Genome wide association identifies common variants at the SERPINA6/SERPINA1 locus influencing plasma cortisol and corticosteroid binding globulin

Jennifer L Bolton, Caroline Hayward, Nese Direk, Lesley A Hill, Anna Anderson, Jennifer Huffman, Harry Campbell, Igor Rudan, Nicholas Hastie, Sarah H Wild, Fleur P Velders, Albert Hofman, Andre G Uitterlinden, Jari Lahti, Katri Räikkönen, Eero Kajantie, Elisabeth Widen, Aarno Palotie, Johan G Eriksson, Marika KaakinenMarjo-Riitta Järvelin, Nicholas J Timpson, George Davey Smith, Susan M Ring, David M Evans, Beate St Pourcain, Toshiko Tanaka, Yuri Milaneschi, Stefania Bandinelli, Luigi Ferrucci, Pim van der Harst, Judith G M Rosmalen, Stephen J L Bakker, Niek Verweij, Robin P F Dullaart, Anubha Mahajan, Cecilia M Lindgren, Andrew Morris, Lars Lind, Erik Ingelsson, Laura N Anderson, Craig E Pennell, Stephen J Lye, Stephen G Matthews, Joel Eriksson, Dan Mellstrom, CORtisol NETwork (CORNET) Consortium

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

102 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)e1004474
JournalPLoS Genetics
Issue number7
Publication statusPublished - Jul 2014


  • Adolescent
  • Adult
  • Aged
  • Aged, 80 and over
  • Cohort Studies
  • Exome
  • Female
  • Genome-Wide Association Study
  • Humans
  • Hydrocortisone
  • Male
  • Middle Aged
  • Mutation
  • Polymorphism, Single Nucleotide
  • Protein Binding
  • Transcortin
  • alpha 1-Antitrypsin


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