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GWAS Uncover Loci Associated with PCOS and Endometriosis

By a GenomeWeb staff reporter

NEW YORK (GenomeWeb News) – A pair of new genome-wide association studies appearing online yesterday in Nature Genetics have uncovered genetic loci associated with two reproduction-related conditions: polycystic ovary syndrome and endometriosis.

In the first of these, Chinese researchers did genome-wide association and replication studies of endometriosis involving nearly 10,000 Han Chinese individuals, identifying three loci associated with the condition. Among the signals detected were multiple SNPs in the genes THADA and DENND1A.

"[T]hese two genes remain the most probable candidate genes in their regions," senior author Yueran Zhao, a reproductive medicine researcher affiliated with Shandong University and the Shandong Key Laboratory of Reproductive Medicine, and co-authors wrote. "It is also possible that more than one functional variant exists in these two genes, and the two variants separately contribute to the risk of PCOS."

In an effort to learn more about the underlying genetics of PCOS — a gynecological and endocrine condition characterized by symptoms such as cysts on the ovaries, excessive androgen hormone production and ovulation that's infrequent, irregular, or absent — the researchers genotyped 744 Han Chinese women with polycystic ovary syndrome and 895 unaffected controls from the same population using the Affymetrix SNP 6.0 array.

They then genotyped the top candidate SNPs from the discovery set, along with SNPs implicated in past studies, in two independent follow-up studies, one involving 2,840 cases and 5,012 controls from northern China and another 498 cases and 780 controls from southern China.

Three loci remained significantly associated with PCOS in the discovery and replication sets, the team reported: two loci on chromosome 2 involving one significant SNP and 21 significant SNPs, respectively, and a third locus on chromosome 9 containing six significant SNPs.

Two of the three loci, 2p21 and 9p33.3, contained multiple SNPs that appear to be independently associated with the condition. The chromosome 2p21 locus contained at least two independently associated SNPs in THADA, the researchers explained, a gene that codes for a thyroid adenoma-associated protein.

The 9p33.3 locus, meanwhile, included two variants in DENND1A, a gene coding for a protein that sometimes binds endoplasmic reticulum aminopeptidase — a protein whose blood levels have previously been linked to PCOS cases involving obesity.

Meanwhile, an international research team did a GWAS of nearly 3,200 affected and more than 7,000 unaffected individuals from Australia and the UK to track down loci linked to another gynecological disorder: endometriosis, a condition that affects as many as ten percent of women and can reduce fertility.

In the process, the researchers detected a chromosome 7 SNP that is not only associated with endometriosis in general, but that's more strongly linked to moderate to severe cases — findings that they subsequently verified in nearly 2,400 additional cases and about 2,300 controls from the US.

"We've known for some time that endometriosis is heritable, but until now we have been unable to find any robust genetic variants that influence a woman's risk of developing the disease, co-senior author Krina Zondervan, a genetics and genomics researcher at the University of Oxford, said in a statement, calling the new study the "first strong evidence that variations in DNA make some women more likely to develop endometriosis."

She and her colleagues used the Illumina Human670Quad BeadArray to genotype 3,194 women with endometriosis who were enrolled through the International Endogene Consortium. They then compared these genotyping patterns with data for 1,870 unaffected individuals who had been genotyped using the Illumina Human610Quad array or the Illumina Human1M-Duo array.

Of the study participants with endometriosis, 1,686 women had been diagnosed with stage I or stage II disease, while 1,364 had stage III or IV disease and another 144 had endometriosis at an unknown stage.

When they looked for variants corresponding to endometriosis in general, the researchers tracked down an associated signal in an intergenic region near the NFE2L3 and HOXA10 genes on chromosome 7. The same region also contains non-coding RNA sequence and may house sequences coding for microRNAs and regulatory elements, they noted.

When they focused in on women with stage III and IV endometriosis, the researchers found that the chromosome 7 locus was even more strongly associated with these moderate to severe cases than with endometriosis in general.

In addition, the team also found hints that two more SNPs might be associated with more serious cases: a chromosome 2 SNP in the fibronectin gene FN1 and a second chromosome 7 SNP in linkage disequilibrium with the variant identified in the first phase of the study.

When they tested the three SNPs in another 2,392 cases and 2,271 controls — along with 70 more variants that appeared to be nominally associated with endometriosis overall — the team verified the chromosome 7 associations but not the association with the variant in FN1.

"We have great confidence that the results of this study will help towards developing less invasive methods of diagnosis and more effective treatments for endometriosis," co-senior author Stephen Kennedy, an obstetrics and gynecology researcher at the University of Oxford, said in a statement.

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