Imprinting methylation in SNRPN and MEST1 in adult blood predicts cognitive ability

Marlene Lorgen-Ritchie; Alison D. Murray; Anne C. Ferguson-Smith; Marcus Richards; Graham W. Horgan; Louise H. Phillips; Gwen Hoad; Ishbel Gall; Kristina Harrison; Geraldine McNeill; Mitsutero Ito; Paul Haggarty

doi:10.1371/journal.pone.0211799

Imprinting methylation in SNRPN and MEST1 in adult blood predicts cognitive ability

Marlene Lorgen-Ritchie, Alison D. Murray, Anne C. Ferguson-Smith, Marcus Richards, Graham W. Horgan, Louise H. Phillips, Gwen Hoad, Ishbel Gall, Kristina Harrison, Geraldine McNeill, Mitsutero Ito, Paul Haggarty^* (Corresponding Author)

^*Corresponding author for this work

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Abstract

Genomic imprinting is important for normal brain development and aberrant imprinting has been associated with impaired cognition. We studied the imprinting status in selected imprints (H19, IGF2, SNRPN, PEG3, MEST1, NESPAS, KvDMR, IG-DMR and ZAC1) by pyrosequencing in blood samples from longitudinal cohorts born in 1936 (n = 485) and 1921 (n = 223), and anterior hippocampus, posterior hippocampus, periventricular white matter, and thalamus from brains donated to the Aberdeen Brain Bank (n = 4). MEST1 imprint methylation was related to childhood cognitive ability score (-0.416 95% CI -0.792,-0.041; p = 0.030), with the strongest effect evident in males (-0.929 95% CI -1.531,-0.326; p = 0.003). SNRPN imprint methylation was also related to childhood cognitive ability (+0.335 95%CI 0.008,0.663; p = 0.045). A significant association was also observed for SNRPN methylation and adult crystallised cognitive ability (+0.262 95%CI 0.007,0.517; p = 0.044). Further testing of significant findings in a second cohort from the same region, but born in 1921, resulted in similar effect sizes and greater significance when the cohorts were combined (MEST1; -0.371 95% CI -0.677,-0.065; p = 0.017; SNRPN; +0.361 95% CI 0.079,0.643; p = 0.012). For SNRPN and MEST1 and four other imprints the methylation levels in blood and in the five brain regions were similar. Methylation of the paternally expressed, maternally methylated genes SNRPN and MEST1 in adult blood was associated with cognitive ability in childhood. This is consistent with the known importance of the SNRPN containing 15q11-q13 and the MEST1 containing 7q31-34 regions in cognitive function. These findings, and their sex specific nature in MEST1, point to new mechanisms through which complex phenotypes such as cognitive ability may be inherited. These mechanisms are potentially relevant to both the heritable and non-heritable components of cognitive ability. The process of epigenetic imprinting—within SNRPN and MEST1 in particular—and the factors that influence it, are worthy of further study in relation to the determinants of cognitive ability.

Original language	English
Article number	e0211799
Number of pages	15
Journal	PloS ONE
Volume	14
Issue number	2
Early online date	1 Feb 2019
DOIs	https://doi.org/10.1371/journal.pone.0211799 https://doi.org/10.1371/journal.pone.0215422
Publication status	Published - 1 Feb 2019

Bibliographical note

Notice of republication
An incorrect version of S1 Data was published in error. This article was republished on April 3, 2019 to correct for this error. In addition, the article’s Data Availability statement has been updated to reflect this change.

Funding: This work was supported by the Economic and Social Research Council/Biotechnology and Biological Sciences Research Council BioSocial initiative (grant number ES/N00048X/1; PH, ADM, LHP, RS, AF-S, MR). PH and GH acknowledge the support of the Scottish Government’s Rural and Environment Science and Analytical Services Division (RESAS). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Keywords

PRADER-WILLI-SYNDROME
WIDE DNA METHYLATION
PRENATAL EXPOSURE
GENE
BRAIN
PEOPLE
AUTISM
SUSCEPTIBILITY
MECHANISMS
DYNAMICS

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10.1371/journal.pone.0211799Licence: CC BY
10.1371/journal.pone.0215422Licence: CC BY

Imprinting methylation in SNRPN and MEST1 in adult blood predicts cognitive ability
Copyright: © 2019 Lorgen-Ritchie et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. https://creativecommons.org/licenses/by/4.0/
Final published version, 1.05 MBLicence: CC BY

Paul Haggarty, Deputy Director
- School of Medicine, Medical Sciences & Nutrition, The Rowett Institute of Nutrition and Health - Personal Chair
Person: Academic

Cite this

Lorgen-Ritchie, M., Murray, A. D., Ferguson-Smith, A. C., Richards, M., Horgan, G. W., Phillips, L. H., Hoad, G., Gall, I., Harrison, K., McNeill, G., Ito, M., & Haggarty, P. (2019). Imprinting methylation in SNRPN and MEST1 in adult blood predicts cognitive ability. PloS ONE, 14(2), Article e0211799. https://doi.org/10.1371/journal.pone.0211799, https://doi.org/10.1371/journal.pone.0215422

