Date Published: February 1, 2019
Publisher: Public Library of Science
Author(s): 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, Mitsuteru Ito, Paul Haggarty, Cheryl S. Rosenfeld.
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.
Human cognitive ability is an important determinant of educational and occupational success, social mobility, health, and longevity  though it is not clear whether higher cognitive ability leads to better health and longevity through improved lifestyle choices and life opportunities or whether there is a common biological basis to a well-functioning brain and body. In addition to uncertainty over the direction of causality, the transgenerational nature of these links suggests that causal pathways may span more than one generation. Cognitive ability is influenced both by genetics and the environment . Epigenetic states are generally erased between generations. However, examples of heritability from parent to offspring with possible relevance to transgenerational transmission of phenotypes have been reported in mouse and human [2,3].
Participants were members of the Aberdeen Birth Cohorts of 1936 (ABC36) and 1921 (ABC21) from whom DNA was collected (n = 485 and n = 223, respectively) . Ethical approval for the study was obtained from the Multi-Centre Research Ethics Committee for Scotland (MREC/01/0/56) and Grampian Research Ethics Committee (LREC/01/0299). The research was conducted in compliance with the Helsinki Declaration and all participants gave written, informed consent.
Imprint methylation data obtained for ABC36 participants are described along with the participant cognitive test scores in Table 1. There were no significant sex differences in MHT, NART or Raven’s test scores. The ABC36 cohort consisted of 50.5% females. Mean weights were 67.5 (SD 12.7) kg in females and 79.3 (SD 11.4) kg in males, (p<0.001). Mean heights were 158.9 (SD 6.1) cm in females and 171.9 (SD 6.0) cm in males, (p<0.001). Mean BMI was 26.8 (SD 4.9) kgm-2 in females and 26.8 (SD 3.5) kgm-2 in males and the difference was not statistically significant. Methylation of the paternally expressed, maternally methylated genes SNRPN and MEST1 in adulthood was associated with cognitive ability in childhood in a longitudinal cohort. The childhood cognitive associations with SNRPN were positive in both sexes, while the associations with MEST1 were negative and strongest in males. This is the first report of an association between SNRPN and MEST1 imprinting methylation and cognitive ability in a normal population. Some strengths and limitations of the current study should be noted. This longitudinal cohort study provides invaluable cognitive data from single individuals across the life course. The numbers in the analyses are effectively halved when considering the sexes separately but this is more likely to result in false negatives, due to reduced power, than in false positives. We did not adjust for multiple testing, but we checked the consistency of significant results in a second older cohort and carried out a combined cohort analysis with adjustment for cohort membership. Participants from both cohorts were recruited from a small geographical area and were born in the same year, 1921 or 1936. They undertook the same childhood cognitive test at the same age, and had the same information collected following recruitment. In terms of wider significance, imprinting is an established biological process that is essential in normal development and therefore the factors that influence imprinting are likely to operate via conserved mechanisms across populations. Source: http://doi.org/10.1371/journal.pone.0211799