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Rank-based genome-wide analysis reveals the association of ryanodine receptor-2 gene variants with childhood asthma among human populations. | LitMetric

AI Article Synopsis

  • The study aimed to identify genetic factors related to childhood asthma using rank-based methods that account for differences across populations of diverse ancestries.
  • Researchers analyzed data from 527 affected offspring trios and found that shared genetic influences were more apparent at the gene and pathway levels, with 11 specific genes identified across populations, including RYR2, which showed strong associations.
  • The findings suggest RYR2 variants are linked to asthma across European, African, and Hispanic populations, highlighting its role in networks related to inflammatory and respiratory diseases.

Article Abstract

Background: The standard approach to determine unique or shared genetic factors across populations is to identify risk alleles in one population and investigate replication in others. However, since populations differ in DNA sequence information, allele frequencies, effect sizes, and linkage disequilibrium patterns, SNP association using a uniform stringent threshold on p values may not be reproducible across populations. Here, we developed rank-based methods to investigate shared or population-specific loci and pathways for childhood asthma across individuals of diverse ancestry. We performed genome-wide association studies on 859,790 SNPs genotyped in 527 affected offspring trios of European, African, and Hispanic ancestry using publically available asthma database in the Genotypes and Phenotypes database.

Results: Rank-based analyses showed that there are shared genetic factors for asthma across populations, more at the gene and pathway levels than at the SNP level. Although the top 1,000 SNPs were not shared, 11 genes (RYR2, PDE4D, CSMD1, CDH13, ROBO2, RBFOX1, PTPRD, NPAS3, PDE1C, SEMA5A, and CTNNA2) mapped by these SNPs were shared across populations. Ryanodine receptor 2 (RYR2, a statin response-related gene) showed the strongest association in European (p value=2.55×10(-7)) and was replicated in African (2.57×10(-4)) and Hispanic (1.18 × 10(-3)) Americans. Imputation analyses based on the 1000 Genomes Project uncovered additional RYR2 variants associated with asthma. Network and functional ontology analyses revealed that RYR2 is an integral part of dermatological or allergic disorder biological networks, specifically in the functional classes involving inflammatory, eosinophilic, and respiratory diseases.

Conclusion: Our rank-based genome-wide analysis revealed for the first time an association of RYR2 variants with asthma and replicated previously discovered PDE4D asthma gene across human populations. The replication of top-ranked asthma genes across populations suggests that such loci are less likely to be false positives and could indicate true associations. Variants that are associated with asthma across populations could be used to identify individuals who are at high risk for asthma regardless of genetic ancestry.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3708719PMC
http://dx.doi.org/10.1186/1479-7364-7-16DOI Listing

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