Researchers used some of the world’s largest biobanks to analyse the genetics of infertility among both men and women. The research shows that although polycystic ovary syndrome and obesity are both associated with an increased risk of infertility, they do not genetically overlap. The study reveals several other surprising results.
One in six couples globally have problems with fertility – but the causes are unknown in one third of these cases. A new genetic study provides surprising answers.
Polycystic ovary syndrome (PCOS) can result in women’s infertility, as can obesity, but there is still no good explanation for one third of infertile couples.
A new study addresses this problem by comprehensively analysing the genetics of infertility for both men and women. The research indicates that biological mechanisms are associated with infertility and that known risk factors for infertility do not genetically overlap.
According to a researcher behind the study, more knowledge is needed on this because infertility is both a major mental burden for couples who have difficulty in having children and a major problem for the economy.
“Fertility and having children drive prosperity in the world. If we cannot have children, the consequences are enormous. That is why the fact that we have very little specific knowledge about the genetic factors underlying infertility and how genetic risk overlaps with known risk factors for infertility is so striking,” explains co-author Cecilia Lindgren, Professor, Big Data Institute, University of Oxford, United Kingdom.
The research, led by Samvida S. Venkatesh, Postdoctoral Fellow at the same Institute, has been published in Nature Genetics.
Genetic data from major biobanks provide new answers
Cecilia Lindgren and colleagues aim to understand the genetic background of diseases, and in the new study they chose to investigate infertility.
They gathered genetic data on hundreds of thousands of men and women from four of the world’s largest biobanks: deCODE genetics in Iceland, the UK Biobank, the Million Veteran Program in the United States and the Danish National Biobank.
They investigated genetic associations with infertility for both men and women and genetic overlaps with other conditions, such as PCOS, obesity, endometriosis and various problems associated with ovulation.
“When this research started, we quickly discovered that not much of this kind of research has been done, that the data are inconsistent and that knowledge is generally lacking about the prevalence of infertility among men. If we move on from here and study the role of genetics in infertility, we can better understand infertility and how it is linked to other diseases,” says Cecilia Lindgren.
She explains that the research required extensive collaboration between doctors, biologists, geneticists and bioinformaticians.
25 DNA changes linked to infertility
The large-scale analysis revealed 25 sites on the genome in which small changes in DNA structure are associated with an increased risk of infertility.
The researchers also found 269 genetic regions associated with the body’s hormone balance – especially sex hormones such as testosterone, estrogen and follicle-stimulating hormone, which all influence fertility. This part of the research revealed that women with rare genetic variants that lower testosterone levels have an increased risk of infertility.
Genetic link between fraternal twins and infertility
The researchers found some correlations between genetic backgrounds for various aspects of infertility but no correlation in some cases. The genetic variants associated with increased likelihood of having fraternal twins are associated with reduced risk of infertility – and vice versa. Both conditions appear to be linked to ovulation.
With this part of the research, scientists suggest how ovulation may have a role in both cases.
The underlying cause of an increased likelihood of having fraternal twins may be hyperovulation – releasing too many eggs from the ovaries – whereas infertility may result from not enough eggs being released.
“With a common link between the two conditions and understanding of the underlying genetics, we can start to think about how to target ovulation with drugs to either increase fertility or reduce the likelihood of having twins. The aim could be to develop drugs that target ovulation without affecting the rest of the body, thereby increasing or decreasing fertility,” explains Cecilia Lindgren.
Male infertility linked to hidden syndrome
The study found answers about male infertility. The researchers used the extensive data from the Million Veteran Program to find that a genetic variant associated with Kallmann syndrome often has a role when men are infertile.
Kallmann syndrome is a rare genetic disorder in which boys do not experience normal puberty. They do not develop male traits such as a deeper voice or body hair – and are often infertile as adults. Having a genetic variant in the same area of the genome often results in infertility.
“The interesting thing is that we can develop medicine for this. We are therefore very excited about this discovery,” says Cecilia Lindgren.
Some diseases are linked to infertility
Further findings also showed that the genetic variants associated with increased risk of infertility also genetically overlap with the genetic basis for endometriosis, in which tissue of the same type as the lining of the uterus (endometrium) is also present outside the uterus.
Women with endometriosis can have difficulty getting pregnant, but the diagnosis is often delayed up to 10 years. This delay may prevent some women from having children.
Cecilia Lindgren therefore thinks that screening for endometriosis can help to identify women who may be genetically predisposed to infertility.
Surprisingly, the researchers found almost no genetic overlap between infertility and PCOS – even though it has long been considered a major cause. The study also found little genetic overlap between obesity and the genetic variants associated with the risk of infertility.
“The results suggest complex interaction between endometriosis, PCOS, obesity and infertility: some are influenced by the same genetics, and others are not. We need to learn more about this to optimally advise and help women who want to get pregnant,” notes Cecilia Lindgren.
Why genetic variants associated with infertility are not deselected
One might think that genetic variants that predispose to infertility would disappear from the human genome over time since they would be less likely to be passed on. However, the study shows that this is not so simple.
Although some genes are associated with increased infertility, they can also benefit the body – such as by strengthening the immune system. They can therefore still be passed on from generation to generation.
“The genetics that predispose to infertility may provide better survival. We therefore did not find the strong evolutionary selection we expected,” explains Cecilia Lindgren.
Improving help for childless couples
The researchers hoped to answer questions about the genetic basis of infertility and how medicine might help depending on the genetic background.
Further, knowledge about the genetics of infertility may also eventually lead to improving screening for people who want to have children but are genetically predisposed to have difficulty.
Finally, knowing more about how the genetics associated with infertility are linked to other conditions can help doctors to understand the dilemmas of their patients who struggle to become pregnant despite conditions such as endometriosis.
“Fertility treatment is a billion-dollar industry, which shows the high priority people place on having children. By analysing the genetic causes of infertility, we hope to enable earlier and more targeted action,” says Cecilia Lindgren.
New knowledge can lead to accurate counselling, screening and treatment – and ultimately help more people have children.
“Knowing your genetic risk can influence life choices – for example, trying to have children earlier or living healthier,” she concludes.
