Journal
JOURNAL OF HUMAN GENETICS
Volume 66, Issue 6, Pages 625-636Publisher
SPRINGERNATURE
DOI: 10.1038/s10038-020-00895-6
Keywords
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Categories
Funding
- Chief Scientist Office of the Scottish Government
- British Heart Foundation
- Wellcome Trust
- Medical Research Council (UK) [G0500877]
- European Commission [LSHG-CT-2006-018947]
- Republic of Croatia Ministry of Science, Education and Sports research grants [108-1080315-0302]
- MRC University Unit Programme Grant [MC_UU_00007/10]
- Chief Scientist Office of the Scottish Executive [CZQ/1/38]
- Pfizer plc.
- DiabetesUK [10/0003985]
- Academy of Finland
- Finnish Diabetes Research Society
- Folkhalsan Research Foundation
- Novo Nordisk Foundation
- Finska Lakaresallskapet
- Juho Vainio Foundation
- Signe and Ane Gyllenberg Foundation
- University of Helsinki
- Ministry of Education
- Ahokas Foundation
- Emil Aaltonen Foundation
- Helmholtz Zentrum Munchen-German Research Centre for Environmental Health - German Federal Ministry of Education and Research (BMBF)
- State of Bavaria
- Munich Centre of Health Sciences (MC-Health)
- Ludwig-Maximilians-Universitat, as part of LMUinnovativ
- Swedish Research Council
- Swedish Foundation for Strategic Research
- ALF/LUA research grant in Gothenburg
- Lundberg Foundation
- Knut and Alice Wallenberg Foundation
- Torsten Soderberg Foundation
- University of Oulu Grant [65354]
- Oulu University Hospital Grant [2/97, 8/97]
- Ministry of Health and Social Affairs Grant [23/251/97, 160/97, 190/97]
- National Institute for Health and Welfare, Helsinki Grant [54121]
- Regional Institute of Occupational Health, Oulu, Finland Grant [50621, 54231]
- Chief Scientist Office of the Scottish Government [CZB/4/276, CZB/4/710]
- Royal Society URF
- MRC Human Genetics Unit quinquennial programme QTL in Health and Disease
- Arthritis Research UK
- European Union [LSHG-CT-2006-018947]
- Wellcome Trust [WT098017, WT064890, WT090532]
- Uppsala University
- Uppsala University Hospital
- Swedish Heart-Lung Foundation
- Dutch Kidney Foundation
- University Medical Centre Groningen
- Dutch Heart Foundation
- National Health and Medical Research Council of Australia [572613, 403981, 1059711]
- Canadian Institutes of Health Research [MOP-82893]
- NHMRC
- Australian Government
- Government of Western Australia
- Erasmus MC University Medical Centre
- Erasmus University Rotterdam
- Netherlands Organisation for Scientific Research (NWO)
- Netherlands Organisation for Health Research and Development (ZonMw)
- Research Institute for Diseases in the Elderly (RIDE)
- Netherlands Genomics Initiative (NGI)
- Ministry of Education, Culture and Science
- Ministry of Health, Welfare and Sports
- European Commission (DG XII)
- Municipality of Rotterdam
- Dutch Ministry of Education, Culture, and Science
- Netherlands Organisation for Scientific Research (NWO grant) [024.001.003]
- NWO-VICI grant [NWO-ZonMW: 016.VICI.170.200]
- German Bundesministerium fuer Forschung und Technology [01 AK 803 A-H, 01 IG 07015 G]
- Office of Research Infrastructure of the National Institutes of Health [S10OD018522, S10OD026880]
- German Federal State of Mecklenburg-West Pomerania
- Medical Research Council
- European Union
- National Institute for Health Research (NIHR)
- Clinical Research Facility and Biomedical Research Centre based at Guy's and St Thomas' NHS Foundation Trust
- King's College London
- MRC Human Genetics Unit quinquennial programme grant QTL in Health and Disease
- MRC [1938124, MC_UU_00007/10] Funding Source: UKRI
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Cortisol plays a role in metabolism, cardiovascular health, mood, inflammation, and cognition. Genetic variants in the SERPINA6/SERPINA1 locus are associated with morning plasma cortisol levels and influence the expression of corticosteroid binding globulin (CBG) and alpha 1-antitrypsin. Genetically-determined increases in morning plasma cortisol are linked to higher odds of chronic ischaemic heart disease and myocardial infarction.
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 similar to 2.2 M to similar 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 alpha 1-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.
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