title: Rank-based genome-wide analysis reveals the association of ryanodine receptor-2 gene variants with childhood asthma among human populations.
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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, OH 45229, USA.
authors.forename: Lili
authors.initials: L
authors.lastname: Ding
authors.forename: Tilahun
authors.initials: T
authors.lastname: Abebe
authors.forename: Joseph
authors.initials: J
authors.lastname: Beyene
authors.forename: Russell A
authors.initials: RA
authors.lastname: Wilke
authors.forename: Arnon
authors.initials: A
authors.lastname: Goldberg
authors.forename: Jessica G
authors.initials: JG
authors.lastname: Woo
authors.forename: Lisa J
authors.initials: LJ
authors.lastname: Martin
authors.forename: Marc E
authors.initials: ME
authors.lastname: Rothenberg
authors.forename: Marepalli
authors.initials: M
authors.lastname: Rao
authors.forename: Gurjit K Khurana
authors.initials: GK
authors.lastname: Hershey
authors.forename: Ranajit
authors.initials: R
authors.lastname: Chakraborty
authors.forename: Tesfaye B
authors.initials: TB
authors.lastname: Mersha
mesh_terms: D000483:Alleles; D001249:Asthma / Q000235:genetics*; D002648:Child; D005787:Gene Frequency / Q000235:genetics; D053263:Gene Regulatory Networks / Q000235:genetics; D020022:Genetic Predisposition to Disease; D005828:Genetics, Population; D055106:Genome-Wide Association Study; D006801:Humans; D015810:Linkage Disequilibrium / Q000235:genetics; D058977:Molecular Sequence Annotation; D010802:Phylogeny; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D015203:Reproducibility of Results; D012307:Risk Factors; D019837:Ryanodine Receptor Calcium Release Channel / Q000235:genetics*
chemical_list: D019837:Ryanodine Receptor Calcium Release Channel