Journal Article

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

Altman, Matthew C., Schoettler, Nathan, Ober, Carole, Carbonetto, Peter, Rosasco, Mario G., Gern, James E., Im, Hae Kyung, Nicolae, Dan L., Dapas, Matthew, Jackson, Daniel J., Stephens, Matthew, Goldstein, Andrew M., Clay, Selene M.

2022

Overview

Background Genome-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. Methods We 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 (COA n =1686; AOA n =3666; controls n =56,063). Results Genetic 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 the HLA-DQA1 *03:01 allele and variation associated with expression of the nonclassical HLA-DQA2 and HLA-DQB2 genes 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. Conclusions We 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 the HLA-DQA2 and HLA-DQB2 genes and HLA-DQA1 *03:01 allele in AOA.

• Publisher: BioMed Central,BioMed Central Ltd,Springer Nature B.V,BMC
• Subject: Adult / Alleles / Amino acids / Amino Acids - genetics / Asthma / Asthma - genetics / Asthma in children / Bayes Theorem / Bayesian analysis / Biobanks / Bioinformatics / Biomedical and Life Sciences / Biomedicine / C protein / Cancer Research / Child / Childhood / Children / Coenzyme A - genetics / Crystals / Disease / DQA1 protein / Epithelial cells / Fine-mapping / Gene expression / Gene mapping / Genes / Genetic Predisposition to Disease / Genetic research / Genetic transcription / Genome-wide association studies / Genome-Wide Association Study / Genomes / Genotype & phenotype / Histocompatibility antigen HLA / Histocompatibility antigens / HLA / HLA histocompatibility antigens / Human Genetics / Humans / Leukocytes, Mononuclear / Lymphoblastoid cell lines / Medicine/Public Health / Metabolomics / Peripheral blood mononuclear cells / Polymorphism / Polymorphism, Single Nucleotide / Quantitative trait loci / Risk factors / Structure / Systems Biology