Genetic variation in LIN28B is associated with the timing of puberty.
paper
Cited
Public
- Authors
- Ong, Ken K; Elks, Cathy E; Li, Shengxu; Zhao, Jing Hua; Luan, Jian'an; Andersen, Lars B; Bingham, Sheila A; Brage, Soren; Smith, George Davey; Ekelund, Ulf; Gillson, Christopher J; Glaser, Beate; Golding, Jean; Hardy, Rebecca; Khaw, Kay-Tee; Kuh, Diana; Luben, Robert; Marcus, Michele; McGeehin, Michael A; Ness, Andrew R; Northstone, Kate; Ring, Susan M; Rubin, Carol; Sims, Matthew A; Song, Kijoung; Strachan, David P; Vollenweider, Peter; Waeber, Gerard; Waterworth, Dawn M; Wong, Andrew; Deloukas, Panagiotis; Barroso, InΓͺs; Mooser, Vincent; Loos, Ruth J; Wareham, Nicholas J
- Year
- 2009
- Journal
- Nature genetics
- PMID
- 19448623
- DOI
- 10.1038/ng.382
- PMCID
- PMC3000552
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 Γ 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 Γ 10(-10); combined P = 3.6 Γ 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 Γ 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.
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 (βlog10 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.
LLM interpretation
This is a regional GWAS plot showing the association between SNPs on chromosome 6 and age at menarche, with $-\log_{10}(P)$ values on the y-axis and genomic position (kb) on the x-axis. A cluster of highly significant SNPs peaks around the *LIN28B* gene, with the lead SNP rs314276 labeled with a P-value of $1.5\text{e-}08$. SNPs are color-coded by their linkage disequilibrium ($r^2$) with rs314276, while a cyan line indicates local recombination rates and green arrows denote the positions and transcription directions of nearby genes (*HACE1*, *LIN28B*, *BVES*, and *POPDC3*).
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.
LLM interpretation
This is a forest plot showing the meta-analysis of the effect of the C allele at rs314276 in *LIN28B* on age at menarche across GWA populations and replication cohorts. The x-axis measures the difference in age at menarche per C allele in years, with all individual cohorts and subtotal diamonds showing a negative effect (earlier age at menarche). The overall regression coefficient estimate is -0.14 (95% CI: -0.17, -0.11), and a p-value of 0.022 indicates significant heterogeneity between the GWA and replication groups.
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.
LLM interpretation
This is a Kaplan-Meier survival plot showing the probability of remaining in a pre-pubertal status (Tanner breast stage 1) by age for three LIN28B rs314276 genotypes (A:A, C:A, and C:C) in a cohort of 3,233 girls. The x-axis represents age in years (from 8 to 12) and the y-axis represents survival probability. The A:A genotype (dotted line) shows a higher probability of remaining pre-pubertal over time compared to the C:A and C:C genotypes, with a statistically significant difference between genotypes (P = 0.001, log-rank test).
Adolescent growth in ALSPAC girls by LIN28B rs314276 genotype. (aβc) Mean (Β± 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).
LLM interpretation
This figure consists of three line graphs (aβc) showing the mean standard deviation scores (SDS) for height, weight, and BMI plotted against age (7 to 11 years) for three LIN28B rs314276 genotypes (A:A, C:A, and C:C). In all three plots, the C:C genotype (triangles) generally maintains the highest SDS, while the A:A genotype (circles) shows a downward trend relative to the others. The legend indicates statistically significant differences in the change of SDS over time by genotype for height (p=0.00008), weight (p=0.0003), and BMI (p=0.03).
