Much literature on deliberation is derived from ideal theory. However, deliberations are inevitably non-ideal in two ways: (1) many deliberative ideals are in tension with each other; and 2) intended balancing of ideals cannot be attained perfectly amidst the messiness of real-world recruitment and conversation. This essay explores both kinds of non-ideality in respect to a case study: the 2011 community deliberative processes on a state public health "biobank," the Michigan BioTrust for Health. We follow two recommendations from major contemporary theorists of deliberation: to be transparent about how competing deliberative goals are negotiated in deliberative design; and to publicize case studies that report associated struggles and results. We present our "hybrid design" that sought to negotiate tensions within three families of deliberative goals: goals of representation and inclusion; goals of discourse-framing; and goals of political impact. We offer deliberative facilitators tentative suggestions based on this case study, concluding deliberations need not be "ideal" to be transformative.
Much literature on deliberation is derived from ideal theory. However, deliberations are inevitably non-ideal in two ways: (1) many deliberative ideals are in tension with each other; and 2) intended balancing of ideals cannot be attained perfectly amidst the messiness of real-world recruitment and conversation. This essay explores both kinds of non-ideality in respect to a case study: the 2011 community deliberative processes on a state public health "biobank," the Michigan BioTrust for Health. We follow two recommendations from major contemporary theorists of deliberation: to be transparent about how competing deliberative goals are negotiated in deliberative design; and to publicize case studies that report associated struggles and results. We present our "hybrid design" that sought to negotiate tensions within three families of deliberative goals: goals of representation and inclusion; goals of discourse-framing; and goals of political impact. We offer deliberative facilitators tentative suggestions based on this case study, concluding deliberations need not be "ideal" to be transformative.
Scholarship on newborn screening, dried bloodspot retention, and large population biobanking call consistently for improved public engagement. Communication with participants likely occurs only in the context of collection, consent, or notification, if at all. We ran an 11-week advertising campaign to inform Michigan Facebook users unlikely to know that their or their children's dried bloodspots (DBSs) were stored in a state biobank. We investigated the pattern and content of comments posted during the campaign, focusing on users' questions, attitudes and concerns, and the role the moderator played in addressing them. We used Facebook data to quantitatively assess engagement and employed conventional content analysis to investigate themes, attitudes, and social dynamics among user and moderator comments. Five ad sets elicited comments during campaign weeks 4–8, reaching ∼800,000 Facebook users ($6000). Gravitating around broad, underlying ethical, legal, and social issues, 180 posts from 129 unique users related to newborn screening or biobanking. Thirty six conveyed negative attitudes and 33 conveyed positive attitudes; 53 posed questions. The most prevalent themes identified were consent, privacy, bloodspot use, identifiability, inclusion criteria, research benefits, (mis)trust, genetics, DBS destruction, awareness, and the role of government. The moderator's 81 posts were responsive—answering questions, correcting or clarifying information, or providing information about opting out. Facebook ad campaigns can improve engagement by pushing out relevant content and creating dynamic, responsive, visible forums for discussion. Reduced control over messaging may be worth the trade-off for creating accessible, transparent, people-centered engagement on public health issues that are sensitive and complex.
Description: Among the two leading causes of death in the United States, each responsible for one in every four deaths, heart disease costs Americans $300 billion, while cancer costs Americans $216 billion per year. They also rank among the top three causes of death in Europe and Asia. In 2012 the University of Michigan Center for Public Health and Community Genomics and Genetic Alliance, with the support of the Centers for Disease Control and Prevention Office of Public Health Genomics, hosted a conference in Atlanta, Georgia to consider related action strategies based on public health genomics. The aim of the conference was consensus building on recommendations to implement genetic screening for three major heritable contributors to these mortality and cost figures: hereditary breast and ovarian cancer (HBOC), familial hypercholesterolemia (FH), and Lynch syndrome (LS). Genetic applications for these three conditions are labeled with a "Tier 1" designation by the U.S. Centers for Disease Control and Prevention because they have been fully validated and clinical practice guidelines based on systematic review support them. Methodology: The conference followed a deliberative sequence starting with nationally recognized clinical and public health presenters for each condition, followed by a Patient and Community Perspectives Panel, working group sessions for each of the conditions, and a final plenary session. The 74 conference participants represented disease research and advocacy, public health, medicine and nursing, genetics, governmental health agencies, and industry. Participants drew on a public health framework interconnecting policy, clinical intervention, surveillance, and educational functions for their deliberations. Results: Participants emphasized the importance of collaboration between clinical, public health, and advocacy groups in implementing Tier 1 genetic screening. Advocacy groups could help with individual and institutional buy-in of Tier 1 programs. Groups differed on funding strategies, with ...
<b><i>Background:</i></b> Michigan's BioTrust for Health, a public health research biobank comprised of residual dried bloodspot (DBS) cards from newborn screening contains over 4 million samples collected without written consent. Participant-centric initiatives are IT tools that hold great promise to address the consent challenges in biobank research. <b><i>Methods:</i></b> Working with Private Access™ Inc., a pioneer in patient-centric web solutions, we created and pilot tested a dynamic informed consent simulation, paired with an educational website, focusing on consent for research utilizing DBSs in Michigan's BioTrust for Health. <b><i>Results:</i></b> Out of 187 pilot testers recruited in 2 groups, 137 completed the consent simulation and exit survey. Over 50% indicated their willingness to set up an account if the simulation went live and to recommend it to others. Participants raised concerns about the process of identity verification and appeared to have little experience with sharing health information online. <b><i>Conclusions:</i></b> Applying online, dynamic approaches to address the consent challenges raised by biobanks with legacy sample collections should be explored, given the positive reaction to our pilot test and the strong preference for active consent. Balancing security and privacy with accessibility and ease of use will continue to be a challenge.
<b><i>Introduction:</i></b> To date scientists and religious leaders have not yet engaged in sustained face-to-face conversation concerning precision public health-related genetic technologies. <b><i>Objectives:</i></b> To elucidate areas of commonality and divergence in scientists' and religious leaders' views of precision genetic technologies, and extract lessons conveyed by religious leaders to scientists, and scientists to religious leaders through participatory dialogue. <b><i>Methods:</i></b> Six 1.5-h dialogue sessions were held between 6 religious leaders, 8 University of Michigan scientists, and 3 additional public health/genetic counseling graduate students between October 2016 and September 2017, followed by an open conference at the Ann Arbor Public Library (<i>n</i> = 46). Statements were organized into thematically arranged duets comparing views of scientists and religious leaders. Duets were further ordered into interpretive levels. Comparative techniques were used to assure category agreement and face validity. <b><i>Results:</i></b> The analysis yielded 20 duets and 3 interpretive levels (expositional; implications and consequences; and integrative, bridging concepts). Scientists emphasized the value of epigenetic testing for health promotion, and cost saving for some forms of early genetic testing for adult-onset conditions. Religious leaders stressed care for an individual's willingness to change over technical fixes for behavioral conditions and, together with public participants, the importance of allocating money for societal needs. Both expressed caution on the use of nuclear transfer for mitochondrial DNA replacement and secondary uses of genetic data. Lay conference participants pointed towards a middle ground on the release of genetically edited mosquitoes for disease eradication. <b><i>Discussion:</i></b> Scientists stressed the value of professional guidance; religious leaders listened to family needs. Dialogues met four literature-based criteria for stakeholder involvement in deliberative processes. <b><i>Conclusion:</i></b> While scientists and religious leaders differ in their points of emphasis and faith orientations (professional competency versus drawing on compassion), they can successfully collaborate in reaching mutual understanding and specific areas of agreement on precision genetic technologies relating to public health.
