Fine-mapping studies distinguish genetic risks for childhood- and adult-onset asthma in the HLA region

Abstract

AbstractBackgroundGenome-wide association studies of asthma have revealed robust associations with variation across the human leukocyte antigen (HLA) complex with independent associations in the HLA class I and class II regions for both childhood-onset asthma (COA) and adult-onset asthma (AOA). However, the specific variants and genes contributing to risk are unknown.MethodsWe used Bayesian approaches to perform genetic fine-mapping for COA and AOA (n=9432 and 21,556, respectively;n=318,167 shared controls) in White British individuals from the UK Biobank and to perform expression quantitative trait locus (eQTL) fine-mapping in immune (lymphoblastoid cell lines,n=398; peripheral blood mononuclear cells,n=132) and airway (nasal epithelial cells,n=188) cells from ethnically diverse individuals. We also examined putatively causal protein coding variation from protein crystal structures and conducted replication studies in independent multi-ethnic cohorts from the UK Biobank (COAn=1686; AOAn=3666; controlsn=56,063).ResultsGenetic fine-mapping revealed both shared and distinct causal variation between COA and AOA in the class I region but only distinct causal variation in the class II region. Both gene expression levels and amino acid variation contributed to risk. Our results from eQTL fine-mapping and amino acid visualization suggested that theHLA-DQA1*03:01 allele and variation associated with expression of the nonclassicalHLA-DQA2andHLA-DQB2genes accounted entirely for the most significant association with AOA in GWAS. Our studies also suggested a potentially prominent role for HLA-C protein coding variation in the class I region in COA. We replicated putatively causal variant associations in a multi-ethnic cohort.ConclusionsWe highlight roles for both gene expression and protein coding variation in asthma risk and identified putatively causal variation and genes in the HLA region. A convergence of genomic, transcriptional, and protein coding evidence implicates theHLA-DQA2andHLA-DQB2genes andHLA-DQA1*03:01 allele in AOA.