Gene expression profiling may be a tool to identify markers of antidepressant treatment response and new potential drug targets. In a first step, we selected 12 male, age- and severity-matched pairs ...of remitters and nonresponders, and analyzed expression profiles in peripheral blood at admission and after 2 and 5 weeks of treatment using Illumina expression arrays. We identified 127 transcripts significantly associated with treatment response with a minimal P-value of 9.41 × 10
−4
(FDR-corrected). Analysis of selected transcripts in an independent replication sample of 142 depressed inpatients confirmed that lower expression of retinoid-related orphan receptor alpha (RORa, P = 6.23 × 10
−4
), germinal center expressed transcript 2 (GCET2, P = 2.08 × 10
−2
) and chitinase 3-like protein 2 (CHI3L2, P = 4.45 × 10
−2
) on admission were associated with beneficial treatment response. In addition, leukocyte-specific protein 1 (LSP1) significantly decreased after 5 weeks of treatment in responders (P = 2.91 × 10
−2
). Additional genetic, in vivo stress responsitivity data and murine gene expression findings corroborate our finding of RORa as a transcriptional marker of antidepressant response. In summary, using a genome-wide transcriptomics approach and subsequent validation studies, we identified several transcripts including the circadian gene transcript RORa that may serve as biomarkers indicating antidepressant treatment response.
This study was supported by DFG (EXC 1010 SyNergy), BMBF (01ES0811)
In 2008, van den Oord et al. identified in a genome-wide association study the MAM domain containing glycosylphosphatidylinositol anchor 2 gene (MDGA2 or MAMDC1) as a new candidate for neuroticism. ...In addition to the replication attempt of this association, we further investigated the role of MDGA2 with respect to harm avoidance (HA), a personality trait highly related to neuroticism. In a sample of mentally healthy volunteers (n=541) and depressed patients (n=199), neuroticism and HA were assessed with Eysenck's Revised Personality Questionnaire and Cloninger's Tridimensional Personality Questionnaire. Genotypic information (Illumina Bead Chip HumanHap300) of 100 single nucleotide polymorphisms (SNPs) located in the MDGA2 gene (±5 kb) was available, and additional four SNPs for replication were imputed. We were able to replicate the association between MDGA2 and neuroticism for the strongest SNPs of the genome-wide association study. It could further be shown that volunteers homozygous for the T-allele of SNP rs2416054 showed higher scores in the HA4 subscale 'Fatigability and asthenia' (Pnominal=0.0006), remaining significant after correction for multiple testing (Pwy-corrected=0.045). The same SNP also showed an association with HA4 in the patients' sample (Pnominal=0.03). Our finding provides further support for a link between variants in the MDGA2 gene and specific neuroticism-related phenotypes.
Since the first report of an association of SNPs in the P2RX7 gene with bipolar disorder (BD) eight subsequent studies have been published testing associations of the non-synonymous P2RX7 SNP ...rs2230912 with BD and/or major depressive disorder (MDD). While three studies reported association of this SNP, other studies did not detect significant associations. P2RX7 encodes a brain-expressed receptor, is involved in Ca
2+
dependent signal pathways and may regulate immune function and neurotransmitter release. We tested rs2230912 for association with MDD in the Munich Antidepressant Response Signature (MARS) study (543 depressed patients versus 542 control subjects) and performed a meta-analysis taking into account the eight published studies as well as the additional ninth study. In our association study with MDD a nominally significant association was observed for rs2230912 for the genotypic and the allelic (nominal p = 0.0251) but not for the dominant or heterozygous-disadvantage model. The association did not withhold correction for testing different modes of inheritance. The meta-analysis however resulted in a significant effect of rs2230912 on MDD/BD case-control status in the heterozygous-disadvantage model (p = 0.0028). This effect is significant after correction for multiple testing. Our association study and the meta-analysis thus further point towards a possible causal role of the non-synonymous P2RX7 SNP rs2230912 in affective disorders.
Bipolar disorder (BD) is a polygenic disorder that shares substantial genetic risk factors with major depressive disorder (MDD). Genetic analyses have reported numerous BD susceptibility genes, while ...some variants, such as single-nucleotide polymorphisms (SNPs) in CACNA1C have been successfully replicated, many others have not and subsequently their effects on the intermediate phenotypes cannot be verified. Here, we studied the MDD-related gene CREB1 in a set of independent BD sample groups of European ancestry (a total of 64888 subjects) and identified multiple SNPs significantly associated with BD (the most significant being SNP rs6785A, P=6.32 × 10−5, odds ratio (OR)=1.090). Risk SNPs were then subjected to further analyses in healthy Europeans for intermediate phenotypes of BD, including hippocampal volume, hippocampal function and cognitive performance. Our results showed that the risk SNPs were significantly associated with hippocampal volume and hippocampal function, with the risk alleles showing a decreased hippocampal volume and diminished activation of the left hippocampus, adding further evidence for their involvement in BD susceptibility. We also found the risk SNPs were strongly associated with CREB1 expression in lymphoblastoid cells (P<0.005) and the prefrontal cortex (P<1.0 × 10−6). Remarkably, population genetic analysis indicated that CREB1 displayed striking differences in allele frequencies between continental populations, and the risk alleles were completely absent in East Asian populations. We demonstrated that the regional prevalence of the CREB1 risk alleles in Europeans is likely caused by genetic hitchhiking due to natural selection acting on a nearby gene. Our results suggest that differential population histories due to natural selection on regional populations may lead to genetic heterogeneity of susceptibility to complex diseases, such as BD, and explain inconsistencies in detecting the genetic markers of these diseases among different ethnic populations.
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DOBA, EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, IZUM, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UILJ, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Correction to: Molecular Psychiatry advance online publication, 9 April 2013; doi:10.1038/mp.2013.37 After the above article was published, the authors noted that L Gan was linked to the wrong ...affiliation. Additionally, LJ Launer’s affiliation was listed incorrectly. The correct affiliations appear below.
Full text
Available for:
DOBA, EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, IZUM, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UILJ, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Background:
Data from clinical studies and results from animal models suggest a major involvement of the neurotrophin system in the pathology of depression and antidepressant treatment response. ...Genetic variations within the genes coding for the brain-derived neurotrophic factor (BDNF) and its key receptor Trkb (NTRK2) may therefore influence the response to antidepressant treatment.
Methods:
We performed a pharmacogenetic study in 398 at least moderately severe depressed Caucasian inpatients participating in the Munich Antidepressant Response Signature (MARS) study. We tested for single marker association of 82 SNPs tagging the BDNF and NTRK2 gene regions with antidepressant treatment response. In an attempt for replicating the results, we genotyped all nominally significant associated SNPs of the discovery analysis in additional 249 patients of the MARS study and 247 depressed inpatients from an independent sample recruited in Münster, Germany.
Results:
We identified several SNPs of the BDNF and NTRK2 gene that were significantly associated with antidepressant treatment response. We could partly replicate these associations in a meta-analysis of all samples (total of 894 patients), withstanding correction for multiple testing and adjustment for confounding variables.
Conclusions:
These findings provide further substantiation for a possible involvement of genetic variations in the BDNF and NTRK2 gene in the antidepressant treatment response.
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