The authors describe the rationale and initial development of a new collaborative initiative, the Genomic Applications in Practice and Prevention Network. The network convened by the Centers for Disease Control and Prevention and the National Institutes of Health includes multiple stakeholders from academia, government, health care, public health, industry and consumers. The premise of Genomic Applications in Practice and Prevention Network is that there is an unaddressed chasm between gene discoveries and demonstration of their clinical validity and utility. This chasm is due to the lack of readily accessible information about the utility of most genomic applications and the lack of necessary knowledge by consumers and providers to implement what is known. The mission of Genomic Applications in Practice and Prevention Network is to accelerate and streamline the effective integration of validated genomic knowledge into the practice of medicine and public health, by empowering and sponsoring research, evaluating research findings, and disseminating high quality information on candidate genomic applications in practice and prevention. Genomic Applications in Practice and Prevention Network will develop a process that links ongoing collection of information on candidate genomic applications to four crucial domains: (1) knowledge synthesis and dissemination for new and existing technologies, and the identification of knowledge gaps, (2) a robust evidence-based recommendation development process, (3) translation research to evaluate validity, utility and impact in the real world and how to disseminate and implement recommended genomic applications, and (4) programs to enhance practice, education, and surveillance.
Publisher's version (útgefin grein) ; Smoking is a potentially causal behavioral risk factor for type 2 diabetes (T2D), but not all smokers develop T2D. It is unknown whether genetic factors partially explain this variation. We performed genome-environment-wide interaction studies to identify loci exhibiting potential interaction with baseline smoking status (ever vs. never) on incident T2D and fasting glucose (FG). Analyses were performed in participants of European (EA) and African ancestry (AA) separately. Discovery analyses were conducted using genotype data from the 50,000-single-nucleotide polymorphism (SNP) ITMAT-Broad-CARe (IBC) array in 5 cohorts from from the Candidate Gene Association Resource Consortium (n = 23,189). Replication was performed in up to 16 studies from the Cohorts for Heart Aging Research in Genomic Epidemiology Consortium (n = 74,584). In meta-analysis of discovery and replication estimates, 5 SNPs met at least one criterion for potential interaction with smoking on incident T2D at p<1x10-7 (adjusted for multiple hypothesis-testing with the IBC array). Two SNPs had significant joint effects in the overall model and significant main effects only in one smoking stratum: rs140637 (FBN1) in AA individuals had a significant main effect only among smokers, and rs1444261 (closest gene C2orf63) in EA individuals had a significant main effect only among nonsmokers. Three additional SNPs were identified as having potential interaction by exhibiting a significant main effects only in smokers: rs1801232 (CUBN) in AA individuals, rs12243326 (TCF7L2) in EA individuals, and rs4132670 (TCF7L2) in EA individuals. No SNP met significance for potential interaction with smoking on baseline FG. The identification of these loci provides evidence for genetic interactions with smoking exposure that may explain some of the heterogeneity in the association between smoking and T2D. ; WHI program is funded by the National Heart, Lung, and Blood Institute, National Institutes of Health, U.S. Department of Health and Human Services through contracts HHSN268201100046C, HSN268201100001C, HHSN268201100002C, HHSN268201100003C, HHSN268201100004C, and HHSN271201100004C. The grant funding of WHI are R21 HL123677, R56 DK104806 and R01 MD012765 to NF. The FamHS was funded by R01HL118305 and R01HL117078 NHLBI grants, and 5R01DK07568102 and 5R01DK089256 NIDDK grant." and "The Healthy Aging in Neighborhoods of Diversity across the Life Span (HANDLS) study was supported by the Intramural Research Program of the National Institute on Aging, National Institutes of Health (project # Z01-AG000513 and human subjects protocol number 09-AGN248). Support for GENOA was provided by the National Heart, Lung and Blood Institute (HL119443, HL087660, HL054464, HL054457, and HL054481) of the National Institutes of Health. Ruth loos is supported by the NIH (R01DK110113, U01HG007417, R01DK101855, R01DK107786). The Rotterdam Study GWAS datasets are supported by the Netherlands Organisation of Scientific Research NWO Investments (nr. 175.010.2005.011, 911-03-012), the Research Institute for Diseases in the Elderly (014-93-015; RIDE2), and the Netherlands Genomics Initiative (NGI)/Netherlands Organisation for Scientific Research (NWO) Netherlands Consortium for Healthy Aging (NCHA), project nr. 050-060-810. The ERF study as a part of EUROSPAN (European Special Populations Research Network) was supported by European Commission FP6 STRP grant number 018947 (LSHG-CT-2006- 01947) and also received funding from the European Community's Seventh Framework Programme (FP7/2007-2013)/grant agreement HEALTH-F4-2007-201413 by the European Commission under the programme "Quality of Life and Management of the Living Resources" of 5th Framework Programme (no. QLG2-CT-2002- 01254). The ERF study was further supported by ENGAGE consortium and CMSB. Highthroughput analysis of the ERF data was supported by joint grant from Netherlands Organisation for Scientific Research and the Russian Foundation for Basic Research (NWORFBR 047.017.043).ERF was further supported by the ZonMw grant (project 91111025), and this work was partially supported by the National Heart, Lung and Blood Institute's Framingham Heart Study (Contract No. N01-HC25195) and its contract with Affymetrix, Inc for genotyping services (Contract No. N02-HL-6- 4278). This study is also supported by National Institute for Diabetes and Digestive and Kidney Diseases (NIDDK) R01 DK078616 to Drs. Meigs, Dupuis and Florez, NIDDK K24 DK080140 to Dr. Meigs, and a Doris Duke Charitable Foundation Clinical Scientist Development Award to Dr. Florez. The HERITAGE Family Study was supported by National Heart, Lung, and Blood Institute grant HL-45670. The Women's Genome Health Study is supported by the National Heart, Lung, and Blood Instutute (HL043851 and HL080467) and the National Cancer Institute (CA047988 and UM1CA182913). Additional support for endpoint collection was provided by the National Heart, Lung, and Blood Institute under ARRA funding (HL099355). HyperGEN (Hypertension Genetic Epidemiology Network): The hypertension network is funded by cooperative agreements (U10) with NHLBI: HL54471, HL54472, HL54473, HL54495, HL54496, HL54497, HL54509, HL54515, and 2 R01 HL55673- 12. The AGES study has been funded by NIH contracts N01-AG-1-2100 and 271201200022C. Caroline Hayward is supported by an MRC University Unit Programme Grant MC_UU_00007/10 (QTL in Health and Disease)"and "Generation Scotland received core funding from the Chief Scientist Office of the Scottish Government Health Directorate CZD/16/6, the Scottish Funding Council HR03006 and the Wellcome Trust through a Strategic Award (reference 104036/Z/14/Z) for Stratifying Resilience and Depression Longitudinally (STRADL). Genotyping was funded by the UK's Medical Research Council. Jose C. Florez, NIDDK K24 DK110550 The MESA project is conducted and supported by the National Heart, Lung, and Blood Institute (NHLBI) in collaboration with MESA investigators. Support for MESA is provided by contracts 75N92020D00001, HHSN268201500003I, N01-HC-95159, 75N92020D00005, N01-HC-95160, 75N92020D00002, N01-HC-95161, 75N92020D00003, N01-HC-95162, 75N92020D00006, N01-HC-95163, 75N92020D00004, N01-HC-95164, 75N92020D00007, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168, N01-HC-95169, UL1-TR-000040, UL1-TR-001079, UL1-TR-001420, UL1-TR-001881, and DK063491. Additionally, one or more authors are affiliated with the following commercial entities: Interleukin Genetics, GlaxoSmithKline, Daiichi-Sankyo, AstraZeneca, Data Tecnica International LLC, Illumina Inc., University of California Healthcare, Janssen Pharmaceuticals, Goldfinch Bio, and Novo Nordisk. Please see the Competing Interests Statement for additional details. The funders provided support in the form of salaries for authors but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the 'author contributions' section. ; Peer Reviewed
