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Mol Psychiatry. 2018 Jan 8. doi: 10.1038/s41380-017-0008-y. [Epub ahead of print]

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

Author information

1
Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, UK. riccardo.marioni@ed.ac.uk.
2
Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK. riccardo.marioni@ed.ac.uk.
3
Institute for Molecular Bioscience, University of Queensland, Brisbane, QLD, Australia. riccardo.marioni@ed.ac.uk.
4
Institute for Molecular Bioscience, University of Queensland, Brisbane, QLD, Australia.
5
Queensland Brain Institute, University of Queensland, Brisbane, QLD, Australia.
6
Human Genetics Center, School of Public Health, University of Texas Health Science Center at Houston, Houston, TX, USA.
7
Columbia University Mailman School of Public Health, New York, NY, USA.
8
Icahn School of Medicine at Mount Sinai, New York, NY, USA.
9
University of Exeter Medical School, Exeter, UK.
10
Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA.
11
Instituto Nacional de Cancerologia, Mexico City, Mexico.
12
Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, MI, USA.
13
Survey Research Center, Institute for Social Research, University of Michigan, Ann Arbor, MI, USA.
14
Harvard Medical School, Boston, MA, USA.
15
Department of Twin Research and Genetic Epidemiology, King's College London, London, UK.
16
Department of Biomedical Sciences, Chang Gung University, Taoyuan City, Taiwan.
17
Division of Allergy, Asthma, and Rheumatology, Department of Pediatrics, Chang Gung Memorial Hospital, Linkou, Taiwan.
18
Department of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands.
19
Department of Data Science, School of Population Health, University of Mississippi Medical Center, Jackson, MS, USA.
20
MIND Center, University of Mississippi Medical Center, Jackson, MS, USA.
21
Framingham Heart Study, Framingham, MA, USA.
22
Population Sciences Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA.
23
Boston University School of Medicine, Boston, MA, USA.
24
Department of Cardiology, Boston Children's Hospital, Boston, MA, USA.
25
Department of Neurology, Boston University School of Medicine, Boston, MA, USA.
26
Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
27
Geriatric Unit, Azienda Sanitaria di Firenze, Florence, Italy.
28
Clinical Research Branch, National Institute on Aging, Baltimore, MD, USA.
29
Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA.
30
Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, UK.
31
Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK.
32
Alzheimer Scotland Dementia Research Centre, University of Edinburgh, Edinburgh, UK.
33
Hebrew SeniorLife Institute for Aging Research, Boston, MA, USA.
34
Harvard T.H. Chan School of Public Health, Boston, MA, USA.
35
Boston University Schools of Public Health and Medicine, Boston, MA, USA.
36
VA Boston Healthcare System, Boston, MA, USA.
37
Department of Neurology, Erasmus University Medical Center, Rotterdam, The Netherlands.
38
Departments of Radiology, Erasmus University Medical Center, Rotterdam, The Netherlands.
39
Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, The Netherlands.
40
Brown Foundation Institute of Molecular Medicine, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, USA.
41
Broad Institute of MIT and Harvard, Cambridge, MA, USA.
42
Department of Medicine, Division of Geriatrics, University of Mississippi Medical Center, Jackson, MS, USA.
43
Glenn Biggs Institute of Alzheimer and Neurodegenerative Diseases, University of Texas Health Sciences Center, San Antonio, TX, USA.
44
Department of Psychology, University of Edinburgh, Edinburgh, UK.

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.

PMID:
29311653
PMCID:
PMC6035894
[Available on 2019-07-08]
DOI:
10.1038/s41380-017-0008-y

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