Genetic variation in LIN28B is associated with the timing of puberty

Abstract

The timing of puberty is highly variable1. 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 processing2, as the first genetic determinant regulating the timing of human pubertal growth and development.Puberty, the transition from childhood to adult body size and sexual maturity, is a complex multistaged process involving growth acceleration, weight gain and the appearance of secondary sexual physical features over a 2-to 3-year period1. Early onset and progression of puberty is seen in some overweight and obese children. In addition to its psycho-social and public health implications, early puberty is associated with increased long-term risk for diseases including obesity, diabetes and cancer3. The stages of puberty and their transitions are difficult to measure accurately1. Epidemiological studies often use age at menarche, the onset of the first menstrual period in girls, to indicate the timing of puberty, as this distinct event is often well recalled many years later1. Girls with earlier menarche are heavier and taller than other girls during childhood; they remain heavier but are shorter as adults3, reflecting their earlier cessation of growth. Twins studies estimate that 44-95% of the variance in age at menarche may be heritable1. However, specific common genetic variants that influence the timing of puberty have not yet been convincingly demonstrated4.To identify common variants associated with the timing of puberty, we conducted a genome-wide association (GWA) study for age at menarche in 4,714 women from two general population studies and one obese case study using the same Affymetrix GeneChip 500K array (Supplementary Note online). Only one SNP, rs314276 in intron 2 of LIN28B on chromosome 6 (MAF 0.33), reached genome-wide statistical significance (P = 1.5 × 10 −8 , Supplementary Fig. 1 online). In these GWA studies overall each major C allele at rs314276 was associated with a mean 0.22 years (95% CI = 0.14-0.29) earlier age at menarche. SNP rs314276 lies in a region of high linkage disequilibrium (LD); although no other SNPs in this region were directly genotyped in these arrays, imputation to HapMap build 35 revealed a further 11 SN...

Association weight matrix for the genetic dissection of puberty in beef cattle

“…This approach is limited for a complex phenotype because it implicates only very few genes. Previous studies used this approach to report associations of the genes CCR3, SPOCK1, LIN28B, ZNF462, TMEM38B, FKTN, FSD1L, and TAL2 with age of puberty in women (11)(12)(13)(14)(15). If we applied only this approach to our data, further research would consider one candidate gene, NMDAR2B, which was strongly associated (P < 0.000015) with AGECL.…”

ENDOCRINOLOGY AND ADOLESCENCE: Deciphering puberty: novel partners, novel mechanisms

“…While one initial study reported an association with the SPOCK locus that has not been replicated (77), four independent papers published in May 2009 identified an association of the age at menarche (AAM) with variability at 6q21, in or near the Lin28B gene (78,79,80,81). The robustness of this finding is reinforced by its recent confirmation in an extensive meta-analysis (82), and the fact that Lin28B had also been linked to breast development and adult height.…”

“…In turn, let7 miRNAs participate in the regulation of Lin28B expression, which is also putatively controlled by other miRNAs, such as mir-132 and mir-145 (as predicted by bioinformatic algorithms), and myc itself. Before the GWAS indicated earlier (78,79,80,81), the potential roles of let7 miRNAs and related factors in the control of puberty or other neuroendocrine functions had not been suspected. On the contrary, let7 miRNAs were initially cataloged as putative tumor suppressors (88).…”

The pursuit of genome-wide association studies: where are we now?

“…The age at menarche and menopause influences the risk of several diseases; for example, the earlier age of menarche and/or later age of menopause increases the risk of breast, ovarian and endometrial cancers. Three studies focused on the age at menarche, [96][97][98] one GWAS studied the age at natural menopause, 99 and the other GWAS investigated both the traits. 100 Several loci were identified for menarche, but all the four studies definitely found an association in the 6p21 locus that contained LIN28B (a height-related gene) and two GWAS detected another locus 9q31.2.…”