Loci identified by a genome-wide association study of carotid artery stenosis in the eMERGE network

the eMERGE Consortium

doi:10.1002/gepi.22360

Loci identified by a genome-wide association study of carotid artery stenosis in the eMERGE network

the eMERGE Consortium

Pharmacology

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

5 Scopus citations

Abstract

Carotid artery atherosclerotic disease (CAAD) is a risk factor for stroke. We used a genome-wide association (GWAS) approach to discover genetic variants associated with CAAD in participants in the electronic Medical Records and Genomics (eMERGE) Network. We identified adult CAAD cases with unilateral or bilateral carotid artery stenosis and controls without evidence of stenosis from electronic health records at eight eMERGE sites. We performed GWAS with a model adjusting for age, sex, study site, and genetic principal components of ancestry. In eMERGE we found 1793 CAAD cases and 17,958 controls. Two loci reached genome-wide significance, on chr6 in LPA (rs10455872, odds ratio [OR] (95% confidence interval [CI]) = 1.50 (1.30–1.73), p = 2.1 × 10⁻⁸) and on chr7, an intergenic single nucleotide variant (SNV; rs6952610, OR (95% CI) = 1.25 (1.16–1.36), p = 4.3 × 10⁻⁸). The chr7 association remained significant in the presence of the LPA SNV as a covariate. The LPA SNV was also associated with coronary heart disease (CHD; 4199 cases and 11,679 controls) in this study (OR (95% CI) = 1.27 (1.13–1.43), p = 5 × 10⁻⁵) but the chr7 SNV was not (OR (95% CI) = 1.03 (0.97–1.09), p =.37). Both variants replicated in UK Biobank. Elevated lipoprotein(a) concentrations ([Lp(a)]) and LPA variants associated with elevated [Lp(a)] have previously been associated with CAAD and CHD, including rs10455872. With electronic health record phenotypes in eMERGE and UKB, we replicated a previously known association and identified a novel locus associated with CAAD.

Original language	English (US)
Pages (from-to)	4-15
Number of pages	12
Journal	Genetic Epidemiology
Volume	45
Issue number	1
DOIs	https://doi.org/10.1002/gepi.22360
State	Published - Feb 2021

Funding

The eMERGE Network is a consortium funded by National Human Genome Research Institute (NHGRI), National Institutes of Health (NIH) since 2007. It includes sites across the United States, with the purpose of linking EHR and genomic data for genomic medicine research. Phenotypes are extracted from EHR by algorithms developed by investigators and applied at each site. It is currently in Phase 3 and includes over 80,000 genotyped participants from nine adults and three pediatric institutions (Chisholm, 2013 ; Crawford et al., 2014 ; Gottesman et al., 2013 ). Enrollment was approved by review boards at each study site and consent obtained, abiding by the Declaration of Helsinki principles. In eMERGE network (Phase 3 ascertainment), this phase of the eMERGE Network was initiated and funded by the NHGRI through the following grants: U01HG8657 (Kaiser Washington/University of Washington); U01HG8685 (Brigham and Women's Hospital); U01HG8672 (Vanderbilt University Medical Center); U01HG8666 (Cincinnati Children's Hospital Medical Center); U01HG6379 (Mayo Clinic); U01HG8679 (Geisinger Clinic); U01HG8680 (Columbia University Health Sciences); U01HG8684 (Children's Hospital of Philadelphia); U01HG8673 (Northwestern University); U01HG8701 (Vanderbilt University Medical Center serving as the Coordinating Center); U01HG8676 (Partners Healthcare/Broad Institute); and U01HG8664 (Baylor College of Medicine). In eMERGE network (Phase 1 and 2 ascertainment), the eMERGE Network was initiated and funded by NHGRI through the following grants: U01HG006828 (Cincinnati Children's Hospital Medical Center/Boston Children's Hospital); U01HG006830 (Children's Hospital of Philadelphia); U01HG006389 (Essentia Institute of Rural Health, Marshfield Clinic Research Foundation and Pennsylvania State University); U01HG006382 (Geisinger Clinic); U01HG006375 (Group Health Cooperative/University of Washington); U01HG006379 (Mayo Clinic); U01HG006380 (Icahn School of Medicine at Mount Sinai); U01HG006388 (Northwestern University); U01HG006378 (Vanderbilt University Medical Center); and U01HG006385 (Vanderbilt University Medical Center serving as the Coordinating Center) with U01HG004438 (CIDR) and U01HG004424 (the Broad Institute) serving as Genotyping Centers. Help from James Linneman and NIH support from NIH NHGRI 5U01HG008701 and NIH NCATS UL1TR002373. The Genotype‐Tissue Expression (GTEx) Project was supported by the Common Fund of the Office of the Director of the National Institutes of Health, and by NCI, NHGRI, NHLBI, NIDA, NIMH, and NINDS. The data used for the analyses described in this manuscript were obtained from the GTEx Portal on 02/26/19. This content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Keywords

carotid artery atherosclerosis
electronic health records
genome-wide association study

