Genome-wide study of resistant hypertension identified from electronic health records

Logan Dumitrescu, Marylyn D Ritchie, Joshua C Denny, Nihal M El Rouby, Caitrin W McDonough, Yuki Bradford, Andrea H Ramirez, Suzette J Bielinski, Melissa A Basford, High Seng Chai, Peggy Peissig, David Carrell, Jyotishman Pathak, Luke V Rasmussen, Xiaoming Wang, Jennifer A Pacheco, Abel N Kho, M Geoffrey Hayes, Martha Matsumoto, Maureen E Smith, Rongling Li, Rhonda M Cooper-DeHoff, Iftikhar J Kullo, Christopher G Chute, Rex L Chisholm, Gail P Jarvik, Eric B Larson, David Carey, Catherine A McCarty, Marc S Williams, Dan M Roden, Erwin Bottinger, Julie A Johnson, Mariza de Andrade, Dana C Crawford, Logan Dumitrescu, Marylyn D Ritchie, Joshua C Denny, Nihal M El Rouby, Caitrin W McDonough, Yuki Bradford, Andrea H Ramirez, Suzette J Bielinski, Melissa A Basford, High Seng Chai, Peggy Peissig, David Carrell, Jyotishman Pathak, Luke V Rasmussen, Xiaoming Wang, Jennifer A Pacheco, Abel N Kho, M Geoffrey Hayes, Martha Matsumoto, Maureen E Smith, Rongling Li, Rhonda M Cooper-DeHoff, Iftikhar J Kullo, Christopher G Chute, Rex L Chisholm, Gail P Jarvik, Eric B Larson, David Carey, Catherine A McCarty, Marc S Williams, Dan M Roden, Erwin Bottinger, Julie A Johnson, Mariza de Andrade, Dana C Crawford

Abstract

Resistant hypertension is defined as high blood pressure that remains above treatment goals in spite of the concurrent use of three antihypertensive agents from different classes. Despite the important health consequences of resistant hypertension, few studies of resistant hypertension have been conducted. To perform a genome-wide association study for resistant hypertension, we defined and identified cases of resistant hypertension and hypertensives with treated, controlled hypertension among >47,500 adults residing in the US linked to electronic health records (EHRs) and genotyped as part of the electronic MEdical Records & GEnomics (eMERGE) Network. Electronic selection logic using billing codes, laboratory values, text queries, and medication records was used to identify resistant hypertension cases and controls at each site, and a total of 3,006 cases of resistant hypertension and 876 controlled hypertensives were identified among eMERGE Phase I and II sites. After imputation and quality control, a total of 2,530,150 SNPs were tested for an association among 2,830 multi-ethnic cases of resistant hypertension and 876 controlled hypertensives. No test of association was genome-wide significant in the full dataset or in the dataset limited to European American cases (n = 1,719) and controls (n = 708). The most significant finding was CLNK rs13144136 at p = 1.00x10-6 (odds ratio = 0.68; 95% CI = 0.58-0.80) in the full dataset with similar results in the European American only dataset. We also examined whether SNPs known to influence blood pressure or hypertension also influenced resistant hypertension. None was significant after correction for multiple testing. These data highlight both the difficulties and the potential utility of EHR-linked genomic data to study clinically-relevant traits such as resistant hypertension.

Conflict of interest statement

Competing Interests: The authors of this manuscript have read the journal's policy and have the following competing interests: Dr. Dana Crawford is an academic editor of PLOS ONE. Dr. Crawford is not involved in the review of this manuscript per journal policy. This disclosed competing interest does not alter the authors' adherence to PLOS ONE editorial policies and criteria. The remaining authors have declared that no competing interests exist.

Figures

Fig 1. Resistant hypertension genome-wide association study…
Fig 1. Resistant hypertension genome-wide association study in the eMERGE Network.
The eMERGE Network conducted a genome-wide association study for resistant hypertension among adults drawn from the two funding phases of the network. The eMERGE Network I study sites that contributed data are denoted in blue and include Group Health/University of Washington in Seattle, WA; Marshfield Clinic in Marshfield, WI; Mayo Clinic in Rochester, MN; Northwestern University in Chicago, IL; and Vanderbilt University in Nashville, TN. The eMERGE Network II study sites that contributed data are denoted in red and include Geisinger Health System in Danville, PA and Mount Sinai School of Medicine in Manhattan, NY. Denoted in gray are eMERGE Phase II pediatric study sites not included in the present study (Boston Children’s Hospital in Boston, MA; Children’s Hospital of Philadelphia in Philadelphia, PA; and Cincinnati Children’s Hospital in Cincinnati, OH).
Fig 2. Genome-wide association analysis of individuals…
Fig 2. Genome-wide association analysis of individuals with resistant hypertension versus controlled hypertensives.
A total of 2,830 cases of resistant hypertension and 876 controlled hypertensives from eMERGE I and II was available for analysis after quality control. After removing imputed genotypes for ESR1 rs9479122, single-SNP tests of association were performed for 2,530,149 SNPs using logistic regression, assuming an additive genetic model, adjusted for sex, decade of birth, median body mass index, genotyping platform, and genetic ancestry (principal components 1 through 10). Results of each test of association are plotted as p-values (expressed as–log10 on the y-axis) by chromosome (x-axis).
Fig 3. Q-Q plot of genome-wide association…
Fig 3. Q-Q plot of genome-wide association analysis of individuals with resistant hypertension versus controlled hypertensives.
The Q-Q plots were re-generated after removal of ESR1 rs9479122.

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