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Teams ID Asthma Risk Loci in Populations from Japan and North America

By a GenomeWeb staff reporter

NEW YORK (GenomeWeb News) – In studies appearing in the early, online edition of Nature Genetics yesterday, two independent research groups describe how they found new and known risk loci for asthma in populations from Japan and North America.

A RIKEN Center for Genomic Medicine-led team did a genome-wide association study involving nearly 5,000 individuals from Japan to find two known and three previously unidentified loci that were significantly associated with a form of adult asthma called bronchial asthma. They then verified these findings in a replication group that included thousands more Japanese individuals with or without the disease.

"[W]e identified five loci that confer susceptibility to adult asthma in the Japanese population at genome-wide significant levels," senior author Mayumi Tamari, a respiratory disease researcher at RIKEN, and co-authors wrote.

"The three new loci identified in our GWAS were not observed in a previous study with a large meta-analysis in which 65.4 percent of the cases were subjects with childhood-onset asthma," they added.

The researchers used the Illumina HumanHap 550v3 and 610-Quad BeadChips to genotype 1,532 Japanese individuals with adult asthma and 3,304 unaffected Japanese controls.

By testing more than 100 suspicious variants in another 5,639 adult asthma patients and 24,608 controls, the team verified asthma associations for dozens of SNPs at five loci in the genome: two loci identified in past studies and three not detected before.

The previously identified loci included a major histocompatibility complex region on chromosome 6 and a locus on chromosome 5 near the TSLP and WDR36 genes, while the new loci fell on chromosome 4 near the USP38 and GAB1 genes and on chromosomes 10 and 12.

The researchers did fine mapping of the four non-major histocompatibility complex sites using the same cases and controls assessed in the discovery phase of the GWAS.

For the second study, researchers involved in the EVE Consortium, an international team comprised of investigators from nine past GWAS of asthma in the US, did a meta-analysis using data collected for these studies. The individuals sampled for these studies came from North American populations with European, African, and Latino ancestry.

"There are differences in asthma prevalence in these three groups, so it's important to understand whether these are caused by environmental exposures or by differences in genetic risk factors," co-senior author and EVE Consortium co-chair Carole Ober, a human genetics researcher at the University of Chicago, said in a statement.

In the process, the team verified asthma associations for four genes previously linked to asthma by the GABRIEL Consortium, which assessed tens of thousands of individuals of European ancestry. The EVE team also tracked down a new asthma risk gene, the chromosome 1 gene PYHIN1, found specifically in those of African ancestry.

"These results suggest that some asthma susceptibility loci are robust to differences in ancestry when sufficiently large sample sizes are investigated," Ober and her co-authors wrote, "and that ancestry-specific associations also contribute to the complex genetic architecture of asthma."

Although several studies have explored asthma genetics in various populations, including a large meta-analysis of Europeans by members of the GABRIEL Consortium, the study authors explained, much of asthma's heritability remains unexplained. That prompted the researchers to band together to form the new EVE Consortium, which secured $5.6 million in funding through an American Recovery and Reinvestment Act of 2009 grant.

"GWAS are often under-powered, and unless you pull together many researchers doing the same thing you're just not going to have the power to find genes," co-senior author Dan Nicolae, a medicine, statistics, and human genetics researcher at the University of Chicago and EVE Consortium co-chair, said in a statement. "That was the motivation for nine groups of investigators coming together to form EVE."

To increase their power to detect genetic variants contributing to asthma risk within and across populations, the team members brought together data for 3,246 North Americans with asthma, 3,385 unaffected controls, and 1,702 trios comprised of individuals with asthma and their parents. They also included 355 family-based asthma cases and 468 family-based controls. The study participants included European American, African American, African Caribbean, and Latino individuals who'd been recruited in the US, Mexico, and Barbados.

Researchers analyzed the samples using meta-analyses of European, African, or Latino ancestry groups and through a combined meta-analysis of all three groups before doing replication studies on thousands more North Americans.

Overall, the team found five loci that were significantly associated with asthma. Four of these loci — including loci near the IL1RL1, TSLP, and IL33 genes and a chromosome 17 locus closest to the GSDMB gene — were reported by members of the GABRIEL Consortium in the New England Journal of Medicine last year.

Their identification as risk variants in all three groups tested in the new study suggests that these loci may be involved in asthma risk across many different populations, researchers explained.

On the other hand, a fifth risk locus near PYHIM1 only seemed to increase asthma risk in individuals of African ancestry, the team reported, noting that "associations with SNPs in PYHIN1 … with asthma are the first genome-wide significant associations reported in African American and African Caribbeans and may be the first asthma susceptibility gene identified that is specific to populations of African descent."

Still, they explained, since the PYHIM1 SNPs with the strongest asthma associations in the African ancestry group haven't been detected in individuals of European descent, it's possible that rare variants in the gene might also elevate asthma risk in other populations.

The EVE Consortium is continuing to mine their dataset to further explore these and other aspects of asthma genetics, including studies looking at the interplay between genetics and the environment in asthma and the genetics behind specific asthma symptoms and phenotypes.

"We anticipate that ongoing studies in the EVE Consortium datasets will identify other loci contributing to asthma risk and ultimately provide a better understanding of the molecular pathways and networks that are common to risk architecture of asthma in diverse populations and those that are specific to certain groups," the researchers concluded.

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