Association studies of common variants in 10 hypogonadotropic hypogonadism genes with age at menarche

Abstract

Context: Although the timing of puberty is a highly heritable trait, little is known about the genes that regulate pubertal timing in the general population. Several genes have been identified that, when mutated, cause disorders of delayed or absent puberty such as hypogonadotropic hypogonadism (HH).

Objective: Because severe variants in HH-related genes cause a severe puberty phenotype, we hypothesized that common subtle variation in these genes could contribute to the population variation in pubertal timing.

Design: We assessed common genetic variation in 10 HH-related genes in 1801 women from the Hawaii and Los Angeles Multiethnic Cohort with either early (age<11 yr) or late (age>14 yr) menarche and in other replication samples. In addition to these common variants, we also studied the most frequently reported HH mutations to assess their role in the population variation in pubertal timing. SETTING AND PATIENTS/OTHER PARTICIPANTS: Within the general community, 1801 women from the Hawaii and Los Angeles Multiethnic Cohort participated.

Main outcome measures: We assessed the association of genetic variation with age at menarche.

Results: We found no significant association between any of the variants tested and age at menarche, although we cannot rule out modest effects of these variants or of other variants at long distances from the coding region. In several self-reported racial/ethnic groups represented in our study, we observed an association between estimated genetic ancestry and age at menarche.

Conclusions: Our results suggest that common variants near 10 HH-related loci do not play a substantial role in the regulation of age at menarche in the general population.

Figure 1

Estimated ancestry and age at menarche by racial/ethnic group. A, Box plots for estimated genetic ancestry by self-reported racial/ethnic group. The y-axis represents the estimated proportion of major ancestry, or the estimated contribution of the ancestry that has the largest contribution to a given self-reported ethnic group. The line within the box is the median of the estimated ancestry for women with early or late menarche; the upper boundary of the box is the 75th percentile; the lower boundary of the box is the 25th percentile. The lines extending from the box represent the adjacent values (the largest and smallest non-outlying values observed in the dataset). Dots represent genetic outliers. For African-Americans, major ethnicity is estimated West African ancestry; for Native Hawaiians, major ethnicity is estimated Native Hawaiian ancestry; for Japanese-Americans, major ethnicity is estimated East Asian ancestry; for Latinas, major ethnicity is estimated European ancestry; and for Whites, major ethnicity is estimated European ancestry. B, Mean ancestry estimates for each self-reported racial/ethnic group separated by early (light grey bars) and late menarche (dark grey bars). Genetic outliers were removed before calculating the means. Major ethnicities are the same as in A. ***, P < 0.01; **, P < 0.05; *, P < 0.1.