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

Autor: Richard Quinton, Brooke Meader, Katie L. Lewis, Janet E. Hall, Corrine K. Welt, Joan E. Bailey-Wilson, Leslie G. Biesecker, Alessandro Albano, Christopher A. Lavender, Natalie Shaw, Angela Delaney, Verónica Mericq, Paulina M. Merino, Stephanie B. Seminara, Adam B. Burkholder, Lacey Plummer, Kathryn A. Martin
Rok vydání: 2020
Předmět:
Adult
0301 basic medicine
Isolated hypogonadotropic hypogonadism
medicine.medical_specialty
Adolescent
Endocrinology
Diabetes and Metabolism
DNA Mutational Analysis
Clinical Biochemistry
Mutation
Missense
030209 endocrinology & metabolism
Context (language use)
Biochemistry
Gonadotropin-Releasing Hormone
Young Adult
03 medical and health sciences
0302 clinical medicine
Endocrinology
Gene Frequency
Hypogonadotropic hypogonadism
Internal medicine
Exome Sequencing
Humans
Medicine
Genetic Predisposition to Disease
Allele
Online Only Articles
Child
Amenorrhea
Gene
Genetic Association Studies
Exome sequencing
Aged
Sequence (medicine)
business.industry
Hypogonadism
Biochemistry (medical)
Kallmann Syndrome
Middle Aged
Heritability
medicine.disease
030104 developmental biology
Case-Control Studies
Female
business
Hypothalamic Diseases
Metabolic Networks and Pathways
Zdroj: J Clin Endocrinol Metab
ISSN: 1945-7197
0021-972X
Popis: 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.
Databáze: OpenAIRE
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