title: Epigenetic and genetic variation at the IGF2/H19 imprinting control region on 11p15.5 is associated with cerebellum weight.
abstract: IGF2 is a paternally expressed imprinted gene with an important role in development and brain function. Allele-specific expression of IGF2 is regulated by DNA methylation at three differentially methylated regions (DMRs) spanning the IGF2/H19 domain on human 11p15.5. We have comprehensively assessed DNA methylation and genotype across the three DMRs and the H19 promoter using tissue from a unique collection of well-characterized and neuropathologically-dissected post-mortem human cerebellum samples (n = 106) and frontal cortex samples (n = 51). We show that DNA methylation, particularly in the vicinity of a key CTCF-binding site (CTCF3) in the imprinting control region (ICR) upstream of H19, is strongly correlated with cerebellum weight. DNA methylation at CTCF3 uniquely explains ~25% of the variance in cerebellum weight. In addition, we report that genetic variation in this ICR is strongly associated with cerebellum weight in a parental-origin specific manner, with maternally-inherited alleles associated with a 16% increase in cerebellum weight compared with paternally-inherited alleles. Given the link between structural brain abnormalities and neuropsychiatric disease, an understanding of the epigenetic and parent-of-origin specific genetic factors associated with brain morphology provides important clues about the etiology of disorders such as schizophrenia and autism.
authors.affiliation: Institute of Psychiatry, King's College London, London, UK.
authors.forename: Ruth
authors.initials: R
authors.lastname: Pidsley
authors.forename: Emma
authors.initials: E
authors.lastname: Dempster
authors.forename: Claire
authors.initials: C
authors.lastname: Troakes
authors.forename: Safa
authors.initials: S
authors.lastname: Al-Sarraj
authors.forename: Jonathan
authors.initials: J
authors.lastname: Mill
mesh_terms: D000483:Alleles; D002531:Cerebellum / Q000033:anatomy & histology*; D002540:Cerebral Cortex / Q000033:anatomy & histology; D002880:Chromosomes, Human, Pair 11 / Q000235:genetics*; D019175:DNA Methylation / Q000235:genetics; D005260:Female; D056426:Genetic Loci / Q000235:genetics; D014644:Genetic Variation; D018392:Genomic Imprinting / Q000235:genetics*; D005838:Genotype; D006801:Humans; D007335:Insulin-Like Growth Factor II / Q000235:genetics*; D008297:Male; D009929:Organ Size / Q000235:genetics; D062085:RNA, Long Noncoding; D022661:RNA, Untranslated / Q000235:genetics*
chemical_list: C094335:H19 long non-coding RNA; C035170:IGF2 protein, human; D062085:RNA, Long Noncoding; D022661:RNA, Untranslated; D007335:Insulin-Like Growth Factor II