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| Replication of genetic loci for ages at menarche and menopause in the multi-ethnic Population Architecture using Genomics and Epidemiology (PAGE) study. | Carty CL et al. | β | 2013 | β |
| Replication of LIN28B SNP association with age of menarche in young Filipino women. | Croteau-Chonka DC et al. | β | 2013 | β |
| The leptin gene family and colorectal cancer: interaction with smoking behavior and family history of cancer. | Liu L et al. | β | 2013 | β |
| The role of miRNAs in regulating gene expression networks. | Gurtan AM et al. | β | 2013 | β |
| Absence of functional LIN28B mutations in a large cohort of patients with idiopathic central precocious puberty. | Silveira-Neto AP et al. | β | 2012 | β |
| A LIN28B polymorphism predicts for colon cancer survival. | Ye Y et al. | β | 2012 | β |
| Analysis of LIN28A in early human ovary development and as a candidate gene for primary ovarian insufficiency. | El-Khairi R et al. | β | 2012 | β |
| A potential mechanism for the sexual dimorphism in the onset of puberty and incidence of idiopathic central precocious puberty in children: sex-specific kisspeptin as an integrator of puberty signals. | Bianco SD | β | 2012 | β |
| A single-nucleotide polymorphism in the EAP1 gene is associated with amenorrhea/oligomenorrhea in nonhuman primates. | Lomniczi A et al. | β | 2012 | β |
| Association of LIN28B with adult adiposity-related traits in females. | Leinonen JT et al. | β | 2012 | β |
| Clinical practice. Delayed puberty. | Palmert MR et al. | β | 2012 | β |
| Common variation at 6q16 within HACE1 and LIN28B influences susceptibility to neuroblastoma. | Diskin SJ et al. | β | 2012 | β |
| Confluence of genes, environment, development, and behavior in a post Genome-Wide Association Study world. | Vrieze SI et al. | β | 2012 | β |
| Data-driven assessment of the human ovarian reserve. | Kelsey TW et al. | β | 2012 | β |
| Deciphering puberty: novel partners, novel mechanisms. | Tena-Sempere M | β | 2012 | β |
| Effects of obesity on human sexual development. | Wagner IV et al. | β | 2012 | β |
| Environmental and genetic factors influence age at menarche in women with polycystic ovary syndrome. | Carroll J et al. | β | 2012 | β |
| Functional study of risk loci of stem cell-associated gene lin-28B and associations with disease survival outcomes in epithelial ovarian cancer. | Lu L et al. | β | 2012 | β |
| Genetic markers of ovarian follicle number and menopause in women of multiple ethnicities. | Schuh-Huerta SM et al. | β | 2012 | β |
| Genetics of age at menarche: a systematic review. | Dvornyk V et al. | β | 2012 | β |
| Genome-wide copy number variation association analyses for age at menarche. | Liu YZ et al. | β | 2012 | β |
| High urinary phthalate concentration associated with delayed pubarche in girls. | Frederiksen H et al. | β | 2012 | β |
| How does Lin28 let-7 control development and disease? | Thornton JE et al. | β | 2012 | β |
| LIN28B induces neuroblastoma and enhances MYCN levels via let-7 suppression. | Molenaar JJ et al. | β | 2012 | β |
| LIN28B polymorphisms are associated with central precocious puberty and early puberty in girls. | Park SW et al. | β | 2012 | β |
| Lin-28 homologue A (LIN28A) promotes cell cycle progression via regulation of cyclin-dependent kinase 2 (CDK2), cyclin D1 (CCND1), and cell division cycle 25 homolog A (CDC25A) expression in cancer. | Li N et al. | β | 2012 | β |
| Reproductive aging-associated common genetic variants and the risk of breast cancer. | He C et al. | β | 2012 | β |
| The genes associated with gonadotropin-releasing hormone-dependent precocious puberty. | Hwang JS | β | 2012 | β |
| Timing of voice breaking in males associated with growth and weight gain across the life course. | Ong KK et al. | β | 2012 | β |
| An assessment of the individual and collective effects of variants on height using twins and a developmentally informative study design. | Vrieze SI et al. | β | 2011 | β |
| Associations between the pubertal timing-related variant in LIN28B and BMI vary across the life course. | Ong KK et al. | β | 2011 | β |
| Association study in Taiwanese girls with precocious puberty. | Chou IC et al. | β | 2011 | β |
| Caenorhabditis elegans reproductive aging: Regulation and underlying mechanisms. | Luo S et al. | β | 2011 | β |
| Child health, developmental plasticity, and epigenetic programming. | Hochberg Z et al. | β | 2011 | β |
| Estimation of odds ratios of genetic variants for the secondary phenotypes associated with primary diseases. | Wang J et al. | β | 2011 | β |
| LIN28B, LIN28A, KISS1, and KISS1R in idiopathic central precocious puberty. | Tommiska J et al. | β | 2011 | β |
