title: Genetics of cortisol secretion and depressive symptoms: a candidate gene and genome wide association approach.
abstract: BACKGROUND
  Depressive patients often have altered cortisol secretion, but few studies have investigated genetic variants in relation to both cortisol secretion and depression. To identify genes related to both these conditions, we: (1) tested the association of single nucleotide polymorphisms (SNPs) in hypothalamic-pituitary-adrenal-axis (HPA-axis) candidate genes with a summary measure of total cortisol secretion during the day (cortisol(AUC)), (2) performed a genome wide association study (GWAS) of cortisol(AUC), and (3) tested the association of identified cortisol-related SNPs with depressive symptoms.
  
  
  METHODS
  We analyzed data on candidate SNPs for the HPA-axis, genome-wide scans, cortisol secretion (n=1711) and depressive symptoms (the Centre for Epidemiology Studies Depression Scale, CES-D) (n=2928) in elderly persons of the Rotterdam Study. We used data from the Whitehall II study (n=2836) to replicate the GWAS findings.
  
  
  RESULTS
  Of the 1456 SNPs in 33 candidate genes, minor alleles of 4 SNPs (rs9470080, rs9394309, rs7748266 and rs1360780) in the FKBP5 gene were associated with a decreased cortisol(AUC) (p<1×10(-4) after correction for multiple testing using permutations). These SNPs were also associated with an increased risk of depressive symptoms (rs9470080: OR 1.19 (95%CI 1.0; 1.4)). The GWAS for cortisol yielded 2 SNPs with p-values of 1×10(-06) (rs8062512, rs2252459), but these associations could not be replicated.
  
  
  CONCLUSIONS
  These results suggest that variation in the FKBP5 gene is associated with both cortisol(AUC) and the likelihood of depressive symptoms.
authors.affiliation: Department of Child and Adolescent Psychiatry, Erasmus Medical Centre - Sophia Children's Hospital, Rotterdam, The Netherlands.
authors.forename: Fleur P
authors.initials: FP
authors.lastname: Velders
authors.forename: Maris
authors.initials: M
authors.lastname: Kuningas
authors.forename: Meena
authors.initials: M
authors.lastname: Kumari
authors.forename: Marieke J
authors.initials: MJ
authors.lastname: Dekker
authors.forename: Andre G
authors.initials: AG
authors.lastname: Uitterlinden
authors.forename: Clemens
authors.initials: C
authors.lastname: Kirschbaum
authors.forename: Karin
authors.initials: K
authors.lastname: Hek
authors.forename: Albert
authors.initials: A
authors.lastname: Hofman
authors.forename: Frank C
authors.initials: FC
authors.lastname: Verhulst
authors.forename: Mika
authors.initials: M
authors.lastname: Kivimaki
authors.forename: Cornelia M
authors.initials: CM
authors.lastname: Van Duijn
authors.forename: Brian R
authors.initials: BR
authors.lastname: Walker
authors.forename: Henning
authors.initials: H
authors.lastname: Tiemeier
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D003863:Depression / Q000209:etiology / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D005828:Genetics, Population; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D006854:Hydrocortisone / Q000235:genetics / Q000378:metabolism*; D007030:Hypothalamo-Hypophyseal System / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D008875:Middle Aged; D010913:Pituitary-Adrenal System / Q000378:metabolism / Q000503:physiopathology; D020641:Polymorphism, Single Nucleotide / Q000502:physiology; D012307:Risk Factors; D055571:Secretory Pathway / Q000235:genetics*
chemical_list: D006854:Hydrocortisone