10.5061/DRYAD.W3R2280NW
Goddard, Pagé
0000-0001-8187-5316
Stanford University
Keys, Kevin
University of California, San Francisco
Mak, Angel
University of California, San Francisco
Lee, Eunice
University of California, San Francisco
Liu, Amy
University of California, San Francisco
Samedy-Bates, Lesly-Anne
University of California, San Francisco
Risse-Adams, Oona
University of California, Santa Cruz
Contreras, Maria
University of California, San Francisco
Elhawary, Jennifer
0000-0003-3326-1680
University of California, San Francisco
Hu, Donglei
University of California, San Francisco
Oh, Sam
University of California, San Francisco
Salazar, Sandra
University of California, San Francisco
Eng, Celeste
University of California, San Francisco
Himes, Blanca
University of Pennsylvania
White, Marquitta
University of California, San Francisco
Burchard, Esteban
0000-0001-7475-2035
University of California, San Francisco
Data from: Integrative genomic analysis in African American children with
asthma finds 3 novel loci associated with lung function
Dryad
dataset
2020
FOS: Medical and health sciences
National Heart Lung and Blood Institute
https://ror.org/012pb6c26
R01HL117004
National Heart Lung and Blood Institute
https://ror.org/012pb6c26
R01HL128439
National Heart Lung and Blood Institute
https://ror.org/012pb6c26
R01HL135156
National Heart Lung and Blood Institute
https://ror.org/012pb6c26
X01HL134589
National Heart Lung and Blood Institute
https://ror.org/012pb6c26
R01HL141992
National Heart Lung and Blood Institute
https://ror.org/012pb6c26
R01HL104608
National Heart Lung and Blood Institute
https://ror.org/012pb6c26
R01HL141845
National Heart Lung and Blood Institute
https://ror.org/012pb6c26
U01HL138626
National Human Genome Research Institute
https://ror.org/00baak391
U01HG007419
National Human Genome Research Institute
https://ror.org/00baak391
U01HG009080
National Institute of Environmental Health Sciences
https://ror.org/00j4k1h63
R01ES015794
National Institute of Environmental Health Sciences
https://ror.org/00j4k1h63
R21ES24844
Eunice Kennedy Shriver National Institute of Child Health and Human Development
https://ror.org/04byxyr05
R01HD085993
National Institute on Minority Health and Health Disparities
https://ror.org/0493hgw16
P60MD006902
National Institute on Minority Health and Health Disparities
https://ror.org/0493hgw16
R01MD010443
National Institute on Minority Health and Health Disparities
https://ror.org/0493hgw16
RL5GM118984
National Institute on Minority Health and Health Disparities
https://ror.org/0493hgw16
R56MD013312
University of California System
https://ror.org/00pjdza24
24RT-0025
University of California System
https://ror.org/00pjdza24
27IR-0030
National Institute of General Medical Sciences
https://ror.org/04q48ey07
TL4GM118986
National Institute of General Medical Sciences
https://ror.org/04q48ey07
1UL1GM118985
National Human Genome Research Institute
https://ror.org/00baak391
T32HG000044
National Heart Lung and Blood Institute
https://ror.org/012pb6c26
R01HL135156-S1
Gordon and Betty Moore Foundation
https://ror.org/006wxqw41
GBMF3834
Alfred P. Sloan Foundation
https://ror.org/052csg198
2013-10-27
National Institute of General Medical Sciences
https://ror.org/04q48ey07
T32GM007546
National Institute of General Medical Sciences
https://ror.org/04q48ey07
T34GM008574
National Heart Lung and Blood Institute
https://ror.org/012pb6c26
R01HL117004-S1
National Institute of General Medical Sciences
https://ror.org/04q48ey07
K12GM081266
National Heart Lung and Blood Institute
https://ror.org/012pb6c26
K01HL140218
2020-08-27T00:00:00Z
2020-08-27T00:00:00Z
en
https://doi.org/10.1101/2020.05.01.045468
https://cnsgenomics.com/software/gcta/#Overview
https://github.com/gkichaev/PAINTOR_V3.0
https://github.com/UW-GAC/GENESIS
https://github.com/asthmacollaboratory/sage-lungfunction.git
6321171154 bytes
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CC0 1.0 Universal (CC0 1.0) Public Domain Dedication
Bronchodilator drugs are commonly prescribed for treatment and management
of obstructive lung function present with diseases such as
asthma. Administration of bronchodilator medication can partially or fully
restore lung function as measured by pulmonary function tests. The
genetics of baseline lung function measures taken prior to bronchodilator
medication has been extensively studied, and the genetics of the
bronchodilator response itself has received some attention. However, few
studies have focused on the genetics of post-bronchodilator lung
function. To address this gap, we analyzed lung function phenotypes in
1,103 subjects from the Study of African Americans, Asthma, Genes, and
Environment (SAGE), a pediatric asthma case-control cohort, using an
integrative genomic analysis approach that
combined genotype, locus-specific genetic ancestry, and functional
annotation information. We integrated genome-wide association study
(GWAS) results with an admixture mapping scan of three pulmonary function
tests (FEV1, FVC, and
FEV1/FVC) taken before and after albuterol bronchodilator administration
on the same subjects, yielding six traits. We identified 18 GWAS loci, and
5 additional loci from admixture mapping, spanning several known and
novel lung function candidate genes. Most loci identified via admixture
mapping exhibited wide variation in minor allele
frequency across genotyped global populations. Functional
fine-mapping revealed an enrichment of epigenetic annotations
from peripheral blood mononuclear cells, fetal lung tissue, and lung
fibroblasts. Our results point to three novel potential genetic drivers
of pre- and post-bronchodilator lung
function: ADAMTS1, RAD54B, and EGLN3.
