The total burden of rare, non-synonymous exome genetic variants is not associated with childhood or late-life cognitive ability

Marioni, Riccardo E.; Penke, Lars; Davies, Gail; Huffman, Jennifer E.; Hayward, Caroline; Deary, Ian J.

doi:10.1098/rspb.2014.0117

Cited by 19 publications

(17 citation statements)

References 57 publications

(80 reference statements)

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“…DNA methylation, which can be used to form an epigenetic biomarker of age acceleration, was associated with cognitive function in the LBC1936, but not cognitive decline over 3 years within old age (Marioni et al 2015a). Apart from cognitive function, the LBC studies showed that a faster running epigenetic clock is associated with earlier death (Marioni et al 2015b). …”

Section: Genetic Influences On Cognitive Level and Cognitive Changementioning

confidence: 99%

Healthy cognitive ageing in the Lothian Birth Cohort studies: marginal gains not magic bullet

2017

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In the face of shifting demographics and an increase in human longevity, it is important to examine carefully what is known about cognitive ageing, and to identify and promote possibly malleable lifestyle and health-related factors that might mitigate age-associated cognitive decline. The Lothian Birth Cohorts of 1921 (LBC1921, n = 550) and 1936 (LBC1936, n = 1091) are longitudinal studies of cognitive and brain ageing based in Scotland. Childhood IQ data are available for these participants, who were recruited in later life and then followed up regularly. This overview summarises some of the main LBC findings to date, illustrating the possible genetic and environmental contributions to cognitive function (level and change) and brain imaging biomarkers in later life. Key associations include genetic variation, health and fitness, psychosocial and lifestyle factors, and aspects of the brain's structure. It addresses some key methodological issues such as confounding by early-life intelligence and social factors and emphasises areas requiring further investigation. Overall, the findings that have emerged from the LBC studies highlight that there are multiple correlates of cognitive ability level in later life, many of which have small effects, that there are as yet few reliable predictors of cognitive change, and that not all of the correlates have independent additive associations. The concept of marginal gains, whereby there might be a cumulative effect of small incremental improvements across a wide range of lifestyle and health-related factors, may offer a useful way to think about and promote a multivariate recipe for healthy cognitive and brain ageing.

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Section: Genetic Influences On Cognitive Level and Cognitive Changementioning

confidence: 99%

Healthy cognitive ageing in the Lothian Birth Cohort studies: marginal gains not magic bullet

2017

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“…Empirical studies so far have failed to find evidence of a link between intelligence and rare variants [25]. These studies have often been limited in scope, with only CNVs or exonic regions being considered, or being limited in statistical power because all rare variants were treated as having the same direction of effect through the use of burden tests [25][26][27][28][29].…”

Section: Introductionmentioning

confidence: 99%

Genomic analysis of family data reveals additional genetic effects on intelligence and personality

et al. 2018

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Pedigree-based analyses of intelligence have reported that genetic differences account for 50-80% of the phenotypic variation. For personality traits these effects are smaller, with 34-48% of the variance being explained by genetic differences. However, molecular genetic studies using unrelated individuals typically report a heritability estimate of around 30% for intelligence and between 0 and 15% for personality variables. Pedigree-based estimates and molecular genetic estimates may differ because current genotyping platforms are poor at tagging causal variants, variants with low minor allele frequency, copy number variants, and structural variants. Using~20,000 individuals in the Generation Scotland family cohort genotyped for~700,000 single-nucleotide polymorphisms (SNPs), we exploit the high levels of linkage disequilibrium (LD) found in members of the same family to quantify the total effect of genetic variants that are not tagged in GWAS of unrelated individuals. In our models, genetic variants in low LD with genotyped SNPs explain over half of the genetic variance in intelligence, education, and neuroticism. By capturing these additional genetic effects our models closely approximate the heritability estimates from twin studies for intelligence and education, but not for neuroticism and extraversion. We then replicated our finding using imputed molecular genetic data from unrelated individuals to show that 50% of differences in intelligence, and~40% of the differences in education, can be explained by genetic effects when a larger number of rare SNPs are included. From an evolutionary genetic perspective, a substantial contribution of rare genetic variants to individual differences in intelligence, and education is consistent with mutation-selection balance.

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“…However, a small initial study purporting to link IQ to rare genetic copy number variant (CNV) load was not replicated [9,10]. A recent exome (the parts of the genome that code for proteins) genotyping study did not find links of accumulated loads of rare variants to intelligence [11].…”

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confidence: 99%

Zeroing in on the Genetics of Intelligence

Arslan

Penke

2015

J. Intell.

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Abstract:Despite the high heritability of intelligence in the normal range, molecular genetic studies have so far yielded many null findings. However, large samples and self-imposed stringent standards have prevented false positives and gradually narrowed down where effects can still be expected. Rare variants and mutations of large effect do not appear to play a main role beyond intellectual disability. Common variants can account for about half the heritability of intelligence and show promise that collaborative efforts will identify more causal genetic variants. Gene-gene interactions may explain some of the remainder, but are only starting to be tapped. Evolutionarily, stabilizing selection and selective (near)-neutrality are consistent with the facts known so far.

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The total burden of rare, non-synonymous exome genetic variants is not associated with childhood or late-life cognitive ability

Cited by 19 publications

References 57 publications

Healthy cognitive ageing in the Lothian Birth Cohort studies: marginal gains not magic bullet

Healthy cognitive ageing in the Lothian Birth Cohort studies: marginal gains not magic bullet

Genomic analysis of family data reveals additional genetic effects on intelligence and personality

Zeroing in on the Genetics of Intelligence

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