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

Riccardo E Marioni^{1

2

3}, Allan F McRae^{4

5}, Jan Bressler⁶, Elena Colicino^{7

8}, Eilis Hannon⁹, Shuo Li¹⁰, Diddier Prada¹¹, Jennifer A Smith^{12

13}, Letizia Trevisi¹⁴, Pei-Chien Tsai^{15

16

17}, Dina Vojinovic¹⁸, Jeannette Simino^{19

20}, Daniel Levy^{21

22}, Chunyu Liu^{10

21

22}, Michael Mendelson^{21

22

23

24}, Claudia L Satizabal^{21

25}, Qiong Yang¹⁰, Min A Jhun^{12

26}, Sharon L R Kardia¹², Wei Zhao¹², Stefania Bandinelli²⁷, Luigi Ferrucci²⁸, Dena G Hernandez²⁹, Andrew B Singleton²⁹, Sarah E Harris^{30

31}, John M Starr^{30

32}, Douglas P Kiel^{14

33}, Robert R McLean^{14

33}, Allan C Just⁸, Joel Schwartz³⁴, Avron Spiro 3rd^{35

36}, Pantel Vokonas^{35

36}, Najaf Amin¹⁸, M Arfan Ikram^{18

37

38}, Andre G Uitterlinden^{18

39}, Joyce B J van Meurs^{18

39}, Tim D Spector¹⁵, Claire Steves¹⁵, Andrea A Baccarelli⁷, Jordana T Bell¹⁵, Cornelia M van Duijn¹⁸, Myriam Fornage^{6

40}, Yi-Hsiang Hsu^{14

33

41}, Jonathan Mill⁸, Thomas H Mosley^{20

42}, Sudha Seshadri^{25

43}, Ian J Deary^{30

44}

Affiliations

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.

PMID: 29311653
PMCID: PMC6035894
DOI: 10.1038/s41380-017-0008-y

Meta-Analysis

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

Riccardo E Marioni et al. Mol Psychiatry. 2018 Nov.

. 2018 Nov;23(11):2133-2144.

doi: 10.1038/s41380-017-0008-y. Epub 2018 Jan 8.

Authors

Affiliations

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.

PMID: 29311653
PMCID: PMC6035894
DOI: 10.1038/s41380-017-0008-y

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.

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Conflict of interest statement

The authors declare that they have no conflict of interest.

Figures

**Fig. 1**
Meta-analysis EWAS Manhattan Plots for the seven cognitive tests—full adjustment models*. ^*Models adjusted for age, sex, age x sex, age², self-reported smoking status, body mass index, white-blood cell counts, technical covariates and principal components (population stratification)

**Fig. 2**
Histogram showing the distribution of beta values for the two significant CpGs in the Lothian Birth Cohort 1936 (n = 920)

**Fig. 3**
Forest plots of the Z-scores by cohort sample size for the two significant CpGs. ARIC Atherosclerosis Risk in the Community, FHS Framingham Heart Study Offspring Cohort, GENOA Genetic Epidemiology Network of Arteriopathy, InCHIANTI Invecchiare in Chianti, LBC Lothian Birth Cohort, MOBILIZE Maintenance of Balance, Independent Living, Intellect and Zest in the Elderly of Boston, NAS Normative Aging Study, RS Rotterdam Study, RS-Bios Rotterdam Study—Biobank-based Integrative Omics Studies

See this image and copyright information in PMC

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

Affiliations

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

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

Publication types

MeSH terms

Grants and funding

LinkOut - more resources

Full Text Sources

Other Literature Sources