The regulation of the onset of menarche is not fully understood. Mean age of menarche is approximately 13 years in Caucasians, but has decreased over time in many populations and this reduction has been attributed to improved nutrition during recent history. One of the triggers for onset of puberty in girls is thought to be an increase in fat mass to greater than approximately 20% body fat. While non-genetic factors are obviously important in menarche, twin and family studies suggest a significant genetic component with at least 50% heritability (1-3), although linkage studies have not identified any strong candidate genes (4).

We have been involved in a meta-analysis of genome wide association studies to identify novel genetic variants associated with age at menarche. In Exeter we analysed imputed genome wide SNP data from the InChianti study of older people and collaborated with other studies from the CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology) consortium: in total, 15,661 women were included in the meta-analysis.

We identified 3 independent signals with p values less than 1x10-6, one of which reached the conventional genome-wide significance threshold of less than 5 x 10-8. In addition there were two SNPs neighbouring genes which are excellent candidates for involvement in variation in age at menarche. We would therefore like to genotype these 5 SNPs in ALSPAC, to replicate our initial findings.

In addition, the ALSPAC study provides an excellent opportunity to investigate the longitudinal role of these genes in childhod growth and development leading to the onset of puberty in both boys and girls.

Genotypes:

We would like to genotype (at Kbioscience) all ~20,000 ALSPAC samples.

The rs numbers of the selected SNPs are given in the appendix.

Phenotypes:

1. Age at menarche (including birth year as covariate) for all mothers and female offspring, as available.

2. Puberty phenotypes, eg. Age of secondary sexual characteristics

3. Growth measures in infancy and childhood (height, leg length, sitting height, weight and BMI, lean/fat/bone mass from DXA scan, waist circumference, WHR, skinfolds, birth weight, length & head circumference (& relevant covariates: gestational age, parity, twins, maternal smoking), where available)

4. Covariates of age at menarche to check if genotype is acting through them/to reduce variance in outcome: year of birth, BMI, height, ethnicity as genotype frequency may alter with ethnic origin and confound analyses.

Plans for meta-analysis:

The ALSPAC data on association with age at menarche will be meta-analysed with the original genome-wide association data and also other replication efforts, including the British Women's Heart & Health Study (BWHHS).

The longitudinal study of ALSPAC children will provide a large dataset on genetic association of confirmed variants that affect age at menarche and their role in pubertal development. However, the effects of the polymorphisms are likely to be modest and we will need to meta-analyse data from multiple studies using our own studies and extensive collaborations. These may include the Northern Finland Birth Cohorts of 1966 and 1986, 1958 British Birth Cohort and 1946 Birth Cohort. The statistical support for true associations with puberty will be greatly increased in the meta-analysis, relative to the individual studies.

References

1. Snieder, H., MacGregor, A.J. and Spector, T.D. (1998) Genes control the cessation of a woman's reproductive life: a twin study of hysterectomy and age at menopause. J Clin Endocrinol Metab, 83, 1875-80.

2. van den Berg, S.M. and Boomsma, D.I. (2007) The familial clustering of age at menarche in extended twin families. Behav Genet, 37, 661-7.

3. Towne, B., Czerwinski, S.A., Demerath, E.W., Blangero, J., Roche, A.F. and Siervogel, R.M. (2005) Heritability of age at menarche in girls from the Fels Longitudinal Study. Am J Phys Anthropol, 128, 210-9.

4. Anderson, C.A., Zhu, G., Falchi, M., van den Berg, S.M., Treloar, S.A., Spector, T.D., Martin, N.G., Boomsma, D.I., Visscher, P.M. and Montgomery, G.W. (2008) A genome-wide linkage scan for age at menarche in three populations of European descent. J Clin Endocrinol Metab, 93, 3965-70.