Natalie Freeman

Systematic analysis of dopamine receptor genes (DRD1-DRD5) in antipsychotic-induced weight gain.

Antipsychotic-induced weight gain has emerged as a serious complication in the treatment of patients with most antipsychotics. We have conducted the first in-depth examination of dopamine receptor genes in antipsychotic-induced weight gain. A total of 206 patients (139 of European descent and 56 African Americans) who underwent treatment for chronic schizophrenia or schizoaffective disorder were evaluated after on average over 6 weeks of treatment. Thirty-six tag single nucleotide polymorphisms (SNPs) and one variable-number tandem repeat, spanning the five dopamine receptor genes (DRD1–DRD5) were analyzed. In the total sample, we found a nominally significant association between the DRD2 rs1079598 marker and weight change using a cutoff of 7% gain (P=0.03). When stratifying the sample according to ethnicity and antipsychotics with highest risk for weight gain, we found significant associations in three DRD2 SNPs: rs6277 (C957T), rs1079598 and rs1800497 (TaqIA). The other genes were primarily negative. We provide evidence that dopamine receptor DRD2 gene variants might be associated with antipsychotic-induced weight gain in chronic schizophrenia patients.

Genes for Emotion-Enhanced Remembering Are Linked to Enhanced Perceiving

Emotionally enhanced memory and susceptibility to intrusive memories after trauma have been linked to a deletion variant (i.e., a form of a gene in which certain amino acids are missing) of ADRA2B, the gene encoding subtype B of the α2-adrenergic receptor, which influences norepinephrine activity. We examined in 207 participants whether variations in this gene are responsible for individual differences in affective influences on initial encoding that alter perceptual awareness. We examined the attentional blink, an attentional impairment during rapid serial visual presentation, for negatively arousing, positively arousing, and neutral target words. Overall, the attentional blink was reduced for emotional targets for ADRA2B-deletion carriers and noncarriers alike, which reveals emotional sparing (i.e., reduction of the attentional impairment for words that are emotionally significant). However, deletion carriers demonstrated a further, more pronounced emotional sparing for negative targets. This finding demonstrates a contribution of genetics to individual differences in the emotional subjectivity of perception, which in turn may be linked to biases in later memory.

Dopaminergic system genes in childhood aggression: Possible role for DRD2

Abstract Excessive or deficient levels of extracellular dopamine have been hypothesized to contribute to a broad spectrum of mood, motor, and thought abnormalities, and dopaminergic system genes have been implicated in aggressive behaviour from animal and human studies. Objective. We examined selected members of the dopaminergic system genes for association with child aggression. Method. We analyzed polymorphisms in the dopamine transporter DAT1/SLC6A3, dopamine receptor DRD2, and DRD4 genes in our sample of pervasive childhood aggression consisting of 144 cases paired with 144 healthy controls, matched for sex and ethnicity. Results. Aggressive children were significantly more likely to have the at least one copy of the G allele for the DRD2 A-241G polymorphism (genotypic P=0.02; allelic P=0.01). The DRD2 rs1079598 CC genotype was overrepresented in aggressive children compared to controls (genotype P=0.04). The DRD2 TaqIA T allele (P=0.01) and the TT genotype (P=0.01) were also significantly overrepresented in aggressive children. Conclusions. Our preliminary results suggest that three polymorphisms in DRD2 are associated with childhood aggression. Future studies are required to replicate the current results and to further explore the relationship between the dopamine system and aggressive behaviour in children.

Association study of the vesicular monoamine transporter gene SLC18A2 with tardive dyskinesia

Tardive dyskinesia (TD) is an involuntary movement disorder that can occur in up to 25% of patients receiving long-term first-generation antipsychotic treatment. Its etiology is unclear, but family studies suggest that genetic factors play an important role in contributing to risk for TD. The vesicular monoamine transporter 2 (VMAT2) is an interesting candidate for genetic studies of TD because it regulates the release of neurotransmitters implicated in TD, including dopamine, serotonin, and GABA. VMAT2 is also a target of tetrabenazine, a drug used in the treatment of hyperkinetic movement disorders, including TD. We examined nine single-nucleotide polymorphisms (SNPs) in the SLC18A2 gene that encodes VMAT2 for association with TD in our sample of chronic schizophrenia patients (n = 217). We found a number of SNPs to be nominally associated with TD occurrence and the Abnormal Involuntary Movement Scale (AIMS), including the rs2015586 marker which was previously found associated with TD in the CATIE sample (Tsai et al., 2010), as well as the rs363224 marker, with the low-expression AA genotype appearing to be protective against TD (p = 0.005). We further found the rs363224 marker to interact with the putative functional D2 receptor rs6277 (C957T) polymorphism (p = 0.001), supporting the dopamine hypothesis of TD. Pending further replication, VMAT2 may be considered a therapeutic target for the treatment and/or prevention of TD.

