Identifying susceptibility genes for primary ovarian insufficiency on the high-risk genetic background of a fragile X premutation

This is the final version. Available on open access from Elsevier via the DOI in this recordObjective: To identify modifying genes that explains the risk of fragile X-associated primary ovarian insufficiency (FXPOI). Design: Gene-based, case/control association study, followed by a functional screen of highly ranked genes using a Drosophila model. Setting: Participants were recruited from academic and clinical settings. Patient(s): Women with a premutation (PM) who experienced FXPOI at the age of 35 years or younger (n = 63) and women with a PM who experienced menopause at the age of 50 years or older (n = 51) provided clinical information and a deoxyribonucleic acid sample for whole genome sequencing. The functional screen was on the basis of Drosophila TRiP lines. Intervention(s): Clinical information and a DNA sample were collected for whole genome sequencing. Main Outcome Measures: A polygenic risk score derived from common variants associated with natural age at menopause was calculated and associated with the risk of FXPOI. Genes associated with the risk of FXPOI were identified on the basis of the P-value from gene-based association test and an altered level of fecundity when knocked down in the Drosophila PM model. Results: The polygenic risk score on the basis of common variants associated with natural age at menopause explained approximately 8% of the variance in the risk of FXPOI. Further, SUMO1 and KRR1 were identified as possible modifying genes associated with the risk of FXPOI on the basis of an untargeted gene analysis of rare variants. Conclusions: In addition to the large genetic effect of a PM on ovarian function, the additive effects of common variants associated with natural age at menopause and the effect of rare modifying variants appear to play a role in FXPOI risk.Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)Fundacion Merck Salu

The delay of gratification test for adults: Validating a behavioral measure of self-motivation in a sample of older people

Most previous delay of gratification tests were developed for children and are inappropriate for application in adults. The authors therefore developed the Delay of Gratification Test for Adults (DoG-A), which includes four types of reward that are meaningful to adults, namely snacks, real money, hypothetical money, and magazines. Four subscores and two composite scores can be calculated. This study is the first to evaluate the DoG-A and to investigate its association with external variables. A community sample of 147 cognitively healthy participants aged between 60 and 94 years completed a questionnaire and cognitive tests measuring delay discounting, self-regulation, motivational self-concept, personality, wellbeing, and cognitive function. The intercorrelations of the subscales were low to medium and the internal consistency of the composite scores was moderate (α = 0.4), indicating relative domain independence of the four reward types. The nomological net established by investigating the relations of the DoG-A with other constructs proved to be fairly meaningful. The correlations of all subscales with the delay discounting rate were significant and moderate. The Snacks subscale showed the most consistent pattern of results in terms of moderate positive correlations with self-reported motivation regulation, optimism, dutifulness, and deliberation. The Snacks subscale also correlated with various measures of wellbeing. A regression analysis showed that DoG Snacks remained a significant predictor of wellbeing when self-reported self-regulation and other variables were controlled. These findings indicate that the DoG-A yields an interpretable behavioral measure of self-motivation and offers a developmentally adequate extension of the delay of gratification paradigm for use with adults