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, Mitsuteru Ito, Paul Haggarty, 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

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.

Conflict of interest statement

The authors have declared that no competing interests exist.

Figures

Fig 1. Brain and blood methylation comparison.
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…
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.

References

    1. Deary IJ. Intelligence. Annu Rev Psychol. 2012;63: 453–482. 10.1146/annurev-psych-120710-100353
    1. Seisenberger S, Andrews S, Krueger F, Arand J, Walter J, Santos F, et al. The Dynamics of Genome-wide DNA Methylation Reprogramming in Mouse Primordial Germ Cells. Mol Cell. 2012;48: 849–862. 10.1016/j.molcel.2012.11.001.
    1. Tang WC, Dietmann S, Irie N, Leitch H, Floros V, Bradshaw C, et al. A Unique Gene Regulatory Network Resets the Human Germline Epigenome for Development. Cell. 2015;161: 1453–1467. 10.1016/j.cell.2015.04.053.
    1. Ferguson-Smith A. Genomic imprinting: the emergence of an epigenetic paradigm. Nat Rev Genet. 2011;12: 565–575. 10.1038/nrg3032
    1. Haggarty P, Ferguson-Smith A. Life course epigenetics and healthy ageing In: Kuh D, Cooper R, Hardy R, Richards M, Ben-Shlomo Y, editors. A Life Course Approach to Healthy Ageing. Oxford: Oxford University Press; 2013.
    1. Haggarty P, Hoad G, Campbell DM, Horgan GW, Piyathilake C, McNeill G. Folate in pregnancy and imprinted gene and repeat element methylation in the offspring. Am J Clin Nutr. 2013;97: 94–99. 10.3945/ajcn.112.042572
    1. Whitelaw N, Bhattacharya S, Hoad G, Horgan GW, Hamilton M, Haggarty P. Epigenetic status in the offspring of spontaneous and assisted conception. Hum Reprod. 2014;29: 1452–1458. 10.1093/humrep/deu094
    1. Haggarty P, Hoad G, Horgan GW, Campbell DM. DNA Methyltransferase Candidate Polymorphisms, Imprinting Methylation, and Birth Outcome. PLoS One. 2013;8: e68896 10.1371/journal.pone.0068896
    1. Coolen MW, Statham AL, Qu W, Campbell MJ, Henders AK, Montgomery GW, et al. Impact of the Genome on the Epigenome Is Manifested in DNA Methylation Patterns of Imprinted Regions in Monozygotic and Dizygotic Twins. PLoS One. 2011;6: e25590 10.1371/journal.pone.0025590
    1. Woodfine K, Huddleston JE, Murrell A. Quantitative analysis of DNA methylation at all human imprinted regions reveals preservation of epigenetic stability in adult somatic tissue. Epigenetics Chromatin. 2011;4.
    1. Levenson JM, Sweatt JD. Epigenetic mechanisms in memory formation. Nat Rev Neurosci. 2005;6: 108–118. 10.1038/nrn1604
    1. Wilkinson LS, Davies W, Isles AR. Genomic imprinting effects on brain development and function. Nat Rev Neurosci. 2007;8: 832–843. 10.1038/nrn2235
    1. Badcock C. The imprinted brain: how genes set the balance between autism and psychosis. Epigenomics. 2011;3: 345–359. 10.2217/epi.11.19
    1. Ferrón SR, Charalambous M, Radford E, McEwen K, Wildner H, Hind E, et al. Postnatal loss of Dlk1 imprinting in stem cells and niche astrocytes regulates neurogenesis. Nature. 2011;475: 381–385. 10.1038/nature10229
    1. Kopsida E, Mikaelsson MA, Davies W. The role of imprinted genes in mediating susceptibility to neuropsychiatric disorders. Horm Behav. 2011;59: 375–382. 10.1016/j.yhbeh.2010.04.005.
    1. Pietschnig J, Voracek M. One Century of Global IQ Gains: A Formal Meta-Analysis of the Flynn Effect (1909–2013). Perspect Psychol Sci. 2015;10: 282–306. 10.1177/1745691615577701
    1. Hanna CW, Peñaherrera MS., Saadeh H, Andrews S, McFadden DE, Kelsey G, et al. Pervasive polymorphic imprinted methylation in the human placenta. Genome Res. 2016;26: 756–767. 10.1101/gr.196139.115
    1. Rijlaarsdam J, Cecil CAM, Walton E, Mesirow MSC, Relton CL, Gaunt TR, et al. Prenatal unhealthy diet, insulin-like growth factor 2 gene (IGF2) methylation, and attention deficit hyperactivity disorder symptoms in youth with early-onset conduct problems. Journal of Child Psychology and Psychiatry. 2017;58: 19–27. 10.1111/jcpp.12589
    1. Lefebvre L, Viville S, Barton SC, Ishino F, Keverne EB, Surani MA. Abnormal maternal behaviour and growth retardation associated with loss of the imprinted gene Mest. Nat Genet. 1998;20: 163–169. 10.1038/2464
