Philip C. Chow

Association of DISC1 and TSNAX genes and affective disorders in the depression case-control (DeCC) and bipolar affective case-control (BACCS) studies.

The gene known as Disrupted-in-Schizophrenia-1, DISC1, was originally discovered in a large family, in which it also co-segregated with bipolar affective disorder (BD) and with major depressive disorder (MDD). The TSNAX (Translin-associated factor X) gene, located immediately upstream of DISC1, has also been suggested as a candidate gene in relation to psychiatric illness, as one transcript resulting from intergenic splicing encodes a novel TSNAX–DISC1 fusion protein. We explored the TSNAX–DISC1 gene region for an association with BD and MDD in a sample of 1984 patients (1469 MDD, 515 BD) and 1376 ethnically matched controls. Eight single nucleotide polymorphisms (SNPs) within the TSNAX–DISC1 region (rs766288, rs3738401, rs2492367, rs6675281, rs12133766, rs1000731, rs7546310 and rs821597) were investigated using the SNPlex Genotyping System. We found a significant allelic and genotypic association of the TSNAX–DISC1 gene region with BD, whereas a haplotypic association was found for both BD and MDD. Therefore, our results suggest an association between the TSNAX–DISC1 region and both forms of affective disorders, and support the hypothesis that a portion of the genotypic overlap between schizophrenia and affective disorders is attributable to this gene.

Association of the dystrobrevin binding protein 1 gene (DTNBP1) in a bipolar case-control study (BACCS).

Recent studies suggest a degree of overlap in genetic susceptibility across the traditional categories of schizophrenia and bipolar disorder. There is some evidence for an association of the dystrobrevin binding protein 1 gene (DTNBP1) with schizophrenia, and, thus, this gene has also become a focus of further investigation in bipolar disorder (BD). The aim of our study is to explore the association of DTNBP1 with BD and with a sub phenotype, presence/absence of psychotic symptoms, in a sample of 515 patients with BD (ICD10/DSMIV) and 1,316 ethnically matched control subjects recruited from the UK. Seven DTNBP1 SNPs: rs2743852 (SNP C), rs760761 (P1320), rs1011313 (P1325), rs3213207 (P1635), rs2619539 (P1655), rs16876571 and rs17470454 were investigated using the SNPlex genotyping system and 1 SNP (rs2619522) genotypes were imputed. Association analyses were conducted in a sample of 452 cases and 956 controls. We found significant differences in genotypic and allelic frequencies of rs3213207 and rs760761 of DTNBP1 between bipolar patients and controls. We also showed a global haplotypic association and an association of a particular haplotype with BD. Our results are consistent with previous studies in term of a general association between DTNBP1 and bipolar disorder and provide additional evidence that a portion of the genotypic overlap between schizophrenia and bipolar affective disorder is attributable to this gene.

Fear of falling (FF): Psychosocial and physical factors among institutionalized older Chinese men in Taiwan

Fear of falling (FF) can have multiple adverse consequences in the elderly. Although there are various fall prevention programs, little is known of FF and its associated characteristics. This study examined FF-associated physical and psychosocial factors in older Chinese men living in a veterans home in southern Taiwan. Subjects with a recent episode of delirium, of bed-ridden or wheelchair-bound status, severe hearing impairment or impaired cognition were excluded. Overall, 371 residents (mean age 82.1 ± 5.11 years, all males) participated. The prevalence of FF was 25.3%. Univariate analysis revealed that subjects in the FF group were older age, having lower education level, poorer sitting and standing balance, poorer activities of daily living (ADL), more depressive symptoms, higher chances of using walking aids, neurologic diseases, and a history of fall within the past 6 months. Logistic regression showed that depressive symptoms (odds ratio = OR = 6.73, 95%CI: 3.03-14.93, p < 0.001), activities of daily living (OR = 2.48, 95%CI: 1.08-5.71, p = 0.033), history of fall in the past 6 months (OR = 2.47, 95%CI: 1.04-5.9, p = 0.041), and neurological diseases (OR = 2.75, 95%CI: 1.15-6.56, p = 0.023) were all independent risk factors for FF.

Association analysis of DAOA and DAO in bipolar disorder: results from two independent case-control studies.

