Rare coding variants and X-linked loci associated with age at menarche

Area of Science:

• Human Genetics
• Reproductive Biology
• Genomics

Background:

• Genome-wide association studies (GWAS) have identified over 100 loci for age at menarche.
• These known loci collectively explain only a small fraction (approximately 3%) of the trait's variance.
• Significant 'missing heritability' remains unexplained for this complex trait.

Purpose of the Study:

• To investigate the contribution of understudied genetic variation to age at menarche.
• Specifically, to examine low-frequency protein-coding variants and X-chromosome variants.
• To identify novel genetic loci associated with menarche timing in European ancestry women.

Main Methods:

• Analysis of a large cohort of 192,974 European ancestry women.
• Utilized genome-wide association studies to identify associations with age at menarche.
• Focused on low-frequency protein-coding variants and variants on the X-chromosome.

Main Results:

• Identified five missense/nonsense variants in genes ALMS1, LAMB2, TNRC6A, TACR3, and PRKAG1 associated with age at menarche.
• Discovered common X-chromosome loci at IGSF1 and FAAH2 significantly associated with menarche timing.
• A mutation in TACR3 (p.W275X) linked to idiopathic hypogonadotropic hypogonadism showed a significant association with later menarche.

Conclusions:

• Low-frequency protein-coding and X-chromosome variants represent important, previously overlooked sources of variation for age at menarche.
• These novel variants collectively explain an additional ~0.5% of the trait variance.
• The identified variants implicate pathways in cellular energy, gene silencing, and fatty-acid signaling in menarche timing.