TY - JOUR

T1 - Whole Genome Sequencing Identifies CRISPLD2 as a Lung Function Gene in Children With Asthma

AU - Kachroo, Priyadarshini

AU - Hecker, Julian

AU - Chawes, Bo L.

AU - Ahluwalia, Tarunveer S.

AU - Cho, Michael H.

AU - Qiao, Dandi

AU - Kelly, Rachel S.

AU - Chu, Su H.

AU - Virkud, Yamini V.

AU - Huang, Mengna

AU - Barnes, Kathleen C.

AU - Burchard, Esteban G.

AU - Eng, Celeste

AU - Hu, Donglei

AU - Celedón, Juan C.

AU - Daya, Michelle

AU - Levin, Albert M.

AU - Gui, Hongsheng

AU - Williams, L. Keoki

AU - Forno, Erick

AU - Mak, Angel C.Y.

AU - Avila, Lydiana

AU - Soto-Quiros, Manuel E.

AU - Cloutier, Michelle M.

AU - Acosta-Pérez, Edna

AU - Canino, Glorisa

AU - Bønnelykke, Klaus

AU - Bisgaard, Hans

AU - Raby, Benjamin A.

AU - Lange, Christoph

AU - Weiss, Scott T.

AU - Lasky-Su, Jessica A.

AU - Abe, Namiko

AU - Abecasis, Goncalo

AU - Albert, Christine

AU - Palmer Allred, Nicholette (Nichole)

AU - Almasy, Laura

AU - Alonso, Alvaro

AU - Ament, Seth

AU - Anderson, Peter

AU - Anugu, Pramod

AU - Applebaum-Bowden, Deborah

AU - Arking, Dan

AU - Arnett, Donna K.

AU - Ashley-Koch, Allison

AU - Aslibekyan, Stella

AU - Assimes, Tim

AU - Auer, Paul

AU - Avramopoulos, Dimitrios

AU - Loos, Ruth

AU - National Heart, Lung, and Blood Institute Trans-Omics for Precision Medicine (TOPMed) Consortium

PY - 2019

Y1 - 2019

N2 - 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.

AB - 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.

KW - airway hyperresponsiveness

KW - asthma

KW - lung function

KW - whole genome sequencing

U2 - 10.1016/j.chest.2019.08.2202

DO - 10.1016/j.chest.2019.08.2202

M3 - Journal article

C2 - 31557467

AN - SCOPUS:85075322046

VL - 156

SP - 1068

EP - 1079

JO - Chest

JF - Chest

SN - 0012-3692

IS - 6

ER -