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)

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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 languageEnglish
Article numbere0211799
Number of pages15
JournalPloS ONE
Volume14
Issue number2
Early online date1 Feb 2019
DOIs
Publication statusPublished - 1 Feb 2019

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snRNP Core Proteins
Aptitude
Methylation
genomic imprinting
methylation
Blood
childhood
blood
brain
Brain
hippocampus
cognition
thalamus
Cognition
Hippocampus
epigenetics
Genetic Epigenesis
Genomic Imprinting
Imprinting (Psychology)
phenotype

Keywords

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

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Imprinting methylation in SNRPN and MEST1 in adult blood predicts cognitive ability. / Lorgen-Ritchie, Marlene; Murray, Alison D.; Ferguson-Smith, Anne C.; Richards, Marcus; Horgan, Graham W.; Phillips, Louise H.; Hoad, Gwen; Gall, Ishbel; Harrison, Kristina; McNeill, Geraldine; Ito, Mitsutero; Haggarty, Paul (Corresponding Author).

In: PloS ONE, Vol. 14, No. 2, e0211799, 01.02.2019.

Research output: Contribution to journalArticle

Lorgen-Ritchie, Marlene ; Murray, Alison D. ; Ferguson-Smith, Anne C. ; Richards, Marcus ; Horgan, Graham W. ; Phillips, Louise H. ; Hoad, Gwen ; Gall, Ishbel ; Harrison, Kristina ; McNeill, Geraldine ; Ito, Mitsutero ; Haggarty, Paul. / Imprinting methylation in SNRPN and MEST1 in adult blood predicts cognitive ability. In: PloS ONE. 2019 ; Vol. 14, No. 2.
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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

VL - 14

JO - PloS ONE

JF - PloS ONE

SN - 1932-6203

IS - 2

M1 - e0211799

ER -