Data Availability: Our study data are now available at the following URL on the AMP T2D Knowledge Portal: http://www.kp4cd.org/dataset_downloads/t2d. Funding: WHI program is funded by the National Heart, Lung, and Blood Institute, National Institutes of Health, U.S. Department of Health and Human Services through contracts HHSN268201100046C, HSN268201100001C, HHSN268201100002C, HHSN268201100003C, HHSN268201100004C, and HHSN271201100004C. The grant funding of WHI are R21 HL123677, R56 DK104806 and R01 MD012765 to NF. The FamHS was funded by R01HL118305 and R01HL117078 NHLBI grants, and 5R01DK07568102 and 5R01DK089256 NIDDK grant." and "The Healthy Aging in Neighborhoods of Diversity across the Life Span (HANDLS) study was supported by the Intramural Research Program of the National Institute on Aging, National Institutes of Health (project # Z01-AG000513 and human subjects protocol number 09-AGN248). Support for GENOA was provided by the National Heart, Lung and Blood Institute (HL119443, HL087660, HL054464, HL054457, and HL054481) of the National Institutes of Health. Ruth loos is supported by the NIH (R01DK110113, U01HG007417, R01DK101855, R01DK107786). The Rotterdam Study GWAS datasets are supported by the Netherlands Organisation of Scientific Research NWO Investments (nr. 175.010.2005.011, 911-03-012), the Research Institute for Diseases in the Elderly (014-93-015; RIDE2), and the Netherlands Genomics Initiative (NGI)/Netherlands Organisation for Scientific Research (NWO) Netherlands Consortium for Healthy Aging (NCHA), project nr. 050-060-810. The ERF study as a part of EUROSPAN (European Special Populations Research Network) was supported by European Commission FP6 STRP grant number 018947 (LSHG-CT-2006- 01947) and also received funding from the European Community's Seventh Framework Programme (FP7/2007-2013)/grant agreement HEALTH-F4-2007-201413 by the European Commission under the programme "Quality of Life and Management of the Living Resources" of 5th Framework Programme (no. QLG2-CT-2002- 01254). The ERF study was further supported by ENGAGE consortium and CMSB. Highthroughput analysis of the ERF data was supported by joint grant from Netherlands Organisation for Scientific Research and the Russian Foundation for Basic Research (NWORFBR 047.017.043).ERF was further supported by the ZonMw grant (project 91111025), and this work was partially supported by the National Heart, Lung and Blood Institute's Framingham Heart Study (Contract No. N01-HC25195) and its contract with Affymetrix, Inc for genotyping services (Contract No. N02-HL-6- 4278). This study is also supported by National Institute for Diabetes and Digestive and Kidney Diseases (NIDDK) R01 DK078616 to Drs. Meigs, Dupuis and Florez, NIDDK K24 DK080140 to Dr. Meigs, and a Doris Duke Charitable Foundation Clinical Scientist Development Award to Dr. Florez. The HERITAGE Family Study was supported by National Heart, Lung, and Blood Institute grant HL-45670. The Women's Genome Health Study is supported by the National Heart, Lung, and Blood Instutute (HL043851 and HL080467) and the National Cancer Institute (CA047988 and UM1CA182913). Additional support for endpoint collection was provided by the National Heart, Lung, and Blood Institute under ARRA funding (HL099355). HyperGEN (Hypertension Genetic Epidemiology Network): The hypertension network is funded by cooperative agreements (U10) with NHLBI: HL54471, HL54472, HL54473, HL54495, HL54496, HL54497, HL54509, HL54515, and 2 R01 HL55673- 12. The AGES study has been funded by NIH contracts N01-AG-1-2100 and 271201200022C. Caroline Hayward is supported by an MRC University Unit Programme Grant MC_UU_00007/10 (QTL in Health and Disease)"and "Generation Scotland received core funding from the Chief Scientist Office of the Scottish Government Health Directorate CZD/16/6, the Scottish Funding Council HR03006 and the Wellcome Trust through a Strategic Award (reference 104036/Z/14/Z) for Stratifying Resilience and Depression Longitudinally (STRADL). Genotyping was funded by the UK's Medical Research Council. Jose C. Florez, NIDDK K24 DK110550 The MESA project is conducted and supported by the National Heart, Lung, and Blood Institute (NHLBI) in collaboration with MESA investigators. Support for MESA is provided by contracts 75N92020D00001, HHSN268201500003I, N01-HC-95159, 75N92020D00005, N01-HC-95160, 75N92020D00002, N01-HC-95161, 75N92020D00003, N01-HC-95162, 75N92020D00006, N01-HC-95163, 75N92020D00004, N01-HC-95164, 75N92020D00007, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168, N01-HC-95169, UL1-TR-000040, UL1-TR-001079, UL1-TR-001420, UL1-TR-001881, and DK063491. Additionally, one or more authors are affiliated with the following commercial entities: Interleukin Genetics, GlaxoSmithKline, Daiichi-Sankyo, AstraZeneca, Data Tecnica International LLC, Illumina Inc., University of California Healthcare, Janssen Pharmaceuticals, Goldfinch Bio, and Novo Nordisk. Please see the Competing Interests Statement for additional details. The funders provided support in the form of salaries for authors but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the 'author contributions' section. ; Peer reviewed ; Publisher PDF
Smoking is a major heritable and modifiable risk factor for many diseases, including cancer, common respiratory disorders and cardiovascular diseases. Fourteen genetic loci have previously been associated with smoking behaviour-related traits. We tested up to 235,116 single nucleotide variants (SNVs) on the exome-array for association with smoking initiation, cigarettes per day, pack-years, and smoking cessation in a fixed effects meta-analysis of up to 61 studies (up to 346,813 participants). In a subset of 112,811 participants, a further one million SNVs were also genotyped and tested for association with the four smoking behaviour traits. SNV-trait associations with P < 5 × 10-8 in either analysis were taken forward for replication in up to 275,596 independent participants from UK Biobank. Lastly, a meta-analysis of the discovery and replication studies was performed. Sixteen SNVs were associated with at least one of the smoking behaviour traits (P < 5 × 10-8) in the discovery samples. Ten novel SNVs, including rs12616219 near TMEM182, were followed-up and five of them (rs462779 in REV3L, rs12780116 in CNNM2, rs1190736 in GPR101, rs11539157 in PJA1, and rs12616219 near TMEM182) replicated at a Bonferroni significance threshold (P < 4.5 × 10-3) with consistent direction of effect. A further 35 SNVs were associated with smoking behaviour traits in the discovery plus replication meta-analysis (up to 622,409 participants) including a rare SNV, rs150493199, in CCDC141 and two low-frequency SNVs in CEP350 and HDGFRP2. Functional follow-up implied that decreased expression of REV3L may lower