Title

Whole Genome Sequencing Identifies CRISPLD2 as a Lung Function Gene in Children With Asthma

Authors

Priyadarshini Kachroo, Brigham and Women's Hospital
Julian Hecker, Brigham and Women's Hospital
Bo L. Chawes, Københavns Universitet
Tarunveer S. Ahluwalia, Københavns Universitet
Michael H. Cho, Brigham and Women's Hospital
Dandi Qiao, Brigham and Women's Hospital
Rachel S. Kelly, Brigham and Women's Hospital
Su H. Chu, Brigham and Women's Hospital
Yamini V. Virkud, Brigham and Women's Hospital
Mengna Huang, Brigham and Women's Hospital
Kathleen C. Barnes, University of Colorado Anschutz Medical Campus
Esteban G. Burchard, University of California, San Francisco
Celeste Eng, University of California, San Francisco
Donglei Hu, University of California, San Francisco
Juan C. Celedón, University of Pittsburgh Medical Center, Children's Hospital of Pittsburgh
Michelle Daya, University of Colorado Anschutz Medical Campus
Albert M. Levin, Henry Ford Health System
Hongsheng Gui, Henry Ford Health System
L. Keoki Williams, Henry Ford Health System
Erick Forno, University of Pittsburgh Medical Center, Children's Hospital of Pittsburgh
Angel C.Y. Mak, University of California, San Francisco
Lydiana Avila, Hospital Nacional de Niños Dr. Carlos Sáenz Herrera
Manuel E. Soto-Quiros, Hospital Nacional de Niños Dr. Carlos Sáenz Herrera
Michelle M. Cloutier, University of Connecticut
Edna Acosta-Pérez, Universidad de Puerto Rico
Glorisa Canino, Universidad de Puerto Rico
Klaus Bønnelykke, Københavns Universitet
Hans Bisgaard, Københavns Universitet
Benjamin A. Raby, Brigham and Women's Hospital
Christoph Lange, Harvard T.H. Chan School of Public Health
Scott T. Weiss, Brigham and Women's Hospital
Jessica A. Lasky-Su, Brigham and Women's Hospital

Document Type

Conference Proceeding

Publication Date

12-1-2019

Journal

Chest

Volume

156

Issue

6

DOI

10.1016/j.chest.2019.08.2202

Keywords

airway hyperresponsiveness; asthma; lung function; whole genome sequencing

Abstract

© 2019 American College of Chest Physicians Background: Asthma is a common respiratory disorder with a highly heterogeneous nature that remains poorly understood. The objective was to use whole genome sequencing (WGS) data to identify regions of common genetic variation contributing to lung function in individuals with a diagnosis of asthma. Methods: WGS data were generated for 1,053 individuals from trios and extended pedigrees participating in the family-based Genetic Epidemiology of Asthma in Costa Rica study. Asthma affection status was defined through a physician's diagnosis of asthma, and most participants with asthma also had airway hyperresponsiveness (AHR) to methacholine. Family-based association tests for single variants were performed to assess the associations with lung function phenotypes. Results: A genome-wide significant association was identified between baseline FEV1/FVC ratio and a single-nucleotide polymorphism in the top hit cysteine-rich secretory protein LCCL domain-containing 2 (CRISPLD2) (rs12051168; P = 3.6 × 10−8 in the unadjusted model) that retained suggestive significance in the covariate-adjusted model (P = 5.6 × 10−6). Rs12051168 was also nominally associated with other related phenotypes: baseline FEV1 (P = 3.3 × 10−3), postbronchodilator (PB) FEV1 (7.3 × 10−3), and PB FEV1/FVC ratio (P = 2.7 × 10−3). The identified baseline FEV1/FVC ratio and rs12051168 association was meta-analyzed and replicated in three independent cohorts in which most participants with asthma also had confirmed AHR (combined weighted z-score P =.015) but not in cohorts without information about AHR. Conclusions: These findings suggest that using specific asthma characteristics, such as AHR, can help identify more genetically homogeneous asthma subgroups with genotype-phenotype associations that may not be observed in all children with asthma. CRISPLD2 also may be important for baseline lung function in individuals with asthma who also may have AHR.

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