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 Zhao; Stefania 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

doi:10.1038/s41380-017-0008-y

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

^*Corresponding author for this work

Department of Biomedical Sciences (Master's Program in Clinical Trials Assessment)

Research output: Contribution to journal › Journal Article › peer-review

61 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 language	English
Pages (from-to)	2133-2144
Number of pages	12
Journal	Molecular Psychiatry
Volume	23
Issue number	11
DOIs	https://doi.org/10.1038/s41380-017-0008-y
State	Published - 01 11 2018

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Publisher Copyright:
© 2017, The Author(s).

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Marioni, R. E., McRae, A. F., Bressler, J., Colicino, E., Hannon, E., Li, S., Prada, D., Smith, J. A., Trevisi, L., Tsai, P. C., Vojinovic, D., Simino, J., Levy, D., Liu, C., Mendelson, M., Satizabal, C. L., Yang, Q., Jhun, M. A., Kardia, S. L. R., ... Deary, I. J. (2018). Meta-analysis of epigenome-wide association studies of cognitive abilities. Molecular Psychiatry, 23(11), 2133-2144. https://doi.org/10.1038/s41380-017-0008-y

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title = "Meta-analysis of epigenome-wide association studies of cognitive abilities",

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.",

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

note = "Publisher Copyright: {\textcopyright} 2017, The Author(s).",

year = "2018",

month = nov,

day = "1",

doi = "10.1038/s41380-017-0008-y",

language = "英语",

volume = "23",

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Marioni, RE, McRae, AF, Bressler, J, Colicino, E, Hannon, E, Li, S, Prada, D, Smith, JA, Trevisi, L, Tsai, PC, Vojinovic, D, Simino, J, Levy, D, Liu, C, Mendelson, M, Satizabal, CL, Yang, Q, Jhun, MA, Kardia, SLR, Zhao, W, Bandinelli, S, Ferrucci, L, Hernandez, DG, Singleton, AB, Harris, SE, Starr, JM, Kiel, DP, McLean, RR, Just, AC, Schwartz, J, Spiro, A, Vokonas, P, Amin, N, Ikram, MA, Uitterlinden, AG, van Meurs, JBJ, Spector, TD, Steves, C, Baccarelli, AA, Bell, JT, van Duijn, CM, Fornage, M, Hsu, YH, Mill, J, Mosley, TH, Seshadri, S & Deary, IJ 2018, 'Meta-analysis of epigenome-wide association studies of cognitive abilities', Molecular Psychiatry, vol. 23, no. 11, pp. 2133-2144. https://doi.org/10.1038/s41380-017-0008-y

TY - JOUR

T1 - Meta-analysis of epigenome-wide association studies of cognitive abilities

AU - Marioni, Riccardo E.

AU - McRae, Allan F.

AU - Bressler, Jan

AU - Colicino, Elena

AU - Hannon, Eilis

AU - Li, Shuo

AU - Prada, Diddier

AU - Smith, Jennifer A.

AU - Trevisi, Letizia

AU - Tsai, Pei Chien

AU - Vojinovic, Dina

AU - Simino, Jeannette

AU - Levy, Daniel

AU - Liu, Chunyu

AU - Mendelson, Michael

AU - Satizabal, Claudia L.

AU - Yang, Qiong

AU - Jhun, Min A.

AU - Kardia, Sharon L.R.

AU - Zhao, Wei

AU - Bandinelli, Stefania

AU - Ferrucci, Luigi

AU - Hernandez, Dena G.

AU - Singleton, Andrew B.

AU - Harris, Sarah E.

AU - Starr, John M.

AU - Kiel, Douglas P.

AU - McLean, Robert R.

AU - Just, Allan C.

AU - Schwartz, Joel

AU - Spiro, Avron

AU - Vokonas, Pantel

AU - Amin, Najaf

AU - Ikram, M. Arfan

AU - Uitterlinden, Andre G.

AU - van Meurs, Joyce B.J.

AU - Spector, Tim D.

AU - Steves, Claire

AU - Baccarelli, Andrea A.

AU - Bell, Jordana T.

AU - van Duijn, Cornelia M.

AU - Fornage, Myriam

AU - Hsu, Yi Hsiang

AU - Mill, Jonathan

AU - Mosley, Thomas H.

AU - Seshadri, Sudha

AU - Deary, Ian J.

PY - 2018/11/1

Y1 - 2018/11/1

N2 - 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.

AB - 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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DO - 10.1038/s41380-017-0008-y

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C2 - 29311653

AN - SCOPUS:85053054360

SN - 1359-4184

VL - 23

SP - 2133

EP - 2144

JO - Molecular Psychiatry

JF - Molecular Psychiatry

IS - 11

ER -

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

Abstract

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