Renata B. Cupertino

SNARE complex in developmental psychiatry: neurotransmitter exocytosis and beyond

Multiple biological processes throughout development require intracellular vesicular trafficking, where the SNARE (soluble N-ethylmaleimide-sensitive factor (NSF) attachment protein (SNAP) receptors) complex plays a major role. The core proteins forming the SNARE complex are SNAP-25 (synaptosomal-associated protein 25), VAMP (vesicle-associated membrane protein) and Syntaxins, besides its regulatory proteins, such as Synaptotagmin. Genes encoding these proteins (SNAP25, VAMP1, VAMP2, STX1A, SYT1 and SYT2) have been studied in relation to psychiatric disorders susceptibility. Here, we review physiological aspects of SNARE complex and genetic association results reported for attention deficit hyperactivity disorder, both in children and adults, autism spectrum disorders, major depressive disorder, bipolar disorder and schizophrenia. Moreover, we included findings from expression, pharmacogenetics and animal model studies regarding these clinical phenotypes. The overall scenario depicted here suggests that the SNARE complex may exert distinct roles throughout development, with age-specific effects of genetic variants in psychiatric disorders. Such perspective should be considered in future studies regarding SNARE complex genes.

NOS1 and SNAP25 polymorphisms are associated with Attention- Deficit/Hyperactivity Disorder symptoms in adults but not in children

Several investigations documented that Attention-Deficit/Hyperactivity Disorder (ADHD) is better conceptualized as a dimensional disorder. At the same time, the disorder seems to have different neurobiological underpinnings and phenotypic presentation in children compared to adults. Neurodevelopmental genes could explain, at least partly these differences. The aim of the present study was to examine possible associations between polymorphisms in SNAP25, MAP1B and NOS1 genes and ADHD symptoms in Brazilian samples of children/adolescents and adults with ADHD. The youth sample consisted of 301 patients whereas the adult sample comprises 485 individuals with ADHD. Diagnoses of ADHD and comorbidities were based on the Diagnostic and Statistical Manual of Mental Disorders-4th edition criteria. The Swanson, Nolan and Pelham Scale-Version IV (SNAP-IV) was applied by psychiatrists blinded to genotype. The total SNAP-IV scores were compared between genotypes. Impulsivity SNAP-IV scores were also compared according to NOS1 genotypes. Adult patients homozygous for the C allele at SNAP25 rs8636 showed significantly higher total SNAP-IV scores (F = 11.215; adjusted P-value = 0.004). Impulsivity SNAP-IV scores were also significantly different according to NOS1 rs478597 polymorphisms in adults with ADHD (F = 6.282; adjusted P-value = 0.026). These associations were not observed in children and adolescents with ADHD. These results suggest that SNAP25 and NOS1 genotypes influence ADHD symptoms only in adults with ADHD. Our study corroborates previous evidences for differences in the genetic contribution to adult ADHD compared with childhood ADHD.

Effects of corticotropin-releasing hormone receptor 1 SNPs on major depressive disorder are influenced by sex and smoking status

BACKGROUND The corticotropin-releasing hormone receptor 1 (CRHR1) gene has been repeatedly implicated in Major Depressive Disorder (MDD) in humans and animal models; however, the findings are not absolutely convergent. Since recent evidence from genome-wide association studies suggests that narrowing the phenotypic heterogeneity may be crucial in genetic studies of MDD, the aim of this study was to evaluate the effects of CRHR1 polymorphisms on MDD while addressing the influence of sex and smoking status. METHODS The association of the CRHR1 SNPs rs12944712, rs110402, and rs878886 with MDD was evaluated in 629 Brazilian adults of European descent recruited from the general population [180 (28.6%) with lifetime MDD]. The sample was subdivided according to sex and smoking status RESULTS: Among nonsmokers, there were nominal associations between MDD and all tested SNPs (rs12944712, P=0.042; rs110402, P=0.031, and rs878886, P=0.040), regardless of sex. In addition, there were significant effects of rs110402 in women (Pcorr=0.034) and rs878886 in men (Pcorr=0.013). Among lifetime smokers, there were no significant associations between CRHR1 SNPs and MDD LIMITATIONS: The lack of a depression rating scale; scarcity of information on the functionality of the CRHR1 SNPs; and relatively small sample sizes in some subgroups. CONCLUSIONS Our results strengthen the evidence for the role of CRHR1 SNPs in MDD susceptibility and suggest that their effects may be modulated by sex and smoking status. These findings suggest the perspective that reducing phenotypic heterogeneity is warranted in genetic studies of MDD.