the probability of smoking initiation. The novel loci will facilitate understanding the genetic aetiology of smoking behaviour and may lead to the identification of potential drug targets for smoking prevention and/or cessation. ; The authors would like to thank the many colleagues who contributed to collection and phenotypic characterisation of the clinical samples, as well as genotyping and analysis of the GWA data. Special mentions are as follows: CGSB participating cohorts: Some of the data utilised in this study were provided by the Understanding Society: The UK Household Longitudinal Study, which is led by the Institute for Social and Economic Research at the University of Essex and funded by the Economic and Social Research Council. The data were collected by NatCen and the genome wide scan data were analysed by the Wellcome Trust Sanger Institute. The Understanding Society DAC have an application system for genetics data and all use of the data should be approved by them. The application form is at: https://www.understandingsociety.ac.uk/about/health/data. The Airwave Health Monitoring Study is funded by the UK Home Office, (Grant number 780-TETRA) with additional support from the National Institute for Health Research Imperial College Health Care NHS Trust and Imperial College Biomedical Research Centre. We thank all participants in the Airwave Health Monitoring Study. This work used computing resources provided by the MRC- funded UK MEDical Bioinformatics partnership programme (UK MED-BIO) (MR/L01632X/1). Paul Elliott wishes to acknowledge the Medical Research Council and Public Health England (MR/L01341X/1) for the MRC-PHE Centre for Environment and Health; and the NIHR Health Protection Research Unit in Health Impact of Environmental Hazards (HPRU-2012-10141). Paul Elliott is supported by the UK Dementia Research Institute which receives its funding from UK DRI Ltd funded by the UK Medical Research Council, Alzheimer's Society and Alzheimer's Research UK. Paul Elliott is associate director of the Health Data Research UK London funded by a consortium led by the UK Medical Research Council. SHIP (Study of Health in Pomerania) and SHIP-TREND both represent population-based studies. SHIP is supported by the German Federal Ministry of Education and Research (Bundesministerium für Bildung und Forschung (BMBF); grants 01ZZ9603, 01ZZ0103, and 01ZZ0403) and the German Research Foundation (Deutsche Forschungsgemeinschaft (DFG); grant GR 1912/5-1). SHIP and SHIP-TREND are part of the Community Medicine Research net (CMR) of the Ernst-Moritz-Arndt University Greifswald (EMAU) which is funded by the BMBF as well as the Ministry for Education, Science and Culture and the Ministry of Labor, Equal Opportunities, and Social Affairs of the Federal State of Mecklenburg-West Pomerania. The CMR encompasses several research projects that share data from SHIP. SNP typing of SHIP and SHIP-TREND using the Illumina Infinium HumanExome BeadChip (version v1.0) was supported by the BMBF (grant 03Z1CN22). LifeLines authors thank Behrooz Alizadeh, Annemieke Boesjes, Marcel Bruinenberg, Noortje Festen, Ilja Nolte, Lude Franke, Mitra Valimohammadi for their help in creating the GWAS database, and Rob Bieringa, Joost Keers, René Oostergo, Rosalie Visser, Judith Vonk for their work related to data-collection and validation. The authors are grateful to the study participants, the staff from the LifeLines Cohort Study and Medical Biobank Northern Netherlands, and the participating general practitioners and pharmacists. LifeLines Scientific Protocol Preparation: Rudolf de Boer, Hans Hillege, Melanie van der Klauw, Gerjan Navis, Hans Ormel, Dirkje Postma, Judith Rosmalen, Joris Slaets, Ronald Stolk, Bruce Wolffenbuttel; LifeLines GWAS Working Group: Behrooz Alizadeh, Marike Boezen, Marcel Bruinenberg, Noortje Festen, Lude Franke, Pim van der Harst, Gerjan Navis, Dirkje Postma, Harold Snieder, Cisca Wijmenga, Bruce Wolffenbuttel. The authors wish to acknowledge the services of the LifeLines Cohort Study, the contributing research centres delivering data to LifeLines, and all the study participants. Niek Verweij was supported by NWO VENI (016.186.125). Fenland authors thank Fenland Study volunteers for their time and help, Fenland Study general Practitioners and practice staff for assistance with recruitment, and Fenland Study Investigators, Co-ordination team and the Epidemiology Field, Data and Laboratory teams for study design, sample/data collection and genotyping. We thank all ASCOT trial participants, physicians, nurses, and practices in the participating countries for their important contribution to the study. In particular we thank Clare Muckian and David Toomey for their help in DNA extraction, storage, and handling. We would also like to acknowledge the Barts and The London Genome Centre staff for genotyping the Exome Chip array. The BRIGHT study is extremely grateful to all the patients who participated in the study and the BRIGHT nursing team. We would also like to thank the Barts Genome Centre staff for their assistance with this project. Patricia B. Munroe, Mark J. Caulfield, and Helen R. Warren wish to acknowledge the NIHR Cardiovascular Biomedical Research Unit at Barts and The London, Queen Mary University of London, UK for support. Mark J. Caulfield are Senior National Institute for Health Research Investigators. EMBRACE Collaborating Centres are: Coordinating Centre, Cambridge: Daniel Barrowdale, Debra Frost, Jo Perkins. North of Scotland Regional Genetics Service, Aberdeen: Zosia Miedzybrodzka, Helen Gregory. Northern Ireland Regional Genetics Service, Belfast: Patrick Morrison, Lisa Jeffers. West Midlands Regional Clinical Genetics Service, Birmingham: Kai-ren Ong, Jonathan Hoffman. South West Regional Genetics Service, Bristol: Alan Donaldson, Margaret James. East Anglian Regional Genetics Service, Cambridge: Joan Paterson, Marc Tischkowitz, Sarah Downing, Amy Taylor. Medical Genetics Services for Wales, Cardiff: Alexandra Murray, Mark T. Rogers, Emma McCann. St James's Hospital, Dublin & National Centre for Medical Genetics, Dublin: M. John Kennedy, David Barton. South East of Scotland Regional Genetics Service, Edinburgh: Mary Porteous, Sarah Drummond. Peninsula Clinical Genetics Service, Exeter: Carole Brewer, Emma Kivuva, Anne Searle, Selina Goodman, Kathryn Hill. West of Scotland Regional Genetics Service, Glasgow: Rosemarie Davidson, Victoria Murday, Nicola Bradshaw, Lesley Snadden, Mark Longmuir, Catherine Watt, Sarah Gibson, Eshika Haque, Ed Tobias, Alexis Duncan. South East Thames Regional Genetics Service, Guy's Hospital London: Louise Izatt, Chris Jacobs, Caroline Langman. North West Thames Regional Genetics Service, Harrow: Huw Dorkins. Leicestershire Clinical Genetics Service, Leicester: Julian Barwell. Yorkshire Regional Genetics Service, Leeds: Julian Adlard, Gemma Serra-Feliu. Cheshire & Merseyside Clinical Genetics Service, Liverpool: Ian Ellis, Claire Foo. Manchester Regional Genetics Service, Manchester: D Gareth Evans, Fiona Lalloo, Jane Taylor. North East Thames Regional Genetics Service, NE Thames, London: Lucy Side, Alison Male, Cheryl Berlin. Nottingham Centre for Medical Genetics, Nottingham: Jacqueline Eason, Rebecca Collier. Northern Clinical Genetics Service, Newcastle: Alex Henderson, Oonagh Claber, Irene Jobson. Oxford Regional Genetics Service, Oxford: Lisa Walker, Diane McLeod, Dorothy Halliday, Sarah Durell, Barbara Stayner. The Institute of Cancer Research and Royal Marsden NHS Foundation Trust: Ros Eeles, Nazneen Rahman, Elizabeth Bancroft, Elizabeth Page, Audrey Ardern-Jones, Kelly Kohut, Jennifer Wiggins, Jenny Pope, Sibel Saya, Natalie Taylor, Zoe Kemp and Angela George. North Trent Clinical