Amber Dahlin
University of California San Francisco, usa
Title: Large-scale genome-wide association study of asthma.
Biography
Biography: Amber Dahlin
Abstract
Asthma, a genetically heterogeneous disease, affects over 300 million persons globally, and susceptibility to asthma is influenced by environmental and genetic risk factors. Identifying the genetic variants associated with asthma through well-powered genome wide association studies (GWAS) in large populations is needed to elucidate the genetic basis of asthma. We conducted a GWAS in 16,272 patients with asthma and 38,269 unaffected controls from the Kaiser Permanente Northern California’s (KPNC) Genetic Epidemiology Research on Adult Health and Aging (GERA), one of the largest real-life asthmatic populations. Genomic DNA was extracted from saliva samples and used to generate over 675,000 genetic markers by Affymetrix Axiom arrays, and genotypes for six million common variants were imputed using the1000 Genomes Project as the reference. The mean age of the population was 60.6 years and 63.5% were female. We identified 15 genes associated with asthma at a genome-wide significance level of 5x10-08 that were discovered in prior GWA studies, including IL33, IL1RL1, WDR36, TSLP, HLA-DQ1, HLA-DQB1, HLA-DRB1, HLA-DRB4, ORMDL3, ZPBP2, GSDMB, MICB, SMAD3, IKZF3, and LRRC3C. In addition, we also identified eight novel significant associations: PTPRC, HLA-DRB3, HLA-DRB5, HLA-DRB6, PORS1C3, LOC105371988, SNU13 and MEI1. The strongest associations were found in a region of chromosome 6 containing the HLA-DQA1 locus (6p21.3). The top-ranked GWAS SNP, rs9272513, [P=2.2x10-15; OR =0.89] present within an intron of HLA-DQA1, was not previously reported as associated with asthma. Among the top ten SNPs in this region, a second SNP, rs1047989 [OR = 0.90; P = 1.3x10-13] encoded a leucine to methionine substitution at amino acid position 8 of HLA-DQA1, and was also in moderate linkage disequilibrium (r2=0.6) with rs9272513. Replication of these results is ongoing.