Pleiotropic effects of Chr15q25 nicotinic gene cluster and the relationship between smoking, cognition and ADHD.

Polymorphisms in the CHRNA5-CHRNA3-CHRNB4 gene cluster (Chr15q25) have been robustly associated with nicotine dependence, including genome-wide studies, as well as with cognitive and neuropsychological measures. In addition, cognitive processes can be influenced by nicotine use through nicotinic acetylcholine receptors (nAChRs). Here, we evaluated the effect of polymorphisms in CHRNA5-CHRNA3-CHRNB4 gene cluster and their interaction with tobacco smoking status on cognition in patients with Attention Deficit/Hyperactivity Disorder (ADHD). Eight SNPs from the CHRNA5-CHRNA3-CHRNB4 gene cluster were evaluated on a clinical sample of 403 adults with ADHD. Cognitive performance was assessed using the Wechsler Adult Intelligence Scale-Revised (WAIS-R). Analyses of covariance were used to assess the influence of single markers and their interaction with smoking status in the Vocabulary and Block Design subtests of WAIS-R. Correction for multiple comparisons was applied. Lifetime smoking was associated to Vocabulary subtest. The TT genotypes of CHRNA5 SNPs rs588765 and rs514743 showed a trend towards association with, respectively, higher and lower scores on the Vocabulary subtest. There was a significant interaction between intergenic SNP rs8023462 and smoking on Vocabulary scores. Our results are consistent with an influence of variants in the CHRNA5-CHRNA3-CHRNB4 gene cluster on cognitive measures. The overall scenario suggests a pleiotropic role of Chr15q25 nicotinic gene cluster with complex influences in ADHD, tobacco smoking and cognitive performance, characteristics that can be partially interdependent and may share underlying genetic factors.

Exocytosis-related genes and response to methylphenidate treatment in adults with ADHD

Experimental studies have demonstrated that methylphenidate (MPH) modulates the synaptic vesicle trafficking and synaptotagmin-1 (SytI) mRNA levels. SytI is a regulatory protein of the SNARE complex, a neurotransmitter exocytosis mediator. Despite this evidence, most SNARE complex-related genes have never been evaluated in attention-deficit/hyperactivity disorder (ADHD) pharmacogenetics. This study evaluates, for we believe the first time, polymorphisms on the SNARE complex-related genes STX1A (rs2228607), VAMP2 (26bp Ins/Del) and SYT1 (rs1880867 and rs2251214) on the response to immediate-release methylphenidate (IR-MPH) in a naturalistic sample of adults with ADHD. The sample comprised 433 subjects, of which 272 (62.8%) have completed the short-term IR-MPH treatment (at least 30 days). The main outcome measure was the categorical variable of short-term response to IR-MPH based on the Swanson, Nolan and Pelham Rating Scale version 4 (SNAP-IV), and on the clinical global impression-improvement scale. Additional analyses evaluated the percentage of SNAP-IV symptom reduction for each dimension as well as short- and long- (7 years) term treatment persistence. SYT1-rs2251214 was associated with the categorical short-term response to IR-MPH (P=0.006, PFDR=0.028), and with the percentage of inattention and oppositional defiant disorder symptoms reduction (P=0.007, PFDR=0.028 and P=0.017, PFDR=0.048, respectively). SYT1-rs2251214 was also associated with short-term treatment persistence (P=0.018, PFDR=0.048), and with months of treatment (P=0.002, PFDR=0.016) in the long-term protocol. Our findings suggest that SYT1-rs2251214 presents a broad influence in IR-MPH response variability in adults with ADHD, being involved with both symptom response and treatment persistence. If such findings are replicated, SytI could represent a key element in MPH pharmacodynamics in adults with ADHD.