Genetics Service, Sheffield: Jackie Cook, Oliver Quarrell, Cathryn Bardsley. South West Thames Regional Genetics Service, London: Shirley Hodgson, Sheila Goff, Glen Brice, Lizzie Winchester, Charlotte Eddy, Vishakha Tripathi, Virginia Attard. Wessex Clinical Genetics Service, Princess Anne Hospital, Southampton: Diana Eccles, Anneke Lucassen, Gillian Crawford, Donna McBride, Sarah Smalley. Understanding Society Scientific Group is funded by the Economic and Social Research Council (ES/H029745/1) and the Wellcome Trust (WT098051). Paul D.P. Pharoah is funded by Cancer Research UK (C490/A16561). SHIP is funded by the German Federal Ministry of Education and Research (BMBF) and the German Research Foundation (DFG); see acknowledgements for details. F.W. Asselbergs is funded by the Netherlands Heart Foundation (2014T001) and supported by UCL Hospitals NIHR Biomedical Research Centre. The LifeLines Cohort Study, and generation and management of GWAS genotype data for the LifeLines Cohort Study is supported by the Netherlands Organization of Scientific Research NWO (grant 175.010.2007.006), the Economic Structure Enhancing Fund (FES) of the Dutch government, the Ministry of Economic Affairs, the Ministry of Education, Culture and Science, the Ministry for Health, Welfare and Sports, the Northern Netherlands Collaboration of Provinces (SNN), the Province of Groningen, University Medical Center Groningen, the University of Groningen, Dutch Kidney Foundation and Dutch Diabetes Research Foundation. Niek Verweij is supported by Horizon 2020, Marie Sklodowska-Curie (661395) and ICIN-NHI. Phenotype collection in the Lothian Birth Cohort 1921 was supported by the UK's Biotechnology and Biological Sciences Research Council (BBSRC), The Royal Society and The Chief Scientist Office of the Scottish Government. Phenotype collection in the Lothian Birth Cohort 1936 was supported by Age UK (The Disconnected Mind project). Genotyping was supported by Centre for Cognitive Ageing and Cognitive Epidemiology (Pilot Fund award), Age UK, and the Royal Society of Edinburgh. The work was undertaken by The University of Edinburgh Centre for Cognitive Ageing and Cognitive Epidemiology, part of the cross council Lifelong Health and Wellbeing Initiative (MR/K026992/1). Funding from the BBSRC and Medical Research Council (MRC) is gratefully acknowledged. Paul W. Franks is supported by Novo Nordisk, the Swedish Research Council, Påhlssons Foundation, Swedish Heart Lung Foundation (2020389), and Skåne Regional Health Authority. Nicholas J Wareham, Claudia Langenberg, Robert A Sacott, and Jian'an Luan are supported by the MRC (MC_U106179471 and MC_UU_12015/1). The BRIGHT study was supported by the Medical Research Council of Great Britain (Grant Number G9521010D); and by the British Heart Foundation (Grant Number PG/02/128). The BRIGHT study is extremely grateful to all the patients who participated in the study and the BRIGHT nursing team. The Exome Chip genotyping was funded by Wellcome Trust Strategic Awards (083948 and 085475). We would also like to thank the Barts Genome Centre staff for their assistance with this project. The ASCOT study and the collection of the ASCOT DNA repository was supported by Pfizer, New York, NY, USA, Servier Research Group, Paris, France; and by Leo Laboratories, Copenhagen, Denmark. Genotyping of the Exome Chip in ASCOT-SC and ASCOT-UK was funded by the National Institutes of Health Research (NIHR). Anna F. Dominiczak was supported by the British Heart Foundation (Grant Numbers RG/07/005/23633, SP/08/005/25115); and by the European Union Ingenious HyperCare Consortium: Integrated Genomics, Clinical Research, and Care in Hypertension (grant number LSHM-C7-2006-037093). Nilesh J. Samani is supported by the British Heart Foundation and is a Senior National Institute for Health Research Investigator. Panos Deloukas is supported by the British Heart Foundation (RG/14/5/30893), and NIHR, where his work forms part of the research themes contributing to the translational research portfolio of Barts Cardiovascular Biomedical Research Centre which is funded by the National Institute for Health Research (NIHR). The LOLIPOP study is supported by the National Institute for Health Research (NIHR) Comprehensive Biomedical Research Centre Imperial College Healthcare NHS Trust, the British Heart Foundation (SP/04/002), the Medical Research Council (G0601966, G0700931), the Wellcome Trust (084723/Z/08/Z, 090532 & 098381) the NIHR (RP-PG-0407-10371), the NIHR Official Development Assistance (ODA, award 16/136/68), the European Union FP7 (EpiMigrant, 279143) and H2020 programs (iHealth-T2D, 643774). We acknowledge support of the MRC-PHE Centre for Environment and Health, and the NIHR Health Protection Research Unit on Health Impact of Environmental Hazards. The work was carried out in part at the NIHR/Wellcome Trust Imperial Clinical Research Facility. The views expressed are those of the author(s) and not necessarily those of the Imperial College Healthcare NHS Trust, the NHS, the NIHR or the Department of Health. We thank the participants and research staff who made the study possible. JC is supported by the Singapore Ministry of Health's National Medical Research Council under its Singapore Translational Research Investigator (STaR) Award (NMRC/STaR/0028/2017). The research was supported by the National Institute for Health Research (NIHR) Exeter Clinical Research Facility and ERC grant 323195; SZ-245 50371-GLUCOSEGENES-FP7-IDEAS-ERC to T.M. Frayling. Hanieh Yaghootkar is funded by Diabetes UK RD Lawrence fellowship (grant:17/0005594) Anna Dominiczak was funded by a BHF Centre of Research Excellence Award (RE/13/5/30177) GSCAN participating cohorts: The Collaborative Study on the Genetics of Alcoholism (COGA), Principal Investigators: B. Porjesz, V. Hesselbrock, H. Edenberg, L. Bierut. The study includes eleven different centers: University of Connecticut (V. Hesselbrock); Indiana University (H.J. Edenberg, J. Nurnberger Jr., T. Foroud); University of Iowa (S. Kuperman, J. Kramer); SUNY Downstate (B. Porjesz); Washington University in St. Louis (L. Bierut, J. Rice, K. Bucholz, A. Agrawal); University of California at San Diego (M. Schuckit); Rutgers University (J. Tischfield, A. Brooks); Department of Biomedical and Health Informatics, The Children's Hospital of Philadelphia; Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia PA (L. Almasy), Virginia Commonwealth University (D. Dick), Icahn School of Medicine at Mount Sinai (A. Goate), and Howard University (R. Taylor). Other COGA collaborators include: L. Bauer (University of Connecticut); J. McClintick, L. Wetherill, X. Xuei, Y. Liu, D. Lai, S. O'Connor, M. Plawecki, S. Lourens (Indiana University); G. Chan (University of Iowa; University of Connecticut); J. Meyers, D. Chorlian, C. Kamarajan, A. Pandey, J. Zhang (SUNY Downstate); J.