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

Bolton, Jennifer L., Hayward, Caroline, Direk, Nese, Lewis, John G., Hammond, Geoffrey L., Hill, Lesley A., Anderson, Anna, Huffman, Jennifer, Wilson, James F., Campbell, Harry, Rudan, Igor, Wright, Alan, Hastie, Nicholas, Wild, Sarah H., Velders, Fleur P., Hofman, Albert, Uitterlinden, Andre G., Lahti, Jari, Raikkonen, Katri, Kajantie, Eero, Widen, Elisabeth, Palotie, Aarno, Eriksson, Johan G., Kaakinen, Marika, Jarvelin, Marjo-Riitta, Timpson, Nicholas J., Smith, George Davey, Ring, Susan M., Evans, David M., St Pourcain, Beate, Tanaka, Toshiko, Milaneschi, Yuri, Bandinelli, Stefania, Ferrucci, Luigi, van der Harst, Pim, Rosmalen, Judith G. M., Bakker, Stephen J. L., Verweij, Niek, Dullaart, Robin P. F., Mahajan, Anubha, Lindgren, Cecilia M., Morris, Andrew, Lind, Lars, Ingelsson, Erik, Anderson, Laura N., Pennell, Craig E., Lye, Stephen J., Matthews, Stephen G., Eriksson, Joel, Mellstrom, Dan, Ohlsson, Claes, Price, Jackie F., Strachan, Mark W. J., Reynolds, Rebecca M., Tiemeier, Henning and Walker, Brian R. (2014) Genome wide association identifies common variants at the SERPINA6/SERPINA1 locus influencing plasma cortisol and corticosteroid binding globulin. PLoS Genetics, 10 7: 1-11. doi:10.1371/journal.pgen.1004474

Author Bolton, Jennifer L.
Hayward, Caroline
Direk, Nese
Lewis, John G.
Hammond, Geoffrey L.
Hill, Lesley A.
Anderson, Anna
Huffman, Jennifer
Wilson, James F.
Campbell, Harry
Rudan, Igor
Wright, Alan
Hastie, Nicholas
Wild, Sarah H.
Velders, Fleur P.
Hofman, Albert
Uitterlinden, Andre G.
Lahti, Jari
Raikkonen, Katri
Kajantie, Eero
Widen, Elisabeth
Palotie, Aarno
Eriksson, Johan G.
Kaakinen, Marika
Jarvelin, Marjo-Riitta
Timpson, Nicholas J.
Smith, George Davey
Ring, Susan M.
Evans, David M.
St Pourcain, Beate
Tanaka, Toshiko
Milaneschi, Yuri
Bandinelli, Stefania
Ferrucci, Luigi
van der Harst, Pim
Rosmalen, Judith G. M.
Bakker, Stephen J. L.
Verweij, Niek
Dullaart, Robin P. F.
Mahajan, Anubha
Lindgren, Cecilia M.
Morris, Andrew
Lind, Lars
Ingelsson, Erik
Anderson, Laura N.
Pennell, Craig E.
Lye, Stephen J.
Matthews, Stephen G.
Eriksson, Joel
Mellstrom, Dan
Ohlsson, Claes
Price, Jackie F.
Strachan, Mark W. J.
Reynolds, Rebecca M.
Tiemeier, Henning
Walker, Brian R.
Title Genome wide association identifies common variants at the SERPINA6/SERPINA1 locus influencing plasma cortisol and corticosteroid binding globulin
Journal name PLoS Genetics   Check publisher's open access policy
ISSN 1553-7404
Publication date 2014-07-10
Year available 2014
Sub-type Article (original research)
DOI 10.1371/journal.pgen.1004474
Open Access Status DOI
Volume 10
Issue 7
Start page 1
End page 11
Total pages 11
Place of publication San Francisco CA, United States
Publisher Public Library of Science
Collection year 2015
Language eng
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.
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status Non-UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Non HERDC
UQ Diamantina Institute Publications
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Created: Wed, 18 Mar 2015, 20:36:20 EST by David Evans on behalf of UQ Diamantina Institute