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Lookup NU author(s): Professor Brian WalkerORCiD
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
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.
Author(s): Bankier S, Crawford A, Altmaier E, Barnes C, Clark D, Ermel R, Friedrich N, van der Harst P, Joshi P, Karhunen V, Lahti J, Mahajan A, Mangino M, Nethander M, Neumann A, Pietzner M, Sukhavasi K, Wang C, Bakker S, Bjorkegren J, Campbell H, Eriksson J, Gieger C, Hayward C, Jarvelin M-R, McLachlan S, Morris A, Ohlsson C, Pennell C, Price J, Rudan I, Ruusalepp A, Spector T, Tiemeier H, Volzke H, Wilson J, Michoel T, Timpson N, Smith GD, Walker B
Publication type: Article
Publication status: Published
Journal: Journal of Human Genetics
Year: 2021
Volume: 66
Pages: 625-636
Print publication date: 01/06/2021
Online publication date: 20/01/2021
Acceptance date: 14/12/2020
Date deposited: 17/12/2020
ISSN (print): 1434-5161
ISSN (electronic): 1435-232X
Publisher: Springer Nature
URL: https://doi.org/10.1038/s10038-020-00895-6
DOI: 10.1038/s10038-020-00895-6
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