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

A gene-based association study of women with a fragile X premutation, followed by a functional screen of prioritized genes, identified SUMO1 and KRR1 as susceptibility genes for primary ovarian insufficiency.

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VOLUME 116, ISSUE 3, P843-854


Cristina E. Trevino, Ph.D., J. Christopher Rounds, Ph.D., Krista Charen, M.S., Lisa Shubeck, B.A., Heather S. Hipp, M.D., Jessica B. Spencer, M.D., H. Richard Johnston, Ph.D., Dave J. Cutler, Ph.D., Michael E. Zwick, Ph.D., Michael P. Epstein, Ph.D., Anna Murray, Ph.D., James N. Macpherson, Ph.D., Montserrat Mila, Ph.D., Laia Rodriguez-Revenga, Ph.D., Elizabeth Berry-Kravis, M.D., Deborah A. Hall, M.D., Maureen A. Leehey, M.D., Ying Liu, M.D., Corrine Welt, M.D., Stephen T. Warren, Ph.D., Stephanie L. Sherman, Ph.D., Peng Jin, Ph.D., Emily G. Allen, Ph.D. 



To identify modifying genes that explains the risk of fragile X-associated primary ovarian insufficiency (FXPOI).


Gene-based, case/control association study, followed by a functional screen of highly ranked genes using a Drosophila model.


Participants were recruited from academic and clinical settings.


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.


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.


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.


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.

Fertility and Sterility

Editorial Office, American Society for Reproductive Medicine

Fertility and Sterility® is an international journal for obstetricians, gynecologists, reproductive endocrinologists, urologists, basic scientists and others who treat and investigate problems of infertility and human reproductive disorders.