Show simple item record

dc.contributor.authorCrawford, Andrew A.
dc.contributor.authorBankier, Sean
dc.contributor.authorAltmaier, Elisabeth
dc.contributor.authorBarnes, Catriona L. K.
dc.contributor.authorClark, David W.
dc.contributor.authorErmel, Raili
dc.contributor.authorFriedrich, Nele
dc.contributor.authorvan der Harst, Pim
dc.contributor.authorJoshi, Peter K.
dc.contributor.authorKarhunen, Ville
dc.contributor.authorLahti, Jari
dc.contributor.authorMahajan, Anubha
dc.contributor.authorMangino, Massimo
dc.contributor.authorNethander, Maria
dc.contributor.authorNeumann, Alexander
dc.contributor.authorPietzner, Maik
dc.contributor.authorSukhavasi, Katyayani
dc.contributor.authorWang, Carol A.
dc.contributor.authorBakker, Stephan J. L.
dc.contributor.authorBjorkegren, Johan L. M.
dc.contributor.authorCampbell, Harry
dc.contributor.authorEriksson, Johan G.
dc.contributor.authorGieger, Christian
dc.contributor.authorHayward, Caroline
dc.contributor.authorJarvelin, Marjo-Riitta
dc.contributor.authorMcLachlan, Stela
dc.contributor.authorMorris, Andrew P.
dc.contributor.authorOhlsson, Claes
dc.contributor.authorPennell, Craig E.
dc.contributor.authorPrice, Jackie
dc.contributor.authorRudan, Igor
dc.contributor.authorRuusalepp, Arno
dc.contributor.authorSpector, Tim
dc.contributor.authorTiemeier, Henning
dc.contributor.authorVölzke, Henry
dc.contributor.authorWilson, James F.
dc.contributor.authorMichoel, Tom Luk Robert
dc.contributor.authorTimpson, Nicolas J.
dc.contributor.authorSmith, George Davey
dc.contributor.authorWalker, Brian R.
dc.description.abstractThe 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.en_US
dc.rightsNavngivelse 4.0 Internasjonal*
dc.titleVariation in the SERPINA6/SERPINA1 locus alters morning plasma cortisol, hepatic corticosteroid binding globulin expression, gene expression in peripheral tissues, and risk of cardiovascular diseaseen_US
dc.typeJournal articleen_US
dc.typePeer revieweden_US
dc.rights.holderCopyright 2021 The Author(s)en_US
dc.source.journalJournal of Human Geneticsen_US
dc.identifier.citationJournal of Human Genetics. 2021, 66 (6), 625-636.en_US

Files in this item


This item appears in the following Collection(s)

Show simple item record

Navngivelse 4.0 Internasjonal
Except where otherwise noted, this item's license is described as Navngivelse 4.0 Internasjonal