Genetic variation in LIN28B is associated with the timing of puberty

Abstract

The timing of puberty is highly variable. We carried out a genome-wide association study for age at menarche in 4,714 women and report an association in LIN28B on chromosome 6 (rs314276, minor allele frequency (MAF) = 0.33, P = 1.5 × 10(-8)). In independent replication studies in 16,373 women, each major allele was associated with 0.12 years earlier menarche (95% CI = 0.08-0.16; P = 2.8 × 10(-10); combined P = 3.6 × 10(-16)). This allele was also associated with earlier breast development in girls (P = 0.001; N = 4,271); earlier voice breaking (P = 0.006, N = 1,026) and more advanced pubic hair development in boys (P = 0.01; N = 4,588); a faster tempo of height growth in girls (P = 0.00008; N = 4,271) and boys (P = 0.03; N = 4,588); and shorter adult height in women (P = 3.6 × 10(-7); N = 17,274) and men (P = 0.006; N = 9,840) in keeping with earlier growth cessation. These studies identify variation in LIN28B, a potent and specific regulator of microRNA processing, as the first genetic determinant regulating the timing of human pubertal growth and development.

Figure 1

Regional plot of the locus around LIN28B associated with age at menarche. SNPs are plotted by position on chromosome 6 against GWAS association with age at menarche (−log₁₀ P value). SNP rs314276 is shown in blue, labeled with its stage 1 P value. Estimated recombination rates (from HapMap) are plotted in cyan to reflect the local LD structure. The directly genotyped or imputed SNPs surrounding rs314276 are color-coded to reflect their LD with rs314276 as in the inset (taken from pairwise r² values from the HapMap CEU database). Genes and their directions of transcription are noted at the bottom of the plot.

Figure 2

A forest plot showing the meta-analysis of the effect of each C allele at rs314276 in LIN28B on earlier age at menarche in the GWA populations, the replication cohorts and in all groups.

Figure 3

Kaplan-Maier plot of survival in pre-pubertal status (Tanner breast stage 1) by age and LIN28B rs314276 genotype in ALSPAC girls (N = 3,233). P = 0.001, log-rank test for genotype difference.

Figure 4

Adolescent growth in ALSPAC girls by LIN28B rs314276 genotype. (a–c) Mean (± s.e.) standard deviation scores (SDS) for tempo of growth (child's height SDS minus mean parental height SDS) (a), weight (b) and BMI (c) are plotted against age from 7 to 11 years by genotype. P values (0.00008, 0.0003 and 0.03 for height, weight and BMI, respectively) are from time-series analyses (repeated measures ANOVA) for the change in SDS over time by genotype (additive genetic models).