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

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.

Trial registration: ClinicalTrials.gov NCT01500447 NCT00494169.

Keywords: GnRH deficiency; exome sequencing; female reproduction; genetics; hypogonadotropic hypogonadism.

Published by Oxford University Press on behalf of the Endocrine Society 2020.

Figures

Figure 1.

Rare sequence variants (RSVs) in women with HA and controls. RSVs in each gene expressed as frequency of variant alleles per gene in HA (black bars) vs control (gray bars) participants. The inset indicates the aggregate total frequency of variant alleles among all genes. No variants were found in either group in the following genes, which are excluded from the figure: DLX1, NSMF, SOX10, STUB1, and TAC3. Excluded from analysis because of being absent from at least one capture probe design: IL17RD, SMCHD1, and TUBB3. *P equal to .007.

Figure 2.

Percentage of participants with a given number of rare sequence variants (RSVs). Women with HA (black bars) were compared with control women (gray bars). *P less than .05.