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

TitleIncreased Burden of Rare Sequence Variants in GnRH-Associated Genes in Women With Hypothalamic Amenorrhea.
Publication TypeJournal Article
Year of Publication2021
AuthorsDelaney, A, Burkholder, AB, Lavender, CA, Plummer, L, Mericq, V, Merino, PM, Quinton, R, Lewis, KL, Meader, BN, Albano, A, Shaw, ND, Welt, CK, Martin, KA, Seminara, SB, Biesecker, LG, Bailey-Wilson, JE, Hall, JE
JournalJ Clin Endocrinol Metab
Date Published2021 Mar 08

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.

Alternate JournalJ Clin Endocrinol Metab
PubMed ID32870266
PubMed Central IDPMC7947783
Grant ListP50 HD028138 / HD / NICHD NIH HHS / United States
UM1 HG006504 / HG / NHGRI NIH HHS / United States
ZIA ES103323 / Im / Intramural NIH HHS / United States
ZIA HD008919 / Im / Intramural NIH HHS / United States
R01 HD043341 / HD / NICHD NIH HHS / United States
K24 HD001290 / HD / NICHD NIH HHS / United States