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

Lili Ding1, Tilahun Abebe2, Joseph Beyene3, Russell A Wilke4, Arnon Goldberg5, Jessica G Woo1, Lisa J Martin1, Marc E Rothenberg1, Marepalli Rao6, Gurjit K Khurana Hershey1, Ranajit Chakraborty7 and Tesfaye B Mersha1*

Author Affiliations

1 Department of Pediatrics, Cincinnati Children’s Hospital Medical Center, University of Cincinnati, Cincinnati, OH 45229, USA

2 Department of Biology, University of Northern Iowa, Cedar Falls, IA 50614, USA

3 Department of Clinical Epidemiology and Biostatistics, Program in Population Genomics, McMaster University, 1280 Main Street West, MDCL 3211, Hamilton, Ontario, L8S 4K1, Canada

4 Department of Medicine, Division of Clinical Pharmacology, Oates Institute for Experimental Therapeutics, Vanderbilt University Medical Center, Nashville, TN 37232, USA

5 Sapir Medical Center, Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv 6997801, Israel

6 Division of Epidemiology and Biostatistics, Department of Environmental Health, University of Cincinnati, Cincinnati, OH 45229, USA

7 Department of Forensic and Investigative Genetics, Center for Computational Genomics, Institute of Applied Genetics, University of North Texas Health Science Center, Fort Worth, TX 76107, USA

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Human Genomics 2013, 7:16  doi:10.1186/1479-7364-7-16

Published: 5 July 2013

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.

Keywords:
Asthma; GWAS; Ancestry; Trans-ancestral analysis; Rank analysis; Imputation; dbGaP; 1000 Genomes project; Networks/pathways, RYR2