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Fine Mapping of Lung Function Association in the MHC Region by Haplotype Imputation Reveals an Amino Acid change Underlying SNP Associations

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conference contribution
posted on 18.05.2020, 16:13 by N Shrine, LV Wain, AP Morris, DP Strachan, IP Hall, MD Tobin

We performed a Genome-wide association study (GWAS) of lung function quantitative traits forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC) and their ratio (FEV1/FVC) in 48,493 samples of European Ancestry (UK BiLEVE study) which, in addition to confirming 4 previously identified lung function signals in the major histocompatibility complex (MHC) on chromosome 6, identified 2 new secondary independent signals.

In order to fine map the MHC GWAS signals, we used a published reference panel to impute HLA classical alleles and amino acid changes and tested their association with lung function traits. The new second most significant signal across the MHC region for both FEV1 (P=5.7×10-13) and FEV1/FVC (P=1.2×10‑20) was an association with HLA-DQB1 amino acid 57 Alanine present/absent (Alanine frequency=36.6%). After conditioning on the amino acid variant, 1 of 2 genome-wide significant (P<5×10‑8) GWAS signals for FEV1 and 5 of 6 for FEV1/FVC were strongly attenuated (minimum P=2.1×10‑5). Stepwise conditional analyses showed that the majority of the MHC lung function association signal could be explained by just the lead independent GWAS SNP and the amino acid change for both traits.

Using haplotype imputation allowed us to build upon lung function GWAS discovery to pinpoint a potential causal variant in the MHC (HLA-DQB1 amino acid change 57, previously linked to type 1 diabetes risk) that explains a substantial proportion of the variance previously attributed to GWAS SNPs in this region.

History

Citation

GENETIC EPIDEMIOLOGY, 2016, 40 (7), pp. 661-661 (1)

Author affiliation

/Organisation/COLLEGE OF LIFE SCIENCES/School of Medicine/Department of Health Sciences

Source

Annual Meeting of the International-Genetic-Epidemiology-Society, Toronto, CANADA

Version

AM (Accepted Manuscript)

Published in

GENETIC EPIDEMIOLOGY

Volume

40

Issue

7

Pagination

661-661 (1)

Publisher

WILEY-BLACKWELL

issn

0741-0395

eissn

1098-2272

Copyright date

2016

Available date

18/10/2016

Publisher version

https://onlinelibrary.wiley.com/doi/10.1002/gepi.22001

Notes

Abstract only

Spatial coverage

Toronto, CANADA

Temporal coverage: start date

24/10/2016

Temporal coverage: end date

26/10/2016

Language

en