-C. Wang, M. Kapoor, S. Bertelsen (Icahn School of Medicine at Mount Sinai); A. Anokhin, V. McCutcheon, S. Saccone (Washington University); J. Salvatore, F. Aliev, B. Cho (Virginia Commonwealth University); and Mark Kos (University of Texas Rio Grande Valley). A. Parsian and M. Reilly are the NIAAA Staff Collaborators. COGA investigators continue to be inspired by their memories of Henri Begleiter and Theodore Reich, founding PI and Co-PI of COGA, and also owe a debt of gratitude to other past organizers of COGA, including Ting-Kai Li, P. Michael Conneally, Raymond Crowe, and Wendy Reich, for their critical contributions. COGA investigators are very grateful to Dr. Bruno Buecher without whom this project would not have existed. The authors also thank all those at the GECCO Coordinating Center for helping bring together the data and people that made this project possible. ASTERISK, a GECCO sub-study, also thanks all those who agreed to participate in this study, including the patients and the healthy control persons, as well as all the physicians, technicians and students. As part of the GECCO sub-studies, CPS-II authors thank the CPS-II participants and Study Management Group for their invaluable contributions to this research. The authors would also like to acknowledge the contribution to this study from central cancer registries supported through the Centers for Disease Control and Prevention National Program of Cancer Registries, and cancer registries supported by the National Cancer Institute Surveillance Epidemiology and End Results program. Another GECCO sub-study, HPFS and NHS investigators would like to acknowledge Patrice Soule and Hardeep Ranu of the Dana Farber Harvard Cancer Center High-Throughput Polymorphism Core who assisted in the genotyping for NHS, HPFS under the supervision of Dr. Immaculata Devivo and Dr. David Hunter, Qin (Carolyn) Guo and Lixue Zhu who assisted in programming for NHS and HPFS. HPFS and NHS investigators also thank the participants and staff of the Nurses' Health Study and the Health Professionals Follow-Up Study, for their valuable contributions as well as the following state cancer registries for their help: AL, AZ, AR, CA, CO, CT, DE, FL, GA, ID, IL, IN, IA, KY, LA, ME, MD, MA, MI, NE, NH, NJ, NY, NC, ND, OH, OK, OR, PA, RI, SC, TN, TX, VA, WA, WY. The authors assume full responsibility for analyses and interpretation of these data. PLCO, a substudy within GECCO, was supported by the Intramural Research Program of the Division of Cancer Epidemiology and Genetics, and additionally supported by contracts from the Division of Cancer Prevention, National Cancer Institute, NIH, DHHS. Additionally, a subset of control samples were genotyped as part of the Cancer Genetic Markers of Susceptibility (CGEMS) Prostate Cancer GWAS1, CGEMS pancreatic cancer scan (PanScan)2, 3, and the Lung Cancer and Smoking study4. The prostate and PanScan study datasets were accessed with appropriate approval through the dbGaP online resource (http://cgems.cancer.gov/data/) accession numbers phs000207.v1.p1 and phs000206.v3.p2, respectively, and the lung datasets were accessed from the dbGaP website (http://www.ncbi.nlm.nih.gov/gap) through accession number phs000093.v2.p2. For the lung study, the GENEVA Coordinating Center provided assistance with genotype cleaning and general study coordination, and the Johns Hopkins University Center for Inherited Disease Research conducted genotyping. The authors thank Drs. Christine Berg and Philip Prorok, Division of Cancer Prevention, National Cancer Institute, the Screening Center investigators and staff or the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial, Mr. Tom Riley and staff, Information Management Services, Inc., Ms. Barbara O'Brien and staff, Westat, Inc., and Drs. Bill Kopp and staff, SAIC-Frederick. Most importantly, we acknowledge the study participants for their contributions to making this study possible. We also thank all participants and staff of the André and France Desmarais Montreal Heart Institute's (MHI) Biobank. The genotyping of the MHI Biobank was done at the MHI Pharmacogenomic Centre and funded by the MHI Foundation. HRS is supported by the National Institute on Aging (NIA U01AG009740). The genotyping was funded separately by the National Institute on Aging (RC2 AG036495, RC4 AG039029). Our genotyping was conducted by the NIH Center for Inherited Disease Research (CIDR) at Johns Hopkins University. Genotyping quality control and final preparation of the data were performed by the University of Michigan School of Public Health. CHDExome+ participating cohorts: BRAVE: The BRAVE study genetic epidemiology working group is a collaboration between the Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, UK, the Centre for Control of Chronic Diseases, icddr,b, Dhaka, Bangladesh and the National Institute of Cardiovascular Diseases, Dhaka, Bangladesh. CCHS, CIHDS, and CGPS collaborators thank participants and staff of the Copenhagen City Heart Study, Copenhagen Ischemic Heart Disease Study, and the Copenhagen General Population Study for their important contributions. EPIC-CVD: CHD case ascertainment and validation, genotyping, and clinical chemistry assays in EPIC-CVD were principally supported by grants awarded to the University of Cambridge from the EU Framework Programme 7 (HEALTH-F2-2012-279233), the UK Medical Research Council (G0800270) and British Heart Foundation (SP/09/002), and the European Research Council (268834). We thank all EPIC participants and staff for their contribution to the study, the laboratory teams at the Medical Research Council Epidemiology Unit for sample management and Cambridge Genomic Services for genotyping, Sarah Spackman for data management, and the team at the EPIC-CVD Coordinating Centre for study coordination and administration. MORGAM: The work by MORGAM collaborators has been sustained by the MORGAM Project's recent funding: European Union FP 7 projects ENGAGE (HEALTH-F4-2007-201413), CHANCES (HEALTH-F3-2010-242244) and BiomarCaRE (278913). This has supported central coordination, workshops and part of the activities of the The MORGAM Data Centre, at THL in Helsinki, Finland. MORGAM Participating Centres are funded by regional and national governments, research councils, charities, and other local sources. PROSPER: collaborators have received funding from the European Union's Seventh Framework Programme (FP7/2007-2013) under grant agreement n° HEALTH-F2-2009-223004 PROMIS: The PROMIS collaborators are are thankful to all the study participants in Pakistan. Recruitment in PROMIS was funded through grants available to investigators at the Center for Non-Communicable Diseases, Pakistan (Danish Saleheen and Philippe Frossard) and investigators at the University of Cambridge, UK (Danish Saleheen and John Danesh). Field-work, genotyping, and standard clinical chemistry assays in PROMIS were principally supported by grants awarded to the University of Cambridge from the British Heart Foundation, UK Medical Research Council, Wellcome Trust, EU Framework 6-funded Bloodomics Integrated Project, Pfizer. We would like to acknowledge the contributions made by the following individuals who were involved in the field work and other administrative aspects of the study: Mohammad Zeeshan Ozair, Usman Ahmed, Abdul Hakeem, Hamza Khalid, Kamran Shahid, Fahad Shuja, Ali Kazmi, Mustafa Qadir Hameed, Naeem Khan, Sadiq Khan, Ayaz Ali, Madad Ali, Saeed Ahmed, Muhammad Waqar Khan, Muhammad Razaq Khan, Abdul Ghafoor, Mir Alam, Riazuddin, Muhammad Irshad Javed, Abdul Ghaffar, Tanveer Baig Mirza, Muhammad Shahid, Jabir Furqan, Muhammad Iqbal Abbasi, Tanveer Abbas, Rana Zulfiqar, Muhammad Wajid, Irfan Ali, Muhammad Ikhlaq, Danish Sheikh and Muhammad Imran. INTERVAL: Participants in the INTERVAL randomised controlled trial were recruited with the active collaboration of NHS Blood and Transplant England (www.nhsbt.nhs.uk), which has supported field work and other elements of the trial. DNA extraction and genotyping was funded by the National Institute of Health Research (NIHR), the NIHR BioResource (http://bioresource.nihr.ac.uk/) and the NIHR Cambridge Biomedical Research Centre (www.cambridge-brc.org.uk). The academic coordinating centre for INTERVAL was supported by core funding from: NIHR Blood and Transplant Research Unit in Donor Health and Genomics, UK Medical Research Council (MR/L003120/1), British Heart Foundation (RG/13/13/30194), and NIHR Research Cambridge Biomedical Research Centre. A complete list of the investigators and contributors to the INTERVAL trial is provided in reference.