    1. Liang F, Diao L, Liu J, Jiang N, Zhang J, Wang H, et al. Paternal ethanol exposure and behavioral abnormities in offspring: Associated alterations in imprinted gene methylation. Neuropharmacology. 2014;81: 126–133. 10.1016/j.neuropharm.2014.01.025.
    1. Cassidy SB, Dykens E, Williams CA. Prader-Willi and Angelman syndromes: sister imprinted disorders. Am J Med Genet. 2000;97: 136–146.
    1. Whittington J, Holland A, Webb T. Relationship between the IQ of people with Prader–Willi syndrome and that of their siblings: evidence for imprinted gene effects. J Intellect Disabil Res. 2009;53: 411–418. 10.1111/j.1365-2788.2009.01157.x
    1. Ubeda F, Gardner A. A model for genomic imprinting in the social brain: juveniles. Evolution. 2010;64: 2587–2600. 10.1111/j.1558-5646.2010.01015.x
    1. Lamb JA, Barnby G, Bonora E, Sykes N, Bacchelli E, Blasi F, et al. Analysis of IMGSAC autism susceptibility loci: evidence for sex limited and parent of origin specific effects. J Med Genet. 2005;42: 132–137. 10.1136/jmg.2004.025668
    1. Whalley LJ, Murray AD, Staff RT, Starr JM, Deary IJ, Fox HC, et al. How the 1932 and 1947 mental surveys of Aberdeen schoolchildren provide a framework to explore the childhood origins of late onset disease and disability. Maturitas. 2011;69: 365–372. 10.1016/j.maturitas.2011.05.010.
    1. Penrose LS. The Trend of Scottish Intelligence: A Comparison of the 1947 and 1932 Surveys of the Intelligence of Eleven-year-old Pupils. Scottish Council for Research in Education. Univ. of London Press Ltd. 1949. Pp. 151 + xxviii. Price 7s. 6d. Annals of Eugenics. 1949;15: 186–187.
    1. Nelson HE. The National Adult Reading Test (NART): test manual. Windsor: NFER-Nelson; 1982.
    1. Raven JC, Court JH, Raven J. Manual for Raven’s Progressive Matrices and Vocabulary Scales. London: Lewis; 1977.
    1. Dupont J, Tost J, Jammes H, Gut IG. De novo quantitative bisulfite sequencing using the pyrosequencing technology. Anal Biochem. 2004;333: 119–127. 10.1016/j.ab.2004.05.007.
    1. Feng W, Marquez RT, Lu Z, Liu J, Lu KH, Issa JJ, et al. Imprinted tumor suppressor genes ARHI and PEG3 are the most frequently down-regulated in human ovarian cancers by loss of heterozygosity and promoter methylation. Cancer. 2008;112: 1489–1502. 10.1002/cncr.23323
    1. White HE, Durston VJ, Harvey JF, Cross NCP. Quantitative Analysis of SRNPN Gene Methylation by Pyrosequencing as a Diagnostic Test for Prader-Willi Syndrome and Angelman Syndrome. Clin Chem. 2006;52: 1005–1013. 10.1373/clinchem.2005.065086
    1. Das R, Lee YK, Strogantsev R, Jin S, Lim YC, Ng PY, et al. DNMT1 and AIM1 Imprinting in human placenta revealed through a genome-wide screen for allele-specific DNA methylation. BMC Genomics. 2013;14: 685 10.1186/1471-2164-14-685
    1. De Jager P,L., Srivastava G, Lunnon K, Burgess J, Schalkwyk LC, Yu L, et al. Alzheimer’s disease: early alterations in brain DNA methylation at ANK1, BIN1, RHBDF2 and other loci. Nat Neurosci. 2014;17: 1156–1163. 10.1038/nn.3786
    1. Houseman EA, Accomando WP, Koestler DC, Christensen BC, Marsit CJ, Nelson HH, et al. DNA methylation arrays as surrogate measures of cell mixture distribution. BMC Bioinformatics. 2012;13: 86 10.1186/1471-2105-13-86
    1. Edwards CA, Ferguson-Smith AC. Mechanisms regulating imprinted genes in clusters. Current Opinion in Cell Biology. 2007;19: 281–289. 10.1016/j.ceb.2007.04.013.
    1. Margolis SS, Sell GL, Zbinden MA, Bird LM. Angelman Syndrome. Neurotherapeutics. 2015;12: 641–650. 10.1007/s13311-015-0361-y
    1. Whittington J, Holland A. Cognition in people with Prader-Willi syndrome: Insights into genetic influences on cognitive and social development. Neurosci Biobehav Rev. 2017;72: 153–167. 10.1016/j.neubiorev.2016.09.013.
    1. Sutcliffe JS, Nakao M, Christian S, Örstavik KH, Tommerup N, Ledbetter DH, et al. Deletions of a differentially methylated CpG island at the SNRPN gene define a putative imprinting control region. Nat Genet. 1994;8: 52–58. 10.1038/ng0994-52
    1. Whittington J, Holland A, Webb T, Butler J, Clarke D, Boer H. Cognitive abilities and genotype in a population-based sample of people with Prader–Willi syndrome. Journal of Intellectual Disability Research. 2004;48: 172–187.
