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