Journal article
Whole Genome Sequencing Identifies CRISPLD2 as a Lung Function Gene in Children With Asthma
Chest, Vol.156(6), pp.1068-1079
12/2019
DOI: 10.1016/j.chest.2019.08.2202
PMCID: PMC6904857
PMID: 31557467
Abstract
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.
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.
A genome-wide significant association was identified between baseline FEV
/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
in the unadjusted model) that retained suggestive significance in the covariate-adjusted model (P = 5.6 × 10
). Rs12051168 was also nominally associated with other related phenotypes: baseline FEV
(P = 3.3 × 10
), postbronchodilator (PB) FEV
(7.3 × 10
), and PB FEV
/FVC ratio (P = 2.7 × 10
). The identified baseline FEV
/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.
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.
Details
- Title: Subtitle
- Whole Genome Sequencing Identifies CRISPLD2 as a Lung Function Gene in Children With Asthma
- Creators
- Priyadarshini Kachroo - Brigham and Women's HospitalJulian HeckerBo L Chawes - University of CopenhagenTarunveer S Ahluwalia - University of CopenhagenMichael H Cho - Brigham and Women's HospitalDandi Qiao - Brigham and Women's HospitalRachel S Kelly - Brigham and Women's HospitalSu H Chu - Brigham and Women's HospitalYamini V VirkudMengna Huang - Brigham and Women's HospitalKathleen C Barnes - University of Colorado Anschutz Medical CampusEsteban G Burchard - University of California, San FranciscoCeleste Eng - University of California, San FranciscoDonglei Hu - University of California, San FranciscoJuan C Celedón - University of PittsburghMichelle Daya - University of Colorado Anschutz Medical CampusAlbert M LevinHongsheng GuiL Keoki WilliamsErick Forno - University of PittsburghAngel C Y Mak - University of California, San FranciscoLydiana Avila - Hospital Nacional de NiñosManuel E Soto-Quiros - Hospital Nacional de NiñosMichelle M Cloutier - Department of Pediatrics, University of Connecticut, Farmington, CTEdna Acosta-Pérez - Behavioral Sciences Research Institute, University of Puerto Rico, San Juan, Puerto RicoGlorisa Canino - Behavioral Sciences Research Institute, University of Puerto Rico, San Juan, Puerto RicoKlaus Bønnelykke - University of CopenhagenHans Bisgaard - University of CopenhagenBenjamin A RabyChristoph Lange - Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MAScott T Weiss - Brigham and Women's HospitalJessica A Lasky-Su - Brigham and Women's HospitalNational Heart, Lung, and Blood Institute Trans-Omics for Precision Medicine (TOPMed) Consortium
- Contributors
- Karin Hoth (Contributor) - University of Iowa, Psychiatry
- Resource Type
- Journal article
- Publication Details
- Chest, Vol.156(6), pp.1068-1079
- DOI
- 10.1016/j.chest.2019.08.2202
- PMID
- 31557467
- PMCID
- PMC6904857
- NLM abbreviation
- Chest
- ISSN
- 0012-3692
- eISSN
- 1931-3543
- Grant note
- P60 MD006902 / NIMHD NIH HHS R01 HL120393 / NHLBI NIH HHS R01 AI132476 / NIAID NIH HHS K01 AG059898 / NIA NIH HHS R01 HL079966 / NHLBI NIH HHS R01 HL138737 / NHLBI NIH HHS K01 HL004370 / NHLBI NIH HHS T32 HL139439 / NHLBI NIH HHS R01 HL118267 / NHLBI NIH HHS R21 ES024844 / NIEHS NIH HHS R01 HL117004 / NHLBI NIH HHS P01 HL132825 / NHLBI NIH HHS R01 HL117626 / NHLBI NIH HHS R01 AI079139 / NIAID NIH HHS R01 MD010443 / NIMHD NIH HHS R01 HL141845 / NHLBI NIH HHS R01 HL141826 / NHLBI NIH HHS R01 HL135156 / NHLBI NIH HHS R01 DK113003 / NIDDK NIH HHS R01 HL128439 / NHLBI NIH HHS K23 AI130408 / NIAID NIH HHS R01 HL123915 / NHLBI NIH HHS R37 HL066289 / NHLBI NIH HHS P50 HL118006 / NHLBI NIH HHS R01 ES015794 / NIEHS NIH HHS R01 HL066289 / NHLBI NIH HHS R01 HL104608 / NHLBI NIH HHS R01 HL117191 / NHLBI NIH HHS K01 HL146980 / NHLBI NIH HHS RL5 GM118984 / NIGMS NIH HHS
- Language
- English
- Date published
- 12/2019
- Academic Unit
- Psychiatry; Iowa Neuroscience Institute
- Record Identifier
- 9984293755402771
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