Please use this identifier to cite or link to this item: https://doi.org/10.1038/s10038-020-00895-6
Title: 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
Authors: Crawford, Andrew A.
Bankier, Sean
Altmaier, Elisabeth
Barnes, Catriona L. K.
Clark, David W.
Ermel, Raili
Friedrich, Nele
Van Der Harst, Pim
Joshi, Peter K.
Karhunen, Ville
Lahti, Jari
Mahajan, Anubha
Mangino, Massimo
Nethander, Maria
Neumann, Alexander
Pietzner, Maik
Sukhavasi, Katyayani
Wang, Carol A.
Bakker, Stephan J. L.
Bjorkegren, Johan L. M.
Campbell, Harry
Eriksson, Johan 
Gieger, Christian
Hayward, Caroline
Jarvelin, Marjo-Riitta
Mclachlan, Stela
Morris, Andrew P.
Ohlsson, Claes
Pennell, Craig E.
Price, Jackie
Rudan, Igor
Ruusalepp, Arno
Spector, Tim
Tiemeier, Henning
Völzke, H.
Wilson, James F.
Michoel, Tom
Timpson, Nicolas J.
Smith, George Davey
Walker, Brian R.
Mellström, D.
on behalf of the CORtisol NETwork (CORNET) consortium.
Issue Date: 20-Jan-2021
Publisher: Springer Nature
Citation: Crawford, Andrew A., Bankier, Sean, Altmaier, Elisabeth, Barnes, Catriona L. K., Clark, David W., Ermel, Raili, Friedrich, Nele, Van Der Harst, Pim, Joshi, Peter K., Karhunen, Ville, Lahti, Jari, Mahajan, Anubha, Mangino, Massimo, Nethander, Maria, Neumann, Alexander, Pietzner, Maik, Sukhavasi, Katyayani, Wang, Carol A., Bakker, Stephan J. L., Bjorkegren, Johan L. M., Campbell, Harry, Eriksson, Johan, Gieger, Christian, Hayward, Caroline, Jarvelin, Marjo-Riitta, Mclachlan, Stela, Morris, Andrew P., Ohlsson, Claes, Pennell, Craig E., Price, Jackie, Rudan, Igor, Ruusalepp, Arno, Spector, Tim, Tiemeier, Henning, Völzke, H., Wilson, James F., Michoel, Tom, Timpson, Nicolas J., Smith, George Davey, Walker, Brian R., Mellström, D., on behalf of the CORtisol NETwork (CORNET) consortium. (2021-01-20). 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. Journal of Human Genetics 66 (6) : 625-636. ScholarBank@NUS Repository. https://doi.org/10.1038/s10038-020-00895-6
Rights: Attribution 4.0 International
Abstract: 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 ?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. © 2021, The Author(s).
Source Title: Journal of Human Genetics
URI: https://scholarbank.nus.edu.sg/handle/10635/232928
ISSN: 1434-5161
DOI: 10.1038/s10038-020-00895-6
Rights: Attribution 4.0 International
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