    1. Piard J, Philippe C, Marvier M, Beneteau C, Roth V, Valduga M, et al. Clinical and molecular characterization of a large family with an interstitial 15q11q13 duplication. Am J Med Genet A. 2010;152A: 1933–1941. 10.1002/ajmg.a.33521
    1. Feinberg JI, Bakulski KM, Jaffe AE, Tryggvadottir R, Brown SC, Goldman LR, et al. Paternal sperm DNA methylation associated with early signs of autism risk in an autism-enriched cohort. Int J Epidemiol. 2015;44: 1199–1210. 10.1093/ije/dyv028
    1. Li H, Zhao P, Xu Q, Shan S, Hu C, Qiu Z, et al. The autism-related gene SNRPN regulates cortical and spine development via controlling nuclear receptor Nr4a1. Scientific Reports. 2016;6: 29878 10.1038/srep29878
    1. Kasai H, Fukuda M, Watanabe S, Hayashi-Takagi A, Noguchi J. Structural dynamics of dendritic spines in memory and cognition. Trends in Neurosciences. 2010;33: 121–129. 10.1016/j.tins.2010.01.001.
    1. Eggermann T, Begemann M, Binder G, Spengler S. Silver-Russell syndrome: genetic basis and molecular genetic testing. Orphanet J Rare Dis. 2010;5: 19 10.1186/1750-1172-5-19
    1. Hannula K, Kere J, Pirinen S, Holmberg C, Lipsanen-Nyman M. Do patients with maternal uniparental disomy for chromosome 7 have a distinct mild Silver-Russell phenotype? J Med Genet. 2001;38: 273–278. 10.1136/jmg.38.4.273
    1. Eggermann T, Schönherr N, Eggermann K, Buiting K, Ranke M, Wollmann H, et al. Use of multiplex ligation-dependent probe amplification increases the detection rate for 11p15 epigenetic alterations in Silver–Russell syndrome. Clin Genet. 2008;73: 79–84. 10.1111/j.1399-0004.2007.00930.x
    1. Noeker M, Wollmann HA. Cognitive development in Silver-Russell syndrome: a sibling-controlled study. Dev Med Child Neurol. 2004;46: 340–346.
    1. Vidal AC, Neelon SEB, Liu Y, Tuli AM, Fuemmeler BF, Hoyo C, et al. Maternal Stress, Preterm Birth, and DNA Methylation at Imprint Regulatory Sequences in Humans. Genet Epigenet. 2014;6: GEG.S18067.
    1. Janssen AB, Capron LE, O’Donnell K, Tunster SJ, Ramchandani PG, Heazell AEP, et al. Maternal prenatal depression is associated with decreased placental expression of the imprinted gene PEG3. Psychol Med. 2016;46: 2999–3011. 10.1017/S0033291716001598
    1. Li S, Lindenberger U, Hommel B, Aschersleben G, Prinz W, Baltes PB. Transformations in the Couplings Among Intellectual Abilities and Constituent Cognitive Processes Across the Life Span. Psychol Sci. 2004;15: 155–163. 10.1111/j.0956-7976.2004.01503003.x
    1. Soubry A, Murphy SK, Wang F, Huang Z, Vidal AC, Fuemmeler BF, et al. Newborns of obese parents have altered DNA methylation patterns at imprinted genes. International Journal of Obesity (2005). 2013;39: 650–657.
    1. Soubry A, Guo L, Huang Z, Hoyo C, Romanus S, Price T, et al. Obesity-related DNA methylation at imprinted genes in human sperm: Results from the TIEGER study. Clinical Epigenetics. 2016;8: 51 10.1186/s13148-016-0217-2
    1. Heijmans BT, Tobi EW, Stein AD, Putter H, Blauw GJ, Susser ES, et al. Persistent epigenetic differences associated with prenatal exposure to famine in humans. Proc Natl Acad Sci USA. 2008;105: 17046 10.1073/pnas.0806560105
    1. Murphy SK, Adigun A, Huang Z, Overcash F, Wang F, Jirtle RL, et al. Gender-specific methylation differences in relation to prenatal exposure to cigarette smoke. Gene. 2012;494: 36–43. 10.1016/j.gene.2011.11.062.
    1. Harrison K, Hoad G, Scott P, Simpson L, Horgan GW, Smyth E, et al. Breast cancer risk and imprinting methylation in blood. Clin Epigenetics. 2015;7: 92 10.1186/s13148-015-0125-x
    1. Schubeler D. Function and information content of DNA methylation. Nature. 2015;517: 321 10.1038/nature14192
    1. Lienert F, Wirbelauer C, Som I, Dean A, Mohn F, Schübeler D. Identification of genetic elements that autonomously determine DNA methylation states. Nat Genet. 2011;43: 1091.
    1. Oliver VF, Miles HL, Cutfield WS, Hofman PL, Ludgate JL, Morison IM. Defects in imprinting and genome-wide DNA methylation are not common in the in vitro fertilization population. Fertil Steril. 2012;97: 147–153. 10.1016/j.fertnstert.2011.10.027.

Source: PubMed

Patrocinadores y Colaboradores

Condiciones médicas

Intervenciones de drogas

3
Suscribir