Deletion variant in the ADRA2B gene increases coupling between emotional responses at encoding and later retrieval of emotional memories.

A deletion variant of the ADRA2B gene that codes for the α2b adrenoceptor has been linked to greater susceptibility to traumatic memory as well as attentional biases in perceptual encoding of negatively valenced stimuli. The goal of the present study was to examine whether emotional enhancements of memory associated with the ADRA2B deletion variant were predicted by encoding, as indexed by the subjectively perceived emotional salience (i.e., arousal) of events at the time of encoding. Genotyping was performed on 186 healthy young adults who rated positive, negative, and neutral scenes for level of emotional arousal and subsequently performed a surprise recognition memory task 1 week later. Experience of childhood trauma was also measured, as well as additional genetic variations associated with emotional biases and episodic memory. Results showed that subjective arousal was linked to memory accuracy and confidence for ADRA2B deletion carriers but not for non-carriers. Our results suggest that carrying the ADRA2B deletion variant enhances the relationship between arousal at encoding and subsequent memory for moderately arousing events.

Neurogenetic Variations in Norepinephrine Availability Enhance Perceptual Vividness

Emotionally salient aspects of the world are experienced with greater perceptual vividness than mundane ones; however, such emotionally enhanced vividness (EEV) may be experienced to different degrees for different people. We examined whether BOLD activity associated with a deletion variant of the ADRA2b gene coding for the α2b adrenoceptor modulates EEV in humans. Relative to noncarriers, ADRA2b deletion carriers showed higher levels of perceptual vividness, with the ventromedial prefrontal cortex (VMPFC) showing greater modulation by EEV. Deletion carriers were also more sensitive to the featural salience of the images, suggesting a more pervasive role of norepinephrine in perceptual encoding. Path analysis revealed that, whereas a simple model by which the amygdala modulated the lateral occipital complex best characterized EEV-related activity in noncarriers, contributions of an additional VMPFC pathway best characterized deletion carriers. Thus, common norepinephrine-related neurogenetic differences enhance the subjective vividness of perceptual experience and its emotional enhancement.

Dopamine D2 receptor gene variants and response to rasagiline in early Parkinson's disease: a pharmacogenetic study.

The treatment of early Parkinsons disease with dopaminergic agents remains the mainstay of symptomatic therapy for this incurable neurodegenerative disorder. However, clinical responses to dopaminergic drugs vary substantially from person to person due to individual-, drug- and disease-related factors that may in part be genetically determined. Using clinical data and DNA samples ascertained through the largest placebo-controlled clinical trial of the monoamine oxidase B inhibitor, rasagiline (ClinicalTrials.gov number, NCT00256204), we examined how polymorphisms in candidate genes associate with the clinical response to rasagiline in early Parkinsons disease. Variants in genes that express proteins involved in the pharmacokinetics and pharmacodynamics of rasagiline, and genes previously associated with the risk to develop Parkinsons disease were genotyped. The LifeTechnologies OpenArray NT genotyping platform and polymerase chain reaction-based methods were used to analyse 204 single nucleotide polymorphisms and five variable number tandem repeats from 30 candidate genes in 692 available DNA samples from this clinical trial. The peak symptomatic response to rasagiline, the rate of symptom progression, and their relation to genetic variation were examined controlling for placebo effects using general linear and mixed effects models, respectively. Single nucleotide polymorphisms, rs2283265 and rs1076560, in the dopamine D2 receptor gene (DRD2) were found to be significantly associated with a favourable peak response to rasagiline at 12 weeks in early Parkinsons disease after controlling for multiple testing. From a linear regression, the betas were 2.5 and 2.38, respectively, with false discovery rate-corrected P-values of 0.032. These polymorphisms were in high linkage disequilibrium with each other (r(2) = 0.96) meaning that the same clinical response signal was identified by each of them. No polymorphisms were associated with slowing the rate of worsening in Parkinson symptoms from Weeks 12 to 36 after correction for multiple testing. This is the largest and most comprehensive pharmacogenetics study to date examining clinical response to an anti-parkinsonian drug and the first to be conducted in patients with early stage Parkinsons disease receiving monotherapy. The results indicate a clinically meaningful benefit to rasagiline in terms of the magnitude of improvement in parkinsonian symptoms for those with the favourable response genotypes. Future work is needed to elucidate the specific mechanisms through which these DRD2 variants operate in modulating the function of the nigrostriatal dopaminergic system.media-1vid110.1093/brain/aww109_video_abstractaww109_video_abstract.

