factors, principally general cognitive ability. The current review provides meta-analyses of age trends in heritability of specific cognitive abilities and considers the profile of genetic and environmental factors contributing to cognitive aging to address the ‘missing heritability’ issue. Our findings, based upon evaluating 27 reports in the literature, suggest that verbal ability demonstrated declining heritability after age 60, as did spatial ability and perceptual speed more modestly. Trends for general memory, working memory, and spatial ability generally indicated stability, or small increases in heritability in mid-life. Equivocal results were found for executive function. A second meta-analysis then considered the gap between twin-based versus SNP-based heritability derived from population-based GWAS studies. Specifically, we considered twin correlation ratios to agnostically re-evaluate biometrical models across age and by cognitive domain. Results modestly suggest that nonadditive genetic variance may become increasingly important with age, especially for verbal ability. If so, this would support arguments that lower SNP-based heritability estimates result in part from uncaptured non-additive influences (e.g., dominance, gene-gene interactions), and possibly gene-environment (GE) correlations. Moreover, consistent with longitudinal twin studies of aging, as rearing environment becomes a distal factor, increasing genetic variance may result in part from nonadditive genetic influences or possible GE correlations. Sensitivity to life course dynamics is crucial to understanding etiological contributions to adult cognitive performance and cognitive aging.

Aging-related magnification of genetic effects on cognitive and brain integrity

“…SNP-based heritability is typically lower than heritability estimates based on twin studies [6], the latter reflecting both general effects of specific genes and gene-gene interactions. By contrast, estimations based on SNPs alone do not capture gene-gene interactions, likely resulting in this discrepancy.…”

“…Environmental exposure may, in turn, enhance expression of a particular gene via epigenetic mechanisms, thereby increasing inter-individual differences [92]. Such gene-environment interactions may partly account for the increased heritability of cognitive measures in old age, as supported by simulation work [93] and a meta-analysis of correlational ratios in twin studies [6]. Although genetically identical twins may choose similar environments resulting in relatively stable monozygotic (MZ) correlations, dizygotic (DZ) twins may become more different over time owing to different genetically driven environmental choices, leading to a lower correlation between dizygotic twins.…”

“…Heritability studies demonstrate increased genetic influences on different types of cognition in aging [5][6][7], and also regarding the rate of cognitive decline [8]. Meta-analytic evidence suggests increased heritability from early to late adulthood, especially for episodic memory (see Glossary), but also for working memory and spatial ability [6].…”

“…Meta-analytic evidence suggests increased heritability from early to late adulthood, especially for episodic memory (see Glossary), but also for working memory and spatial ability [6]. In addition, it has been shown that one-third of individual differences in global cognitive changes from 65 to 96 years of age are attributable to genetic factors [8].…”

The beauty, logic and limitations of twin studies

“…In general there is reasonable agreement that the missing heritability phenomenon is not due to invalid findings from twin studies, but rather that current techniques to examine effects of single genes are limited. GWA studies typically only capture common variants of SNPs, do not capture interactions between loci, and require extremely large sample sizes to obtain sufficient power to identify small effects when using necessary GWA-controlled significance levels (Goldman, 2014;Plomin, 2013;Reynolds & Finkel, 2015;Yang et al, 2010). We will argue that the current missing heritability should also be seen as parallel to missing environmentality.…”