Whole Genome Sequencing Identifies CRISPLD2 as a Lung Function Gene in Children With Asthma
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Whole Genome Sequencing Identifies CRISPLD2 as a Lung Function Gene in Children With Asthma. / Kachroo, Priyadarshini; Hecker, Julian; Chawes, Bo L.; Ahluwalia, Tarunveer S.; Cho, Michael H.; Qiao, Dandi; Kelly, Rachel S.; Chu, Su H.; Virkud, Yamini V.; Huang, Mengna; Barnes, Kathleen C.; Burchard, Esteban G.; Eng, Celeste; Hu, Donglei; Celedón, Juan C.; Daya, Michelle; Levin, Albert M.; Gui, Hongsheng; Williams, L. Keoki; Forno, Erick; Mak, Angel C.Y.; Avila, Lydiana; Soto-Quiros, Manuel E.; Cloutier, Michelle M.; Acosta-Pérez, Edna; Canino, Glorisa; Bønnelykke, Klaus; Bisgaard, Hans; Raby, Benjamin A.; Lange, Christoph; Weiss, Scott T.; Lasky-Su, Jessica A.; Abe, Namiko; Abecasis, Goncalo; Albert, Christine; Palmer Allred, Nicholette (Nichole); Almasy, Laura; Alonso, Alvaro; Ament, Seth; Anderson, Peter; Anugu, Pramod; Applebaum-Bowden, Deborah; Arking, Dan; Arnett, Donna K.; Ashley-Koch, Allison; Aslibekyan, Stella; Assimes, Tim; Auer, Paul; Avramopoulos, Dimitrios; Loos, Ruth; National Heart, Lung, and Blood Institute Trans-Omics for Precision Medicine (TOPMed) Consortium.
In: Chest, Vol. 156, No. 6, 2019, p. 1068-1079.Research output: Contribution to journal › Journal article › Research › peer-review
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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 -
ID: 235778254