Lorgen-Ritchie, M , Murray, AD, Ferguson-Smith, AC, Richards, M, Horgan, GW , Phillips, LH, Hoad, G, Gall, I, Harrison, K, McNeill, G, Ito, M & Haggarty, P 2019, 'Imprinting methylation in SNRPN and MEST1 in adult blood predicts cognitive ability', PloS ONE, vol. 14, no. 2, e0211799. https://doi.org/10.1371/journal.pone.0211799, https://doi.org/10.1371/journal.pone.0215422

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title = "Imprinting methylation in SNRPN and MEST1 in adult blood predicts cognitive ability",

abstract = "Genomic imprinting is important for normal brain development and aberrant imprinting has been associated with impaired cognition. We studied the imprinting status in selected imprints (H19, IGF2, SNRPN, PEG3, MEST1, NESPAS, KvDMR, IG-DMR and ZAC1) by pyrosequencing in blood samples from longitudinal cohorts born in 1936 (n = 485) and 1921 (n = 223), and anterior hippocampus, posterior hippocampus, periventricular white matter, and thalamus from brains donated to the Aberdeen Brain Bank (n = 4). MEST1 imprint methylation was related to childhood cognitive ability score (-0.416 95% CI -0.792,-0.041; p = 0.030), with the strongest effect evident in males (-0.929 95% CI -1.531,-0.326; p = 0.003). SNRPN imprint methylation was also related to childhood cognitive ability (+0.335 95%CI 0.008,0.663; p = 0.045). A significant association was also observed for SNRPN methylation and adult crystallised cognitive ability (+0.262 95%CI 0.007,0.517; p = 0.044). Further testing of significant findings in a second cohort from the same region, but born in 1921, resulted in similar effect sizes and greater significance when the cohorts were combined (MEST1; -0.371 95% CI -0.677,-0.065; p = 0.017; SNRPN; +0.361 95% CI 0.079,0.643; p = 0.012). For SNRPN and MEST1 and four other imprints the methylation levels in blood and in the five brain regions were similar. Methylation of the paternally expressed, maternally methylated genes SNRPN and MEST1 in adult blood was associated with cognitive ability in childhood. This is consistent with the known importance of the SNRPN containing 15q11-q13 and the MEST1 containing 7q31-34 regions in cognitive function. These findings, and their sex specific nature in MEST1, point to new mechanisms through which complex phenotypes such as cognitive ability may be inherited. These mechanisms are potentially relevant to both the heritable and non-heritable components of cognitive ability. The process of epigenetic imprinting—within SNRPN and MEST1 in particular—and the factors that influence it, are worthy of further study in relation to the determinants of cognitive ability.",

keywords = "PRADER-WILLI-SYNDROME, WIDE DNA METHYLATION, PRENATAL EXPOSURE, GENE, BRAIN, PEOPLE, AUTISM, SUSCEPTIBILITY, MECHANISMS, DYNAMICS",

author = "Marlene Lorgen-Ritchie and Murray, {Alison D.} and Ferguson-Smith, {Anne C.} and Marcus Richards and Horgan, {Graham W.} and Phillips, {Louise H.} and Gwen Hoad and Ishbel Gall and Kristina Harrison and Geraldine McNeill and Mitsutero Ito and Paul Haggarty",

note = "Notice of republication An incorrect version of S1 Data was published in error. This article was republished on April 3, 2019 to correct for this error. In addition, the article{\textquoteright}s Data Availability statement has been updated to reflect this change. Funding: This work was supported by the Economic and Social Research Council/Biotechnology and Biological Sciences Research Council BioSocial initiative (grant number ES/N00048X/1; PH, ADM, LHP, RS, AF-S, MR). PH and GH acknowledge the support of the Scottish Government{\textquoteright}s Rural and Environment Science and Analytical Services Division (RESAS). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. ",

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T1 - Imprinting methylation in SNRPN and MEST1 in adult blood predicts cognitive ability

AU - Lorgen-Ritchie, Marlene

AU - Murray, Alison D.

AU - Ferguson-Smith, Anne C.

AU - Richards, Marcus

AU - Horgan, Graham W.

AU - Phillips, Louise H.

