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Cited by 21

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Increased Burden of Rare Sequence Variants in GnRH-Associated Genes in Women With Hypothalamic Amenorrhea

Delaney, Angela, Burkholder, Adam B, Lavender, Christopher A, Plummer, Lacey, Mericq, Veronica, Merino, Paulina M, Quinton, Richard, Lewis, Katie L, Meader, Brooke N, Albano, Alessandro, Shaw, Natalie D, Welt, Corrine K, Martin, Kathryn A, Seminara, Stephanie B, Biesecker, Leslie G, Bailey-Wilson, Joan E, Hall, Janet E·2021·The Journal of Clinical Endocrinology & Metabolism
DOI 10.1210/clinem/dgaa609
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Abstract

Context: Functional hypothalamic amenorrhea (HA) is a common, acquired form of hypogonadotropic hypogonadism that occurs in the setting of energy deficits and/or stress. Variability in individual susceptibility to these stressors, HA heritability, and previous identification of several rare sequence variants (RSVs) in genes associated with the rare disorder, isolated hypogonadotropic hypogonadism (IHH), in individuals with HA suggest a possible genetic contribution to HA susceptibility. Objective: We sought to determine whether the burden of RSVs in IHH-related genes is greater in women with HA than controls. Design: We compared patients with HA to control women. Setting: The study was conducted at secondary referral centers. Patients and Other Participants: Women with HA (n = 106) and control women (ClinSeq study; n = 468). Interventions: We performed exome sequencing in all patients and controls. Main Outcome Measure(s): The frequency of RSVs in 53 IHH-associated genes was determined using rare variant burden and association tests. Results: RSVs were overrepresented in women with HA compared with controls (P = .007). Seventy-eight heterozygous RSVs in 33 genes were identified in 58 women with HA (36.8% of alleles) compared to 255 RSVs in 41 genes among 200 control women (27.2%). Conclusions: Women with HA are enriched for RSVs in genes that cause IHH, suggesting that variation in genes associated with gonadotropin-releasing hormone neuronal ontogeny and function may be a major determinant of individual susceptibility to developing HA in the face of diet, exercise, and/or stress.

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Cited by

Metadata

Authors
Delaney, A., Burkholder, A. B., Lavender, C. A., Plummer, L., Mericq, V., Merino, P. M., Quinton, R., Lewis, K. L., Meader, B. N., Albano, A., Shaw, N. D., Welt, C. K., Martin, K. A., Seminara, S. B., Biesecker, L. G., Bailey-Wilson, J. E., & Hall, J. E.
Affiliations
  • National Institute of Environmental Health Sciences, National Institutes of Health (NIH), Research Triangle Park, North Carolina
  • Harvard Reproductive Sciences Center and Reproductive Endocrine Unit, Massachusetts General Hospital, Boston, Massachusetts
  • Institute of Maternal and Child Research, University of Chile, Santiago, Chile
  • Institute of Genetic Medicine, Newcastle University, Newcastle-upon-Tyne, UK
  • Medical Genomics & Metabolic Genetics Branch, National Human Genome Research Institute, NIH, Bethesda, Maryland
  • Division of Endocrinology, Metabolism and Diabetes, University of Utah, Salt Lake City, Utah
  • Computational and Statistical Genomics Branch, National Human Genome Research Institute, NIH, Baltimore, Maryland
ORCID
Venue
The Journal of Clinical Endocrinology & Metabolism
Publisher
The Endocrine Society
Published
2020-09-01
Volume
106
Issue
3
Pages
e1441-e1452
ISSN
  • 0021-972X
  • 1945-7197
DOI
10.1210/clinem/dgaa609
Cited by
21
References
6
Language
en
Funders
  • National Institute of Environmental Health Sciences (ZID ES103323-01)
  • Eunice Kennedy Shriver National Institute of Child Health and Human Development (ZIAHD008919)
  • Harvard Reproductive Endocrine Sciences Center (P50 HD028138, K24 HD01290, R01 HD043341)
  • National Institutes of Health
  • National Human Genome Research Institute
  • Yale Center for Mendelian Genomics (M#UM1HG006504-05)
  • National Heart, Lung, and Blood Institute

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