Genome-wide association studies identify loci associated with age at menarche and age at natural menopause

He, Chufeng; Kraft, Peter; Chen, Constance; Buring, Julie E.; Paré, Guillaume; Hankinson, Susan E.; Chanock, Stephen J.; Ridker, Paul M.; Hunter, David J.; Chasman, Daniel I.

doi:10.1038/ng.385

Cited by 359 publications

(329 citation statements)

References 29 publications

Supporting

Mentioning

301

Contrasting

Unclassified

Order By: Relevance

“…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.…”

Section: Role Of Nesfatin-1 In Puberty Onset: Supporting Evidencementioning

confidence: 64%

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

Tena‐Sempere

2012

European Journal of Endocrinology

View full text Add to dashboard Cite

Puberty is a fascinating developmental phase that involves the attainment of reproductive capacity and the completion of sexual and somatic maturation. As a life-changing event, puberty onset is precisely controlled by interconnected regulatory pathways that are sensitive to numerous endogenous signals and environmental cues. The mechanisms of normal puberty and its potential deviations have been thoroughly studied in humans and model species. Yet, characterization of the neurobiological basis of puberty is still incomplete. Progress on this front is not only relevant from a physiological perspective but would also help to unravel the underlying causes for the observed changes in the timing of puberty in humans, with a trend for earlier puberty onset, especially in girls. In this review, we will provide a synoptic overview of some recent developments in the field that have deepened our understanding of the neuroendocrine and molecular basis for the control of puberty onset. These include not only the demonstration of the involvement of the hypothalamic Kiss1 system in the control of puberty and its modulation by metabolic cues but also the identification of the roles of other neuropeptide pathways and molecular mediators in the regulation of puberty. In addition, the potential contribution of novel regulatory mechanisms, such as epigenetics, in the central control of puberty will be briefly discussed. Characterization of these novel players and regulatory mechanisms will improve our understanding of the basis of normal puberty and its eventual alterations in various pathological conditions. European Journal of Endocrinology 167 733-747

show abstract

Section: Role Of Nesfatin-1 In Puberty Onset: Supporting Evidencementioning

confidence: 64%

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

Tena‐Sempere

2012

European Journal of Endocrinology

View full text Add to dashboard Cite

show abstract

“…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.…”

Section: Discussionmentioning

confidence: 99%

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

Fortes

Reverter

Zhang

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

129

148

View full text Add to dashboard Cite

We describe a systems biology approach for the genetic dissection of complex traits based on applying gene network theory to the results from genome-wide associations. The associations of singlenucleotide polymorphisms (SNP) that were individually associated with a primary phenotype of interest, age at puberty in our study, were explored across 22 related traits. Genomic regions were surveyed for genes harboring the selected SNP. As a result, an association weight matrix (AWM) was constructed with as many rows as genes and as many columns as traits. Each {i, j} cell value in the AWM corresponds to the z-score normalized additive effect of the ith gene (via its neighboring SNP) on the jth trait. Columnwise, the AWM recovered the genetic correlations estimated via pedigree-based restricted maximum-likelihood methods. Rowwise, a combination of hierarchical clustering, gene network, and pathway analyses identified genetic drivers that would have been missed by standard genome-wide association studies. Finally, the promoter regions of the AWM-predicted targets of three key transcription factors (TFs), estrogen-related receptor γ (ESRRG), Pal3 motif, bound by a PPAR-γ homodimer, IR3 sites (PPARG), and Prophet of Pit 1, PROP paired-like homeobox 1 (PROP1), were surveyed to identify binding sites corresponding to those TFs. Applied to our case, the AWM results recapitulate the known biology of puberty, captured experimentally validated binding sites, and identified candidate genes and genegene interactions for further investigation.bovine | complex traits | fertility | reproduction | systems biology T he analysis of genome-wide association studies (GWASs) applied to complex traits remains a challenge (1). Addressing a complex trait by a single, often binary, phenotypic measure is common practice but is limiting. It is not easy to find the right balance between applying a conservative significance threshold that gives rise to a small number of strong and hopefully biologically meaningful associations and applying a relaxed threshold yielding numerous associations, many of which are new but potentially false. In addition, an increase in sample size coupled with a denser chip results in a larger number of associations that, on average, have a much smaller effect (2). Accepting a large number of associations while simultaneously reducing the number of false positives would be ideal. It is reasonable to propose that a holistic approach applied to a relaxed significance threshold could be the solution. Such a strategy would be particularly useful when investigating the genetic basis of complex traits that, by definition, are influenced by numerous genes and pathways.In our study, age at puberty was the complex phenotype considered. Puberty, or the progression to sexual maturity, is a developmental process with genetic drivers conserved among species (3). It is an important phenotype for the beef industry because late puberty has negative effects on reproduction rates and profitability (4). Age at puberty is moderately heritab...

show abstract

“…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. In addition, two convincing loci were also identified for menopause, 19q13.42 (BRSK1) and 20p12.3 (MCM8).…”

Section: The Recent 2 Years: 2008 and 2009mentioning

confidence: 99%

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

et al. 2010

View full text Add to dashboard Cite

It is now 5 years since the first genome-wide association studies (GWAS), published in 2005, identified a common risk allele with large effect size for age-related macular degeneration in a small sample set. Following this exciting finding, researchers have become optimistic about the prospect of the genome-wide association approach. However, most of the risk alleles identified in the subsequent GWAS for various complex diseases are common with small effect sizes (odds ratio o1.5). So far, more than 450 GWAS have been published and the associations of greater than 2000 single nucleotide polymorphisms (SNPs) or genetic loci were reported. The aim of this review paper is to give an overview of the evolving field of GWAS, discuss the progress that has been made by GWAS and some of the interesting findings, and summarize what we have learned over the past 5 years about the genetic basis of human complex diseases. This review will focus on GWAS of SNPs association for complex diseases but not studies of copy number variations.

show abstract

Genome-wide association studies identify loci associated with age at menarche and age at natural menopause

Cited by 359 publications

References 29 publications

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

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

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

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

Contact Info

Product

Resources

About