Further evidence for association of polymorphisms in the CNR1 gene with cocaine addiction: confirmation in an independent sample and meta-analysis.

Genetic research on cocaine dependence (CD) may help clarify our understanding of the disorder as well as provide insights for effective treatment. As endocannabinoid signaling and dopamine neurotransmission have been shown to be involved in drug reward, genes related to these systems are plausible candidates for susceptibility to CD. The cannabinoid receptor 1 protein regulates both the endocannabinoid and dopaminergic neurobiological systems, and polymorphisms in the cannabinoid receptor gene, CNR1, have been associated previously with substance dependence. In this study, we attempt to replicate findings associating CNR1 with CD in African Americans. Cocaine-addicted individuals (n=860) and unaffected controls (n=334) of African descent were genotyped for two single nucleotide polymorphisms (SNPs) in CNR1 (rs6454674, rs806368). We observed a significant difference in genotype frequencies between cases and controls for both SNPs (P≤0.042). A meta-analysis was also performed combining our data with that of Zuo et al. who also studied these polymorphisms in African American cocaine addicts (total n=1253 cases versus 543 controls). When our data were combined, rs6454674 increased in significance to P=0.027; however, rs806368 was no longer significant. This study confirms the association between rs6454674 and CD. However, because there is considerable co-morbidity of CD with other drugs of abuse, additional studies are necessary to determine whether polymorphisms in CNR1 induce a general susceptibility to substance dependence or are specific to cocaine addiction. Furthermore, as this population consists of American individuals of African descent, the possibility of population stratification should not be excluded.

Association between polymorphisms in the metallophosphoesterase (MPPE1) gene and bipolar disorder.

Genetic linkage studies in bipolar disorder (BPD) suggest that a susceptibility locus exists on chromosome 18p11. The metallophosphoesterase (MPPE1) gene maps to this region. Dysregulation of protein phosphorylation and subsequent abnormal cellular signaling has been postulated to be involved in neuropsychiatric disorders thus making MPPE1 a plausible biological candidate gene for BPD. In this study, we hypothesized that genetic variation in the MPPE1 gene contributes to BPD. We tested this hypothesis by genotyping four SNPs (rs871044; rs3974590; rs593713; rs602201) in BPD patients (n = 570) and healthy controls (n = 725). Genotypes and allele frequencies were compared between groups using Chi square contingency analysis. Linkage disequilibrium (LD) between markers was calculated and estimated haplotype frequencies were compared between groups. Single marker analysis revealed an association of rs3974590 with BPD (P = 0.009; permutation corrected P = 0.046). Haplotype analysis did not show any significant association with disease after permutation correction. Our results provide evidence of an association between a polymorphism in the MPPE1 gene and BPD. Additional studies are necessary to confirm and elucidate the role of MPPE1 as a susceptibility gene for BPD on chromosome 18p.

Acupuncture for Analgesia During Transurethral Resection of Bladder Tumor.

Background: Acupuncture has been widely studied, and theories regarding its analgesic mechanism of action have been proposed. It has been used for procedural analgesia; however, no reports of its use in urologic surgery have been reported. In this case report, we demonstrate how acupuncture can be used as an alternative to general anesthesia for transurethral resection of bladder tumor (TURBT). This may serve as an attractive option for bladder cancer patients with medical comorbidities, which predispose them to high risk for general anesthesia. Case Presentation: A 65-year-old Caucasian female with toxicant-induced loss of tolerance (TILT) was found to have a bladder mass. TURBT was discussed, and in light of her TILT syndrome, she elected to undergo the procedure with acupuncture in lieu of general anesthesia for fear of an adverse reaction. Acupuncture was performed by a trained practitioner with therapeutic needles placed in the ears, hands, abdomen, and lower extremities bilaterally. She was subsequently taken to the operating room where we performed a TURBT of a bladder tumor overlying the left ureteral orifice. The procedure was generally well tolerated and the patient experienced mild pain. There were no perioperative complications. The tumor was estimated to be 3 cm in largest diameter, and a total of 8 g of aggregate tissue was sent to our pathologists. Pathology analysis demonstrated adequate resection with detrusor muscle present in the sample. The bladder tumor was low-grade papillary urothelial cell carcinoma (Stage Ta). She has had tumor recurrence and has undergone repeat TURBT, but to date, she is 22 months free of bladder cancer. Conclusion: In this case report, we demonstrate that acupuncture is a safe and effective alternative to general anesthesia for patients undergoing TURBT. Since tobacco use is prevalent among bladder cancer patients, many of these individuals have associated medical comorbidities, which predispose them to high risk with general anesthesia. Therefore, acupuncture may serve as an attractive alternative for certain patients in this population.

