Novel methylation markers of the dysexecutive-psychiatric phenotype in FMR1 premutation women

Objective: To examine the epigenetic basis of psychiatric symptoms and dysexecutive impairments in FMR1 premutation (PM: 55 to 199 CGG repeats) women. Methods: A total of 35 FMR1 PM women aged between 22 and 55 years and 35 age- and IQ-matched women controls (CGG <45) participated in this study. All participants completed a range of executive function tests and self-reported symptoms of psychiatric disorders. The molecular measures included DNA methylation of the FMR1 CpG island in blood, presented as FMR1 activation ratio (AR), and 9 CpG sites located at the FMR1 exon1/intron 1 boundary, CGG size, and FMR1 mRNA levels. Results: We show that FMR1 intron 1 methylation levels could be used to dichotomize PM women into greater and lower risk categories (p 0.006 to 0.037; odds ratio 14-24.8), with only FMR1 intron 1 methylation, and to a lesser extent AR, being significantly correlated with the likelihood of probable dysexecutive or psychiatric symptoms (p < 0.05). Furthermore, the significant relationships between methylation and social anxiety were found to be mediated by executive function performance, but only in PM women. FMR1 exon 1 methylation, CGG size, and FMR1 mRNA could not predict probable dysexecutive/psychiatric disorders in PM women. Conclusions: This is the first study supporting presence of specific epigenetic etiology associated with increased risk of developing comorbid dysexecutive and social anxiety symptoms in PM women. These findings could have implications for early intervention and risk estimate recommendations aimed at improving the outcomes for PM women and their families.