PMID- 35606880 OWN - NLM STAT- MEDLINE DCOM- 20220525 LR - 20230916 IS - 1756-994X (Electronic) IS - 1756-994X (Linking) VI - 14 IP - 1 DP - 2022 May 24 TI - Fine-mapping studies distinguish genetic risks for childhood- and adult-onset asthma in the HLA region. PG - 55 LID - 10.1186/s13073-022-01058-2 [doi] LID - 55 AB - 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. CI - (c) 2022. The Author(s). FAU - Clay, Selene M AU - Clay SM AUID- ORCID: 0000-0002-7204-9570 AD - Department of Human Genetics, University of Chicago, Chicago, IL, 60637, USA. seleneclay@uchicago.edu. FAU - Schoettler, Nathan AU - Schoettler N AD - Section of Pulmonary and Critical Care, Department of Medicine, University of Chicago, Chicago, IL, 60637, USA. FAU - Goldstein, Andrew M AU - Goldstein AM AD - Department of Statistics, University of Chicago, Chicago, IL, 60637, USA. FAU - Carbonetto, Peter AU - Carbonetto P AD - Department of Human Genetics, University of Chicago, Chicago, IL, 60637, USA. FAU - Dapas, Matthew AU - Dapas M AD - Department of Human Genetics, University of Chicago, Chicago, IL, 60637, USA. FAU - Altman, Matthew C AU - Altman MC AD - Division of Allergy and Infectious Diseases, Department of Medicine, University of Washington, Seattle, WA, 98109, USA. AD - Systems Immunology Program, Benaroya Research Institute, Seattle, WA, 98101, USA. FAU - Rosasco, Mario G AU - Rosasco MG AD - Systems Immunology Program, Benaroya Research Institute, Seattle, WA, 98101, USA. FAU - Gern, James E AU - Gern JE AD - Department of Pediatrics, University of Wisconsin, School of Medicine and Public Health, Madison, WI, 53706, USA. FAU - Jackson, Daniel J AU - Jackson DJ AD - Department of Pediatrics, University of Wisconsin, School of Medicine and Public Health, Madison, WI, 53706, USA. FAU - Im, Hae Kyung AU - Im HK AD - Section of Genetic Medicine, Department of Medicine, University of Chicago, Chicago, IL, 60637, USA. FAU - Stephens, Matthew AU - Stephens M AD - Department of Statistics, University of Chicago, Chicago, IL, 60637, USA. FAU - Nicolae, Dan L AU - Nicolae DL AD - Department of Human Genetics, University of Chicago, Chicago, IL, 60637, USA. AD - Department of Statistics, University of Chicago, Chicago, IL, 60637, USA. FAU - Ober, Carole AU - Ober C AD - Department of Human Genetics, University of Chicago, Chicago, IL, 60637, USA. c-ober@genetics.uchicago.edu. LA - eng GR - MC_PC_17228/MRC_/Medical Research Council/United Kingdom GR - R01 HL085197/NH/NIH HHS/United States GR - T32 GM007197/NH/NIH HHS/United States GR - TL1 TR002388/NH/NIH HHS/United States GR - K08 HL153955/NH/NIH HHS/United States GR - K08 HL153955/HL/NHLBI NIH HHS/United States GR - T32 GM007197/GM/NIGMS NIH HHS/United States GR - R01 HD021244/HD/NICHD NIH HHS/United States GR - P30 DK020595/DK/NIDDK NIH HHS/United States GR - MC_QA137853/MRC_/Medical Research Council/United Kingdom GR - UM1 AI114271/NH/NIH HHS/United States GR - T32 HL007605/HL/NHLBI NIH HHS/United States GR - UM1 AI160040/AI/NIAID NIH HHS/United States GR - U19 AI162310/AI/NIAID NIH HHS/United States GR - UG3 OD023282/NH/NIH HHS/United States GR - U19 AI62310/NH/NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural DEP - 20220524 PL - England TA - Genome Med JT - Genome medicine JID - 101475844 RN - 0 (Amino Acids) RN - SAA04E81UX (Coenzyme A) SB - IM MH - Adult MH - Amino Acids/genetics MH - *Asthma/genetics MH - Bayes Theorem MH - Child MH - Coenzyme A/genetics MH - Genetic Predisposition to Disease MH - *Genome-Wide Association Study MH - Humans MH - Leukocytes, Mononuclear MH - Polymorphism, Single Nucleotide PMC - PMC9128203 OTO - NOTNLM OT - Asthma OT - Fine-mapping OT - HLA COIS- The authors declare that they have no competing interests. EDAT- 2022/05/24 06:00 MHDA- 2022/05/26 06:00 PMCR- 2022/05/24 CRDT- 2022/05/23 23:55 PHST- 2021/10/22 00:00 [received] PHST- 2022/05/12 00:00 [accepted] PHST- 2022/05/23 23:55 [entrez] PHST- 2022/05/24 06:00 [pubmed] PHST- 2022/05/26 06:00 [medline] PHST- 2022/05/24 00:00 [pmc-release] AID - 10.1186/s13073-022-01058-2 [pii] AID - 1058 [pii] AID - 10.1186/s13073-022-01058-2 [doi] PST - epublish SO - Genome Med. 2022 May 24;14(1):55. doi: 10.1186/s13073-022-01058-2.