ISSN 1662-4009 (online)

ESPE Yearbook of Paediatric Endocrinology (2019) 16 7.6 | DOI: 10.1530/ey.16.7.6


To read the full abstract: Nat Commun. 2018 May. 17;9(1):1977.

This population study reports 26 loci for ages at menarche and menopause in a Japanese population and demonstrates widespread differences in allele frequencies and effect estimates between Japanese and European variants.

Over the past decade, genome-wide association study (GWAS) meta-analyses have explored the genetic architecture of reproductive ageing (1–4), but were limited by their large circumscription to European population. Here, the authors highlight the benefits and challenges of large-scale trans-ethnic approaches to succeed in the detection of key genes and pathways that are poorly represented in European populations.

This article is based on a GWAS for ages at menarche and menopause in 67,029 women of Japanese ancestry from the BioBank Japan Project (5). The authors report multiple novel loci for ages at menarche or menopause and thus identify novel genes and pathways involved in human reproductive ageing, particularly in the Japanese population. In particular, a deleterious variant in GNRH1, a known signal of menarche, was identified as a novel locus for menopause timing, suggesting a role for the hypothalamic-pituitary axis in the onset of menopause. This study, together with rodent data, also support a role for receptor-like protein tyrosine phosphatases (PTPRs) in the regulation of puberty timing (6).

The replication at genome-wide significance in the Japanese population of 14 known European signals for menarche or menopause supports a largely shared genetic architecture of reproductive ageing, despite population differences in heritability. However, both effect allele frequencies and effect estimates varied considerably between populations, likely due to a combination of differential genetic drift, selection, recombination and possibly environmental factors. Future studies, both within populations and across populations, should be conducted to comprehensively assess environmental interactions with variants at the level of individual loci and overall heritability. Likewise, additional functional works are required to help further understand the role of all of these genes in the regulation of puberty and menopause.

References: 1. Perry JR, et al. 2009 Meta-analysis of genome-wide association data identifies two loci influencing age at menarche. Nat. Genet. 41: 648–650.

2. Elks CE, et al. 2010 Thirty new loci for age at menarche identified by a meta-analysis of genome-wide association studies. Nat. Genet. 42: 1077–1085.

3. Perry JR, et al. 2014 Parent-of-origin-specific allelic associations among 106 genomic loci for age at menarche Nature. 514: 92–97.

4. Day FR, et al. 2017 Genomic analyses identify hundreds of variants associated with age at menarche and support a role for puberty timing in cancer risk. Nat. Genet. 10: 1–19.

5. Nagai A, Hirata M, Kamatani Y, Muto K, Matsuda K, Kiyohara Y, Ninomiya T, Tamakoshi A, Yamagata Z, Mushiroda T, Murakami Y, Yuji K, Furukawa Y, Zembutsu H, Tanaka T, Ohnishi Y, Nakamura Y; BioBank Japan Cooperative Hospital Group & Kubo M. 2017 Overview of the BioBank Japan Project: study design and profile. J. Epidemiol. 27: S2–S8.

6. Parent AS, Mungenast AE, Lomniczi A, Sandau US, Peles E, Bosch MA, Rønnekleiv OK & Ojeda SR. 2007 A contactin-receptor-like protein tyrosine phosphatase β complex mediates adhesive communication between astroglial cells and gonadotrophin-releasing hormone neurones. J. Neuroendocrinol. 19:847–858

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