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.
Abstract
Motivation: Genome-wide association studies (GWASs) aim to identify genetic susceptibility to complex diseases by assaying and analyzing
hundreds of thousands of single nucleotide polymorphisms (SNPs). Although traditional single-locus statistical tests have
identified many genetic determinants of susceptibility, those findings cannot completely explain genetic contributions to
complex diseases. Marchini and coauthors demonstrated the importance of testing two-locus associations allowing for interactions
through a wide range of simulation studies. However, such a test is computationally demanding as we need to test hundreds
of billions of SNP pairs in GWAS. Here, we provide a method to address this computational burden for dichotomous phenotypes.
Results: We have applied our method on nine datasets from GWAS, including the aged-related macular degeneration (AMD) dataset, the
Parkinson’s disease dataset and seven datasets from the Wellcome Trust Case Control Consortium (WTCCC). Our method has discovered
many associations that were not identified before. The running time for the AMD dataset, the Parkinson’s disease dataset and
each of seven WTCCC datasets are 2.5, 82 and 90 h on a standard 3.0 GHz desktop with 4 G memory running Windows XP system.
Our experiment results demonstrate that our method is feasible for the full-scale analyses of both single- and two-locus associations
allowing for interactions in GWAS.
Availability: http://bioinformatics.ust.hk/SNPAssociation.zip
Contact: nelsontang{at}cuhk.edu.hk; eeyu{at}ust.hk;
Supplementary information: Supplementary data are available at Bioinformatics online.
This study resulted in the following publication: Polymorphisms in the vitamin D receptor and risk of ovarian cancer in four studies. Tworoger SS, Gates MA, Lee IM, Buring JE, Titus-Ernstoff L, Cramer D, Hankinson SE. Cancer Res. 2009 Mar ;69(5):1885-91 PI: D. HunterHSPH A genome-wide association study identifies alleles in FGFR2 associated with risk of sporadic postmenopausal breast cancer. A genome-wide association study (GWAS) of breast cancer was conducted by genotyping 528,173 SNPs on 1,145 post-menopausal women of European Ancestry with invasive breast cancer and 1,142 controls. Four SNPs in intron 2 of FGFR2 were highly associated with breast cancer. This association was confirmed in three additional studies, all four SNPs were highly statisticall...
By Justin Petrone
Illumina is preparing to launch more focused whole-genome genotyping arrays for use in genome-wide association studies, even as it gathers content for its next major BeadChip release, the Omni5, which is scheduled to launch next year.
Chief Financial Officer Christian Henry said this week that adoption of the firm’s HumanOmni2.5-Quad DNA Analysis BeadChip is “ahead of expectations,” and that its customers are “converting to the 2.5M from the 1M and other legacy products.”
Henry made his remarks during a presentation at Morgan Stanley’s Global Health Care Conference, held this week in New York.
Illumina launched the 2.5M in June. The chip contains common and rare variants from the 1000 Genomes Project, is available in a four-sample format composed of approximately 10 million markers per array, and is compatible with the company’s iScan or HiScan system (BAN 6/8/2010).
While Illumina moves customers to the 2.5M, the firm is planning more arrays to serve GWAS customers, starting with a 5-million SNP BeadChip that Illumina anticipates will launch next year. Beyond that, the company imagines making more focused genotyping arrays available to clients.
“We have launched the 2.5M, we will launch the 5M sometime later next year, and we will have the ability to launch a whole suite of products that will be dependent on various ethnicities,” Henry said. He added that the firm is ready to make and sell “different flavors of 2.5M or 5M or 1M, depending on what the customer base is telling us,” and hinted at even denser genotyping arrays. “Our new platform allows extension into 5M and even beyond that,” he said.
Illumina’s interest in making population-focused arrays available is not new. For instance, the firm has in the past sold a HumanHap650Y Genotyping BeadChip for studying African populations. At the same time, its main rival in the GWAS market, Affymetrix, has also pledged to introduce ethnicity-themed arrays to the marketplace, beginning with an Asian population-themed array later this year (BAN 8/3/2010).
While Illumina last year predicted that the GWAS market would return to high levels of growth in the second half of 2010, Henry this week said that this resurgence will occur next year instead.
“In 2009, we saw the business decline,” Henry said. “Our view was that people were waiting for content to come out of 1000 Genomes Project to reinitiate studies,” he said. “What we have seen in the first half of this year is that people are getting back into arrays, repowering studies with additional content, and are contemplating or starting to work on new studies.”
These early studies will “be foundational in driving what the next wave of GWAS will look like for the company,” Henry said. “Sometime in the first half of next year you will see that resurgence.”
Henry added that the fact that Illumina has seen its latest generation chips adopted in new projects is a sign of a market revival. “Just having new projects getting initiated gives you inertia,” he said. “Researchers talk to each other,” said Henry. “I think we have turned the corner overall.”
