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.

Fig 1. Brain and blood methylation comparison.

DNA methylation in the imprints H19ICR, IGF2, IG-DMR, KvDMR, MEST1, NESPAS, PEG3, SNRPN and ZAC1 in blood from ABC36 (n = 485) and five selected regions from four brains sampled post-mortem (AH: Anterior Hippocampus. BG: Basal ganglia. PH: Posterior Hippocampus. PWM: Periventricular white matter. TH: Thalamus). The individual methylation values for each brain sample are shown with cases (individuals with evidence of Alzheimer’s Disease) represented by open circles and controls (no apparent neurodegeneration beyond that expected for age) by closed circles. The population distribution of methylation levels in blood are shown on the same methylation scale.

Fig 2. SNRPN and MEST1 methylation in ABC cohorts.

Regression coefficients with 95% CIs from regressions between SNRPN and MEST1 methylation in ABC36, ABC21 and the combined cohort and childhood cognitive ability measured at age 11 using the Moray House Test (MHT). All regressions were adjusted for sex, adult socioeconomic circumstance (index of multiple deprivation decile), plate and the combined cohort was additionally adjusted for cohort.