Authors:
N. Vince (Nantes, FR)
M. Daya (Aurora, CO, US)
J. Hollenbach (San Francisco, US)
A. Lizée (San Francisco, US)
M. Pino-Yanes (Santa Cruz de Tenerife, ES)
S. Salzberg (Baltimore, MD, US)
D. Kim (Baltimore, MD, US)
T. Beaty (Baltimore, MD, US)
M. Taub (Baltimore, MD, US)
I. Ruczinski (Baltimore, MD, US)
R. Mathias (Baltimore, MD, US)
N. Rafaels (Aurora, CO, US)
C. (CAAPA) (Baltimore, MD, US)
K. Barnes (Aurora, CO, US)
D. Torgerson (San Francisco, CA, US)
P. Gourraud (Nantes, FR)
Asthma is a complex chronic inflammatory disease that can be divided into several phenotypes. Several genome-wide association studies (GWASs) have found strong association with SNPs in the MHC region in European and Japanese populations. However, these studies did not investigate associations with HLA alleles. Examining HLA alleles is required to decipher the precise contribution of variation within the MHC region on asthma susceptibility, rather than restricting analyses to non-functional SNP variants. We explored the role of HLA polymorphisms in asthma in the CAAPA consortium using both SNP genotypes and NGS HLA typing. We imputed HLA alleles in 3509 asthma cases and 4847 controls, all with African ancestry, deeply genotyped in the MHC region. HLA alleles were imputed using the R package HIBAG, by building our own reference panel with 917 individuals from CAAPA with NGS HLA typing and 28,781 common MHC SNPs between NGS and genotype data. This represents one of the largest resources for NGS HLA typing and genetic variation inside the MHC for populations with African ancestry. We performed association testing for each HLA allele using linear regression including ancestry as a co-variable. We further implemented an innovative haplotype-based analysis. In order to account for the large linkage disequilibrium in the HLA locus a step-wise regression was used to identify independent HLA allele associations. Overall our results demonstrate the importance of variation in the MHC to asthma in populations with African ancestry, and highlight the need to further develop population-appropriate reference panels to examine the role of HLA alleles in genetic studies of complex disease.