Variation in the SERPINA6/SERPINA1 locus alters morning plasma cortisol, hepatic corticosteroid binding globulin expression, gene expression in peripheral tissues, and risk of cardiovascular disease

Andrew A. Crawford, Sean Bankier, Elisabeth Altmaier, Catriona L.K. Barnes, David W. Clark, Raili Ermel, Nele Friedrich, Pim van der Harst, Peter K. Joshi, Ville Karhunen, Jari Lahti, Anubha Mahajan, Massimo Mangino, Maria Nethander, Alexander Neumann, Maik Pietzner, Katyayani Sukhavasi, Carol A. Wang, Stephan J.L. Bakker, Johan L.M. BjorkegrenHarry Campbell, Johan Eriksson, Christian Gieger, Caroline Hayward, Marjo Riitta Jarvelin, Stela McLachlan, Andrew P. Morris, Claes Ohlsson, Craig E. Pennell, Jackie Price, Igor Rudan, Arno Ruusalepp, Tim Spector, Henning Tiemeier, Henry Völzke, James F. Wilson, Tom Michoel, Nicolas J. Timpson, George Davey Smith, Brian R. Walker*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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The stress hormone cortisol modulates fuel metabolism, cardiovascular homoeostasis, mood, inflammation and cognition. The CORtisol NETwork (CORNET) consortium previously identified a single locus associated with morning plasma cortisol. Identifying additional genetic variants that explain more of the variance in cortisol could provide new insights into cortisol biology and provide statistical power to test the causative role of cortisol in common diseases. The CORNET consortium extended its genome-wide association meta-analysis for morning plasma cortisol from 12,597 to 25,314 subjects and from ~2.2 M to ~7 M SNPs, in 17 population-based cohorts of European ancestries. We confirmed the genetic association with SERPINA6/SERPINA1. This locus contains genes encoding corticosteroid binding globulin (CBG) and α1-antitrypsin. Expression quantitative trait loci (eQTL) analyses undertaken in the STARNET cohort of 600 individuals showed that specific genetic variants within the SERPINA6/SERPINA1 locus influence expression of SERPINA6 rather than SERPINA1 in the liver. Moreover, trans-eQTL analysis demonstrated effects on adipose tissue gene expression, suggesting that variations in CBG levels have an effect on delivery of cortisol to peripheral tissues. Two-sample Mendelian randomisation analyses provided evidence that each genetically-determined standard deviation (SD) increase in morning plasma cortisol was associated with increased odds of chronic ischaemic heart disease (0.32, 95% CI 0.06–0.59) and myocardial infarction (0.21, 95% CI 0.00–0.43) in UK Biobank and similarly in CARDIoGRAMplusC4D. These findings reveal a causative pathway for CBG in determining cortisol action in peripheral tissues and thereby contributing to the aetiology of cardiovascular disease.

Original languageEnglish
Pages (from-to)625-636
Number of pages12
JournalJournal of Human Genetics
Issue number6
Early online date20 Jan 2021
Publication statusPublished - Jun 2021

