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

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

doi:10.1002/gepi.22360

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

Genet Epidemiol. 2021 Feb;45(1):4-15. doi: 10.1002/gepi.22360. Epub 2020 Sep 22.

Authors

Melody R Palmer¹, Daniel S Kim², David R Crosslin³, Ian B Stanaway³, Elisabeth A Rosenthal¹, David S Carrell⁴, David J Cronkite⁴, Adam Gordon⁵, Xiaomeng Du⁶, Yatong K Li², Marc S Williams⁷, Chunhua Weng⁸, Qiping Feng⁹, Rongling Li¹⁰, Sarah A Pendergrass¹¹, Hakon Hakonarson¹², David Fasel⁸, Sunghwan Sohn¹³, Patrick Sleiman¹⁴, Samuel K Handelman¹⁵, Elizabeth Speliotes¹⁵, Iftikhar J Kullo¹⁶, Eric B Larson⁴; eMERGE Consortium¹⁷; Gail P Jarvik¹

Affiliations

¹ Division of Medical Genetics, School of Medicine, University of Washington, Seattle, Washington, USA.
² Department of Biostatistics, Center for Statistical Genetics, University of Michigan, Ann Arbor, Michigan, USA.
³ Department of Biomedical Informatics and Medical Education, School of Medicine, University of Washington, Seattle, Washington, USA.
⁴ Kaiser Permanente Washington Health Research Institute, Seattle, Washington, USA.
⁵ Center for Genetic Medicine, Northwestern University, Chicago, Illinois, USA.
⁶ Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA.
⁷ Genomic Medicine Institute, Geisinger, Danville, Pennsylvania, USA.
⁸ Department of Biomedical Informatics, Columbia University, New York, New York, USA.
⁹ Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
¹⁰ Division of Genomic Medicine, National Human Genome Research Institute, Bethesda, Maryland, USA.
¹¹ Geisinger Research, Rockville, Maryland, USA.
¹² Department of Pediatrics, The Center for Applied Genomics, Children's Hospital of Philadelphia, The Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
¹³ Mayo Clinic, Rochester, Minnesota, USA.
¹⁴ Department of Pediatrics, The Children's Hospital of Philadelphia, The Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
¹⁵ Division of Gastroenterology, Department of Internal Medicine and Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, Michigan, USA.
¹⁶ Department of Cardiovascular Medicine, Mayo Clinic, Rochester, Minnesota, USA.
¹⁷ The electronic Medical Records and GEnomics Network, NHGRI, NIH, Bethesda, Maryland, USA.

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.

MeSH terms

Carotid Stenosis*
Electronic Health Records
Genetic Predisposition to Disease
Genome-Wide Association Study*
Genomics
Humans
Lipoprotein(a) / genetics
Models, Genetic
Polymorphism, Single Nucleotide

Substances

Lipoprotein(a)

Abstract

MeSH terms

Substances

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