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A Large-Scale Multi-ancestry Genome-wide Study Accounting for Smoking Behavior Identifies Multiple Significant Loci for Blood Pressure

Sung, Yun J.; Winkler, Thomas W.; de las Fuentes, Lisa; Bentley, Amy R.; Brown, Michael R.; Kraja, Aldi T.; Schwander, Karen; Ntalla, Ioanna; Guo, Xiuqing and Franceschini, Nora, et al. (2018) In American Journal of Human Genetics 102(3). p.375-400
Abstract

Genome-wide association analysis advanced understanding of blood pressure (BP), a major risk factor for vascular conditions such as coronary heart disease and stroke. Accounting for smoking behavior may help identify BP loci and extend our knowledge of its genetic architecture. We performed genome-wide association meta-analyses of systolic and diastolic BP incorporating gene-smoking interactions in 610,091 individuals. Stage 1 analysis examined ∼18.8 million SNPs and small insertion/deletion variants in 129,913 individuals from four ancestries (European, African, Asian, and Hispanic) with follow-up analysis of promising variants in 480,178 additional individuals from five ancestries. We identified 15 loci that were genome-wide... (More)

Genome-wide association analysis advanced understanding of blood pressure (BP), a major risk factor for vascular conditions such as coronary heart disease and stroke. Accounting for smoking behavior may help identify BP loci and extend our knowledge of its genetic architecture. We performed genome-wide association meta-analyses of systolic and diastolic BP incorporating gene-smoking interactions in 610,091 individuals. Stage 1 analysis examined ∼18.8 million SNPs and small insertion/deletion variants in 129,913 individuals from four ancestries (European, African, Asian, and Hispanic) with follow-up analysis of promising variants in 480,178 additional individuals from five ancestries. We identified 15 loci that were genome-wide significant (p < 5 × 10−8) in stage 1 and formally replicated in stage 2. A combined stage 1 and 2 meta-analysis identified 66 additional genome-wide significant loci (13, 35, and 18 loci in European, African, and trans-ancestry, respectively). A total of 56 known BP loci were also identified by our results (p < 5 × 10−8). Of the newly identified loci, ten showed significant interaction with smoking status, but none of them were replicated in stage 2. Several loci were identified in African ancestry, highlighting the importance of genetic studies in diverse populations. The identified loci show strong evidence for regulatory features and support shared pathophysiology with cardiometabolic and addiction traits. They also highlight a role in BP regulation for biological candidates such as modulators of vascular structure and function (CDKN1B, BCAR1-CFDP1, PXDN, EEA1), ciliopathies (SDCCAG8, RPGRIP1L), telomere maintenance (TNKS, PINX1, AKTIP), and central dopaminergic signaling (MSRA, EBF2).

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keywords
blood pressure, GWAS, GxE interactions, lifestyle, multi-ancestry, smoking
in
American Journal of Human Genetics
volume
102
issue
3
pages
26 pages
publisher
Cell Press
external identifiers
  • scopus:85042027943
ISSN
0002-9297
DOI
10.1016/j.ajhg.2018.01.015
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English
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yes
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94d1d7be-1bdc-499e-a529-3154e8d71284
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2018-03-23 13:37:04
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2019-02-03 05:31:19
@article{94d1d7be-1bdc-499e-a529-3154e8d71284,
  abstract     = {<p>Genome-wide association analysis advanced understanding of blood pressure (BP), a major risk factor for vascular conditions such as coronary heart disease and stroke. Accounting for smoking behavior may help identify BP loci and extend our knowledge of its genetic architecture. We performed genome-wide association meta-analyses of systolic and diastolic BP incorporating gene-smoking interactions in 610,091 individuals. Stage 1 analysis examined ∼18.8 million SNPs and small insertion/deletion variants in 129,913 individuals from four ancestries (European, African, Asian, and Hispanic) with follow-up analysis of promising variants in 480,178 additional individuals from five ancestries. We identified 15 loci that were genome-wide significant (p &lt; 5 × 10<sup>−8</sup>) in stage 1 and formally replicated in stage 2. A combined stage 1 and 2 meta-analysis identified 66 additional genome-wide significant loci (13, 35, and 18 loci in European, African, and trans-ancestry, respectively). A total of 56 known BP loci were also identified by our results (p &lt; 5 × 10<sup>−8</sup>). Of the newly identified loci, ten showed significant interaction with smoking status, but none of them were replicated in stage 2. Several loci were identified in African ancestry, highlighting the importance of genetic studies in diverse populations. The identified loci show strong evidence for regulatory features and support shared pathophysiology with cardiometabolic and addiction traits. They also highlight a role in BP regulation for biological candidates such as modulators of vascular structure and function (CDKN1B, BCAR1-CFDP1, PXDN, EEA1), ciliopathies (SDCCAG8, RPGRIP1L), telomere maintenance (TNKS, PINX1, AKTIP), and central dopaminergic signaling (MSRA, EBF2).</p>},
  author       = {Sung, Yun J. and Winkler, Thomas W. and de las Fuentes, Lisa and Bentley, Amy R. and Brown, Michael R. and Kraja, Aldi T. and Schwander, Karen and Ntalla, Ioanna and Guo, Xiuqing and Franceschini, Nora and Lu, Yingchang and Cheng, Ching Yu and Sim, Xueling and Vojinovic, Dina and Marten, Jonathan and Musani, Solomon K. and Li, Changwei and Feitosa, Mary F. and Kilpeläinen, Tuomas O. and Richard, Melissa A. and Noordam, Raymond and Aslibekyan, Stella and Aschard, Hugues and Bartz, Traci M. and Dorajoo, Rajkumar and Liu, Yongmei and Manning, Alisa K. and Rankinen, Tuomo and Smith, Albert Vernon and Tajuddin, Salman M. and Tayo, Bamidele O. and Warren, Helen R. and Zhao, Wei and Zhou, Yanhua and Matoba, Nana and Sofer, Tamar and Alver, Maris and Amini, Marzyeh and Boissel, Mathilde and Chai, Jin Fang and Chen, Xu and Divers, Jasmin and Gandin, Ilaria and Gao, Chuan and Giulianini, Franco and Goel, Anuj and Harris, Sarah E. and Varga, Tibor V. and Renström, Frida and Franks, Paul W. and ,  and ,  and ,  and , },
  issn         = {0002-9297},
  keyword      = {blood pressure,GWAS,GxE interactions,lifestyle,multi-ancestry,smoking},
  language     = {eng},
  month        = {03},
  number       = {3},
  pages        = {375--400},
  publisher    = {Cell Press},
  series       = {American Journal of Human Genetics},
  title        = {A Large-Scale Multi-ancestry Genome-wide Study Accounting for Smoking Behavior Identifies Multiple Significant Loci for Blood Pressure},
  url          = {http://dx.doi.org/10.1016/j.ajhg.2018.01.015},
  volume       = {102},
  year         = {2018},
}