Bibliographical note

Funding Information:
Acknowledgements CORNET consortium: CORNET has been supported by grants from the Chief Scientist Office of the Scottish Government, the British Heart Foundation and Wellcome Trust. ALSPAC: Ethical approval for the study was obtained from the ALSPAC Ethics and Law Committee and the Local Research Ethics Committees. Consent for biological samples has been collected in accordance with the Human Tissue Act (2004). Informed consent for the use of data collected via questionnaires and clinics was obtained from participants following the recommendations of the ALSPAC Ethics and Law Committee at the time. We are extremely grateful to all the families who took part in this study, the midwives for their help in recruiting them, and the whole ALSPAC team, which includes interviewers, computer and laboratory technicians, clerical workers, research scientists, volunteers, managers, receptionists and nurses. Croatia Vis, Korcula, Split: The CROATIA_Vis,CROATIA_Korcula and CROATIA_Split studies were funded by grants from the Medical Research Council (UK), European Commission Framework 6 project EURO-SPAN (Contract No. LSHG-CT-2006-018947) and Republic of Croatia Ministry of Science, Education and Sports research grants. (108-1080315-0302). We would like to acknowledge the staff of several institutions in Croatia that supported the field work, including but not limited to The University of Split and Zagreb Medical Schools, Institute for Anthropological Research in Zagreb and Croatian Institute for Public Health. CH is supported by an MRC University Unit Programme Grant MC_UU_00007/10 (QTL in Health and Disease. ET2DS: The sponsor for the ET2DS was the University of Edinburgh. The study was funded by the Medical Research Council (UK) (Pro-jectGrant G0500877), the Chief Scientist Office of the Scottish Executive (Programme Support Grant CZQ/1/38), Pfizer plc. and DiabetesUK (Clinical Research Fellowship 10/0003985). The funders had no other role in the design, analysis or writing of this paper. HBCS: We thank all study participants as well as everybody involved in the Helsinki Birth Cohort Study. Helsinki Birth Cohort Study has been supported by grants from the Academy of Finland, the Finnish Diabetes Research Society, Folkhälsan Research Foundation, Novo Nordisk Foundation, Finska Läkaresällskapet, Juho Vainio Foundation, Signe and Ane Gyllenberg Foundation, University of Helsinki, Ministry of Education, Ahokas Foundation, Emil Aalto-nen Foundation. KORA: The KORA study was initiated and financed by the Helmholtz Zentrum München—German Research Centre for Environmental Health, which is funded by the German Federal Ministry of Education and Research (BMBF) and by the State of Bavaria. Furthermore, KORA research was supported within the Munich Centre of Health Sciences (MC-Health), Ludwig-Maximilians-Universität, as part of LMUinnovativ. The KORA-Study Group consists of A. Peters (speaker), J. Heinrich, R. Holle, R. Leidl, C. Meisinger, K. Strauch and their co-workers, who are responsible for the design and conduct of the KORA studies. We gratefully acknowledge the contribution of all members of field staff conducting the KORA study. Finally, we are grateful to all study participants of KORA for their invaluable contributions to this study. All KORA participants have given written informed consent and the study was approved by the Ethics Committee of the Bavarian Medical Association. MrOS Sweden: MrOS in Sweden is supported by the Swedish Research Council, the Swedish Foundation for Strategic Research, the ALF/LUA research grant in Gothenburg, the Lundberg Foundation, the Knut and Alice Wallenberg Foundation, the Torsten Soderberg Foundation, and the Novo Nordisk Foundation. North Finland Birth Cohort (1966): NFBC1966 Acknowledgements: We thank all cohort members and researchers who participated in the 31 years study. We also wish to acknowledge the work of the NFBC project centre. Funding: NFBC1966 received financial support from University of Oulu Grant no. 65354, Oulu University Hospital Grant no. 2/97, 8/97, Ministry of Health and Social Affairs Grant no. 23/251/97, 160/97, 190/97, National Institute for Health and Welfare, Helsinki Grant no. 54121, Regional Institute of Occupational Health, Oulu, Finland Grant no. 50621, 54231. ORCADES: The Orkney Complex Disease Study (ORCADES) was supported by the Chief Scientist Office of the Scottish Government (CZB/4/276, CZB/4/710), a Royal Society URF to JFW, the MRC Human Genetics Unit quinquennial programme “QTL in Health and Disease”, Arthritis Research UK and the European Union framework programme 6 EUROSPAN project (contract no. LSHG-CT-2006-018947). DNA extractions were performed at the Edinburgh Clinical Research Facility, University of Edinburgh. We would like to acknowledge the invaluable contributions of the research nurses in Orkney, the administrative team in Edinburgh and the people of Orkney. PIVUS: Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) was supported by Wellcome Trust Grants (WT098017, WT064890, WT090532), Uppsala University, Uppsala University Hospital, the Swedish Research Council and the Swedish Heart-Lung Foundation. PREVEND: The PREVEND study programme has been made possible by an initial grant of the Dutch Kidney Foundation. Its continuation has been made possible by grants from the University Medical Centre Groningen, the Dutch Kidney Foundation and the Dutch Heart Foundation. The Raine Study: The Raine Study was supported by the National Health and Medical Research Council of Australia [grant numbers 572613, 403981 and 1059711] and the Canadian Institutes of Health Research [grant number MOP-82893]. The authors are grateful to the Raine Study participants and their families, and to the Raine Study team for cohort coordination and data collection. The authors gratefully acknowledge the NHMRC for their long term funding to the study over the last 30 years and also the following institutes for providing funding for Core Management of the Raine Study: The University of Western Australia (UWA), Curtin University, Women and Infants Research Foundation, Telethon Kids Institute, Edith Cowan University, Murdoch University, The University of Notre Dame Australia and The Raine Medical Research Foundation. This work was supported by resources provided by the Pawsey Supercomputing Centre with funding from the Australian Government and Government of Western Australia. Rotterdam: The Rotterdam Study is supported by the Erasmus MC University Medical Centre and Erasmus University Rotterdam; The Netherlands Organisation for Scientific Research (NWO); The Netherlands Organisation for Health Research and Development (ZonMw); the Research Institute for Diseases in the Elderly (RIDE); The Netherlands Genomics Initiative (NGI); the Ministry of Education, Culture and Science; the Ministry of Health, Welfare and Sports; the European Commission (DG XII); and the Municipality of Rotterdam. The contribution of inhabitants, general practitioners and pharmacists of the Ommoord district to the Rotterdam Study is gratefully acknowledged. AN and HT were supported by a grant of the Dutch Ministry of Education, Culture, and Science and the Netherlands Organisation for Scientific Research (NWO grant No. 024.001.003, Consortium on Individual Development). The work of HT is further supported by a NWO-VICI grant (NWO-ZonMW: 016.VICI.170.200). We would like to thank Anis Abuseiris, Karol Estrada, Tobias A. Knoch and Rob de Graaf as well as their institutions, the Biophysical Genomics, Erasmus MC Rotterdam, The Netherlands, and especially the national German MediGRID and Services@MediGRID part of the German D-Grid, both funded by the German Bundesministerium fuer Forschung und Technology under grants #01 AK 803 A-H and # 01 IG 07015 G for access to their grid resources. Scientific computing at Mount Sinai: This work was supported in part through the computational resources and staff expertise provided by Scientific Computing at the Icahn School of Medicine at Mount Sinai. Research reported in this paper was supported by the Office of Research Infrastructure of the National Institutes of Health under award numbers S10OD018522 and S10OD026880. SHIP: SHIP is part of the Community Medicine Research Net of the University Medicine Greifswald, which is supported by the German Federal State of Mecklenburg-West Pomer-ania. TwinsUK: TwinsUK is funded by the Wellcome Trust, Medical Research Council, European Union, the National Institute for Health Research (NIHR)-funded BioResource, Clinical Research Facility and Biomedical Research Centre based at Guy’s and St Thomas’ NHS Foundation Trust in partnership with King’s College London. VIKING: The Viking Health Study—Shetland (VIKING) was supported by the MRC Human Genetics Unit quinquennial programme grant “QTL in Health and Disease”. DNA extractions and genotyping were performed at the Edinburgh Clinical Research Facility, University of Edinburgh. We would like to acknowledge the invaluable contributions of the research nurses in Shetland, the administrative team in Edinburgh and the people of Shetland.

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