Joint test of allelic dosage and local ancestry identifies INTS3 as new susceptibility gene for asthma among african american individuals.

Introduction/Rational: African American individuals have a higher prevalence rate and complication rate for asthma when compared with European Americans. We sought to identify genetic variants related to asthma status utilizing methods which leverage information on both genetic association and genetic ancestry. Methods: The Study of Asthma Phenotypes and Pharmacogenomic Interactions by Race-ethnicity (SAPPHIRE) is a longitudinal asthma cohort study from a large health system serving southeast Michigan. The analytic sample consisted of asthma case and control individuals who self-identified as African American and who had genome-wide SNP array data (Affymetrix Axiom AFR GeneChip). Two approaches were used to identify risk alleles: 1) a standard GWAS association analysis using logistic regression and the software package GENESIS to assess the relationship between each single nucleotide polymorphism (SNP) and asthma status, and 2) a joint association test using the software package MIXSCORE to estimate the combined effect of SNP dosage and local ancestry state on asthma status. Genetic ancestry at each marker (i.e., local ancestry) was determined using the program RFMix. All the association models included covariates to adjust for age, sex, BMI, smoking status, and global ancestry. Results: Data were available for 1891 African American study participants (1325 asthma cases and 566 controls). Using the standard genome-wide association approach, we did not identify a single allele that met the conservative, Bonferronicorrected threshold (5x10-8) for statistical significance. However, using the joint association approach, we identified a SNP, rs114682783, that did reach genome-wide statistical significance (P=4.23x10-8). This SNP is located in an intron of the INTS3 gene in the chromosomal region 1q21.3; its minor allele frequency was 4.4% in our African American sample, but much rarer (\u3c1%) in European population from 1000 Genome. Whole blood transcriptomic data (RNAsequence) data was available on a portion of the study sample (85 cases [asthma control test score ≤19] and 179 controls). INTS3 was differentially expressed between cases and controls (P=0.015, FDR \u3c0.05). Conclusion: Leveraging information from both genetic association and genetic ancestry assisted in the identification of a novel variant associated with asthma status among African American individuals. Although expression data supported the function of this SNP on gene expression, additional validation is needed, including replication in independent cohorts