Whole Genome Sequencing Identifies CRISPLD2 as a Lung Function Gene in Children With Asthma
Kachroo P, Hecker J, Chawes B, Ahluwalia TS, Cho M, Qiao D, Kelly RS, Chu SH, Virkud YV, Huang M, Barnes KC, Burchard EG, Eng C, Hu D, Celedón JC, Daya M, Levin AM, Gui H, Williams LK, Forno E, Mak ACY, Avila L, Soto-Quiros M, Cloutier MM, Acosta-Pérez E, Canino G, Bønnelykke K, Bisgaard H, Raby BA, Lange C, Weiss ST, and Lasky-Su J. Whole Genome Sequencing Identifies CRISPLD2 as a Lung Function Gene in Children with asthma. Chest 2019.
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 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 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.