African-specific alleles modify risk for asthma at the 17q12-q21 locus in African Americans

CAAPA

doi:10.1186/s13073-022-01114-x

African-specific alleles modify risk for asthma at the 17q12-q21 locus in African Americans

CAAPA

Research output: Contribution to journal › Article › peer-review

3 Scopus citations

Abstract

Background: Asthma is the most common chronic disease in children, occurring at higher frequencies and with more severe disease in children with African ancestry. Methods: We tested for association with haplotypes at the most replicated and significant childhood-onset asthma locus at 17q12-q21 and asthma in European American and African American children. Following this, we used whole-genome sequencing data from 1060 African American and 100 European American individuals to identify novel variants on a high-risk African American–specific haplotype. We characterized these variants in silico using gene expression and ATAC-seq data from airway epithelial cells, functional annotations from ENCODE, and promoter capture (pc)Hi-C maps in airway epithelial cells. Candidate causal variants were then assessed for correlation with asthma-associated phenotypes in African American children and adults. Results: Our studies revealed nine novel African-specific common variants, enriched on a high-risk asthma haplotype, which regulated the expression of GSDMA in airway epithelial cells and were associated with features of severe asthma. Using ENCODE annotations, ATAC-seq, and pcHi-C, we narrowed the associations to two candidate causal variants that are associated with features of T2 low severe asthma. Conclusions: Previously unknown genetic variation at the 17q12-21 childhood-onset asthma locus contributes to asthma severity in individuals with African ancestries. We suggest that many other population-specific variants that have not been discovered in GWAS contribute to the genetic risk for asthma and other common diseases.

Original language	English (US)
Article number	112
Journal	Genome Medicine
Volume	14
Issue number	1
DOIs	https://doi.org/10.1186/s13073-022-01114-x
State	Published - Dec 2022
Externally published	Yes

Keywords

Asthma
Fine mapping
Health disparities
Integrated omics
Whole-genome sequencing

ASJC Scopus subject areas

Molecular Medicine
Molecular Biology
Genetics
Genetics(clinical)

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10.1186/s13073-022-01114-x

Cite this

@article{a29bd6c5593143f58deb81239d07e486,

title = "African-specific alleles modify risk for asthma at the 17q12-q21 locus in African Americans",

abstract = "Background: Asthma is the most common chronic disease in children, occurring at higher frequencies and with more severe disease in children with African ancestry. Methods: We tested for association with haplotypes at the most replicated and significant childhood-onset asthma locus at 17q12-q21 and asthma in European American and African American children. Following this, we used whole-genome sequencing data from 1060 African American and 100 European American individuals to identify novel variants on a high-risk African American–specific haplotype. We characterized these variants in silico using gene expression and ATAC-seq data from airway epithelial cells, functional annotations from ENCODE, and promoter capture (pc)Hi-C maps in airway epithelial cells. Candidate causal variants were then assessed for correlation with asthma-associated phenotypes in African American children and adults. Results: Our studies revealed nine novel African-specific common variants, enriched on a high-risk asthma haplotype, which regulated the expression of GSDMA in airway epithelial cells and were associated with features of severe asthma. Using ENCODE annotations, ATAC-seq, and pcHi-C, we narrowed the associations to two candidate causal variants that are associated with features of T2 low severe asthma. Conclusions: Previously unknown genetic variation at the 17q12-21 childhood-onset asthma locus contributes to asthma severity in individuals with African ancestries. We suggest that many other population-specific variants that have not been discovered in GWAS contribute to the genetic risk for asthma and other common diseases.",

keywords = "Asthma, Fine mapping, Health disparities, Integrated omics, Whole-genome sequencing",

author = "CAAPA and Charles Washington and Matthew Dapas and Arjun Biddanda and Magnaye, {Kevin M.} and Ivy Aneas and Helling, {Britney A.} and Brooke Szczesny and Boorgula, {Meher Preethi} and Taub, {Margaret A.} and Eimear Kenny and Mathias, {Rasika A.} and Barnes, {Kathleen C.} and Monica Campbell and Camila Figueiredo and Hansel, {Nadia N.} and Carole Ober and Olopade, {Christopher O.} and Rotimi, {Charles N.} and Harold Watson and {Khurana Hershey}, {Gurjit K.} and Kercsmar, {Carolyn M.} and Gereige, {Jessica D.} and Melanie Makhija and Gruchalla, {Rebecca S.} and Gill, {Michelle A.} and Liu, {Andrew H.} and Deepa Rastogi and William Busse and Gergen, {Peter J.} and Visness, {Cynthia M.} and Gold, {Diane R.} and Tina Hartert and Johnson, {Christine C.} and Lemanske, {Robert F.} and Martinez, {Fernando D.} and Miller, {Rachel L.} and Dennis Ownby and Seroogy, {Christine M.} and Wright, {Anne L.} and Zoratti, {Edward M.} and Bacharier, {Leonard B.} and Meyer Kattan and O{\textquoteright}Connor, {George T.} and Wood, {Robert A.} and Nobrega, {Marcelo A.} and Altman, {Matthew C.} and Jackson, {Daniel J.} and Gern, {James E.} and McKennan, {Christopher G.} and Carole Ober",

note = "Publisher Copyright: {\textcopyright} 2022, The Author(s).",

year = "2022",

month = dec,

doi = "10.1186/s13073-022-01114-x",

language = "English (US)",

volume = "14",

journal = "Genome Medicine",

issn = "1756-994X",

publisher = "BioMed Central Ltd.",

number = "1",

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TY - JOUR

T1 - African-specific alleles modify risk for asthma at the 17q12-q21 locus in African Americans

AU - CAAPA

AU - Washington, Charles

AU - Dapas, Matthew

AU - Biddanda, Arjun

AU - Magnaye, Kevin M.

