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

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CORtisol Network CORNET Consortium , Crawford , A A , Bankier , S , Altmaier , E , Lahti , J , Eriksson , J & Walker , B R 2021 , ' 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 , vol. 66 , no. 6 , pp. 625-636 . 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
Author: CORtisol Network CORNET Consortium; Crawford, Andrew A.; Bankier, Sean; Altmaier, Elisabeth; Lahti, Jari; Eriksson, Johan; Walker, Brian R.
Contributor: University of Helsinki, Department of Psychology and Logopedics
University of Helsinki, Clinicum
Date: 2021-06
Language: eng
Number of pages: 12
Belongs to series: Journal of Human Genetics
ISSN: 1434-5161
URI: http://hdl.handle.net/10138/334019
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 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.
Subject: LD SCORE REGRESSION
LOW-BIRTH-WEIGHT
BLOOD-PRESSURE
HERITABILITY
VISUALIZATION
METAANALYSIS
RESPONSES
INSULIN
STRESS
3142 Public health care science, environmental and occupational health
515 Psychology
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