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

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 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).

SUBMITTER: Sung YJ

PROVIDER: S-EPMC5985266 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature

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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 YJ Winkler Thomas W TW de las Fuentes Lisa L Bentley Amy R AR Brown Michael R MR Kraja Aldi T AT Schwander Karen K Ntalla Ioanna I Guo Xiuqing X Franceschini Nora N Lu Yingchang Y Cheng Ching-Yu CY Sim Xueling X Vojinovic Dina D Marten Jonathan J Musani Solomon K SK Li Changwei C Feitosa Mary F MF Kilpeläinen Tuomas O TO Richard Melissa A MA Noordam Raymond R Aslibekyan Stella S Aschard Hugues H Bartz Traci M TM Dorajoo Rajkumar R Liu Yongmei Y Manning Alisa K AK Rankinen Tuomo T Smith Albert Vernon AV Tajuddin Salman M SM Tayo Bamidele O BO Warren Helen R HR Zhao Wei W Zhou Yanhua Y Matoba Nana N Sofer Tamar T Alver Maris M Amini Marzyeh M Boissel Mathilde M Chai Jin Fang JF Chen Xu X Divers Jasmin J Gandin Ilaria I Gao Chuan C Giulianini Franco F Goel Anuj A Harris Sarah E SE Hartwig Fernando Pires FP Horimoto Andrea R V R ARVR Hsu Fang-Chi FC Jackson Anne U AU Kähönen Mika M Kasturiratne Anuradhani A Kühnel Brigitte B Leander Karin K Lee Wen-Jane WJ Lin Keng-Hung KH 'an Luan Jian J McKenzie Colin A CA Meian He H Nelson Christopher P CP Rauramaa Rainer R Schupf Nicole N Scott Robert A RA Sheu Wayne H H WHH Stančáková Alena A Takeuchi Fumihiko F van der Most Peter J PJ Varga Tibor V TV Wang Heming H Wang Yajuan Y Ware Erin B EB Weiss Stefan S Wen Wanqing W Yanek Lisa R LR Zhang Weihua W Zhao Jing Hua JH Afaq Saima S Alfred Tamuno T Amin Najaf N Arking Dan D Aung Tin T Barr R Graham RG Bielak Lawrence F LF Boerwinkle Eric E Bottinger Erwin P EP Braund Peter S PS Brody Jennifer A JA Broeckel Ulrich U Cabrera Claudia P CP Cade Brian B Caizheng Yu Y Campbell Archie A Canouil Mickaël M Chakravarti Aravinda A Chauhan Ganesh G Christensen Kaare K Cocca Massimiliano M Collins Francis S FS Connell John M JM de Mutsert Renée R de Silva H Janaka HJ Debette Stephanie S Dörr Marcus M Duan Qing Q Eaton Charles B CB Ehret Georg G Evangelou Evangelos E Faul Jessica D JD Fisher Virginia A VA Forouhi Nita G NG Franco Oscar H OH Friedlander Yechiel Y Gao He H Gigante Bruna B Graff Misa M Gu C Charles CC Gu Dongfeng D Gupta Preeti P Hagenaars Saskia P SP Harris Tamara B TB He Jiang J Heikkinen Sami S Heng Chew-Kiat CK Hirata Makoto M Hofman Albert A Howard Barbara V BV Hunt Steven S Irvin Marguerite R MR Jia Yucheng Y Joehanes Roby R Justice Anne E AE Katsuya Tomohiro T Kaufman Joel J Kerrison Nicola D ND Khor Chiea Chuen CC Koh Woon-Puay WP Koistinen Heikki A HA Komulainen Pirjo P Kooperberg Charles C Krieger Jose E JE Kubo Michiaki M Kuusisto Johanna J Langefeld Carl D CD Langenberg Claudia C Launer Lenore J LJ Lehne Benjamin B Lewis Cora E CE Li Yize Y Lim Sing Hui SH Lin Shiow S Liu Ching-Ti CT Liu Jianjun J Liu Jingmin J Liu Kiang K Liu Yeheng Y Loh Marie M Lohman Kurt K KK Long Jirong J Louie Tin T Mägi Reedik R Mahajan Anubha A Meitinger Thomas T Metspalu Andres A Milani Lili L Momozawa Yukihide Y Morris Andrew P AP Mosley Thomas H TH Munson Peter P Murray Alison D AD Nalls Mike A MA Nasri Ubaydah U Norris Jill M JM North Kari K Ogunniyi Adesola A Padmanabhan Sandosh S Palmas Walter R WR Palmer Nicholette D ND Pankow James S JS Pedersen Nancy L NL Peters Annette A Peyser Patricia A PA Polasek Ozren O Raitakari Olli T OT Renström Frida F Rice Treva K TK Ridker Paul M PM Robino Antonietta A Robinson Jennifer G JG Rose Lynda M LM Rudan Igor I Sabanayagam Charumathi C Salako Babatunde L BL Sandow Kevin K Schmidt Carsten O CO Schreiner Pamela J PJ Scott William R WR Seshadri Sudha S Sever Peter P Sitlani Colleen M CM Smith Jennifer A JA Snieder Harold H Starr John M JM Strauch Konstantin K Tang Hua H Taylor Kent D KD Teo Yik Ying YY Tham Yih Chung YC Uitterlinden André G AG Waldenberger Melanie M Wang Lihua L Wang Ya X YX Wei Wen Bin WB Williams Christine C Wilson Gregory G Wojczynski Mary K MK Yao Jie J Yuan Jian-Min JM Zonderman Alan B AB Becker Diane M DM Boehnke Michael M Bowden Donald W DW Chambers John C JC Chen Yii-Der Ida YI de Faire Ulf U Deary Ian J IJ Esko Tõnu T Farrall Martin M Forrester Terrence T Franks Paul W PW Freedman Barry I BI Froguel Philippe P Gasparini Paolo P Gieger Christian C Horta Bernardo Lessa BL Hung Yi-Jen YJ Jonas Jost B JB Kato Norihiro N Kooner Jaspal S JS Laakso Markku M Lehtimäki Terho T Liang Kae-Woei KW Magnusson Patrik K E PKE Newman Anne B AB Oldehinkel Albertine J AJ Pereira Alexandre C AC Redline Susan S Rettig Rainer R Samani Nilesh J NJ Scott James J Shu Xiao-Ou XO van der Harst Pim P Wagenknecht Lynne E LE Wareham Nicholas J NJ Watkins Hugh H Weir David R DR Wickremasinghe Ananda R AR Wu Tangchun T Zheng Wei W Kamatani Yoichiro Y Laurie Cathy C CC Bouchard Claude C Cooper Richard S RS Evans Michele K MK Gudnason Vilmundur V Kardia Sharon L R SLR Kritchevsky Stephen B SB Levy Daniel D O'Connell Jeff R JR Psaty Bruce M BM van Dam Rob M RM Sims Mario M Arnett Donna K DK Mook-Kanamori Dennis O DO Kelly Tanika N TN Fox Ervin R ER Hayward Caroline C Fornage Myriam M Rotimi Charles N CN Province Michael A MA van Duijn Cornelia M CM Tai E Shyong ES Wong Tien Yin TY Loos Ruth J F RJF Reiner Alex P AP Rotter Jerome I JI Zhu Xiaofeng X Bierut Laura J LJ Gauderman W James WJ Caulfield Mark J MJ Elliott Paul P Rice Kenneth K Munroe Patricia B PB Morrison Alanna C AC Cupples L Adrienne LA Rao Dabeeru C DC Chasman Daniel I DI

