New genetic variants found to influence puberty timing and cancer risk

In the largest study of its kind researchers at the University of Cambridge have identified more than 380 genetic variants associated with the timing of puberty in men and women.

The study more than quadruples the number of variants identified in previous research that are known to be associated with the timing of puberty. The study also confirms a previous finding from the same team that while boys and girls have obvious physical differences in their development many of the underlying biological processes are the same.

Led by scientists at Cambridge’s Medical Research Council (MRC) Epidemiology Unit, the study adds a new layer of data to our knowledge of the risks around certain adult diseases as well, because early puberty is associated with such things as an increased risk for breast and ovarian cancer in women and prostate cancer in men. In the case of breast cancer, these associations may be stronger for hormone-sensitive cancers.

“Our current study identifies direct causal links between earlier puberty timing itself and increased cancer risk,” said John Perry, the lead author of the study and a senior investigator scientist at MRC. “This link could possibly be explained by higher levels of sex hormones throughout life, but we need to do more work to understand the exact mechanisms involved. We aim to understand these disease links and thereby contribute to the prevention of diseases in later life.”

Puberty marks the transition from childhood into physical and sexual maturity, but its timing varies widely among individuals. That difference is influenced by genetics, nutrition, and environmental factors. Studying how they inter-relate could also help in the study of why early puberty is also associated with certain diseases and conditions later in life.

In the past, genetic studies were only able to identify a small fraction of what were believed to be hundreds of thousands of genetic variants involved in the timing of puberty. But, this study was able to identify a much larger portion of the genes that influence puberty by combining several very large datasets from multiple sources — including 23andMe, the 1000 Genomes Project, the ReproGen Consortium, the UK Biobank and the Icelandic company DeCode

This more than doubled the size of the group’s previous puberty study and quadrupled the number of variants found to be associated with the timing of puberty. Looking at genetic data from more than 329,345 women that were part of 40 different study cohorts, the researchers identified 389 genetic variants associated with the timing of puberty in women, known as the age of menarche. Of that total 23andMe contributed data from about 77,000  women who are customers and also consented to participate in research. The associations found in this portion of the study were then replicated using data contributed by deCode.

In turn the researchers then looked at additional data from 23andMe,  and the UK Biobank regarding the onset of puberty in boys, determined by the year at which their voice broke.  Data from about 56,000 men who are customers with 23andMe who also consented to research were used for this portion of the study. About 327 of the 389 genetic variants found to be associated with puberty in women were also found to have an impact on puberty in men.

In looking at those genetic variants that the researchers discovered, many were found in genes or gene regions involved in neural tissue. Interestingly, variants in some genes can have different effects on the timing of puberty depending on whether they were inherited from a participant’s mother or father.   

Variants in two genes in particular, MKRN3 and DLK1, had larger effects on puberty in girls when inherited paternally. In addition, in females, the variants discovered here tended to have a stronger impact on early puberty compared to late puberty. However, some of the same variants had a stronger impact on late puberty in males.

“One of the more remarkable findings concerns the role of certain types of genes called imprinted genes, which are only active in your body when inherited specifically from one parent but not the other,” said Ken Ong, also of the MRC Epidemiology Unit and a co-senior author of the paper. “We identified rare variants in two genes, which both lower the age of puberty when inherited from your father, but have no effect when inherited from your mother. This is intriguing as it suggests that mothers and fathers might benefit differently from puberty occurring at earlier or later ages in their children.”

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