ASJC Scopus subject areas

Genetics(clinical)
Epidemiology

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10.1002/gepi.22360

Cite this

@article{0ce1ba7ee3a248e4b375fc49ecbeec62,

title = "Loci identified by a genome-wide association study of carotid artery stenosis in the eMERGE network",

abstract = "Carotid artery atherosclerotic disease (CAAD) is a risk factor for stroke. We used a genome-wide association (GWAS) approach to discover genetic variants associated with CAAD in participants in the electronic Medical Records and Genomics (eMERGE) Network. We identified adult CAAD cases with unilateral or bilateral carotid artery stenosis and controls without evidence of stenosis from electronic health records at eight eMERGE sites. We performed GWAS with a model adjusting for age, sex, study site, and genetic principal components of ancestry. In eMERGE we found 1793 CAAD cases and 17,958 controls. Two loci reached genome-wide significance, on chr6 in LPA (rs10455872, odds ratio [OR] (95% confidence interval [CI]) = 1.50 (1.30–1.73), p = 2.1 × 10−8) and on chr7, an intergenic single nucleotide variant (SNV; rs6952610, OR (95% CI) = 1.25 (1.16–1.36), p = 4.3 × 10−8). The chr7 association remained significant in the presence of the LPA SNV as a covariate. The LPA SNV was also associated with coronary heart disease (CHD; 4199 cases and 11,679 controls) in this study (OR (95% CI) = 1.27 (1.13–1.43), p = 5 × 10−5) but the chr7 SNV was not (OR (95% CI) = 1.03 (0.97–1.09), p =.37). Both variants replicated in UK Biobank. Elevated lipoprotein(a) concentrations ([Lp(a)]) and LPA variants associated with elevated [Lp(a)] have previously been associated with CAAD and CHD, including rs10455872. With electronic health record phenotypes in eMERGE and UKB, we replicated a previously known association and identified a novel locus associated with CAAD.",

keywords = "carotid artery atherosclerosis, electronic health records, genome-wide association study",

author = "{the eMERGE Consortium} and Palmer, {Melody R.} and Kim, {Daniel S.} and Crosslin, {David R.} and Stanaway, {Ian B.} and Rosenthal, {Elisabeth A.} and Carrell, {David S.} and Cronkite, {David J.} and Adam Gordon and Xiaomeng Du and Li, {Yatong K.} and Williams, {Marc S.} and Chunhua Weng and Qiping Feng and Rongling Li and Pendergrass, {Sarah A.} and Hakon Hakonarson and David Fasel and Sunghwan Sohn and Patrick Sleiman and Handelman, {Samuel K.} and Elizabeth Speliotes and Kullo, {Iftikhar J.} and Larson, {Eric B.} and Jarvik, {Gail P.}",

