Whole Genome Sequencing Identifies CRISPLD2 as a Lung Function Gene in Children with asthma
2019
ABSTRACT Background Asthma is a common respiratory disorder with a highly heterogeneous nature that remains poorly understood. The objective was to identify regions of common genetic variation contributing to lung function in individuals diagnosed with asthma, utilizing whole-genome sequencing (WGS) data. 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 doctor’s diagnosis of asthma and the majority of asthma cases 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 plausible association was identified between baseline FEV1/FVC-ratio and a SNP in our top hit CRISPLD2 (rs12051168, p=3.6x10-8 in unadjusted model) that retained suggestive significance in the covariate-adjusted model (p=5.6x10-6). Rs12051168 was also nominally associated with other related phenotypes: baseline FEV1 (p=3.3x10-3), post-bronchodilator (PB) FEV1 (7.3x10-3), PB FEV1/FVC (p=5.1x10-5). The identified baseline FEV1/FVC-ratio and rs12051168 association was meta-analyzed and replicated in three independent cohorts where the majority of asthmatics also had confirmed AHR (combined weighted Z p-value=0.015) but not in cohorts without information on AHR. Conclusions These findings suggest that utilizing specific asthma characteristics, such as AHR, can identify more genetically homogenous asthma subgroups with genotype-phenotype associations that may not be observed in all children with asthma. CRISPLD2 may also be important for baseline lung function in individuals with asthma that may also have AHR.
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