title: Gene expression in major depressive disorder.
abstract: The search for genetic variants underlying major depressive disorder (MDD) has not yet provided firm leads to its underlying molecular biology. A complementary approach is to study gene expression in relation to MDD. We measured gene expression in peripheral blood from 1848 subjects from The Netherlands Study of Depression and Anxiety. Subjects were divided into current MDD (N=882), remitted MDD (N=635) and control (N=331) groups. MDD status and gene expression were measured again 2 years later in 414 subjects. The strongest gene expression differences were between the current MDD and control groups (129 genes at false-discovery rate, FDR<0.1). Gene expression differences across MDD status were largely unrelated to antidepressant use, inflammatory status and blood cell counts. Genes associated with MDD were enriched for interleukin-6 (IL-6)-signaling and natural killer (NK) cell pathways. We identified 13 gene expression clusters with specific clusters enriched for genes involved in NK cell activation (downregulated in current MDD, FDR=5.8 × 10(-5)) and IL-6 pathways (upregulated in current MDD, FDR=3.2 × 10(-3)). Longitudinal analyses largely confirmed results observed in the cross-sectional data. Comparisons of gene expression results to the Psychiatric Genomics Consortium (PGC) MDD genome-wide association study results revealed overlap with DVL3. In conclusion, multiple gene expression associations with MDD were identified and suggest a measurable impact of current MDD state on gene expression. Identified genes and gene clusters are enriched with immune pathways previously associated with the etiology of MDD, in line with the immune suppression and immune activation hypothesis of MDD.
authors.affiliation: Department of Psychiatry, VU University Medical Center, Neuroscience Campus Amsterdam, Amsterdam, The Netherlands.
authors.forename: R
authors.initials: R
authors.lastname: Jansen
authors.affiliation: Department of Psychiatry, VU University Medical Center, Neuroscience Campus Amsterdam, Amsterdam, The Netherlands.
authors.forename: B W J H
authors.initials: BW
authors.lastname: Penninx
authors.affiliation: Department of Biostatistics, University of North Carolina, Chapel Hill, NC, USA.
authors.forename: V
authors.initials: V
authors.lastname: Madar
authors.affiliation: Department of Psychiatry, University of North Carolina, Chapel Hill, NC, USA.
authors.forename: K
authors.identifier: http://orcid.org/0000-0001-8254-4092
authors.initials: K
authors.lastname: Xia
authors.affiliation: Department of Psychiatry, VU University Medical Center, Neuroscience Campus Amsterdam, Amsterdam, The Netherlands.
authors.forename: Y
authors.initials: Y
authors.lastname: Milaneschi
authors.affiliation: Department of Biological Psychology, VU University Amsterdam, Neuroscience Campus Amsterdam, Amsterdam, The Netherlands.
authors.forename: J J
authors.initials: JJ
authors.lastname: Hottenga
authors.affiliation: Department of Complex Trait Genetics, VU University Amsterdam, Center for Neurogenomics and Cognitive Research, Neuroscience Campus Amsterdam, Amsterdam, The Netherlands.
authors.forename: A R
authors.initials: AR
authors.lastname: Hammerschlag
authors.affiliation: Department of Psychiatry, VU University Medical Center, Neuroscience Campus Amsterdam, Amsterdam, The Netherlands.
authors.forename: A
authors.initials: A
authors.lastname: Beekman
authors.affiliation: Department of Psychiatry, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: N
authors.initials: N
authors.lastname: van der Wee
authors.affiliation: Department of Psychiatry, VU University Medical Center, Neuroscience Campus Amsterdam, Amsterdam, The Netherlands.
authors.forename: J H
authors.initials: JH
authors.lastname: Smit
authors.affiliation: Department of Genetics and the Human Genetics Institute, RUCDR Infinite Biologics, Rutgers University, New Brunswick, NJ, USA.
authors.forename: A I
authors.initials: AI
authors.lastname: Brooks
authors.affiliation: Department of Genetics and the Human Genetics Institute, RUCDR Infinite Biologics, Rutgers University, New Brunswick, NJ, USA.
authors.forename: J
authors.initials: J
authors.lastname: Tischfield
authors.affiliation: Department of Complex Trait Genetics, VU University Amsterdam, Center for Neurogenomics and Cognitive Research, Neuroscience Campus Amsterdam, Amsterdam, The Netherlands.|Department of Clinical Genetics, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: D
authors.initials: D
authors.lastname: Posthuma
authors.affiliation: Department of Psychiatry, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: R
authors.initials: R
authors.lastname: Schoevers
authors.affiliation: Department of Psychiatry, VU University Medical Center, Neuroscience Campus Amsterdam, Amsterdam, The Netherlands.
authors.forename: G
authors.initials: G
authors.lastname: van Grootheest
authors.affiliation: Department of Biological Psychology, VU University Amsterdam, Neuroscience Campus Amsterdam, Amsterdam, The Netherlands.
authors.forename: G
authors.initials: G
authors.lastname: Willemsen
authors.affiliation: Department of Biological Psychology, VU University Amsterdam, Neuroscience Campus Amsterdam, Amsterdam, The Netherlands.
authors.forename: E J
authors.initials: EJ
authors.lastname: de Geus
authors.affiliation: Department of Biological Psychology, VU University Amsterdam, Neuroscience Campus Amsterdam, Amsterdam, The Netherlands.
authors.forename: D I
authors.initials: DI
authors.lastname: Boomsma
authors.affiliation: Department of Biostatistics, University of North Carolina, Chapel Hill, NC, USA.|Department of Statistics, North Carolina State University, Raleigh, NC, USA.|Department of Biological Sciences, North Carolina State University, Raleigh, NC, USA.
authors.forename: F A
authors.initials: FA
authors.lastname: Wright
authors.affiliation: Department of Biostatistics, University of North Carolina, Chapel Hill, NC, USA.
authors.forename: F
authors.initials: F
authors.lastname: Zou
authors.affiliation: Department of Genetics, University of North Carolina, Chapel Hill, NC, USA.
authors.forename: W
authors.initials: W
authors.lastname: Sun
authors.affiliation: Department of Genetics, University of North Carolina, Chapel Hill, NC, USA.|Department of Psychiatry, University of North Carolina, Chapel Hill, NC, USA.
authors.forename: P F
authors.initials: PF
authors.lastname: Sullivan
mesh_terms: D000328:Adult; D001008:Anxiety Disorders / Q000235:genetics*; D003430:Cross-Sectional Studies; D003865:Major Depressive Disorder / Q000175:diagnosis / Q000235:genetics*; D005260:Female; D015870:Gene Expression / Q000235:genetics*; D005786:Gene Expression Regulation / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D055106:Genome-Wide Association Study; D006801:Humans; D015850:Interleukin-6 / Q000235:genetics* / Q000378:metabolism; D007694:Killer Cells, Natural / Q000378:metabolism; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D015398:Signal Transduction / Q000235:genetics
chemical_list: C508600:IL6 protein, human; D015850:Interleukin-6