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.

Keywords: airway hyperresponsiveness; asthma; lung function; whole genome sequencing.

Figure 1

LocusZoom plot highlighting the top hit (rs12051168) of the single-variant whole genome sequencing family-based association test analysis. The plot shows the covariate-unadjusted results with −log¹⁰ P values (y-axis 1), recombination rates (y-axis 2), and genome-wide significance threshold (dashed line) for SNPs (rs12051168 as highlighted by the red dashed line, rs12919905 adjacent to rs12051168 as highlighted by the gray dashed line) in the CRISPLD2 gene on chromosome 16. cM = centimorgan; Mb = Megabase; SNP = single-nucleotide polymorphism.

Figure 2

The figure provides a haplotype overview of the SNPs in the CRISPLD2 gene on chromosome 16 showing linkage disequilibrium (LD) between the SNPs and corresponding haplotype blocks. TSS = transcription start site.