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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.

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