title: Genome wide association identifies common variants at the SERPINA6/SERPINA1 locus influencing plasma cortisol and corticosteroid binding globulin.
abstract: 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 α1-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.
authors.affiliation: University/BHF Centre for Cardiovascular Science, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Bolton
authors.affiliation: MRC Human Genetics Unit, Institute for Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Caroline
authors.initials: C
authors.lastname: Hayward
authors.affiliation: Department of Epidemiology, Erasmus Medical Centre, Rotterdam, The Netherlands.
authors.forename: Nese
authors.initials: N
authors.lastname: Direk
authors.affiliation: Canterbury Health Laboratories, Christchurch, New Zealand.
authors.forename: John G
authors.initials: JG
authors.lastname: Lewis
authors.affiliation: Department of Cellular and Physiological Sciences, Life Sciences Institute, University of British Columbia, Vancouver, Canada.
authors.forename: Geoffrey L
authors.initials: GL
authors.lastname: Hammond
authors.affiliation: Department of Cellular and Physiological Sciences, Life Sciences Institute, University of British Columbia, Vancouver, Canada.
authors.forename: Lesley A
authors.initials: LA
authors.lastname: Hill
authors.affiliation: University/BHF Centre for Cardiovascular Science, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Anna
authors.initials: A
authors.lastname: Anderson
authors.affiliation: MRC Human Genetics Unit, Institute for Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Huffman
authors.affiliation: Centre for Population Health Sciences, Institute for Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: James F
authors.initials: JF
authors.lastname: Wilson
authors.affiliation: Centre for Population Health Sciences, Institute for Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Harry
authors.initials: H
authors.lastname: Campbell
authors.affiliation: Centre for Population Health Sciences, Institute for Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Igor
authors.initials: I
authors.lastname: Rudan
authors.affiliation: MRC Human Genetics Unit, Institute for Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Alan
authors.initials: A
authors.lastname: Wright
authors.affiliation: MRC Human Genetics Unit, Institute for Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Hastie
authors.affiliation: Centre for Population Health Sciences, Institute for Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Sarah H
authors.initials: SH
authors.lastname: Wild
authors.affiliation: Department of Epidemiology, Erasmus Medical Centre, Rotterdam, The Netherlands.
authors.forename: Fleur P
authors.initials: FP
authors.lastname: Velders
authors.affiliation: Department of Epidemiology, Erasmus Medical Centre, Rotterdam, The Netherlands.
authors.forename: Albert
authors.initials: A
authors.lastname: Hofman
authors.affiliation: Department of Epidemiology, Erasmus Medical Centre, Rotterdam, The Netherlands.
authors.forename: Andre G
authors.initials: AG
authors.lastname: Uitterlinden
authors.affiliation: Institute of Behavioural Sciences, University of Helsinki, Helsinki, Finland.
authors.forename: Jari
authors.initials: J
authors.lastname: Lahti
authors.affiliation: Institute of Behavioural Sciences, University of Helsinki, Helsinki, Finland.
authors.forename: Katri
authors.initials: K
authors.lastname: Räikkönen
authors.affiliation: National Institute for Health and Welfare, Helsinki, Finland.
authors.forename: Eero
authors.initials: E
authors.lastname: Kajantie
authors.affiliation: Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Widen
authors.affiliation: Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland; Department of Medical Genetics, University of Helsinki and University Central Hospital, Helsinki, Finland.
authors.forename: Aarno
authors.initials: A
authors.lastname: Palotie
authors.affiliation: National Institute for Health and Welfare, Helsinki, Finland; Department of General Practice and Primary Health Care, University of Helsinki, Helsinki, Finland; Helsinki University Central Hospital, Unit of General Practice, Helsinki, Finland; Folkhalsan Research Centre, Helsinki, Finland; Vasa Central Hospital, Vasa, Finland.
authors.forename: Johan G
authors.initials: JG
authors.lastname: Eriksson
authors.affiliation: Institute of Health Sciences and Biocenter Oulu, University of Oulu, Oulu, Finland.
authors.forename: Marika
authors.initials: M
authors.lastname: Kaakinen
authors.affiliation: Institute of Health Sciences and Biocenter Oulu, University of Oulu, Oulu, Finland; Department of Children and Young People and Families, National Institute for Health and Welfare, Oulu, Finland; Department of Epidemiology and Biostatistics, MRC-HPA Centre for Environment and Health, Imperial College London, London, United Kingdom; Unit of Primary Care, Oulu University Hospital, Oulu, Finland.
authors.forename: Marjo-Riitta
authors.initials: MR
authors.lastname: Järvelin
authors.affiliation: MRC Centre for Causal Analyses in Translational Epidemiology, School of Social and Community Medicine, University of Bristol, Bristol, United Kingdom.