note = "Funding Information: The eMERGE Network is a consortium funded by National Human Genome Research Institute (NHGRI), National Institutes of Health (NIH) since 2007. It includes sites across the United States, with the purpose of linking EHR and genomic data for genomic medicine research. Phenotypes are extracted from EHR by algorithms developed by investigators and applied at each site. It is currently in Phase 3 and includes over 80,000 genotyped participants from nine adults and three pediatric institutions (Chisholm, 2013 ; Crawford et al., 2014 ; Gottesman et al., 2013 ). Enrollment was approved by review boards at each study site and consent obtained, abiding by the Declaration of Helsinki principles. Funding Information: In eMERGE network (Phase 3 ascertainment), this phase of the eMERGE Network was initiated and funded by the NHGRI through the following grants: U01HG8657 (Kaiser Washington/University of Washington); U01HG8685 (Brigham and Women's Hospital); U01HG8672 (Vanderbilt University Medical Center); U01HG8666 (Cincinnati Children's Hospital Medical Center); U01HG6379 (Mayo Clinic); U01HG8679 (Geisinger Clinic); U01HG8680 (Columbia University Health Sciences); U01HG8684 (Children's Hospital of Philadelphia); U01HG8673 (Northwestern University); U01HG8701 (Vanderbilt University Medical Center serving as the Coordinating Center); U01HG8676 (Partners Healthcare/Broad Institute); and U01HG8664 (Baylor College of Medicine). In eMERGE network (Phase 1 and 2 ascertainment), the eMERGE Network was initiated and funded by NHGRI through the following grants: U01HG006828 (Cincinnati Children's Hospital Medical Center/Boston Children's Hospital); U01HG006830 (Children's Hospital of Philadelphia); U01HG006389 (Essentia Institute of Rural Health, Marshfield Clinic Research Foundation and Pennsylvania State University); U01HG006382 (Geisinger Clinic); U01HG006375 (Group Health Cooperative/University of Washington); U01HG006379 (Mayo Clinic); U01HG006380 (Icahn School of Medicine at Mount Sinai); U01HG006388 (Northwestern University); U01HG006378 (Vanderbilt University Medical Center); and U01HG006385 (Vanderbilt University Medical Center serving as the Coordinating Center) with U01HG004438 (CIDR) and U01HG004424 (the Broad Institute) serving as Genotyping Centers. Help from James Linneman and NIH support from NIH NHGRI 5U01HG008701 and NIH NCATS UL1TR002373. The Genotype‐Tissue Expression (GTEx) Project was supported by the Common Fund of the Office of the Director of the National Institutes of Health, and by NCI, NHGRI, NHLBI, NIDA, NIMH, and NINDS. The data used for the analyses described in this manuscript were obtained from the GTEx Portal on 02/26/19. This content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Publisher Copyright: {\textcopyright} 2020 The Authors. Genetic Epidemiology published by Wiley Periodicals LLC",

year = "2021",

month = feb,

doi = "10.1002/gepi.22360",

language = "English (US)",

volume = "45",

pages = "4--15",

journal = "Genetic Epidemiology",

issn = "0741-0395",

publisher = "Wiley-Liss Inc.",

number = "1",

}

TY - JOUR

T1 - Loci identified by a genome-wide association study of carotid artery stenosis in the eMERGE network

AU - the eMERGE Consortium

AU - Palmer, Melody R.

AU - Kim, Daniel S.

AU - Crosslin, David R.

AU - Stanaway, Ian B.

AU - Rosenthal, Elisabeth A.

AU - Carrell, David S.

AU - Cronkite, David J.

AU - Gordon, Adam

AU - Du, Xiaomeng

AU - Li, Yatong K.

AU - Williams, Marc S.

AU - Weng, Chunhua

AU - Feng, Qiping

AU - Li, Rongling

AU - Pendergrass, Sarah A.

AU - Hakonarson, Hakon

AU - Fasel, David

AU - Sohn, Sunghwan

AU - Sleiman, Patrick

AU - Handelman, Samuel K.

AU - Speliotes, Elizabeth

AU - Kullo, Iftikhar J.

AU - Larson, Eric B.

AU - Jarvik, Gail P.

N1 - Funding Information: The eMERGE Network is a consortium funded by National Human Genome Research Institute (NHGRI), National Institutes of Health (NIH) since 2007. It includes sites across the United States, with the purpose of linking EHR and genomic data for genomic medicine research. Phenotypes are extracted from EHR by algorithms developed by investigators and applied at each site. It is currently in Phase 3 and includes over 80,000 genotyped participants from nine adults and three pediatric institutions (Chisholm, 2013 ; Crawford et al., 2014 ; Gottesman et al., 2013 ). Enrollment was approved by review boards at each study site and consent obtained, abiding by the Declaration of Helsinki principles. Funding Information: In eMERGE network (Phase 3 ascertainment), this phase of the eMERGE Network was initiated and funded by the NHGRI through the following grants: U01HG8657 (Kaiser Washington/University of Washington); U01HG8685 (Brigham and Women's Hospital); U01HG8672 (Vanderbilt University Medical Center); U01HG8666 (Cincinnati Children's Hospital Medical Center); U01HG6379 (Mayo Clinic); U01HG8679 (Geisinger Clinic); U01HG8680 (Columbia University Health Sciences); U01HG8684 (Children's Hospital of Philadelphia); U01HG8673 (Northwestern University); U01HG8701 (Vanderbilt University Medical Center serving as the Coordinating Center); U01HG8676 (Partners Healthcare/Broad Institute); and U01HG8664 (Baylor College of Medicine). In eMERGE network (Phase 1 and 2 ascertainment), the eMERGE Network was initiated and funded by NHGRI through the following grants: U01HG006828 (Cincinnati Children's Hospital Medical Center/Boston Children's Hospital); U01HG006830 (Children's Hospital of Philadelphia); U01HG006389 (Essentia Institute of Rural Health, Marshfield Clinic Research Foundation and Pennsylvania State University); U01HG006382 (Geisinger Clinic); U01HG006375 (Group Health Cooperative/University of Washington); U01HG006379 (Mayo Clinic); U01HG006380 (Icahn School of Medicine at Mount Sinai); U01HG006388 (Northwestern University); U01HG006378 (Vanderbilt University Medical Center); and U01HG006385 (Vanderbilt University Medical Center serving as the Coordinating Center) with U01HG004438 (CIDR) and U01HG004424 (the Broad Institute) serving as Genotyping Centers. Help from James Linneman and NIH support from NIH NHGRI 5U01HG008701 and NIH NCATS UL1TR002373. The Genotype‐Tissue Expression (GTEx) Project was supported by the Common Fund of the Office of the Director of the National Institutes of Health, and by NCI, NHGRI, NHLBI, NIDA, NIMH, and NINDS. The data used for the analyses described in this manuscript were obtained from the GTEx Portal on 02/26/19. This content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Publisher Copyright: © 2020 The Authors. Genetic Epidemiology published by Wiley Periodicals LLC

