Research reportDISC1-TSNAX and DAOA genes in major depression and citalopram efficacy
Introduction
Major depressive disorder (MDD) is a common disease involving high functional morbidity, an increased rate of suicide, high risk of recurrence, and considerable health service utilization (Judd et al., 2000). Currently only half of patients shows a satisfying response to pharmacotherapy (Kemp et al., 2008), which is partly due to the lack of reliable predictors of response. Both MDD pathogenesis and mechanisms of antidepressant action are thought to have a strong genetic component. Indeed, the prevalence of MDD in proband first-degree relatives is 15%, against the 5.4% of the general population (Gershon, 1992), and antidepressant response shows a familiar clustering (Franchini et al., 1998). Interestingly, several genes were identified as putative predictors of both MDD susceptibility and antidepressant response (Lekman et al., 2008, Tsai et al., 2008), consistently with the hypothesis that antidepressants reverse the biological unbalances involved in MDD. Among these genes, distrupted in schizophrenia 1 (DISC1), translin-associated factor X (TSNAX) and D-amino acid oxidase activator (DAOA) seem to have a cross-sectional role among major psychiatric diagnosis.
Composed of 13 alternatively spliced exons, DISC1 gene is expressed most highly during periods of neurogenesis (Lipska et al., 2006). In the adult mammalian brain it plays a critical role in neurite outgrowth and neuronal migration, particularly in the hippocampus (Carless et al., 2011). Interestingly, non-synonymous SNPs rs821616 (Cys704Ser) and rs6675281 (Leu607Phe) were associated with the expression of DISC1 splice variants, that encode truncated proteins. In particular, rs6675281 predicted higher expression of these transcripts in the hippocampus (Nakata et al., 2009) and was associated with altered hippocampal structure and function in healthy subjects (Callicott et al., 2005). DISC1 was firstly identified as a candidate gene for schizophrenia (St Clair et al., 1990), but following studies suggested it may be a factor influencing phenotypes related to several psychiatric diseases. Indeed, DISC1 sequence variations were associated with brain-related phenotypes (e.g. hippocampal gray matter volume and function (Di Giorgio et al., 2008), recall and memory, verbal and visuospatial ability, psychomotor processing (Palo et al., 2007)), MDD (Hashimoto et al., 2006, Schosser et al., 2010, Carless et al., 2011, Thomson et al., 2014) and bipolar disorder (Palo et al., 2007, Hennah et al., 2009). Furthermore, DISC1 SNPs have been associated with anxiety, depression, emotional stability and neuroticism (Harris et al., 2010). DISC1 knockdown leads to a reduction of VGF (i.e. nerve growth factor inducible, that has potent antidepressant effects), suggesting a possible molecular mechanism explaining the role of DISC1 in MDD (Ramos et al., 2014).
TSNAX gene is located immediately upstream of DISC1, and has been shown to undergo intergenic splicing with DISC1 (Millar et al., 2000). TSNAX protein is known to form a brain enriched complex with translin, that can bind single-stranded DNA and RNA through which it is involved in protein regulation (Finkenstadt et al., 2000). The TSNAX–DISC1 region was found associated with the risk of schizophrenia and bipolar disorder (Thomson et al., 2005, Palo et al., 2007), but some studies suggested it may be involved also in MDD risk (Hashimoto et al., 2006, Okuda et al., 2010), even if one negative study exists (Schosser et al., 2010).
DAOA (or G72) gene encodes for a protein that binds to and activates the D-serine amino acid oxidase that acts as a coactivator of the glycine binding site on the glutamatergic N-methyl D-aspartate (NMDA) receptor (Mustafa et al., 2004). Subsequently, it influences NMDA excitatory transmission (Panatier et al., 2006) and several lines of evidence suggested a strong role of the glutamatergic system in MDD pathogenesis (Drago et al., 2011). Further interesting issues are that DAOA gene generates several splice variants expressed in the brain (Grigoroiu-Serbanescu et al., 2010) and influences neuronal dendritic arborization (Kvajo et al., 2008). DAOA gene overlaps with G30 building a complex described as a susceptibility locus for various neuro-psychiatric disorders (Abou Jamra et al., 2006), i.e. schizophrenia and bipolar disorder (Grigoroiu-Serbanescu et al., 2010), history of affective episodes in bipolar disorder and schizophrenia (Williams et al., 2006, Corvin et al., 2007), panic disorder (Schumacher et al., 2005), and MDD (Rietschel et al., 2008, Gawlik et al., 2010, Chen et al., 2012). On the other hand, a recent meta-analysis did not demonstrate any evidence of involvement of rs2391191, rs947267 and rs3918342 in MDD risk (Tan et al., 2014), calling into question the hypothesis of DAOA contribution to the disease.
