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

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningfagfællebedømt

Yun J Sung, Thomas W Winkler, Lisa de Las Fuentes, Amy R Bentley, Michael R Brown, Aldi T Kraja, Karen Schwander, Ioanna Ntalla, Xiuqing Guo, Nora Franceschini, Yingchang Lu, Ching-Yu Cheng, Xueling Sim, Dina Vojinovic, Jonathan Marten, Solomon K Musani, Changwei Li, Mary F Feitosa, Tuomas O Kilpeläinen, Melissa A Richard & 30 andre Raymond Noordam, Stella Aslibekyan, Hugues Aschard, Traci M Bartz, Rajkumar Dorajoo, Yongmei Liu, Alisa K Manning, Tuomo Rankinen, Albert Vernon Smith, Salman M Tajuddin, Bamidele O Tayo, Helen R Warren, Wei Zhao, Yanhua Zhou, Nana Matoba, Tamar Sofer, Maris Alver, Marzyeh Amini, Mathilde Boissel, Jin Fang Chai, Xu Chen, Jasmin Divers, Ilaria Gandin, Chuan Gao, Franco Giulianini, Anuj Goel, Sarah E Harris, Fernando Pires Hartwig, Kaare Christensen, Ruth J F Loos

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).

OriginalsprogEngelsk
TidsskriftAmerican Journal of Human Genetics
Vol/bind102
Udgave nummer3
Sider (fra-til)375-400
Antal sider26
ISSN0002-9297
DOI
StatusUdgivet - 2018

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