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Timpson
authors.affiliation: MRC Centre for Causal Analyses in Translational Epidemiology, School of Social and Community Medicine, University of Bristol, Bristol, United Kingdom.
authors.forename: George
authors.initials: G
authors.lastname: Davey Smith
authors.affiliation: School of Social and Community Medicine, University of Bristol, Bristol, United Kingdom.
authors.forename: Susan M
authors.initials: SM
authors.lastname: Ring
authors.affiliation: MRC Centre for Causal Analyses in Translational Epidemiology, School of Social and Community Medicine, University of Bristol, Bristol, United Kingdom.
authors.forename: David M
authors.initials: DM
authors.lastname: Evans
authors.affiliation: School of Social and Community Medicine, University of Bristol, Bristol, United Kingdom.
authors.forename: Beate
authors.initials: B
authors.lastname: St Pourcain
authors.affiliation: Longitudinal Studies Section, Clinical Research Branch, National Institute on Aging, Baltimore, Maryland, United States of America.
authors.forename: Toshiko
authors.initials: T
authors.lastname: Tanaka
authors.affiliation: Longitudinal Studies Section, Clinical Research Branch, National Institute on Aging, Baltimore, Maryland, United States of America; Department of Psychiatry, VU University Medical Center/GGZ inGeest, Amsterdam, The Netherlands.
authors.forename: Yuri
authors.initials: Y
authors.lastname: Milaneschi
authors.affiliation: Geriatric Unit, ASF, Florence, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Bandinelli
authors.affiliation: Longitudinal Studies Section, Clinical Research Branch, National Institute on Aging, Baltimore, Maryland, United States of America.
authors.forename: Luigi
authors.initials: L
authors.lastname: Ferrucci
authors.affiliation: University of Groningen, University Medical Center Groningen, Department of Cardiology, Groningen, The Netherlands; University of Groningen, University Medical Center Groningen, Department of Genetics, Groningen, The Netherlands; Durrer Center for Cardiogenetic Research, ICIN-Netherlands Heart Institute, Utrecht, The Netherlands.
authors.forename: Pim
authors.initials: P
authors.lastname: van der Harst
authors.affiliation: University of Groningen, University Medical Center Groningen, Interdisciplinary Center for Psychiatric Epidemiology, Groningen, The Netherlands.
authors.forename: Judith G M
authors.initials: JG
authors.lastname: Rosmalen
authors.affiliation: University of Groningen, University Medical Center Groningen, Department of Internal Medicine, Groningen, The Netherlands.
authors.forename: Stephen J L
authors.initials: SJ
authors.lastname: Bakker
authors.affiliation: University of Groningen, University Medical Center Groningen, Department of Cardiology, Groningen, The Netherlands.
authors.forename: Niek
authors.initials: N
authors.lastname: Verweij
authors.affiliation: University of Groningen, University Medical Center Groningen, Department of Internal Medicine, Groningen, The Netherlands.
authors.forename: Robin P F
authors.initials: RP
authors.lastname: Dullaart
authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom.
authors.forename: Anubha
authors.initials: A
authors.lastname: Mahajan
authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom.
authors.forename: Cecilia M
authors.initials: CM
authors.lastname: Lindgren
authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom.
authors.forename: Andrew
authors.initials: A
authors.lastname: Morris
authors.affiliation: Department of Medical Sciences, Uppsala University, Uppsala, Sweden.
authors.forename: Lars
authors.initials: L
authors.lastname: Lind
authors.affiliation: Department of Medical Sciences, Uppsala University, Uppsala, Sweden.
authors.forename: Erik
authors.initials: E
authors.lastname: Ingelsson
authors.affiliation: Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada.
authors.forename: Laura N
authors.initials: LN
authors.lastname: Anderson
authors.affiliation: School of Women's and Infant's Health, The University of Western Australia, Crawley, Australia.
authors.forename: Craig E
authors.initials: CE
authors.lastname: Pennell
authors.affiliation: Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Lye
authors.affiliation: Department of Physiology, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Stephen G
authors.initials: SG
authors.lastname: Matthews
authors.affiliation: Center for Bone and Arthritis Research, Institute of Medicin, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
authors.forename: Joel
authors.initials: J
authors.lastname: Eriksson
authors.affiliation: Center for Bone and Arthritis Research, Institute of Medicin, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
authors.forename: Dan
authors.initials: D
authors.lastname: Mellstrom
authors.affiliation: Center for Bone and Arthritis Research, Institute of Medicin, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
authors.forename: Claes
authors.initials: C
authors.lastname: Ohlsson
authors.affiliation: Centre for Population Health Sciences, Institute for Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Jackie F
authors.initials: JF
authors.lastname: Price
authors.affiliation: University/BHF Centre for Cardiovascular Science, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Mark W J
authors.initials: MW
authors.lastname: Strachan
authors.affiliation: University/BHF Centre for Cardiovascular Science, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Rebecca M
authors.initials: RM
authors.lastname: Reynolds
authors.affiliation: Department of Epidemiology, Erasmus Medical Centre, Rotterdam, The Netherlands.
authors.forename: Henning
authors.initials: H
authors.lastname: Tiemeier
authors.affiliation: University/BHF Centre for Cardiovascular Science, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Brian R
authors.initials: BR
authors.lastname: Walker
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015331:Cohort Studies; D059472:Exome / Q000235:genetics; D005260:Female; D055106:Genome-Wide Association Study; D006801:Humans; D006854:Hydrocortisone / Q000097:blood*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011485:Protein Binding; D014156:Transcortin / Q000235:genetics* / Q000378:metabolism; D000515:alpha 1-Antitrypsin / Q000235:genetics* / Q000378:metabolism
chemical_list: C043392:SERPINA1 protein, human; C534935:SERPINA6 protein, human; D000515:alpha 1-Antitrypsin; D014156:Transcortin; D006854:Hydrocortisone