Loci identified by a genome‐wide association study of carotid artery stenosis in the eMERGE network,Genetic Epidemiology

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Loci identified by a genome‐wide association study of carotid artery stenosis in the eMERGE network
Genetic Epidemiology ( IF 1.7 ) Pub Date : 2020-09-22 , DOI: 10.1002/gepi.22360
Melody R Palmer ₁ , Daniel S Kim ₂ , David R Crosslin ₃ , Ian B Stanaway ₃ , Elisabeth A Rosenthal ₁ , David S Carrell ₄ , David J Cronkite ₄ , Adam Gordon ₅ , Xiaomeng Du ₆ , Yatong K Li ₂ , Marc S Williams ₇ , Chunhua Weng ₈ , Qiping Feng ₉ , Rongling Li ₁₀ , Sarah A Pendergrass ₁₁ , Hakon Hakonarson ₁₂ , David Fasel ₈ , Sunghwan Sohn ₁₃ , Patrick Sleiman ₁₄ , Samuel K Handelman ₁₅ , Elizabeth Speliotes ₁₅ , Iftikhar J Kullo ₁₆ , Eric B Larson ₄ , ₁₇ , Gail P Jarvik ₁

Affiliation

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

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.

中文翻译：

通过 eMERGE 网络中颈动脉狭窄的全基因组关联研究确定的位点

颈动脉粥样硬化疾病（CAAD）是中风的危险因素。我们使用全基因组关联 (GWAS) 方法在电子病历和基因组学 (eMERGE) 网络的参与者中发现与 CAAD 相关的遗传变异。我们从八个 eMERGE 站点的电子健康记录中确定了单侧或双侧颈动脉狭窄的成人 CAAD 病例和对照组。我们使用调整了年龄、性别、研究地点和祖先遗传主要成分的模型进行了 GWAS。在 eMERGE 中，我们发现了 1793 个 CAAD 病例和 17,958 个对照。两个位点在 LPA 中的 chr6 上达到全基因组显着性（rs10455872，优势比 [OR]（95% 置信区间 [CI]）= 1.50（1.30–1.73），p = 2.1 × 10 ^-8) 和在 chr7 上，一种基因间单核苷酸变异 (SNV; rs6952610, OR (95% CI) = 1.25 (1.16–1.36), p = 4.3 × 10 ^-8 )。在 LPA SNV 作为协变量存在的情况下，chr7 关联仍然显着。在本研究中，LPA SNV 也与冠心病（CHD；4199 例和 11,679 例对照）有关（OR (95% CI) = 1.27 (1.13–1.43)，p = 5 × 10 ^-5），但 chr7 SNV 是不是 (OR (95% CI) = 1.03 (0.97–1.09), p = .37）。两种变体均在 UK Biobank 中复制。升高的脂蛋白 (a) 浓度 ([Lp(a)]) 和与升高的 [Lp(a)] 相关的 LPA 变体以前曾与 CAAD 和 CHD 相关，包括 rs10455872。通过 eMERGE 和 UKB 中的电子健康记录表型，我们复制了先前已知的关联并确定了与 CAAD 相关的新位点。

更新日期：2020-09-22

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