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 BjörkegrenHarry Campbell, Johan Eriksson, Christian Gieger, Caroline Hayward, Marjo-Riitta Jarvelin, Stela McLachlan, Andrew P Morris, Claes Ohlsson, Craig E Pennell, Jackie F Price, Igor Rudan, Arno Ruusalepp, Timothy D Spector, Henning Tiemeier, Henry Völzke, James R M Wilson, Tom Michoel, Nicholas John Timpson, George Davey Smith, Brian R Walker*

*Corresponding author for this work

Research output: Contribution to journalArticle (Academic Journal)peer-review

2 Citations (Scopus)
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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 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
Volume66
Issue number6
Early online date20 Jan 2021
DOIs
Publication statusPublished - 20 Jan 2021

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