PY - 2021/2

Y1 - 2021/2

N2 - Carotid artery atherosclerotic disease (CAAD) is a risk factor for stroke. We used a genome-wide association (GWAS) approach to discover genetic variants associated with CAAD in participants in the electronic Medical Records and Genomics (eMERGE) Network. We identified adult CAAD cases with unilateral or bilateral carotid artery stenosis and controls without evidence of stenosis from electronic health records at eight eMERGE sites. We performed GWAS with a model adjusting for age, sex, study site, and genetic principal components of ancestry. In eMERGE we found 1793 CAAD cases and 17,958 controls. Two loci reached genome-wide significance, on chr6 in LPA (rs10455872, odds ratio [OR] (95% confidence interval [CI]) = 1.50 (1.30–1.73), p = 2.1 × 10−8) and on chr7, an intergenic single nucleotide variant (SNV; rs6952610, OR (95% CI) = 1.25 (1.16–1.36), p = 4.3 × 10−8). The chr7 association remained significant in the presence of the LPA SNV as a covariate. The LPA SNV was also associated with coronary heart disease (CHD; 4199 cases and 11,679 controls) in this study (OR (95% CI) = 1.27 (1.13–1.43), p = 5 × 10−5) but the chr7 SNV was not (OR (95% CI) = 1.03 (0.97–1.09), p =.37). Both variants replicated in UK Biobank. Elevated lipoprotein(a) concentrations ([Lp(a)]) and LPA variants associated with elevated [Lp(a)] have previously been associated with CAAD and CHD, including rs10455872. With electronic health record phenotypes in eMERGE and UKB, we replicated a previously known association and identified a novel locus associated with CAAD.

AB - Carotid artery atherosclerotic disease (CAAD) is a risk factor for stroke. We used a genome-wide association (GWAS) approach to discover genetic variants associated with CAAD in participants in the electronic Medical Records and Genomics (eMERGE) Network. We identified adult CAAD cases with unilateral or bilateral carotid artery stenosis and controls without evidence of stenosis from electronic health records at eight eMERGE sites. We performed GWAS with a model adjusting for age, sex, study site, and genetic principal components of ancestry. In eMERGE we found 1793 CAAD cases and 17,958 controls. Two loci reached genome-wide significance, on chr6 in LPA (rs10455872, odds ratio [OR] (95% confidence interval [CI]) = 1.50 (1.30–1.73), p = 2.1 × 10−8) and on chr7, an intergenic single nucleotide variant (SNV; rs6952610, OR (95% CI) = 1.25 (1.16–1.36), p = 4.3 × 10−8). The chr7 association remained significant in the presence of the LPA SNV as a covariate. The LPA SNV was also associated with coronary heart disease (CHD; 4199 cases and 11,679 controls) in this study (OR (95% CI) = 1.27 (1.13–1.43), p = 5 × 10−5) but the chr7 SNV was not (OR (95% CI) = 1.03 (0.97–1.09), p =.37). Both variants replicated in UK Biobank. Elevated lipoprotein(a) concentrations ([Lp(a)]) and LPA variants associated with elevated [Lp(a)] have previously been associated with CAAD and CHD, including rs10455872. With electronic health record phenotypes in eMERGE and UKB, we replicated a previously known association and identified a novel locus associated with CAAD.

KW - carotid artery atherosclerosis

KW - electronic health records

KW - genome-wide association study

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JO - Genetic Epidemiology

JF - Genetic Epidemiology

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ER -

Loci identified by a genome-wide association study of carotid artery stenosis in the eMERGE network

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