Cohort Subset of the SAGE II cohort (Study of African Americans, Asthma,
Genes, and Environments), described in full elsewhere (Borrell et al.,
2013; Nishimura et al., 2013; Thakur et al., 2013; Mak et al., 2018)
Selected participants are self-identified as US-born, non-Hispanic African
American and self-reported that all four grandparents were also US-born,
non-Hispanic African Americans. Selected participants had pre- or pre- and
post-bronchodilator spirometry measurements available (FEV1, FVC,
FEV1/FVC), and full covariate data (age, sex, BMI, asthma status, maternal
educational attainment) Final cohort: 1,103 individuals (831 cases)
Genotyping, Ancestry Inference, and Quality Control DNA isolated from
whole blood and extracted using Wizard® Genomic DNA Purification kits
(Promega, Fitchburg, WI). Genotyping performed with Affymetrix Axion LAT1
array Imputation was performed via the Michigan Imputation Server with the
1000 Genomes Project reference panel QC performed in PLINK v1.9 (Filters
for retention: biallelic SNP, genotype missingness < 5%, MAF
> 1%, no deviation from HWE [p > 0.001]) Local ancestry was
called with RFMix for 454,322 genotyped SNPs that were successfully phased
Final genotyped set: 660,802 markers Final imputed set: 15,954,804 markers
Genetic Association Analyses Genetic Relatedness Matrices (GRMs) were
constructed with the GENESIS pipeline Genotype association testing
executed with the MLMA-LOCO algorithm from GCTA, correcting for age
(continuous), sex (male, female), obesity status (obese, overweight,
normal), maternal educational attainment (years of) and the first 3
principle components, as well as asthma status for pre-bronchodilator
measurements. Admixture mapping analysis were performed with linear
regression models in R after regressing phenotypes onto ancestral allele
counts (0, 1, or 2 African ancestral alleles) for each SNP, including age,
sex, obesity status, maternal education, and global African ancestry
proportion as covariates, with asthma status as an additional covariate
for pre-bronchodilator measurements. Fine-mapping Functional fine-mapping
was performed with PAINTOR according to the recommended approach, using a
subset of lung- and blood-related duncation annotations from the Roadmap
project and ENCODE consortium. The top 5 minimally correlated annotations
were selected for the final PAINTOR model at each locus. Fine-mapping was
performed on the GWAS summary statistics within the regions identified by
admixture mapping.
Full code used to produce the datasets is available
here: https://github.com/asthmacollaboratory/sage-lungfunction
gwas.*.mlma - file per phenotype (6 total) of GWAS results, corrected for
age, sex, obesity status, maternal education, height, PCs 1-3, and, for
pre-bronchodilator phenotypes, asthma status admixmap.*.SAGE_ALLCHR.txt -
file per phenotype (6 total) of admixture mapping analysis results,
corrected for age, sex, obesity status, maternal education, height, global
African ancestry, and, for pre-bronchodilator phenotypes, asthma status
*.paintor.results - file per locus (5 total) of posterior probabilities at
each SNP *.annotations.pval file per locus (5 total) of p-values of
annotations tested used at each locus *.annotations.top file per locus (5
total) for the top 5 annotations used per locus, visible in the CANVIS
figures