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

Abstract

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.

• Authors: Priyadarshini Kachroo, Julian Hecker, Bo L Chawes, Tarunveer S Ahluwalia, Michael H Cho, Dandi Qiao, Rachel S Kelly, Su H Chu, Yamini V Virkud, Mengna Huang, Kathleen C Barnes, Esteban G Burchard, Celeste Eng, Donglei Hu, Juan C Celedón, Michelle Daya, Albert M Levin, Hongsheng Gui, L Keoki Williams, Erick Forno, Angel C Y Mak, Lydiana Avila, Manuel E Soto-Quiros, Michelle M Cloutier, Edna Acosta-Pérez, Glorisa Canino, Klaus Bønnelykke, Hans Bisgaard, Benjamin A Raby, Christoph Lange, Scott T Weiss, Jessica A Lasky-Su, National Heart, Lung, and Blood Institute Trans-Omics for Precision Medicine (TOPMed) Consortium
• Journal: Chest (Chest) Vol. 156 Issue 6 Pg. 1068-1079 (12 2019) ISSN: 1931-3543 [Electronic] United States
• PMID: 31557467 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: Copyright © 2019 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.

Chemical References

• CRISPLD2 protein, human
• Cell Adhesion Molecules
• Interferon Regulatory Factors

Topics

• Adolescent
• Adult
• Asthma (genetics, physiopathology)
• Cell Adhesion Molecules (genetics)
• Child
• Child, Preschool
• Costa Rica
• Female
• Forced Expiratory Volume (genetics)
• Humans
• Interferon Regulatory Factors (genetics)
• Male
• Middle Aged
• Respiratory Physiological Phenomena (genetics)
• Vital Capacity (genetics)
• Whole Genome Sequencing
• Young Adult