American journal of human genetics 20180215 3

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 var ...[more]

PMID: 29455858

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Project description:While genome wide association studies (GWASs) of Alzheimer's Disease (AD) in European (EUR) ancestry cohorts have identified approximately 83 potentially independent AD risk loci, progress in non-European populations has lagged. In this study, data from the Million Veteran Program (MVP), a biobank which includes genetic data from more than 650,000 US Veteran participants, was used to examine dementia genetics in an African descent (AFR) cohort. A GWAS of Alzheimer's disease and related dementias (ADRD), an expanded AD phenotype including dementias such as vascular and non-specific dementia that included 4012 cases and 18,435 controls age 60+ in AFR MVP participants was performed. A proxy dementia GWAS based on survey-reported parental AD or dementia (n = 4385 maternal cases, 2256 paternal cases, and 45,970 controls) was also performed. These two GWASs were meta-analyzed, and then subsequently compared and meta-analyzed with the results from a previous AFR AD GWAS from the Alzheimer's Disease Genetics Consortium (ADGC). A meta-analysis of common variants across the MVP ADRD and proxy GWASs yielded GWAS significant associations in the region of APOE (p = 2.48 × 10-101), in ROBO1 (rs11919682, p = 1.63 × 10-8), and RNA RP11-340A13.2 (rs148433063, p = 8.56 × 10-9). The MVP/ADGC meta-analysis yielded additional significant SNPs near known AD risk genes TREM2 (rs73427293, p = 2.95 × 10-9), CD2AP (rs7738720, p = 1.14 × 10-9), and ABCA7 (rs73505251, p = 3.26 × 10-10), although the peak variants observed in these genes differed from those previously reported in EUR and AFR cohorts. Of the genes in or near suggestive or genome-wide significant associated variants, nine (CDA, SH2D5, DCBLD1, EML6, GOPC, ABCA7, ROS1, TMCO4, and TREM2) were differentially expressed in the brains of AD cases and controls. This represents the largest AFR GWAS of AD and dementia, finding non-APOE GWAS-significant common SNPs associated with dementia. Increasing representation of AFR participants is an important priority in genetic studies and may lead to increased insight into AD pathophysiology and reduce health disparities.

Dataset Information

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

Publications

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

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