| Title: | Fine-mapping studies distinguish genetic risks for childhood- and adult-onset asthma in the HLA region |
| Journal: | Genome Medicine |
| Published: | 24 May 2022 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/35606880/ |
| DOI: | https://doi.org/10.1186/s13073-022-01058-2 |
| URL: | https://genomemedicine.biomedcentral.com/counter/pdf/10.1186/s13073-022-01058-2 |
Publication 10279
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Abstract
BackgroundGenome-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 (COA n=1686; AOA n=3666; controls n=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 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.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 the HLA-DQA2 and HLA-DQB2 genes and HLA-DQA1*03:01 allele in AOA.</p>
13 Authors
- Selene M. Clay
- Nathan Schoettler
- Andrew M. Goldstein
- Peter Carbonetto
- Matthew Dapas
- Matthew C. Altman
- Mario G. Rosasco
- James E. Gern
- Daniel J. Jackson
- Hae Kyung Im
- Matthew Stephens
- Dan L. Nicolae
- Carole Ober
1 Application
| Application ID | Title |
|---|---|
| 44300 | Genetic Studies of Inflammatory and Immune-Mediated Traits |
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