NEW YORK – An international team has uncovered common genetic variants contributing to infertility and hormone levels in women and men, based on data for more than 1.5 million individuals.
"Taken together, we provide a comprehensive view of the genetic determinants of infertility across multiple diagnostic criteria," senior and co-corresponding author Cecilia Lindgren, a researcher affiliated with the University of Oxford and the Broad Institute, and her colleagues wrote in a paper published in Nature Genetics on Monday.
For their study, researchers from the UK, Estonia, the US, and elsewhere brought together genetic, primary care, and hospital electronic health record data spanning more than 1.5 million participants from seven cohorts. Using those data, they performed an infertility genome-wide association study and GWAS meta-analysis that involved up to 42,629 female cases and more than 740,600 unaffected female controls as well as 10,886 male cases and 995,982 male controls.
The team's analyses led to 25 infertility-linked loci, including 22 with genome-wide significant ties to female infertility and three associated with infertility in male participants.
Variants in PKHD1L1 or WNT4 gene introns, for example, were associated with multiple female infertility subtypes or reproductive traits. On the other hand, the male infertility-focused analyses led to variants in or around the UMODL1, ENO4, and NCKAP5 genes.
In a series of hormone-focused, sex-specific meta-analyses including between 6,095 and nearly 246,900 participants, the investigators highlighted hundreds more loci linked to levels of reproduction-related hormones such as estradiol, follicle-stimulating hormone, luteinizing hormone, or testosterone. They did not detect genetic variants with significant ties to progesterone.
By bringing in exome sequence data for hundreds of thousands of UK Biobank participants with or without infertility, the researchers tracked down rare variants in dozens of genes that appeared to dial down testosterone levels and boost infertility risk in women — patterns that were validated using additional exome or whole-genome sequences for thousands more participants in the community-based Genes and Health study or in a dataset from Decode Genetics.
More broadly, the authors explained, a series of polygenic overlap analyses that brought in GWAS summary statistics for female infertility and several other reproductive conditions, hormone levels, or obesity-related traits revealed genetic overlap between infertility and conditions such as polycystic ovary syndrome and endometriosis.
"The strongest genetic correlation of 71 percent between idiopathic infertility and endometriosis may indicate that some proportion of idiopathic cases are due to underdiagnosis of endometriosis, whose early treatment may prevent future infertility," the authors reported, noting that "subtype-specific analyses highlight the value in dissecting heterogeneous causes of infertility."
In contrast, the team did not see clear genetic overlap between female infertility and obesity, which has been implicated in fertility problems in the past.
"Weight loss for overweight patients is often recommended as beneficial for fertility, but we did not find substantial genetic correlation between obesity and infertility," the authors reported, noting that "[w]e did not find evidence that reproductive hormone dysregulation and obesity are strongly correlated with infertility at the population level, but instead nominate individual hormone-associated genes with effects on fertility."