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

Riccardo E. Marioni, Allan F. McRae, Jan Bressler, Elena Colicino, Eilis Hannon, Shuo Li, Diddier Prada, Jennifer A. Smith, Letizia Trevisi, Pei Chien Tsai, Dina Vojinovic, Jeannette Simino, Daniel Levy, Chunyu Liu, Michael Mendelson, Claudia L. Satizabal, Qiong Yang, Min A. Jhun, Sharon L.R. Kardia, Wei ZhaoStefania Bandinelli, Luigi Ferrucci, Dena G. Hernandez, Andrew B. Singleton, Sarah E. Harris, John M. Starr, Douglas P. Kiel, Robert R. McLean, Allan C. Just, Joel Schwartz, Avron Spiro, Pantel Vokonas, Najaf Amin, M. Arfan Ikram, Andre G. Uitterlinden, Joyce B.J. van Meurs, Tim D. Spector, Claire Steves, Andrea A. Baccarelli, Jordana T. Bell, Cornelia M. van Duijn, Myriam Fornage, Yi Hsiang Hsu, Jonathan Mill, Thomas H. Mosley, Sudha Seshadri, Ian J. Deary

Research output: Contribution to journalArticle

21 Scopus citations

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 × 10-8) associations for global cognitive function (cg21450381, P = 1.6 × 10-8), and phonemic verbal fluency (cg12507869, P = 2.5 × 10-9). 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 × 10-5 and 4 × 10-13 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.

Original languageEnglish (US)
Pages (from-to)2133-2144
Number of pages12
JournalMolecular psychiatry
Volume23
Issue number11
DOIs
StatePublished - Nov 1 2018

ASJC Scopus subject areas

  • Molecular Biology
  • Psychiatry and Mental health
  • Cellular and Molecular Neuroscience

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