Given the well-established familial clustering of MDD, schizophrenia, bipolar disorder, and anxiety disorders (Gershon et al., 1988, Alonso et al., 2004, Kessler et al., 2005) and previous findings about DISC1, TSNAX and DAOA, association between these genes and MDD is plausible but still needs to be confirmed. Even fewer data are available about the role of these genes in antidepressant efficacy, that remains to be investigated. Indeed, only some negative findings were reported for TSNAX (Okuda et al., 2010) and DAOA (Chiesa et al., 2012).
The aims of the present paper are therefore to investigate the role of DISC1, TSNAX and DAOA variants in MDD risk through a case-control study and their possible effect on citalopram efficacy in a pharmacogenetic subsample. The possible impact of these genes on citalopram efficacy was then validated in an independent sample (Sequenced Treatment Alternatives to Relieve Depression or STAR⁎D).
Section snippets
Spanish sample
320 MDD outpatients were recruited at the Centre de Salut Mental Esquerre de Eixample (Hospital Clinic I Provincial de Barcelona, Spain). All patients fulfilled DSM-IV criteria for a current MDD episode. Exclusion criteria were diagnosis of bipolar disorder, substance abuse or dependence, mental retardation and medical diseases that could impair evaluation. The 21-item Hamilton Depression Rating Scale (HDRS) was used to evaluate clinical severity at recruitment. Detailed data about severity
Case-control study
Clinical-demographic features and genotype/allele frequencies of cases and controls are shown in Supplementary Table 1 and Supplementary Table 2, respectively. Genotype distribution of all SNPs was found to be in Hardy–Weinberg equilibrium in the MDD sample, as well as in the control sample (Supplementary Table 2).
Rs3738401 (DISC1), rs1615409 and rs766288 (TSNAX) showed genotypic and allelic evidence of association with the risk of MDD (Supplementary Table 2). Logistic regression models
Discussion
The present study investigated the still poorly known role of DISC1, TSNAX and DAOA genes in MDD susceptibility and antidepressant efficacy through a case-control study and a pharmacogenetic study in two independent samples both treated with citalopram. The case-control study found evidence of genotypic, allelic and haplotypic association among rs3738401 (DISC1), rs1615409 and rs766288 (TSNAX) and MDD (Table 1; Supplementary Tables 2–4), with a stronger effect of rs3738401 and rs1615409 in
Limitations
Some limitations of the present study should be considered. Firstly, the study was focused on the effect of 13 SNPs harbored by DISC1, TSNAX and DAOA genes, while both MDD and antidepressant response are thought to be affected by a high number of loci. On the other hand, the chosen candidate genes are supported in earlier literature regarding their involvement in MDD. Limited overlap among SNPs genotyped in the Spanish sample and in the STAR⁎D was found, even after imputation (only rs3738401
Conclusion
Keeping in mind both the strengths and limitations, the present study supported the role of DISC1-TSNAX variants in MDD susceptibility, confirming the relevance of these genes across major psychiatric disorders. On the other hand, genetic regions around DAOA rs778294 and DISC1 rs6675281-rs1000731 may influence citalopram efficacy. Given the poorly amount of data available so far, confirmation of these results is required.
Role of funding source
This study was supported through research projects funded by the Ministry of Science and Innovation (IT2009-0016, SAF2008-05674-C03-00/03 and FIS07/08152) and the Institute of Health Carlos III, CIBER of Mental Health (CIBERSAM) and also by the Comissionat per a Universitats I Recerca del DIUE of the Generalitat de Catalunya (2009SGR827).
Ministero dell’Istruzione, dell’Università e della Ricerca Azioni Integrate Italia- Spagna. prot. IT08447BDE. Pharmacogenetic of Antidepressants.
Conflict of interest
Dr. Serretti is or has been a consultant/speaker for: Abbott, Astra Zeneca, Clinical Data, Boheringer, Bristol Myers Squibb, Eli Lilly, GlaxoSmithKline, Janssen, Lundbeck, Pfizer, Sanofi, and Servier. The other authors declare that they have no conflicts of interest. Other authors declare they have no potential conflict of interest.
Acknowledgments
STAR⁎D data and biomaterials were obtained from the limited access datasets distributed from the NIH-supported “Sequenced Treatment Alternatives to Relieve Depression” (STAR⁎D). STAR⁎D focused on non-psychotic major depressive disorder in adults seen in outpatient settings. The primary purpose of this research study was to determine which treatments work best if the first treatment with medication does not produce an acceptable response. The study was supported by NIMH Contract no. N01MH90003
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