Menarche, Age At, Quantitative Trait Locus 1

Description

Age at menarche is a marker of timing of puberty in females. It varies widely between individuals and is a heritable trait (summary by Perry et al., 2014).

Genetic Heterogeneity of Age at Menarche

Age at menarche has been associated with variation on chromosome 22q13. Other quantitative trait loci (QTLs) associated with age at menarche include MENAQ2 (612882) on chromosome 6q21 and MENAQ3 (612883) on chromosome 9q31.

Mapping

MENAQ1

Age at menarche, an important anthropologic variable with major implications for a woman's health later in life, is influenced by genetic contributions. Guo et al. (2006) performed a large-scale genomewide linkage scan in 2,461 Caucasian women from 402 pedigrees to identify quantitative trait loci underlying variations in age at menarche. All subjects were genotyped with 410 microsatellite markers spaced approximately 8.9 cM apart across the human genome. The strongest linkage signal was obtained at the genomic region of 22q13, with a lod score of 3.70 obtained at marker UT7136. The other 2 suggestive linkages were on 22q11 (lod = 2.68 at marker AGAT120) and 11q23 (lod = 1.98 between markers GATA23E06 and GATA64D03), respectively. Guo et al. (2006) also detected significant epistatic interaction between genomic regions 22q13 and 3q13.

Associations Pending Confirmation

Perry et al. (2014) performed a metaanalysis using genomewide and custom-genotyping arrays in up to 182,416 women of European descent from 57 studies, and found robust evidence (p less than 5 x 10(-8)) for 123 signals at 106 genomic loci associated with age at menarche. Many loci were associated with other pubertal traits in both sexes, and there was substantial overlap with genes implicated in body mass index (BMI) and various diseases, including rare disorders of puberty. Menarche signals were enriched in imprinted regions, with 3 loci demonstrating parent-of-origin-specific associations concordant with known parental expression patterns. These loci were DLK1 (176290)-WDR25 on chromosome 14q32, MKRN3 (603856)-MAGEL2 (605283) on chromosome 15q11, and KCNK9 (605874) on chromosome 8q24. Pathway analyses implicated nuclear hormone receptors, particularly retinoic acid and gamma-aminobutyric acid-B2 receptor signaling, among novel mechanisms that regulate pubertal timing in humans. Perry et al. (2014) concluded that their findings suggested a genetic architecture involving at least hundreds of common variants in the coordinated timing of the pubertal transition.