CGG Repeats in the FMR1 Gene as Predictor of Visuospatial Working Memory

Abstract

AbstractBackgroundThe FMR1 premutation, defined by an expansion of 55–200 CGG repeats on the FMR1 gene, occurs in 1 in 150 women in the US. The premutation is related to complications, including risk for neurodegenerative disease (Fragile X‐associated tremor/ataxia syndrome; FXTAS) and broader neurocognitive features occurring outside of the context of FXTAS. Understanding the premutation’s effect on cognition, such as visuospatial working memory (VWM), will provide a more comprehensive understanding of cognitive symptoms associated with the FMR1 premutation genotype. Previous findings demonstrated that premutation males with high CGG repeats perform worse on VWM tasks (Hocking et al., 2012). Few studies examined VWM in female carriers, who typically show milder symptoms. This study examined VWM in female carriers and its relationship with CGG repeat length.MethodsParticipants were 33 premutation carrier women and 22 neurotypical controls aged 27‐59 (M=45) years. Groups did not significantly differ in age (p=.132), education (p=.682), or race (p=.661). Participants completed Spatial Addition test of the WMS‐IV (Weschler, 2009). DNA from buccal swabs was analyzed for CGG repeat length using the Asuragen AmplideX kit.ResultsGiven the incomplete penetrance the FMR1 premutation phenotype, where only a subgroup of women experience symptoms, analyses focused on identifying those who obtained low/at‐risk standard scores (1+SD below the mean), as opposed comparing mean performance across groups. Chi‐squared analyses indicated that premutation carrier women were more likely score 1+ SD below the mean on the Spatial Addition test (30% vs 0% of controls), X 2=8.14, p=.004. Logistic regression indicated that CGG repeat length was a significant predictor of scoring 1+SD below the mean, after controlling for education level, (χ2=‐7.50, p=.032). For every unit increase in CGG repeat length, the odds of scoring 1+SD below the mean increased by a factor of 1.07 (95% CI: 1.00, 1.12).ConclusionsFemale premutation carriers were more likely to show VWM difficulties, which were associated with genetic liability (i.e., CGG repeat length). Future research may explore VWM deficits in relation to FXTAS risk.