The authors have read the journal's policy and the authors of this manuscript have the following competing interests: Bruce M. Psaty (BMP) serves on the DSMB of a clinical trial funded by Zoll Lifecor and on the Steering Committee of the Yale Open Data Access Project funded by Johnson & Johnson. Barbara V. Howard (BVH) has a contract from National Heart, Lung, and Blood Institute (NHLBI). Brenda W.J.H. Penninx (BWJHP) has received research funding (non-related to the work reported here) from Jansen Research and Boehringer Ingelheim. Mike A. Nalls (MAN) is supported by a consulting contract between Data Tecnica International LLC and the National Institute on Aging (NIA), National Institutes of Health (NIH), Bethesda, MD, USA. MAN also consults for Illumina Inc., the Michael J. Fox Foundation, and the University of California Healthcare. MAN also has commercial affiliation with Data Tecnica International, Glen Echo, MD, USA. Mark J. Caulfield (MJC) has commercial affiliation and is Chief Scientist for Genomics England, a UK government company. OHF is supported by grants from Metagenics (on women's health and epigenetics) and from Nestlé (on child health). Peter S. Sever (PSS) is financial supported from several pharmaceutical companies which manufacture either blood pressure lowering or lipid lowering agents, or both, and consultancy fees. Paul W. Franks (PWF) has been a paid consultant in the design of a personalized nutrition trial (PREDICT) as part of a private-public partnership at Kings College London, UK, and has received research support from several pharmaceutical companies as part of European Union Innovative Medicines Initiative (IMI) projects. Terho Lehtimäki (TL) is employed by Fimlab Ltd. Ozren Polašek (OP) is employed by Gen‐info Ltd. There are no patents, products in development, or marked products to declare. All the other authors have declared no competing interests exist. This does not alter the authors' adherence to PLOS ONE policies on sharing data and materials. ; International audience ; Heavy alcohol consumption is an established risk factor for hypertension; the mechanism by which alcohol consumption impact blood pressure (BP) regulation remains unknown. We hypothesized that a genome-wide association study accounting for gene-alcohol consumption interaction for BP might identify additional BP loci and contribute to the understanding of alcohol-related BP regulation. We conducted a large two-stage investigation incorporating joint testing of main genetic effects and single nucleotide variant (SNV)-alcohol consumption interactions. In Stage 1, genome-wide discovery meta-analyses in ≈131K individuals across several ancestry groups yielded 3,514 SNVs (245 loci) with suggestive evidence of association (P < 1.0 x 10-5). In Stage 2, these SNVs were tested for independent external replication in ≈440K individuals across multiple ancestries. We identified and replicated (at Bonferroni correction threshold) five novel BP loci (380 SNVs in 21 genes) and 49 previously reported BP loci (2,159 SNVs in 109 genes) in European ancestry, and in multi-ancestry meta-analyses (P < 5.0 x 10-8). For African ancestry samples, we detected 18 potentially novel BP loci (P < 5.0 x 10-8) in Stage 1 that warrant further replication. Additionally, correlated meta-analysis identified eight novel BP loci (11 genes). Several genes in these loci (e.g., PINX1, GATA4, BLK, FTO and GABBR2) have been previously reported to be associated with alcohol consumption. These findings provide insights into the role of alcohol consumption in the genetic architecture of hypertension.
The authors have read the journal's policy and the authors of this manuscript have the following competing interests: Bruce M. Psaty (BMP) serves on the DSMB of a clinical trial funded by Zoll Lifecor and on the Steering Committee of the Yale Open Data Access Project funded by Johnson & Johnson. Barbara V. Howard (BVH) has a contract from National Heart, Lung, and Blood Institute (NHLBI). Brenda W.J.H. Penninx (BWJHP) has received research funding (non-related to the work reported here) from Jansen Research and Boehringer Ingelheim. Mike A. Nalls (MAN) is supported by a consulting contract between Data Tecnica International LLC and the National Institute on Aging (NIA), National Institutes of Health (NIH), Bethesda, MD, USA. MAN also consults for Illumina Inc., the Michael J. Fox Foundation, and the University of California Healthcare. MAN also has commercial affiliation with Data Tecnica International, Glen Echo, MD, USA. Mark J. Caulfield (MJC) has commercial affiliation and is Chief Scientist for Genomics England, a UK government company. OHF is supported by grants from Metagenics (on women's health and epigenetics) and from Nestlé (on child health). Peter S. Sever (PSS) is financial supported from several pharmaceutical companies which manufacture either blood pressure lowering or lipid lowering agents, or both, and consultancy fees. Paul W. Franks (PWF) has been a paid consultant in the design of a personalized nutrition trial (PREDICT) as part of a private-public partnership at Kings College London, UK, and has received research support from several pharmaceutical companies as part of European Union Innovative Medicines Initiative (IMI) projects. Terho Lehtimäki (TL) is employed by Fimlab Ltd. Ozren Polašek (OP) is employed by Gen‐info Ltd. There are no patents, products in development, or marked products to declare. All the other authors have declared no competing interests exist. This does not alter the authors' adherence to PLOS ONE policies on sharing data and materials. ; International audience ; Heavy alcohol consumption is an established risk factor for hypertension; the mechanism by which alcohol consumption impact blood pressure (BP) regulation remains unknown. We hypothesized that a genome-wide association study accounting for gene-alcohol consumption interaction for BP might identify additional BP loci and contribute to the understanding of alcohol-related BP regulation. We conducted a large two-stage investigation incorporating joint testing of main genetic effects and single nucleotide variant (SNV)-alcohol consumption interactions. In Stage 1, genome-wide discovery meta-analyses in ≈131K individuals across several ancestry groups yielded 3,514 SNVs (245 loci) with suggestive evidence of association (P < 1.0 x 10-5). In Stage 2, these SNVs were tested for independent external replication in ≈440K individuals across multiple ancestries. We identified and replicated (at Bonferroni correction threshold) five novel BP loci (380 SNVs in 21 genes) and 49 previously reported BP loci (2,159 SNVs in 109 genes) in European ancestry, and in multi-ancestry meta-analyses (P < 5.0 x 10-8). For African ancestry samples, we detected 18 potentially novel BP loci (P < 5.0 x 10-8) in Stage 1 that warrant further replication. Additionally, correlated meta-analysis identified eight novel BP loci (11 genes). Several genes in these loci (e.g., PINX1, GATA4, BLK, FTO and GABBR2) have been previously reported to be associated with alcohol consumption. These findings provide insights into the role of alcohol consumption in the genetic architecture of hypertension.
