Genes which affect female development

Gene Expression
By Razib Khan
May 18, 2009 5:41 PMNov 5, 2019 9:38 AM


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There are several papers and letters in Nature Genetics on the relationship between menarche, menopause, etc. and genetics. Meta-analysis of genome-wide association data identifies two loci influencing age at menarche:

We conducted a meta-analysis of genome-wide association data to detect genes influencing age at menarche in 17,510 women. The strongest signal was at 9q31.2 (P = 1.7 10-9), where the nearest genes include TMEM38B, FKTN, FSD1L, TAL2 and ZNF462. The next best signal was near the LIN28B gene (rs7759938; P = 7.0 10-9), which also influences adult height. We provide the first evidence for common genetic variants influencing female sexual maturation.

Loci at chromosomes 13, 19 and 20 influence age at natural menopause:

We conducted a genome-wide association study for age at natural menopause in 2,979 European women and identified six SNPs in three loci associated with age at natural menopause: chromosome 19q13.4 (rs1172822; -0.4 year per T allele (39%); P = 6.3 10-11), chromosome 20p12.3 (rs236114; +0.5 year per A allele (21%); P = 9.7 10-11) and chromosome 13q34 (rs7333181; +0.5 year per A allele (12%); P = 2.5 10-8). These common genetic variants regulate timing of ovarian aging, an important risk factor for breast cancer, osteoporosis and cardiovascular disease.

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

Age at menarche and age at natural menopause are associated with causes of substantial morbidity and mortality such as breast cancer and cardiovascular disease. We conducted a joint analysis of two genome-wide association studies of these two traits in a total of 17,438 women from the Nurses' Health Study (NHS, N = 2,287) and the Women's Genome Health Study (WGHS, N = 15,151). For age at menarche, we identified ten associated SNPs (P = 1 10-7-3 10-13) clustered at 6q21 (in or near the gene LIN28B) and 9q31.2 (in an intergenic region). For age at natural menopause, we identified 13 associated SNPs (P = 1 10-7-1 10-21) clustered at 20p12.3 (in the gene MCM8), 19q13.42 (in or near the gene BRSK1), 5q35.2 (in or near genes UIMC1 and HK3) and 6p24.2 (in the gene SYCP2L). These newly identified loci might expand understanding of the biological pathways regulating these two traits.

Genetic variation in LIN28B is associated with the timing of puberty:

The timing of puberty is highly variable1. 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 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 10-10; combined P = 3.6 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 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 processing2, as the first genetic determinant regulating the timing of human pubertal growth and development.

Genome-wide association study identifies sequence variants on 6q21 associated with age at menarche:

Earlier menarche correlates with shorter adult height1 and higher childhood body fat2. We conducted a genome-wide association study of age at menarche (AAM) on 15,297 Icelandic women. Combined analysis with replication sets from Iceland, Denmark and the Netherlands (N = 10,040) yielded a significant association between rs314280[T] on 6q21, near the LIN28B gene, and AAM (effect = 1.2 months later per allele; P = 1.8 10-14). A second SNP within the same linkage disequilibrium (LD) block, rs314277, splits rs314280[T] into two haplotypes with different effects (0.9 months and 1.9 months per allele). These variants have been associated with greater adult height3, 4. The association with adult height did not account for the association with AAM or vice versa. Other variants, previously associated with height...did not associate significantly with AAM. Given the link between body fat and AAM, we also assessed 11 variants recently associated with higher body mass index (BMI)...and 5 of those associated with earlier AAM.

These work are interesting because if the genetic mechanisms by which menopause occurs are elucidated, perhaps the question of whether it is an adaptation, or not, will be resolved (or greater clarity attained). Below are some figures on the global distribution of some of the larger effect SNPs identified from the HGDP browser. rs314277 on LIN28B, with "A" variant increasing menarche by 0.0963 years.

rs1172822, -0.4 year per "T" allele for age at menopause.

rs236114; +0.5 year per "A" allele for age at menopause. I think the labels for the HGDP are off here. Pubmed agrees with the paper, so I suspect T = A, and C = G.

rs7333181; +0.5 year per "A" allele for age at menopause.

rs314276, "C" allele, 0.12 years earlier menarche, earlier breast development, earlier voice breaking and more advanced pubic hair development (in boys), faster tempo of height growth in girls and shorter adult height in both sexes.

1) Be careful to compare across populations obviously. Effect sizes (or perhaps direction) might differ for a given variant. 2) The fact that these loci are implicated in lots of traits is not surprising, but intriguing. One of the arguments for the timing of menopause is that is adaptive for older women to aid in the rearing of their daughter's offspring, as opposed to risking further pregnancy. These data suggest a connection between onset of puberty and menopause. All things equal shifting the onset of puberty will have a much bigger direct fitness effect it seems to me than the secondary effects of grandmothers.

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