Genetic variants in the cocaine- and amphetamine-regulated transcript gene (CARTPT) and cocaine dependence.

Dopaminergic brain systems have been implicated to play a major role in drug reward, thus making genes involved in these circuits plausible candidates for susceptibility to substance use disorders. The cocaine- and amphetamine-regulated transcript peptide (CARTPT) is involved in reward and feeding behavior and has functional characteristics of an endogenous psychostimulant. In this study we tested the hypothesis that variation in the CARTPT gene increases susceptibility to cocaine dependence in individuals of African descent. Genotypes of three HapMap tagging SNPs (rs6894758; rs11575893; rs17358300) across the CARTPT gene region were obtained in cocaine dependent individuals (n=348) and normal controls (n=256). All subjects were of African descent. There were no significant differences in allele, genotype or haplotype frequencies between cases and controls for any of the tested SNPs. Our results do not support an association of the CARTPT gene with cocaine dependence; however, additional studies using larger samples, comprehensive SNP coverage, and different populations are necessary to conclusively rule out CARTPT as a contributing factor in the etiology of cocaine dependence.

Association between polymorphisms in the vesicular monoamine transporter 1 gene (VMAT1/SLC18A1) on chromosome 8p and schizophrenia.

Linkage studies have suggested a susceptibility locus for schizophrenia (SZ) exists on chromosome 8p21-22. The vesicular monoamine transporter 1 gene (VMAT1), also known as SLC18A1, maps to this SZ susceptibility locus. Vesicular monoamine transporters are involved in the presynaptic vesicular packaging of monoamine neurotransmitters, which have been postulated to play a role in the etiology of SZ. Variations in the VMAT1 gene might affect transporter function and/or expression, and might be involved in the etiology of SZ. Genotypes of 62 patients with SZ and 188 control subjects were obtained for 4 missense single nucleotide polymorphisms (Thr4Pro, Thr98Ser, Thr136Ile, Val392Leu) and 2 noncoding single nucleotide polymorphisms (rs988713, rs2279709). All cases and controls were of European descent. The frequency of the minor allele of the Thr4Pro polymorphism was significantly increased in SZ patients when compared to controls (p = 0.0140; d.f. = 1; OR = 1.69; 95% CI = 1.11-2.57). Assuming a recessive mode of inheritance, the frequency of homozygote 4Pro carriers was significantly increased in the SZ patients when compared to controls (24 vs. 8%, respectively; p = 0.0006; d.f. = 1; OR = 3.74; 95% CI = 1.703-8.21). Haplotype analysis showed nominal significance for an individual risk haplotype (p = 0.013); however, after permutation correction, the global p value did not attain a statistically significant level (p = 0.07). Results suggest that variations in the VMAT1 gene may confer susceptibility to SZ in patients of European descent. Further studies are necessary to confirm this effect, and to elucidate the role of VMAT1 in central nervous system physiology and possible involvement in the genetic origins of SZ.

Association analysis between polymorphisms in the myo-inositol monophosphatase 2 (IMPA2) gene and bipolar disorder.