The authors have read the journal's policy and the authors of this manuscript have the following competing interests: Bruce M. Psaty (BMP) serves on the DSMB of a clinical trial funded by Zoll Lifecor and on the Steering Committee of the Yale Open Data Access Project funded by Johnson & Johnson. Barbara V. Howard (BVH) has a contract from National Heart, Lung, and Blood Institute (NHLBI). Brenda W.J.H. Penninx (BWJHP) has received research funding (non-related to the work reported here) from Jansen Research and Boehringer Ingelheim. Mike A. Nalls (MAN) is supported by a consulting contract between Data Tecnica International LLC and the National Institute on Aging (NIA), National Institutes of Health (NIH), Bethesda, MD, USA. MAN also consults for Illumina Inc., the Michael J. Fox Foundation, and the University of California Healthcare. MAN also has commercial affiliation with Data Tecnica International, Glen Echo, MD, USA. Mark J. Caulfield (MJC) has commercial affiliation and is Chief Scientist for Genomics England, a UK government company. OHF is supported by grants from Metagenics (on women's health and epigenetics) and from Nestlé (on child health). Peter S. Sever (PSS) is financial supported from several pharmaceutical companies which manufacture either blood pressure lowering or lipid lowering agents, or both, and consultancy fees. Paul W. Franks (PWF) has been a paid consultant in the design of a personalized nutrition trial (PREDICT) as part of a private-public partnership at Kings College London, UK, and has received research support from several pharmaceutical companies as part of European Union Innovative Medicines Initiative (IMI) projects. Terho Lehtimäki (TL) is employed by Fimlab Ltd. Ozren Polašek (OP) is employed by Gen‐info Ltd. There are no patents, products in development, or marked products to declare. All the other authors have declared no competing interests exist. This does not alter the authors' adherence to PLOS ONE policies on sharing data and materials. ; International audience ; Heavy alcohol consumption is an established risk factor for hypertension; the mechanism by which alcohol consumption impact blood pressure (BP) regulation remains unknown. We hypothesized that a genome-wide association study accounting for gene-alcohol consumption interaction for BP might identify additional BP loci and contribute to the understanding of alcohol-related BP regulation. We conducted a large two-stage investigation incorporating joint testing of main genetic effects and single nucleotide variant (SNV)-alcohol consumption interactions. In Stage 1, genome-wide discovery meta-analyses in ≈131K individuals across several ancestry groups yielded 3,514 SNVs (245 loci) with suggestive evidence of association (P < 1.0 x 10-5). In Stage 2, these SNVs were tested for independent external replication in ≈440K individuals across multiple ancestries. We identified and replicated (at Bonferroni correction threshold) five novel BP loci (380 SNVs in 21 genes) and 49 previously reported BP loci (2,159 SNVs in 109 genes) in European ancestry, and in multi-ancestry meta-analyses (P < 5.0 x 10-8). For African ancestry samples, we detected 18 potentially novel BP loci (P < 5.0 x 10-8) in Stage 1 that warrant further replication. Additionally, correlated meta-analysis identified eight novel BP loci (11 genes). Several genes in these loci (e.g., PINX1, GATA4, BLK, FTO and GABBR2) have been previously reported to be associated with alcohol consumption. These findings provide insights into the role of alcohol consumption in the genetic architecture of hypertension.
Publisher's version (útgefin grein). ; Heavy alcohol consumption is an established risk factor for hypertension; the mechanism by which alcohol consumption impact blood pressure (BP) regulation remains unknown. We hypothesized that a genome-wide association study accounting for gene-alcohol consumption interaction for BP might identify additional BP loci and contribute to the understanding of alcohol-related BP regulation. We conducted a large two-stage investigation incorporating joint testing of main genetic effects and single nucleotide variant (SNV)-alcohol consumption interactions. In Stage 1, genome-wide discovery meta-analyses in ≈131K individuals across several ancestry groups yielded 3, 514 SNVs (245 loci) with suggestive evidence of association (P < 1.0 × 10-5). In Stage 2, these SNVs were tested for independent external replication in ≈440K individuals across multiple ancestries. We identified and replicated (at Bonferroni correction threshold) five novel BP loci (380 SNVs in 21 genes) and 49 previously reported BP loci (2, 159 SNVs in 109 genes) in European ancestry, and in multi-ancestry meta-analyses (P < 5.0 × 10-8). For African ancestry samples, we detected 18 potentially novel BP loci (P < 5.0 × 10-8) in Stage 1 that warrant further replication. Additionally, correlated meta-analysis identified eight novel BP loci (11 genes). Several genes in these loci (e.g., PINX1, GATA4, BLK, FTO and GABBR2) have been previously reported to be associated with alcohol consumption. These findings provide insights into the role of alcohol consumption in the genetic architecture of hypertension. ; The following authors declare commercial private and/or governmental affiliations: Bruce M. Psaty (BMP) serves on the DSMB of a clinical trial funded by Zoll Lifecor and on the Steering Committee of the Yale Open Data Access Project funded by Johnson & Johnson. Barbara V. Howard (BVH) has a contract from National Heart, Lung, and Blood Institute (NHLBI). Brenda W.J.H. Penninx (BWJHP) has received research funding (non-related to the work reported here) from Jansen Research and Boehringer Ingelheim. Mike A. Nalls (MAN) is supported by a consulting contract between Data Tecnica International LLC and the National Institute on Aging (NIA), National Institutes of Health (NIH), Bethesda, MD, USA. MAN also consults for Illumina Inc., the Michael J. Fox Foundation, and the University of California Healthcare. MAN also has commercial affiliation with Data Tecnica International, Glen Echo, MD, USA. Mark J. Caulfield (MJC) has commercial affiliation and is Chief Scientist for Genomics England, a UK government company. Oscar H Franco (OHF) is supported by grants from Metagenics (on women's health and epigenetics) and from Nestlé (on child health). Peter S. Sever (PSS) is financial supported from several pharmaceutical companies which manufacture either blood pressure lowering or lipid lowering agents, or both, and consultancy fees. Paul W. Franks (PWF) has been a paid consultant in the design of a personalized nutrition trial (PREDICT) as part of a private-public partnership at Kings College London, UK, and has received research support from several pharmaceutical companies as part of European Union Innovative Medicines Initiative (IMI) projects. Fimlab LTD provided support in the form of salaries for author Terho Lehtimäki (TL) but did not have any additional role in the study design to publish, or preparation of the manuscript. Gen‐info Ltd provided support in the form of salaries for author Ozren Polašek (OP) but did not have any additional role in the study design to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the 'author contributions' section. There are no patents, products in development, or marked products to declare. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. ; Peer Reviewed