Replicated association of Synaptotagmin (SYT1) with ADHD and its broader influence in externalizing behaviors

Attention-Deficit/Hyperactivity Disorder (ADHD) is a common psychiatric disorder, affecting both children and adults. The Soluble N-ethylmaleimide sensitive factor Attachment REceptors (SNARE) complex has been implicated in ADHD pathophysiology since it is a key component of neurotransmitter release events and neurodevelopment processes, and SNPs in this complex have been associated with ADHD. Here we aim to analyze the effects of SNARE complex variants on ADHD susceptibility and its clinical heterogeneity in affected adults. We tested the association between ADHD and polymorphisms on the SNARE genes STX1A (rs2228607), SYT1 (rs1880867 and rs2251214), VAMP2 (26bp Ins/Del) and SNAP25 (rs6108461 and rs8636) on a sample comprised of 548 adults with ADHD and 644 non-affected controls. Regarding clinical heterogeneity, we further investigated the effects of associated SNPs on age at onset of impairment due to ADHD and on relevant externalizing behaviors (i.e. school suspensions/expulsions and problems with law/authority) and comorbidities (i.e. Substance Use Disorder, Oppositional Defiant Disorder, Conduct Disorder and Antisocial Personality Disorder). We replicated a previously reported association between SYT1-rs2251214 and ADHD in adulthood. This SNP was also associated with age at onset of impairment due to ADHD symptoms and with a range of externalizing phenotypes. These findings involving SYT1 suggest that variation in neurotransmitter exocytosis mechanisms may represent an underlying genetic factor shared by a spectrum of externalizing behaviors and disorders, including - but not restricted to - ADHD.

Childhood Maltreatment Linked with a Deterioration of Psychosocial Outcomes in Adult Life for Southern Brazilian Transgender Women

A history of childhood maltreatment (HCM) has been associated with detrimental psychiatric outcomes. This is particularly true for transgender, for whom there is initial evidence that HCM may be associated with psychiatric morbidity. Our study aimed to further characterize the relationship between HCM and the development of mental disorder in adult life, based on a sample of Brazilian transgender women. Cross-sectional data were collected from a consecutive sample of 289 transgender women who attended the Hospital Clínicas clinic for gender dysphoria, in Porto Alegre, between 1998 and 2014. Our results demonstrated a greater risk of deteriorating mental health amongst participants who had experienced HCM. Given the disproportionally high rate of HCM in transgender persons, we advocate for greater assistance for transgender persons.

Further replication of the synergistic interaction between LPHN3 and the NTAD gene cluster on ADHD and its clinical course throughout adulthood

Attention-Deficit/Hyperactivity Disorder (ADHD) is a common and highly heritable neuropsychiatric disorder. Despite the high heritability, the unraveling of specific genetic factors related to ADHD is hampered by its considerable genetic complexity. Recent evidence suggests that gene-gene interactions can explain part of this complexity. We examined the impact of strongly supported interaction effects between the LPHN3 gene and the NTAD gene cluster (NCAM1-TTC12-ANKK1-DRD2) in a 7-year follow-up of a clinical sample of adults with ADHD, addressing associations with susceptibility, symptomatology and stability of diagnosis. The sample comprises 548 adults with ADHD and 643 controls. Entropy-based analysis indicated a potential interaction between the LPHN3-rs6551665 and TTC12-rs2303380 SNPs influencing ADHD symptom counts. Further analyses revealed significant interaction effects on ADHD total symptoms (p=0.002), and with hyperactivity/impulsivity symptom counts (p=0.005). In the group composed by predominantly hyperactive/impulsive and combined presentation, the presence of LPHN3-rs6551665 G allele was related to increased ADHD risk only in individuals carrying the TTC12-rs2303380 AA genotype (p=0.026). Also, the same allelic constellation is involved in maintenance of ADHD in a predominantly hyperactive/impulsive or combined presentation after a 7-year follow-up (p=0.008). These observations reinforce and replicate previous evidence suggesting that an interaction effect between the LPHN3 gene and the NTAD cluster may have a role in the genetic substrate associated to ADHD also in adults. Moreover, it is possible that the interactions between LPHN3 and NTAD are specific factors contributing to the development of an ADHD phenotype with increased hyperactivity/impulsivity that is maintained throughout adulthood.