Linkage studies in bipolar disorder (BPD) suggest that a susceptibility locus exists on chromosome 18p11. The myo-inositol monophosphatase 2 gene (IMPA2) maps to this genomic region. Myo-inositol monophosphatase dephosphorylates inositol monophosphate, regenerating free inositol. Lithium, a common treatment for BPD, has been shown to inhibit IMPA2 activity and decrease levels of inositol. It is hypothesized that lithium conveys its therapeutic effect for BPD patients partially through inositol regulation. Hence, dysfunction of inositol caused by IMPA2 irregularity may contribute to the pathophysiology of BPD. In this study, we hypothesize that genetic variations in the IMPA2 gene contributes to increased susceptibility to BPD. We tested this hypothesis by genotyping 9 SNPs (rs1787984; rs585247; rs3974759; rs650727; rs589247; rs669838; rs636173; rs3786285; rs613993) in BPD patients (n=556) and controls (n=735). Genotype and allele frequencies were compared between groups using Chi square contingency analysis. Linkage disequilibrium (LD) between markers was calculated and estimated haplotype frequencies were compared between groups. Single marker analysis revealed several associations between IMPA2 variations and BPD, which were subsequently rendered non-significant after correction for multiple testing. Although our study did not show strong support for an association between the tested IMPA2 polymorphisms and susceptibility to BPD, additional larger studies are necessary to comprehensively investigate a role of the IMPA2 gene in the pathophysiology of BPD.

Association analysis between polymorphisms in the dopamine D2 receptor (DRD2) and dopamine transporter (DAT1) genes with cocaine dependence.

Genetic research on cocaine dependence (CD) may help clarify our understanding of the disorder as well as provide novel insights for effective treatment. Since dopamine neurotransmission has been shown to be involved in drug reward, related genes are plausible candidates for susceptibility to CD. The dopamine receptor D(2) (DRD2) protein and dopamine transporter (DAT1) protein play regulatory roles in dopamine neurotransmission. The TaqI A single-nucleotide polymorphism (SNP) in the DRD2 gene and the 3' variable number tandem repeat (VNTR) polymorphism in the DAT1 gene have been implicated in psychiatric disorders and drug addictions. In this study, we hypothesize that these polymorphisms contribute to increased risk for CD. Cocaine-dependent individuals (n=347) and unaffected controls (n=257) of African descent were genotyped for the polymorphisms in the DRD2 and DAT1 genes. We observed no statistically significant differences or trends in allele or genotype frequencies between cases and controls for either of the tested polymorphisms. Our study suggests that there is no association between the DRD2 and DAT1 polymorphisms and CD. However, additional studies using larger sample sizes and clinically homogenous populations are necessary before confidently excluding these variants as contributing genetic risk factors for CD.

Association analysis between polymorphisms in the conserved dopamine neurotrophic factor (CDNF) gene and cocaine dependence.

Cocaine-induced neuroplasticity changes in the mesocorticolimbic dopamine systems are thought to be involved in the pathophysiology of cocaine dependence. Since neurotrophic factors have been observed to prevent/reverse and mimic cocaine-induced neurobiological changes in the brain, related genes are plausible candidates for susceptibility to cocaine dependence. The novel conserved dopamine neurotrophic factor protein (CDNF) promotes the survival, growth, and function of dopamine-specific neurons and is expressed in brain regions that undergo cocaine-induced neuroplasticity. In this study, we hypothesize that polymorphisms in the CDNF gene (CDNF/ARMETL1) contribute to increased risk for cocaine dependence. Cocaine dependent individuals (n=351) and unaffected controls (n=257) of African descent were genotyped for four single nucleotide polymorphisms (SNPs) in the CDNF gene (rs11259365, rs7094179, rs7900873, rs2278871). We observed no significant differences in allele, genotype, or haplotype frequencies between cases and controls for any of the tested SNPs. Our study suggests that there is no association between variants in the CDNF gene and cocaine dependence. However, additional studies using larger sample sizes, comprehensive SNP coverage, and clinically homogenous populations are necessary before confidently excluding CDNF as a significant genetic risk factor for cocaine dependence.

Association between polymorphisms in the vesicle-associated membrane protein-associated protein A (VAPA) gene on chromosome 18p and bipolar disorder.

