Genetics of cortisol secretion and depressive symptoms: a candidate gene and genome wide association approach

Fleur P Velders; Maris Kuningas; Meena Kumari; Marieke J Dekker; Andre G Uitterlinden; Clemens Kirschbaum; Karin Hek; Albert Hofman; Frank C Verhulst; Mika Kivimaki; Cornelia M Van Duijn; Brian R Walker; Henning Tiemeier

doi:10.1016/j.psyneuen.2011.01.003

Genetics of cortisol secretion and depressive symptoms: a candidate gene and genome wide association approach

Fleur P Velders, Maris Kuningas, Meena Kumari, Marieke J Dekker, Andre G Uitterlinden, Clemens Kirschbaum, Karin Hek, Albert Hofman, Frank C Verhulst, Mika Kivimaki, Cornelia M Van Duijn, Brian R Walker, Henning Tiemeier^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

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.

Original language	English
Pages (from-to)	1053-1061
Number of pages	9
Journal	Psychoneuroendocrinology
Volume	36
Issue number	7
DOIs	https://doi.org/10.1016/j.psyneuen.2011.01.003
Publication status	Published - Aug 2011
Externally published	Yes

Keywords

Aged
Aged, 80 and over
Depression/etiology
Female
Genetic Association Studies
Genetic Predisposition to Disease
Genetics, Population
Genome-Wide Association Study
Genotype
Humans
Hydrocortisone/genetics
Hypothalamo-Hypophyseal System/metabolism
Male
Middle Aged
Pituitary-Adrenal System/metabolism
Polymorphism, Single Nucleotide/physiology
Risk Factors
Secretory Pathway/genetics

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10.1016/j.psyneuen.2011.01.003

Cite this

Velders, F. P., Kuningas, M., Kumari, M., Dekker, M. J., Uitterlinden, A. G., Kirschbaum, C., Hek, K., Hofman, A., Verhulst, F. C., Kivimaki, M., Van Duijn, C. M., Walker, B. R., & Tiemeier, H. (2011). Genetics of cortisol secretion and depressive symptoms: a candidate gene and genome wide association approach. Psychoneuroendocrinology, 36(7), 1053-1061. https://doi.org/10.1016/j.psyneuen.2011.01.003

@article{0cdd00cd68b74c74892640615b945d0a,

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.",

keywords = "Aged, Aged, 80 and over, Depression/etiology, Female, Genetic Association Studies, Genetic Predisposition to Disease, Genetics, Population, Genome-Wide Association Study, Genotype, Humans, Hydrocortisone/genetics, Hypothalamo-Hypophyseal System/metabolism, Male, Middle Aged, Pituitary-Adrenal System/metabolism, Polymorphism, Single Nucleotide/physiology, Risk Factors, Secretory Pathway/genetics",

author = "Velders, {Fleur P} and Maris Kuningas and Meena Kumari and Dekker, {Marieke J} and Uitterlinden, {Andre G} and Clemens Kirschbaum and Karin Hek and Albert Hofman and Verhulst, {Frank C} and Mika Kivimaki and {Van Duijn}, {Cornelia M} and Walker, {Brian R} and Henning Tiemeier",

year = "2011",

month = aug,

doi = "10.1016/j.psyneuen.2011.01.003",

language = "English",

volume = "36",

pages = "1053--1061",

journal = "Psychoneuroendocrinology",

issn = "0306-4530",

publisher = "Elsevier Limited",

number = "7",

}

Velders, FP, Kuningas, M, Kumari, M, Dekker, MJ, Uitterlinden, AG, Kirschbaum, C, Hek, K, Hofman, A, Verhulst, FC, Kivimaki, M, Van Duijn, CM, Walker, BR & Tiemeier, H 2011, 'Genetics of cortisol secretion and depressive symptoms: a candidate gene and genome wide association approach', Psychoneuroendocrinology, vol. 36, no. 7, pp. 1053-1061. https://doi.org/10.1016/j.psyneuen.2011.01.003

TY - JOUR

T1 - Genetics of cortisol secretion and depressive symptoms

T2 - a candidate gene and genome wide association approach

AU - Velders, Fleur P

AU - Kuningas, Maris

AU - Kumari, Meena

AU - Dekker, Marieke J

AU - Uitterlinden, Andre G

AU - Kirschbaum, Clemens

AU - Hek, Karin

AU - Hofman, Albert

AU - Verhulst, Frank C

AU - Kivimaki, Mika

AU - Van Duijn, Cornelia M

AU - Walker, Brian R

AU - Tiemeier, Henning

PY - 2011/8

Y1 - 2011/8

N2 - 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.

AB - 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.

KW - Aged

KW - Aged, 80 and over

KW - Depression/etiology

KW - Female

KW - Genetic Association Studies

KW - Genetic Predisposition to Disease

KW - Genetics, Population

KW - Genome-Wide Association Study

KW - Genotype

KW - Humans

KW - Hydrocortisone/genetics

KW - Hypothalamo-Hypophyseal System/metabolism

KW - Male

KW - Middle Aged

KW - Pituitary-Adrenal System/metabolism

KW - Polymorphism, Single Nucleotide/physiology

KW - Risk Factors

KW - Secretory Pathway/genetics

U2 - 10.1016/j.psyneuen.2011.01.003

DO - 10.1016/j.psyneuen.2011.01.003

M3 - Article

C2 - 21316860

SN - 0306-4530

VL - 36

SP - 1053

EP - 1061

JO - Psychoneuroendocrinology

JF - Psychoneuroendocrinology

IS - 7

ER -

Genetics of cortisol secretion and depressive symptoms: a candidate gene and genome wide association approach

Abstract

Keywords

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