title: Brain structure and intragenic DNA methylation are correlated, and predict executive dysfunction in fragile X premutation females.
abstract: DNA methylation of the Fragile X mental retardation 1 (FMR1) exon 1/intron 1 boundary has been associated with executive dysfunction in female carriers of a FMR1 premutation (PM: 55-199 CGG repeats), whereas neuroanatomical changes have been associated with executive dysfunction in PM males. To our knowledge, this study for the first time examined the inter-relationships between executive function, neuroanatomical structure and molecular measures (DNA methylation and FMR1 mRNA levels in blood) in PM and control (<44 CGG repeats) females. In the PM group, FMR1 intron 1 methylation was positively associated with executive function and cortical thickness in middle and superior frontal gyri, and left inferior parietal gyrus. By contrast, in the control group, FMR1 intron 1 methylation was negatively associated with cortical thickness of the left middle frontal gyrus and superior frontal gyri. No significant associations were revealed for either group between FMR1 mRNA and neuroanatomical structure or executive function. In the PM group, the lack of any significant association between FMR1 mRNA levels and phenotypic measures found in this study suggests that either FMR1 expression is not well conserved between tissues, or that FMR1 intron 1 methylation is linked to neuroanatomical and cognitive phenotype in PM females via a different mechanism.
authors.affiliation: School of Psychological Sciences and Monash Institute of Cognitive and Clinical Neurosciences, Faculty of Medicine, Nursing and Health Sciences, Monash University, Melbourne, VIC, Australia.
authors.forename: A L
authors.initials: AL
authors.lastname: Shelton
authors.affiliation: School of Psychological Sciences and Monash Institute of Cognitive and Clinical Neurosciences, Faculty of Medicine, Nursing and Health Sciences, Monash University, Melbourne, VIC, Australia.
authors.forename: K M
authors.initials: KM
authors.lastname: Cornish
authors.affiliation: Department of Anatomy and Neuroscience, University of Melbourne, Melbourne, VIC, Australia.
authors.forename: S
authors.initials: S
authors.lastname: Kolbe
authors.affiliation: School of Psychological Sciences and Monash Institute of Cognitive and Clinical Neurosciences, Faculty of Medicine, Nursing and Health Sciences, Monash University, Melbourne, VIC, Australia.
authors.forename: M
authors.initials: M
authors.lastname: Clough
authors.affiliation: Cyto-molecular Diagnostic Research Laboratory, Murdoch Childrens Research Institute and Victorian Clinical Genetics Services, Parkville, VIC, Australia.|Department of Paediatrics, University of Melbourne, Melbourne, VIC, Australia.
authors.forename: H R
authors.initials: HR
authors.lastname: Slater
authors.affiliation: Cyto-molecular Diagnostic Research Laboratory, Murdoch Childrens Research Institute and Victorian Clinical Genetics Services, Parkville, VIC, Australia.
authors.forename: X
authors.initials: X
authors.lastname: Li
authors.affiliation: School of Psychological Sciences and Monash Institute of Cognitive and Clinical Neurosciences, Faculty of Medicine, Nursing and Health Sciences, Monash University, Melbourne, VIC, Australia.|Cyto-molecular Diagnostic Research Laboratory, Murdoch Childrens Research Institute and Victorian Clinical Genetics Services, Parkville, VIC, Australia.
authors.forename: C M
authors.initials: CM
authors.lastname: Kraan
authors.affiliation: Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, University of Melbourne, Melbourne, VIC, Australia.
authors.forename: Q M
authors.initials: QM
authors.lastname: Bui
authors.affiliation: Cyto-molecular Diagnostic Research Laboratory, Murdoch Childrens Research Institute and Victorian Clinical Genetics Services, Parkville, VIC, Australia.
authors.forename: D E
authors.initials: DE
authors.lastname: Godler
authors.affiliation: School of Psychological Sciences and Monash Institute of Cognitive and Clinical Neurosciences, Faculty of Medicine, Nursing and Health Sciences, Monash University, Melbourne, VIC, Australia.|Department of Medicine, University of Melbourne, Melbourne, VIC, Australia.
authors.forename: J
authors.initials: J
authors.lastname: Fielding
mesh_terms: D000328:Adult; D001921:Brain / Q000473:pathology*; D019175:DNA Methylation / Q000235:genetics*; D004252:DNA Mutational Analysis; D056344:Executive Function / Q000502:physiology*; D005091:Exons / Q000235:genetics; D005260:Female; D005600:Fragile X Syndrome / Q000150:complications / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology*; D006801:Humans; D007438:Introns / Q000235:genetics; D008279:Magnetic Resonance Imaging; D008875:Middle Aged; D009483:Neuropsychological Tests; D010641:Phenotype; D013223:Statistics as Topic; D018911:Trinucleotide Repeats / Q000235:genetics; D055815:Young Adult