AU - Aneas, Ivy

AU - Helling, Britney A.

AU - Szczesny, Brooke

AU - Boorgula, Meher Preethi

AU - Taub, Margaret A.

AU - Kenny, Eimear

AU - Mathias, Rasika A.

AU - Barnes, Kathleen C.

AU - Campbell, Monica

AU - Figueiredo, Camila

AU - Hansel, Nadia N.

AU - Ober, Carole

AU - Olopade, Christopher O.

AU - Rotimi, Charles N.

AU - Watson, Harold

AU - Khurana Hershey, Gurjit K.

AU - Kercsmar, Carolyn M.

AU - Gereige, Jessica D.

AU - Makhija, Melanie

AU - Gruchalla, Rebecca S.

AU - Gill, Michelle A.

AU - Liu, Andrew H.

AU - Rastogi, Deepa

AU - Busse, William

AU - Gergen, Peter J.

AU - Visness, Cynthia M.

AU - Gold, Diane R.

AU - Hartert, Tina

AU - Johnson, Christine C.

AU - Lemanske, Robert F.

AU - Martinez, Fernando D.

AU - Miller, Rachel L.

AU - Ownby, Dennis

AU - Seroogy, Christine M.

AU - Wright, Anne L.

AU - Zoratti, Edward M.

AU - Bacharier, Leonard B.

AU - Kattan, Meyer

AU - O’Connor, George T.

AU - Wood, Robert A.

AU - Nobrega, Marcelo A.

AU - Altman, Matthew C.

AU - Jackson, Daniel J.

AU - Gern, James E.

AU - McKennan, Christopher G.

AU - Ober, Carole

PY - 2022/12

Y1 - 2022/12

N2 - Background: Asthma is the most common chronic disease in children, occurring at higher frequencies and with more severe disease in children with African ancestry. Methods: We tested for association with haplotypes at the most replicated and significant childhood-onset asthma locus at 17q12-q21 and asthma in European American and African American children. Following this, we used whole-genome sequencing data from 1060 African American and 100 European American individuals to identify novel variants on a high-risk African American–specific haplotype. We characterized these variants in silico using gene expression and ATAC-seq data from airway epithelial cells, functional annotations from ENCODE, and promoter capture (pc)Hi-C maps in airway epithelial cells. Candidate causal variants were then assessed for correlation with asthma-associated phenotypes in African American children and adults. Results: Our studies revealed nine novel African-specific common variants, enriched on a high-risk asthma haplotype, which regulated the expression of GSDMA in airway epithelial cells and were associated with features of severe asthma. Using ENCODE annotations, ATAC-seq, and pcHi-C, we narrowed the associations to two candidate causal variants that are associated with features of T2 low severe asthma. Conclusions: Previously unknown genetic variation at the 17q12-21 childhood-onset asthma locus contributes to asthma severity in individuals with African ancestries. We suggest that many other population-specific variants that have not been discovered in GWAS contribute to the genetic risk for asthma and other common diseases.

AB - Background: Asthma is the most common chronic disease in children, occurring at higher frequencies and with more severe disease in children with African ancestry. Methods: We tested for association with haplotypes at the most replicated and significant childhood-onset asthma locus at 17q12-q21 and asthma in European American and African American children. Following this, we used whole-genome sequencing data from 1060 African American and 100 European American individuals to identify novel variants on a high-risk African American–specific haplotype. We characterized these variants in silico using gene expression and ATAC-seq data from airway epithelial cells, functional annotations from ENCODE, and promoter capture (pc)Hi-C maps in airway epithelial cells. Candidate causal variants were then assessed for correlation with asthma-associated phenotypes in African American children and adults. Results: Our studies revealed nine novel African-specific common variants, enriched on a high-risk asthma haplotype, which regulated the expression of GSDMA in airway epithelial cells and were associated with features of severe asthma. Using ENCODE annotations, ATAC-seq, and pcHi-C, we narrowed the associations to two candidate causal variants that are associated with features of T2 low severe asthma. Conclusions: Previously unknown genetic variation at the 17q12-21 childhood-onset asthma locus contributes to asthma severity in individuals with African ancestries. We suggest that many other population-specific variants that have not been discovered in GWAS contribute to the genetic risk for asthma and other common diseases.

KW - Asthma

KW - Fine mapping

KW - Health disparities

KW - Integrated omics

KW - Whole-genome sequencing

UR - http://www.scopus.com/inward/record.url?scp=85138974652&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85138974652&partnerID=8YFLogxK

U2 - 10.1186/s13073-022-01114-x

DO - 10.1186/s13073-022-01114-x

M3 - Article

C2 - 36175932

AN - SCOPUS:85138974652

SN - 1756-994X

VL - 14

JO - Genome Medicine

JF - Genome Medicine

IS - 1

M1 - 112

ER -

African-specific alleles modify risk for asthma at the 17q12-q21 locus in African Americans

Abstract

Keywords

ASJC Scopus subject areas

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