| LIN28B polymorphisms influence susceptibility to epithelial ovarian cancer. | Permuth-Wey J et al. | β | 2011 | β |
| Linking nutrition, maturation and aging: from thrifty genes to the spendthrift phenotype. | Stipp D | β | 2011 | β |
| MAB-10/NAB acts with LIN-29/EGR to regulate terminal differentiation and the transition from larva to adult in C. elegans. | Harris DT et al. | β | 2011 | β |
| Molecular basis for interaction of let-7 microRNAs with Lin28. | Nam Y et al. | β | 2011 | β |
| New genetic factors implicated in human GnRH-dependent precocious puberty: the role of kisspeptin system. | Teles MG et al. | β | 2011 | β |
| Power and instrument strength requirements for Mendelian randomization studies using multiple genetic variants. | Pierce BL et al. | β | 2011 | β |
| Regulation of pre-miRNA Processing. | Lehrbach NJ et al. | β | 2011 | β |
| Reproductive biology: bone returns the favour. | Schuh-Huerta SM et al. | β | 2011 | β |
| Second to fourth digit ratio: a predictor of adult penile length. | Choi IH et al. | β | 2011 | β |
| The efficacy of detecting variants with small effects on the Affymetrix 6.0 platform using pooled DNA. | Chiang CW et al. | β | 2011 | β |
| The genetics of bone loss: challenges and prospects. | Mitchell BD et al. | β | 2011 | β |
| Whole genome associated studies for age at menarche. | Elks CE et al. | β | 2011 | β |
| A large-scale candidate gene association study of age at menarche and age at natural menopause. | He C et al. | β | 2010 | β |
| Association weight matrix for the genetic dissection of puberty in beef cattle. | Fortes MR et al. | β | 2010 | β |
| A variant in LIN28B is associated with 2D:4D finger-length ratio, a putative retrospective biomarker of prenatal testosterone exposure. | Medland SE et al. | β | 2010 | β |
| Child and adolescent psychiatric genetics. | Hebebrand J et al. | β | 2010 | β |
| Determinants of menarche. | Karapanou O et al. | β | 2010 | β |
| Distinct variants at LIN28B influence growth in height from birth to adulthood. | WidΓ©n E et al. | β | 2010 | β |
| Environmental factors and their timing in adult-onset multiple sclerosis. | Handel AE et al. | β | 2010 | β |
| Gene networks and the neuroendocrine regulation of puberty. | Ojeda SR et al. | β | 2010 | β |
| Genetic determinants of pubertal timing in the general population. | Gajdos ZK et al. | β | 2010 | β |
| Genetics basis for GnRH-dependent pubertal disorders in humans. | Silveira LF et al. | β | 2010 | β |
| Grand challenges in pediatric endocrinology. | Cianfarani S | β | 2010 | β |
| Hypothesis: exposure to endocrine-disrupting chemicals may interfere with timing of puberty. | Mouritsen A et al. | β | 2010 | β |
| Identification of microRNAs regulating reprogramming factor LIN28 in embryonic stem cells and cancer cells. | Zhong X et al. | β | 2010 | β |
| Lin28a transgenic mice manifest size and puberty phenotypes identified in human genetic association studies. | Zhu H et al. | β | 2010 | β |
| Metabolic control of puberty onset: new players, new mechanisms. | Roa J et al. | β | 2010 | β |
| miRNAs give worms the time of their lives: small RNAs and temporal control in Caenorhabditis elegans. | Resnick TD et al. | β | 2010 | β |
| Non-coding RNAs: regulators of disease. | Taft RJ et al. | β | 2010 | β |
| Prepubertal adrenarchal androgens and animal protein intake independently and differentially influence pubertal timing. | Remer T et al. | β | 2010 | β |
| TGF-Ξ² and insulin signaling regulate reproductive aging via oocyte and germline quality maintenance. | Luo S et al. | β | 2010 | β |
| The exon 3 deleted growth hormone receptor gene is associated with small birth size and early pubertal onset in healthy boys. | SΓΈrensen K et al. | β | 2010 | β |
| The nuclear receptor gene nhr-25 plays multiple roles in the Caenorhabditis elegans heterochronic gene network to control the larva-to-adult transition. | Hada K et al. | β | 2010 | β |
| The pursuit of genome-wide association studies: where are we now? | Ku CS et al. | β | 2010 | β |
| The transcriptional control of female puberty. | Ojeda SR et al. | β | 2010 | β |
| Thirty new loci for age at menarche identified by a meta-analysis of genome-wide association studies. | Elks CE et al. | β | 2010 | β |
| Genetics of reproductive lifespan. | Hartge P | β | 2009 | β |
| Lin28 recruits the TUTase Zcchc11 to inhibit let-7 maturation in mouse embryonic stem cells. | Hagan JP et al. | β | 2009 | β |
| Pathogenesis of adolescent idiopathic scoliosis in girls - a double neuro-osseous theory involving disharmony between two nervous systems, somatic and autonomic expressed in the spine and trunk: possible dependency on sympathetic nervous system and hormones with implications for medical therapy. | Burwell RG et al. | β | 2009 | β |