Association study of polymorphisms in cholecystokinin gene and its receptors with antipsychotic induced weight gain in schizophrenia patients

Cholecystokinin (CCK) gene and its receptors play an important role in several biological processes including satiety signaling. Administration of exogenous or endogenously secreted CCK leads to decreased food intake in both rats and humans. Similarly, in rats pretreated with intraperitoneal CCK, antagonists of the CCKA receptor prevent decrease in food intake. The CCKB receptor plays an important role in anxiety and gastric acid secretion. We investigated the role of polymorphisms in the CCK gene (2 SNPs) and its receptors CCKA (4 SNPs) and CCKB (4SNPs, 1 microsatellite, CTn) in antipsychotic induced weight gain (n=215). Weight change (%) from baseline was compared across genotypic groups using analysis of covariance. In the European ancestry patients treated with clozapine or olanzapine a trend of association was observed with the SNP rs2929183 (p=0.10) in CCKBR gene. Carriers of the genotype AA (3.23%±4.8) gained less weight than the AG and GG genotypes (6.50%±6.5; p=0.035). A similar trend was observed for the CTn repeat, where carriers of the LL genotype gained less weight (3.73%±5.41) than the S allele carrying genotypes (6.29%±6.2, p=0.05). In the subjects of African ancestry we observed similar marginal association although with the opposite allele. However, none of these observations would survive corrections for multiple testing. None of the other polymorphisms in either CCK or CCKA receptor genes was associated with weight change (%). In conclusion, CCKB receptor gene may play a role in antipsychotic induced weight gain. However, these observations need to be replicated in a larger and independent sample set.

Association study of early-immediate genes in childhood-onset mood disorders and suicide attempt

Childhood-onset mood disorders (COMD) are serious affective disorders with deleterious developmental sequelae including interpersonal dysfunction, psychotic symptoms and suicidal behavior. The current study examines 10 markers from two early-immediate genes for association with COMD and suicide attempt (SA) - HOMER1 and human neuronal pentraxin II (NPTX2). We examined individuals diagnosed with COMD versus matched controls, as well as individuals with COMD and a history of at least one lifetime SA versus COMD participants with no history of SA. No significant genotypic association was noted between any of the single nucleotide polymorphisms (SNPs) and COMD. Our sample yielded a nominally significant allelic association between the HOMER1 rs7713917 SNP and COMD. We report significant genotype associations between HOMER1 rs2290639 and SA , and between NPTX2 markers rs705315 and rs1681248 and SA, findings that remained statistically significant after multiple test correction. A three-way interaction was observed among HOMER1 rs4704560, rs2290639 and NPTX2 rs705318. The associations we describe for HOMER1 and NPTX2 with SA should be considered preliminary until replicated.

SNP genotyping using TaqMan® technology: the CYP2D6*17 assay conundrum

CYP2D6 contributes to the metabolism of many clinically used drugs and is increasingly tested to individualize drug therapy. The CYP2D6 gene is challenging to genotype due to the highly complex nature of its gene locus. TaqMan® technology is widely used in the clinical and research settings for genotype analysis due to assay reliability, low cost, and the availability of commercially available assays. The assay identifying 1023C>T (rs28371706) defining a reduced function (CYP2D6*17) and several nonfunctional alleles, produced a small number of unexpected diplotype calls in three independent sets of samples, i.e. calls suggested the presence of a CYP2D6*4 subvariant containing 1023C>T. Gene resequencing did not reveal any unknown SNPs in the primer or probe binding sites in any of the samples, but all affected samples featured a trio of SNPs on their CYP2D6*4 allele between one of the PCR primer and probe binding sites. While the phenomenon was ultimately overcome by an alternate assay utilizing a PCR primer excluding the SNP trio, the mechanism causing this phenomenon remains elusive. This rare and unexpected event underscores the importance of assay validation in samples representing a variety of genotypes, but also vigilance of assay performance in highly polymorphic genes such as CYP2D6.