Genome Wide Association Identifies Common Variants at the SERPINA 6 / SERPINA 1 Locus Influencing Plasma Cortisol and Corticosteroid Binding Globulin

Variation in plasma levels of cortisol, an essential hormone in the stress response, is associated in population-based studies with cardio-metabolic, inflammatory and neuro-cognitive traits and diseases. Heritability of plasma cortisol is estimated at 30–60% but no common genetic contribution has been identified. The CORtisol NETwork (CORNET) consortium undertook genome wide association meta-analysis for plasma cortisol in 12,597 Caucasian participants, replicated in 2,795 participants. The results indicate that ,1% of variance in plasma cortisol is accounted for by genetic variation in a single region of chromosome 14. This locus spans SERPINA6, encoding corticosteroid binding globulin (CBG, the major cortisol-binding protein in plasma), and SERPINA1, encoding a1-antitrypsin (which inhibits cleavage of the reactive centre loop that releases cortisol from CBG). Three partially independent signals were identified within the region, represented by common SNPs; detailed biochemical investigation in a nested sub-cohort showed all these SNPs were associated with variation in total cortisol binding activity in plasma, but some variants influenced total CBG concentrations while the top hit (rs12589136) influenced the immunoreactivity of the reactive centre loop of CBG. Exome chip and 1000 Genomes imputation analysis of this locus in the CROATIA-Korcula cohort identified missense mutations in SERPINA6 and SERPINA1 that did not account for the effects of common variants. These findings reveal a novel common genetic source of variation in binding of cortisol by CBG, and reinforce the key role of CBG in determining plasma cortisol levels. In turn this genetic variation may contribute to cortisol-associated degenerative diseases. PLOS Genetics | www.plosgenetics.org 1 July 2014 | Volume 10 | Issue 7 | e1004474 Citation: Bolton JL, Hayward C, Direk N, Lewis JG, Hammond GL, et al. (2014) Genome Wide Association Identifies Common Variants at the SERPINA6/SERPINA1 Locus Influencing Plasma Cortisol and Corticosteroid Binding Globulin. PLoS Genet 10(7): e1004474. doi:10.1371/journal.pgen.1004474 Editor: Gonçalo R. Abecasis, University of Michigan, United States of America Received November 29, 2013; Accepted May 15, 2014; Published July 10, 2014 This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication. Funding: The CORtisol NETwork Consortium is funded by the Chief Scientist Office of the Scottish Government (grant CZB-4-733) and the British Heart Foundation (grant RG11/4/28734). The CROATIA-Vis, CROATIA-Korcula and CROATIA-Split studies were funded by grants from the Medical Research Council (UK), the Republic of Croatia Ministry of Science, Education and Sports research grants to IR (108-1080315-0302), and European Commission Framework 6 project EUROSPAN (Contract No. LSHG-CT-2006-018947). ORCADES was supported by the Chief Scientist Office of the Scottish Government, the Royal Society, the MRC Human Genetics Unit, Arthritis Research UK and the European Union framework program 6 EUROSPAN project (contract no. LSHG-CT-2006-018947). In the Rotterdam Study, the generation and management of genome-wide association study genotype data are supported by the Netherlands Organisation of Scientific Research Investments (number 175.010.2005.011, 911-03-012). This study is funded by the Research Institute for Diseases in the Elderly (014-93-015) and the Netherlands Genomics Initiative/Netherlands Organisation for Scientific Research project number 050-060-810. The Rotterdam Study is funded by Erasmus MC and Erasmus University, Rotterdam, the Netherlands Organization for the Health Research and Development, the Ministry of Education, Culture and Science, the Ministry for Health, Welfare and Sports, the European Commission (Directorate-General XII), and the Municipality of Rotterdam. HT was supported by the Vidi Grant of Netherlands Organization for the Health Research and Development (2009-017.106.370). ND was supported by the Netherlands Consortium for Healthy Ageing. The Helsinki Birth Cohort Study has been supported by grants from the Academy of Finland, the Finnish Diabetes Research Society, Folkhälsan Research Foundation, Novo Nordisk Foundation, Finska Läkaresällskapet, Signe and Ane Gyllenberg Foundation, University of Helsinki, European Science Foundation (EUROSTRESS), Ministry of Education, Ahokas Foundation, Emil Aaltonen Foundation, Juho Vainio Foundation, and Wellcome Trust (grant number WT089062). The Northern Finland Birth Cohort 1966 study is supported by the Academy of Finland [project grants 104781, 120315, 129418, Center of Excellence in Complex Disease Genetics and Public Health Challenges Research Program (SALVE)], University Hospital Oulu, Biocenter, University of Oulu, Finland (75617), the European Commission [EUROBLCS, Framework 5 award QLG1-CT-2000-01643], The National Heart, Lung and Blood Institute [5R01HL087679-02] through the SNP Typing for Association with Multiple Phenotypes from Existing Epidemiologic Data (STAMPEED) program [1RL1MH083268-01], The National Institute of Health/The National Institute of Mental Health [5R01MH63706:02], European Network of Genomic and Genetic Epidemiology (ENGAGE) project and grant agreement [HEALTH-F42007-201413], and the Medical Research Council, UK [G0500539, G0600705, PrevMetSyn/Public Health Challenges Research Program (SALVE)]. ALSPAC was funded by the UK Medical Research Council and the Wellcome Trust (Grant ref: 092731) and the University of Bristol. The InCHIANTI study has been supported by the Italian Ministry of Health and the U.S. National Institute on Aging. The PIVUS study was supported by Wellcome Trust Grants WT098017, WT064890, WT090532, Uppsala University, Uppsala University Hospital, the Swedish Research Council and the Swedish Heart-Lung Foundation. The PREVEND Study has been supported by the Dutch Kidney Foundation (Grant E.033), the Groningen University Medical Center (Beleidsruimte), Bristol Myers Squibb, Dade Behring, Ausam, Roche, Abbott, The Netherlands Organization of Scientific Research, The Dutch Heart Foundation, and the De Cock Foundation. The Edinburgh Type 2 Diabetes Study was funded by the UK Medical Research Council (G0500877). For the Raine Study, this work was supported by funding for the 17 year follow-up and genotyping provided by the National Health and Medical Research Council of Australia (353514, 572613, 403981) and the Canadian Institutes of Health Research (MOP82893). Core funding for the Raine Study is provided by the University of Western Australia (UWA), Raine Medical Research Foundation, the Telethon Institute for Child Health Research, UWA Faculty of Medicine, Dentistry and Health Sciences, the Women and Infants Research Foundation and Curtin University. The MrOS-Sweden study was supported by the Swedish Research Council, the Swedish Foundation for Strategic Research, European Commission Grant QLK4-CT2002-02528, the ALF/LUA research grant in Gothenburg, the Lundberg Foundation, the Torsten and Ragnar Söderber’s Foundation, Petrus and Augusta Hedlunds Foundation, and the Novo Nordisk Foundation. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. * Email: b.walker@ed.ac.uk . These authors contributed equally to this work.