AU - Hoad, Gwen

AU - Gall, Ishbel

AU - Harrison, Kristina

AU - McNeill, Geraldine

AU - Ito, Mitsutero

AU - Haggarty, Paul

N1 - Notice of republication An incorrect version of S1 Data was published in error. This article was republished on April 3, 2019 to correct for this error. In addition, the article’s Data Availability statement has been updated to reflect this change. Funding: This work was supported by the Economic and Social Research Council/Biotechnology and Biological Sciences Research Council BioSocial initiative (grant number ES/N00048X/1; PH, ADM, LHP, RS, AF-S, MR). PH and GH acknowledge the support of the Scottish Government’s Rural and Environment Science and Analytical Services Division (RESAS). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

PY - 2019/2/1

Y1 - 2019/2/1

N2 - Genomic imprinting is important for normal brain development and aberrant imprinting has been associated with impaired cognition. We studied the imprinting status in selected imprints (H19, IGF2, SNRPN, PEG3, MEST1, NESPAS, KvDMR, IG-DMR and ZAC1) by pyrosequencing in blood samples from longitudinal cohorts born in 1936 (n = 485) and 1921 (n = 223), and anterior hippocampus, posterior hippocampus, periventricular white matter, and thalamus from brains donated to the Aberdeen Brain Bank (n = 4). MEST1 imprint methylation was related to childhood cognitive ability score (-0.416 95% CI -0.792,-0.041; p = 0.030), with the strongest effect evident in males (-0.929 95% CI -1.531,-0.326; p = 0.003). SNRPN imprint methylation was also related to childhood cognitive ability (+0.335 95%CI 0.008,0.663; p = 0.045). A significant association was also observed for SNRPN methylation and adult crystallised cognitive ability (+0.262 95%CI 0.007,0.517; p = 0.044). Further testing of significant findings in a second cohort from the same region, but born in 1921, resulted in similar effect sizes and greater significance when the cohorts were combined (MEST1; -0.371 95% CI -0.677,-0.065; p = 0.017; SNRPN; +0.361 95% CI 0.079,0.643; p = 0.012). For SNRPN and MEST1 and four other imprints the methylation levels in blood and in the five brain regions were similar. Methylation of the paternally expressed, maternally methylated genes SNRPN and MEST1 in adult blood was associated with cognitive ability in childhood. This is consistent with the known importance of the SNRPN containing 15q11-q13 and the MEST1 containing 7q31-34 regions in cognitive function. These findings, and their sex specific nature in MEST1, point to new mechanisms through which complex phenotypes such as cognitive ability may be inherited. These mechanisms are potentially relevant to both the heritable and non-heritable components of cognitive ability. The process of epigenetic imprinting—within SNRPN and MEST1 in particular—and the factors that influence it, are worthy of further study in relation to the determinants of cognitive ability.

AB - Genomic imprinting is important for normal brain development and aberrant imprinting has been associated with impaired cognition. We studied the imprinting status in selected imprints (H19, IGF2, SNRPN, PEG3, MEST1, NESPAS, KvDMR, IG-DMR and ZAC1) by pyrosequencing in blood samples from longitudinal cohorts born in 1936 (n = 485) and 1921 (n = 223), and anterior hippocampus, posterior hippocampus, periventricular white matter, and thalamus from brains donated to the Aberdeen Brain Bank (n = 4). MEST1 imprint methylation was related to childhood cognitive ability score (-0.416 95% CI -0.792,-0.041; p = 0.030), with the strongest effect evident in males (-0.929 95% CI -1.531,-0.326; p = 0.003). SNRPN imprint methylation was also related to childhood cognitive ability (+0.335 95%CI 0.008,0.663; p = 0.045). A significant association was also observed for SNRPN methylation and adult crystallised cognitive ability (+0.262 95%CI 0.007,0.517; p = 0.044). Further testing of significant findings in a second cohort from the same region, but born in 1921, resulted in similar effect sizes and greater significance when the cohorts were combined (MEST1; -0.371 95% CI -0.677,-0.065; p = 0.017; SNRPN; +0.361 95% CI 0.079,0.643; p = 0.012). For SNRPN and MEST1 and four other imprints the methylation levels in blood and in the five brain regions were similar. Methylation of the paternally expressed, maternally methylated genes SNRPN and MEST1 in adult blood was associated with cognitive ability in childhood. This is consistent with the known importance of the SNRPN containing 15q11-q13 and the MEST1 containing 7q31-34 regions in cognitive function. These findings, and their sex specific nature in MEST1, point to new mechanisms through which complex phenotypes such as cognitive ability may be inherited. These mechanisms are potentially relevant to both the heritable and non-heritable components of cognitive ability. The process of epigenetic imprinting—within SNRPN and MEST1 in particular—and the factors that influence it, are worthy of further study in relation to the determinants of cognitive ability.

KW - PRADER-WILLI-SYNDROME

KW - WIDE DNA METHYLATION

KW - PRENATAL EXPOSURE

KW - GENE

KW - BRAIN

KW - PEOPLE

KW - AUTISM

KW - SUSCEPTIBILITY

KW - MECHANISMS

KW - DYNAMICS

U2 - 10.1371/journal.pone.0211799

DO - 10.1371/journal.pone.0211799

M3 - Article

SN - 1932-6203

VL - 14

JO - PloS ONE

JF - PloS ONE

IS - 2

M1 - e0211799

ER -

Imprinting methylation in SNRPN and MEST1 in adult blood predicts cognitive ability

Abstract

Bibliographical note

Keywords

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Paul Haggarty, Deputy Director

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