Genome wide association identifies common variants at the SERPINA6/SERPINA1 locus influencing plasma cortisol and corticosteroid binding globulin.
Bolton JL., Hayward C., Direk N., Lewis JG., Hammond GL., Hill LA., Anderson A., Huffman J., Wilson JF., Campbell H., Rudan I., Wright A., Hastie N., Wild SH., Velders FP., Hofman A., Uitterlinden AG., Lahti J., Räikkönen K., Kajantie E., Widen E., Palotie A., Eriksson JG., Kaakinen M., Järvelin M-R., Timpson NJ., Davey Smith G., Ring SM., Evans DM., St Pourcain B., Tanaka T., Milaneschi Y., Bandinelli S., Ferrucci L., van der Harst P., Rosmalen JGM., Bakker SJL., Verweij N., Dullaart RPF., Mahajan A., Lindgren CM., Morris A., Lind L., Ingelsson E., Anderson LN., Pennell CE., Lye SJ., Matthews SG., Eriksson J., Mellstrom D., Ohlsson C., Price JF., Strachan MWJ., Reynolds RM., Tiemeier H., Walker BR.
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.