Genomic analyses identify hundreds of variants associated with age at menarche and support a role for puberty timing in cancer risk

Date
2017
Authors
Language
English
Embargo Lift Date
Committee Members
Degree
Degree Year
Department
Grantor
Journal Title
Journal ISSN
Volume Title
Found At
Nature
Abstract

The timing of puberty is a highly polygenic childhood trait that is epidemiologically associated with various adult diseases. Using 1000 Genomes Project–imputed genotype data in up to ∼370,000 women, we identify 389 independent signals (P < 5 × 10−8) for age at menarche, a milestone in female pubertal development. In Icelandic data, these signals explain ∼7.4% of the population variance in age at menarche, corresponding to ∼25% of the estimated heritability. We implicate ∼250 genes via coding variation or associated expression, demonstrating significant enrichment in neural tissues. Rare variants near the imprinted genes MKRN3 and DLK1 were identified, exhibiting large effects when paternally inherited. Mendelian randomization analyses suggest causal inverse associations, independent of body mass index (BMI), between puberty timing and risks for breast and endometrial cancers in women and prostate cancer in men. In aggregate, our findings highlight the complexity of the genetic regulation of puberty timing and support causal links with cancer susceptibility.

Description
item.page.description.tableofcontents
item.page.relation.haspart
Cite As
Day, F. R., Thompson, D. J., Helgason, H., McCarthy, M., LifeLines Cohort Study, InterAct Consortium, ... & PRACTICAL consortium. (2017). Genomic analyses identify hundreds of variants associated with age at menarche and support a role for puberty timing in cancer risk. Nature Genetics, 49, 834-841. https://doi.org/10.1038/ng.3841
ISSN
Publisher
Series/Report
Sponsorship
Major
Extent
Identifier
Relation
Journal
Nature Genetics
Rights
Publisher Policy
Source
Author
Alternative Title
Type
Article
Number
Volume
Conference Dates
Conference Host
Conference Location
Conference Name
Conference Panel
Conference Secretariat Location
Version
Author's manuscript
Full Text Available at
This item is under embargo {{howLong}}