The adolescent brain: Genes play role in puberty timing, sexual behavior, age at first birth

ORLANDO, Fla. — Recent genome-wide association studies have revealed some surprising links between genetic variants and a range of adolescent traits, from puberty timing to sexual behavior and even what are thought of as individual personality quirks, according to a speaker here.

Speaking during the plenary discussion “Coming of Age in the Teenage Brain,” John R.B. Perry, PhD, a senior investigator scientist at the MRC Epidemiology Unit at the University of Cambridge, United Kingdom, said epidemiologic data, combined with genetic study data, can help researchers to determine which genes influence important traits such as age of puberty, age at first sexual intercourse and age at first birth, and better understand the interactions between social and genetic determinants and their consequences.

There are many determinants behind traits such as pubertal timing and sexual behavior, and they vary widely in the population, Perry said. Body weight, nutrition, early-life stress and physical activity, for example, are often associated with pubertal timing, whereas for age at first intercourse or age at first birth, many assume factors such as family values, religious beliefs, peer pressure or personality play the greatest role.

“But, believe it or not, genetics plays a role in each of these traits as well,” Perry said during his presentation. “And for these three traits, the heritability estimates range from 25% to 50%. These traits are a product of both nature and nurture.”

In their research, Perry and colleagues focused on alleles that are common in the general population and generally low in frequency. Individually, Perry said, such varying alleles have a small effect on phenotype. Cumulatively, they add up to explain some of the variation seen in the normal population.

Secrets in larger samples

In 2009, a large meta-analysis of 18,000 women across eight studies identified the first common loci associated with puberty timing in the general population, Perry said.

“It took this large number of studies because the effect sizes were absolutely tiny,” he said. “In the genome ... the largest effect [found] was a 5-week shift in puberty timing.”

Upon publishing the research, Perry and colleagues were surprised to hear from three other groups with similar findings, he said. The groups decided to collaborate as the Reproductive Genetics Consortium, or ReproGen, pooling their samples to improve their power to identify more loci associated with puberty timing.

Currently, Perry said, new research that will soon be published analyzing data from 330,000 women across 100 studies has identified 400 regions of the genome associated with puberty timing. Effect sizes range from 1 week to up to 1 year for rarer alleles.

“Cumulatively, we explain about 25% of the heritability of puberty timing in these studies,” Perry said, adding that the effects have also been observed in pubertal timing in men, typically defined as when the voice breaks.

“You can see, remarkably, there is an allele that changes puberty timing in girls by an average of 4 weeks, and that will change puberty timing in boys by 4 weeks,” Perry said. “The consistency of effect sizes is quite remarkable.”

One gene; many effects

One key observation of the consortium is that individual genes can harbor a broad spectrum of genetic effects of varying allele frequency. The neurokinin B gene TACR3, which encodes the tachykinin receptor 3 protein, is perhaps the best example of this, Perry said.

“We know from rare-disorder studies that individuals who are a double-knockout for TACR3 ... which one in a million people are, will experience delayed or absent puberty — a very extreme phenotype,” he said. “In an intermediate state, if you lose just on copy of TACR3, which one in 1,000 people do, there’s a much more modest 1.25-year delay in puberty timing. Likewise, noncoding variants in TACR3, which are common in the population, shift puberty timing by just 2.5 weeks per allele.”

More than half of all known rare-disorder puberty genes have a common GY signal, Perry said. Researchers are now beginning to see cases in which novel rare-disorder genes are being identified by prioritizing GY loci.

Researchers can also integrate gene expression data to identify individual genes and relevant tissue and cell types. Many identified genes, for example, appear to act as a “molecular brake” on gonadotropin-releasing hormone secretion, Perry said.

Predicting reproductive behavior

Finding associations between specific genetic variants and traits such as age at first intercourse and age at first birth has been “much slower work,” Perry said, as these traits are typically “noisier” and the genetic architecture is different from a trait like puberty timing.

“Last year, we identified the first variants of these traits, and it took some enormous sample sizes,” he said. The research involved 125,000 people, with replications in other large data sets.

“We identified the first genetic loci associated with age at first sexual intercourse, a trait that has a heritability of about 30% in the general population,” Perry said. “Recent research has found that 38 genetic loci are associated with age at first sexual intercourse, two loci are associated with age at first birth and two loci are associated with number of children.”

The identified loci, he said, demonstrate pleiotropic effects across many reproductive and behavioral traits.

“We looked at these 38 loci across a range of reproductive behavior and traits,” Perry said. “And what we saw is that there was a general clustering. ... We found a set of genes for reproductive traits and a set of genes more driven by personality and behavioral traits.”

Some genes play a role in personality, he said. Classic behavioral traits — from altruism to a higher inclination to take risks — have between 5% and 20% heritability. Researchers have worked to integrate personality/gene data with findings for age at first intercourse and age at first birth, to determine whether any loci identified had a primary role in personality or risk-taking behavior.

“The short answer is, yes, they did,” Perry said. The gene CADM2, for example, predicted earlier age at first intercourse, a higher number of sexual partners and greater number of children. The allele promoting these behaviors is also associated with risk-taking behavior.

The MSRA gene, in contrast, was shown in research to promote later age at first intercourse and a more neurotic personality type, Perry said.

“These are two examples of variance in the genome with primary effects on risk taking and other aspects on the personality that are having knock-on effects on reproductive choices,” he said.

P ublic health consequence s

Traits like intercourse at an early age are associated in research with poor school performance, ill health and psychiatric problems, Perry said, making genetic research in this area important.

“This is really the motivation for studying these traits from a public health perspective,” he said.

Earlier puberty, too, is linked to increased risk for diseases, such as obesity and type 2 diabetes, whereas later puberty is associated with psychiatric disease and later age at first birth.

Researchers must ascertain whether such relationships are causal, Perry said.

“We can now explain enough of the heritability of these traits to use the genetic variants we’re identifying to inform epidemiology and public health interventions, and this work is just beginning,” he said. “We believe that [genome-wide association studies] are a powerful tool for providing biological insights into the etiology of reproductive aging, complementing other rare disorder and animal model approaches.” – by Regina Schaffer

Reference:

Perry JRB. Identifying genetic determinants for reproductive ability, behavior and success. Presented at: The Endocrine Society Annual Meeting; April 1-4, 2017; Orlando, Fla.

Disclosure: Perry reports no relevant financial disclosures.