Abstract
FMR1 CGG repeat length was assayed in 5499 research participants (2637 men and 2862 women) in the Wisconsin Longitudinal Study (WLS), a population-based cohort. Most past research has focused on clinically-ascertained individuals with expansions in CGG repeats, either those with fragile X syndrome (> 200 CGG repeats), the FMR1 premutation (55–200 repeats), or in the gray zone (variously defined as 45–54 or 41–54 repeats). In contrast, the WLS is a unique source of data that was obtained from an unselected cohort of individuals from the general population for whom FMR1 CGG repeat length was assayed. The WLS is a random sample of one-third of all high school seniors in the state of Wisconsin in 1957. The most recent round of data collection was in 2011; thus, the study spanned over 50 years. Saliva samples were obtained from 69% of surviving members of the cohort in 2008 and 2011, from which CGG repeats were assayed. With one exception, the CGG repeat length of all members of this cohort was below 100 (ranging from 7 to 84). The present study evaluated the genotype-phenotype associations of CGG repeat number and IQ, college graduation, age at menopause, number of biological children, having a child with intellectual or developmental disabilities, and the likelihood of experiencing an episode of depression during adulthood. Linear and curvilinear effects were probed. Although effect sizes were small, significant associations were found between CGG repeat length and high school IQ score, college graduation, number of biological children, age at menopause, and the likelihood of having an episode of depression. However, there was no significant association between repeat length and having a child diagnosed with an IDD condition. This study demonstrates a continuum of phenotype effects with FMR1 repeat lengths and illustrates how research inspired by a rare genetic condition (such as fragile X syndrome) can be used to probe genotype-phenotype associations in the general population.
Highlights
The FMR1 gene on the X chromosome plays a critically important role in the development and functioning of the nervous system, as its protein product normally regulates the translation of ∼30% of all transcripts in the pre- and postsynaptic proteomes critical for synaptic plasticity [1]
The key question asked in the present study was, to what extent is polymorphism in FMR1 CGG repeat number associated with individual variation in phenotypic characteristics? there have been previous studies of genotype-phenotype associations using FMR1 CGG repeat data derived from participants in the Wisconsin Longitudinal Study (WLS), there are three major differences between the previously reported WLS studies and the present research
Because some of the key phenotypes analyzed for the present study may have reflected societal trends that change over time, we focused on an age cohort (i.e., 1957 high school graduates) to control for the influence of these secular trends
Summary
The FMR1 gene on the X chromosome plays a critically important role in the development and functioning of the nervous system, as its protein product normally regulates the translation of ∼30% of all transcripts in the pre- and postsynaptic proteomes critical for synaptic plasticity [1]. In 2003, Chen et al [7] reported the results from studies of synthetic human FMR1 promoter sequences driving a luciferase reporter in transfected cell lines, showing that CGG repeats had no significant effect on transcription. Compared to the modal number of approximately 30 CGGs, both lower and higher numbers of CGG repeats negatively affected translation of luciferase mRNA into protein, suggesting that the modal number of 30 may maximize translational efficiency. This observation predicts that repeats across the CGG range, above and below 30, may be associated with varying degrees in the efficiency of translation of the FMR1 transcript, and may be associated with phenotypic variability. Wang et al [9] have suggested that even subtle changes in both protein and mRNA levels could have wide-ranging effects both on brain structure and working memory in healthy adult men with normal FMR1 alleles
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