Linkage studies in bipolar disorder (BPD) suggest that a susceptibility locus exists on chromosome 18p11. The vesicle-associated membrane protein-associated protein A (VAPA) gene maps to this region. VAPA interacts with presynaptic proteins and is necessary for vesicular neurotransmission. Dysregulation of synaptic neurotransmission might contribute to the pathophysiology of BPD. In this study, we hypothesize that genetic variations in the VAPA gene contribute to BPD. We tested this hypothesis by genotyping 6 SNPs (rs494015; rs29193; rs29162; rs29145; rs29067; rs29066) in BPD patients (n = 570) and healthy controls (n = 730). Genotype and allele frequencies were compared between groups using Chi square contingency analysis. Linkage disequilibrium (LD) between markers was calculated and estimated haplotype frequencies were compared between groups. Single marker analysis revealed an association of rs29067 and rs29066 with BPD; however, after permutation correction, only rs29066 showed a trend towards an allelic association (P = 0.066). Haplotype analysis did not show any significant association with disease after permutation correction. Our results provide suggestive evidence of an association between SNPs in the 3'UTR of the VAPA gene and BPD. Interestingly, these SNPs are in close proximity to the microsatellite marker D18S464, which showed significant signals in previous linkage studies of BPD. Additional studies are necessary to confirm and elucidate the role of VAPA as a susceptibility gene for BPD on chromosome 18p.

Association analysis of the pituitary adenylate cyclase-activating polypeptide (PACAP/ADCYAP1) gene in bipolar disorder.

BACKGROUND: Linkage studies in bipolar disorder (BPD) suggest that a susceptibility locus exists on chromosome 18p11. The pituitary adenylate cyclase-activating polypeptide/adenylate cyclase-activating polypeptide 1 (pituitary) (PACAP/ADCYAP1) gene maps to this region. PACAP is a neuropeptide involved in neurotransmission in both the peripheral nervous system and central nervous system and is required for catecholamine secretion. Animal models of PACAP mutations show remarkable behavioral defects, including hyperactivity and increased exploratory behavior. OBJECTIVE: In this study we tested the hypothesis that genetic variations in the human PACAP gene contribute to BPD. METHODS: Genotyping of seven single nucleotide polymorphisms (rs1893154; rs2846811; rs8192595; rs2856966; rs928978; rs2231187; rs1610037) was performed in BPD patients (n=570) and healthy controls (n=710). Genotypes and allele frequencies were compared between groups using chi contingency analysis. Linkage disequilibrium between markers was calculated and estimated haplotype frequencies were compared between groups. MAIN RESULTS: There were no significant differences between groups on the allele, genotype or haplotype level for any of the tested single nucleotide polymorphisms. CONCLUSION: Our results provide no evidence of an association of the PACAP gene with BPD in this group of patients and controls. Additional studies are necessary to elucidate the BPD susceptibility locus on chromosome 18p.

Association between the catechol-O-methyltransferase Val158Met polymorphism and cocaine dependence.

Dopaminergic brain systems have been documented to have a major role in drug reward, thus making genes involved in these circuits plausible candidates for susceptibility to substance use disorders. The catechol-O-methyltransferase (COMT) is involved in the degradation of catecholamines and a functional polymorphism (Val158Met) has been suggested to influence enzyme activity. In this study we hypothesize that genetic variation in the COMT gene contributes to increased risk for cocaine dependence. Cocaine-dependent individuals (n=330) and screened unaffected normal controls (n=255) were genotyped for three SNPs in the COMT gene (rs737865, rs4680 (Val158Met), rs165599). All cases and controls were of African descent. Genotype and allele frequencies differed significantly for the Val158Met polymorphism between cases (f(Met)=35%) and controls (f(Met)=27%) (p=0.004; corrected p=0.014; OR 1.44; 95% CI 1.12-1.86). Haplotype analysis showed a significant association for a two-marker haplotype rs737865-Val158Met (p=0.005). Results suggest that variation in COMT increases risk for cocaine dependence. The low enzyme activity 158Met allele or haplotypes containing this variant might have functional effects on dopamine-derived reward processes and cortical functions resulting in increased susceptibility for cocaine dependence. Additional studies are required to elucidate the role of COMT in the pathophysiology of substance use disorders.