Identification of Functional Variants in the FAM13A Chronic Obstructive Pulmonary Disease Genome-Wide Association Study Locus by Massively Parallel Reporter Assays.

Am J Respir Crit Care Med
Authors
Keywords
Abstract

RATIONALE: The identification of causal variants responsible for disease associations from genome-wide association studies (GWASs) facilitates functional understanding of the biological mechanisms by which those genetic variants influence disease susceptibility.

OBJECTIVE: We aim to identify causal variants in or near the FAM13A (family with sequence similarity member 13A) GWAS locus associated with chronic obstructive pulmonary disease (COPD).

METHODS: We used an integrated approach featuring conditional genetic analysis, massively parallel reporter assays (MPRAs), traditional reporter assays, chromatin conformation capture assays, and clustered regularly interspaced short palindromic repeats (CRISPR)-based gene editing to characterize COPD-associated regulatory variants in the FAM13A region in human bronchial epithelial cell lines.

MEASUREMENTS AND MAIN RESULTS: Conditional genetic association suggests the presence of two independent COPD association signals in FAM13A. MPRAs identified 45 regulatory variants within FAM13A, among which six variants were prioritized for further investigation. Three COPD-associated variants demonstrated significant allele-specific activity in reporter assays. One of three variants, rs2013701, was tested in the endogenous genomic context by CRISPR-based genome editing that confirmed its allele-specific effects on FAM13A expression and on cell proliferation, providing functional characterization for this COPD-associated variant.

CONCLUSIONS: The human GWAS association near FAM13A may contain independent association signals. MPRAs identified multiple functional variants in this region, including rs2013701, a putative COPD-causing variant with allele-specific regulatory activity.

Year of Publication
2019
Journal
Am J Respir Crit Care Med
Volume
199
Issue
1
Pages
52-61
Date Published
2019 01 01
ISSN
1535-4970
DOI
10.1164/rccm.201802-0337OC
PubMed ID
30079747
PubMed Central ID
PMC6353020
Links
Grant list
R01 HL113264 / HL / NHLBI NIH HHS / United States
R01 HL135142 / HL / NHLBI NIH HHS / United States
R33 HL120794 / HL / NHLBI NIH HHS / United States
P01 HL105339 / HL / NHLBI NIH HHS / United States
R01 HL126596 / HL / NHLBI NIH HHS / United States
R01 HG006785 / HG / NHGRI NIH HHS / United States
R01 HL137927 / HL / NHLBI NIH HHS / United States
K01 HL129039 / HL / NHLBI NIH HHS / United States
R01 HL124233 / HL / NHLBI NIH HHS / United States
P01 HL132825 / HL / NHLBI NIH HHS / United States
R01 HL127200 / HL / NHLBI NIH HHS / United States
P01 HL114501 / HL / NHLBI NIH HHS / United States