Depression and anxiety symptoms among women who carry the <i>FMR1</i> premutation: Impact of raising a child with fragile X syndrome is moderated by <i>CRHR1</i> polymorphisms

Hunter, Jessica Ezzell; Leslie, Mary; Novak, Gloria; Hamilton, Debra; Shubeck, Lisa; Charen, Krista; Abramowitz, Ann; Epstein, Michael P.; Lori, Adriana; Binder, Elisabeth B.; Cubells, Joseph F.; Sherman, Stephanie L.

doi:10.1002/ajmg.b.32061

Cited by 35 publications

(37 citation statements)

References 54 publications

(77 reference statements)

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“…Because we did not have activation ratio data, one X chromosome was selected for analysis in the present study as follows. Although we considered alternative approaches [Kline et al, 2014; Gustin et al, 2015], we followed the approach of Hunter et al [2012]. We selected the longer allele in mothers who had one expanded (i.e., > 40 CGGs) allele and one normal allele (n = 218) and in the one case who had two expanded alleles.…”

Section: Methodsmentioning

confidence: 99%

FMR1 genotype interacts with parenting stress to shape health and functional abilities in older age

Mailick

Hong

Greenberg

et al. 2017

American J of Med Genetics Pt B

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This study investigated the association of genotype (CGG repeats in FMR1) and the health and well-being of 5628 aging adults (mean age = 71) in a population-based study. Two groups were contrasted: aging parents who had adult children with developmental or mental health disabilities (n = 785; the high-stress parenting group) and aging parents of healthy children who did not have disabilities (n = 4843; the low-stress parenting group). There were significant curvilinear interaction effects between parenting stress group and CGG repeats for body mass index and indicators of health and functional limitations, and the results were suggestive of interactions for limitations in cognitive functioning. Parents who had adult children with disabilities and whose genotype was two standard deviations above or below the mean numbers of CGGs had poorer health and functional outcomes at age 71 than parents with average numbers of CGGs. In contrast, parents who had healthy adult children and who had similarly high or low numbers of CGG repeats had better health and functional outcomes than parents with average numbers of CGGs. This pattern of gene by environment interactions was consistent with differential susceptibility or the flip-flop phenomenon. This study illustrates how research that begins with a rare genetic condition (such as fragile X syndrome) can lead to insights about the general population and contributes to understanding of how genetic differences shape the way people respond to environments.

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Section: Methodsmentioning

confidence: 99%

FMR1 genotype interacts with parenting stress to shape health and functional abilities in older age

Mailick

Hong

Greenberg

et al. 2017

American J of Med Genetics Pt B

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“…At least in part this may be the result of genetic variation (for example, CRHR1 polymorphisms and release of cortisol) moderating the stress of raising a child with FXS [75,76]. However, one recent study has shown that poorer inhibitory control and working memory are associated with elevated social anxiety, depression, and attention deficit hyperactivity disorder (predominantly inattentive symptoms) among women with the FMR1 premutation [37].…”

Section: Reviewmentioning

confidence: 99%

The cognitive neuropsychological phenotype of carriers of the FMR1 premutation

Grigsby

Cornish

Hocking

et al. 2014

J Neurodevelop Disord

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The fragile X-associated tremor/ataxia syndrome (FXTAS) is a late-onset neurodegenerative disorder affecting a subset of carriers of the FMR1 (fragile X mental retardation 1) premutation. Penetrance and expression appear to be significantly higher in males than females. Although the most obvious aspect of the phenotype is the movement disorder that gives FXTAS its name, the disorder is also accompanied by progressive cognitive impairment. In this review, we address the cognitive neuropsychological and neurophysiological phenotype for males and females with FXTAS, and for male and female unaffected carriers. Despite differences in penetrance and expression, the cognitive features of the disorder appear similar for both genders, with impairment of executive functioning, working memory, and information processing the most prominent. Deficits in these functional systems may be largely responsible for impairment on other measures, including tests of general intelligence and declarative learning. FXTAS is to a large extent a white matter disease, and the cognitive phenotypes observed are consistent with what some have described as white matter dementia, in contrast to the impaired cortical functioning more characteristic of Alzheimer’s disease and related disorders. Although some degree of impaired executive functioning appears to be ubiquitous among persons with FXTAS, the data suggest that only a subset of unaffected carriers of the premutation - both female and male - demonstrate such deficits, which typically are mild. The best-studied phenotype is that of males with FXTAS. The manifestations of cognitive impairment among asymptomatic male carriers, and among women with and without FXTAS, are less well understood, but have come under increased scrutiny.

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“…Anxiety in women with the premutation has been linked with environmental factors such as child problem behaviors [75], with the impact of the stress of raising a child with fragile X syndrome moderated by variation on CRHR1 , a gene involved in cortisol regulation [97]. Epigenetic changes associated with abnormal methylation have also been implicated, with one study showing that methylation of the CpG10-12 sites located at the FMR1 intron 1 boundary predicted social anxiety with 92% sensitivity in women with the FMR1 premutation [98].…”

Section: Introductionmentioning

confidence: 99%

Reduced vagal tone in women with the FMR1 premutation is associated with FMR1 mRNA but not depression or anxiety

Klusek

LaFauci

Adayev

et al. 2017

J Neurodevelop Disord

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BackgroundAutonomic dysfunction is implicated in a range of psychological conditions, including depression and anxiety. The fragile X mental retardation-1 (FMR1) premutation is a common genetic mutation that affects ~1:150 women and is associated with psychological vulnerability. This study examined cardiac indicators of autonomic function among women with the FMR1 premutation and control women as potential biomarkers for psychological risk that may be linked to FMR1.MethodsBaseline inter-beat interval and respiratory sinus arrhythmia (a measure of parasympathetic vagal tone) were measured in 35 women with the FMR1 premutation and 28 controls. The women completed anxiety and depression questionnaires. FMR1 genetic indices (i.e., CGG repeat, quantitative FMRP, FMR1 mRNA, activation ratio) were obtained for the premutation group.ResultsRespiratory sinus arrhythmia was reduced in the FMR1 premutation group relative to controls. While depression symptoms were associated with reduced respiratory sinus arrhythmia among control women, these variables were unrelated in the FMR1 premutation. Elevated FMR1 mRNA was associated with higher respiratory sinus arrhythmia.ConclusionsWomen with the FMR1 premutation demonstrated autonomic dysregulation characterized by reduced vagal tone. Unlike patterns observed in the general population and in study controls, vagal activity and depression symptoms were decoupled in women with the FMR1 premutation, suggesting independence between autonomic regulation and psychopathological symptoms that is atypical and potentially specific to the FMR1 premutation. The association between vagal tone and mRNA suggests that molecular variation associated with FMR1 plays a role in autonomic regulation.

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Depression and anxiety symptoms among women who carry the FMR1 premutation: Impact of raising a child with fragile X syndrome is moderated by CRHR1 polymorphisms

Cited by 35 publications

References 54 publications

FMR1 genotype interacts with parenting stress to shape health and functional abilities in older age

FMR1 genotype interacts with parenting stress to shape health and functional abilities in older age

The cognitive neuropsychological phenotype of carriers of the FMR1 premutation

Reduced vagal tone in women with the FMR1 premutation is associated with FMR1 mRNA but not depression or anxiety

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