Meta-analysis of epigenome-wide association studies of cognitive abilities.

Mol Psychiatry
Authors
Keywords
Abstract

Cognitive functions are important correlates of health outcomes across the life-course. Individual differences in cognitive functions are partly heritable. Epigenetic modifications, such as DNA methylation, are susceptible to both genetic and environmental factors and may provide insights into individual differences in cognitive functions. Epigenome-wide meta-analyses for blood-based DNA methylation levels at ~420,000 CpG sites were performed for seven measures of cognitive functioning using data from 11 cohorts. CpGs that passed a Bonferroni correction, adjusting for the number of CpGs and cognitive tests, were assessed for: longitudinal change; being under genetic control (methylation QTLs); and associations with brain health (structural MRI), brain methylation and Alzheimer's disease pathology. Across the seven measures of cognitive functioning (meta-analysis n range: 2557-6809), there were epigenome-wide significant (P  1.7 × 10) associations for global cognitive function (cg21450381, P = 1.6 × 10), and phonemic verbal fluency (cg12507869, P = 2.5 × 10). The CpGs are located in an intergenic region on chromosome 12 and the INPP5A gene on chromosome 10, respectively. Both probes have moderate correlations (~0.4) with brain methylation in Brodmann area 20 (ventral temporal cortex). Neither probe showed evidence of longitudinal change in late-life or associations with white matter brain MRI measures in one cohort with these data. A methylation QTL analysis suggested that rs113565688 was a cis methylation QTL for cg12507869 (P = 5 × 10 and 4 × 10 in two lookup cohorts). We demonstrate a link between blood-based DNA methylation and measures of phonemic verbal fluency and global cognitive ability. Further research is warranted to understand the mechanisms linking genomic regulatory changes with cognitive function to health and disease.

Year of Publication
2018
Journal
Mol Psychiatry
Volume
23
Issue
11
Pages
2133-2144
Date Published
2018 11
ISSN
1476-5578
DOI
10.1038/s41380-017-0008-y
PubMed ID
29311653
PubMed Central ID
PMC6035894
Links
Grant list
CZB/4/505 / CSO_ / Chief Scientist Office / United Kingdom
R01 AG054076 / AG / NIA NIH HHS / United States
U01 HL096917 / HL / NHLBI NIH HHS / United States
R01 NS087541 / NS / NINDS NIH HHS / United States
Z99 AG999999 / ImNIH / Intramural NIH HHS / United States
MR/K026992/1 / MRC_ / Medical Research Council / United Kingdom
P30 ES023515 / ES / NIEHS NIH HHS / United States
U01 HL096814 / HL / NHLBI NIH HHS / United States
Z01 AG000949-02 / ImNIH / Intramural NIH HHS / United States
BB/F019394/1 / BB_ / Biotechnology and Biological Sciences Research Council / United Kingdom
R21 AR056405 / AR / NIAMS NIH HHS / United States
U01 HL096812 / HL / NHLBI NIH HHS / United States
R01 NS017950 / NS / NINDS NIH HHS / United States
U01 HL096902 / HL / NHLBI NIH HHS / United States
MR/M013111/1 / MRC_ / Medical Research Council / United Kingdom
G1001245 / MRC_ / Medical Research Council / United Kingdom
Z01 AG000932-01 / ImNIH / Intramural NIH HHS / United States
G0701120 / MRC_ / Medical Research Council / United Kingdom
U01 AG052409 / AG / NIA NIH HHS / United States
R01 HL133221 / HL / NHLBI NIH HHS / United States
U01 HL096899 / HL / NHLBI NIH HHS / United States
P30 AG010129 / AG / NIA NIH HHS / United States
R00 ES023450 / ES / NIEHS NIH HHS / United States
K99 HL136875 / HL / NHLBI NIH HHS / United States