D-amino acid oxidase activator gene [DAOA (previously G72)] is located in a region with a positive linkage peak for bipolar disorder (BD) (13q33.2) (1). The results of case-control and family-based studies of DAOA in BD are inconsistent, with some reporting positive single marker or haplotype association (2–8) and others reporting no association (9, 10). Two meta-analyses of DAOA in BD have also provided conflicting results: one reported positive association (11), while another failed to find evidence for association (12). DAOA is an activator of DAO protein (13); both proteins are involved in the metabolism of D-serine, which plays a role in glutamatergic neurotransmission (14). Thus, there is a clear biological motivation for testing epitasis between these two genes. We explored the association of DAOA and DAO with BD and their statistical interaction in two independent case-control samples from the UK and Canada. The UK sample consisted of 515 BD patients (65% women) with a mean age (SD) of 48.0 (11.4) years. The diagnosis of BD was defined by DSMIV operational criteria using Schedules for Clinical Assessment in Neuropsychiatry (SCAN) (15). Patients with BD were classified as having a positive history of psychosis if they scored positive on at least one of the SCAN items of delusions or hallucinations (n = 232). The control sample consisted of 1,316 subjects (58% women) with a mean age (SD) of 41.7 (13.2) years, screened for lifetime absence of psychiatric disorder. The Canadian sample consisted of 385 patients (63% women) with a mean age (SD) of 46.0 (12.5) years and 312 controls (54% women) with a mean age (SD) of 43.7 (13.1) years. All enrolled subjects were of white European parentage. Both studies were approved by the local Research Ethics Committees and informed written consent was obtained from all participants. Genotyping of 10 single nucleotide polymorphisms (SNPs) was performed using SNPlex Genotyping System (Applied Biosystems, Carlsbad, CA, USA). Five DAOA SNPs: M12, M15, M18, M23, and M24, and DAO SNP were chosen on the basis of previously reported association findings. Others were chosen to get better coverage of the gene area. Overall, 9 markers cover a 95 kb region, including the 5¢ and 3¢ flanking regions of the DAOA locus, constituting the region of interest for linkage disequilibrium (LD) mapping. In total, 1,619 UK and 697 Canadian samples were genotyped. An 80% threshold was applied for the call rate across the SNP set. The call rate for each SNP varied between 94.5% and 99.7%. A total of 176 samples were regenotyped with 100% consistency. For statistical analysis, 1,408 UK and 644 Canadian samples were available. Genotype and allele frequencies were assessed for association with BD using chi-squared tests. Risk magnitudes were estimated by calculating odds ratios (OR) with 95% confidence intervals. Haplotype analysis was conducted using UNPHASED (16). Interaction analysis was performed using the Genetic Association Interaction Analysis (GAIA) application (17). We applied the Bonferroni correction for the number of genes and the number of samples investigated, and assumed that four independent tests were applied (a = 0.013). Allele frequencies of the SNPs are shown in Table 1. All genotype distributions were consistent with Hardy-Weinberg equilibrium (p > 0.05). There were no significant differences in allele or genotype frequency between cases and controls in either the UK or Canadian sample, or in the combined sample. The analysis in the subgroup with psychotic traits did not show any significant differences either (data not shown). No significant differences in global haplotype distribution or individual haplotype frequency were revealed between cases and controls in the investigated samples (Table 2). The pattern of intermarker LD of the DAOA in the two samples was similar to each other and to that in a HapMap Centre d Etude du Polymorphisme Humain (CEPH) sample (http://www.hapmap.org). Bipolar Disorders 2010: 12: 579–581 a 2010 The Authors Journal compilation a 2010 Blackwell Munksgaard

Association analysis of DAOA and DAO in bipolar disorder: Results from two independent case-control studies

D-amino acid oxidase activator gene [DAOA (previously G72)] is located in a region with a positive linkage peak for bipolar disorder (BD) (13q33.2) (1). The results of case-control and family-based studies of DAOA in BD are inconsistent, with some reporting positive single marker or haplotype association (2–8) and others reporting no association (9, 10). Two meta-analyses of DAOA in BD have also provided conflicting results: one reported positive association (11), while another failed to find evidence for association (12). DAOA is an activator of DAO protein (13); both proteins are involved in the metabolism of D-serine, which plays a role in glutamatergic neurotransmission (14). Thus, there is a clear biological motivation for testing epitasis between these two genes. We explored the association of DAOA and DAO with BD and their statistical interaction in two independent case-control samples from the UK and Canada. The UK sample consisted of 515 BD patients (65% women) with a mean age (SD) of 48.0 (11.4) years. The diagnosis of BD was defined by DSMIV operational criteria using Schedules for Clinical Assessment in Neuropsychiatry (SCAN) (15). Patients with BD were classified as having a positive history of psychosis if they scored positive on at least one of the SCAN items of delusions or hallucinations (n = 232). The control sample consisted of 1,316 subjects (58% women) with a mean age (SD) of 41.7 (13.2) years, screened for lifetime absence of psychiatric disorder. The Canadian sample consisted of 385 patients (63% women) with a mean age (SD) of 46.0 (12.5) years and 312 controls (54% women) with a mean age (SD) of 43.7 (13.1) years. All enrolled subjects were of white European parentage. Both studies were approved by the local Research Ethics Committees and informed written consent was obtained from all participants. Genotyping of 10 single nucleotide polymorphisms (SNPs) was performed using SNPlex Genotyping System (Applied Biosystems, Carlsbad, CA, USA). Five DAOA SNPs: M12, M15, M18, M23, and M24, and DAO SNP were chosen on the basis of previously reported association findings. Others were chosen to get better coverage of the gene area. Overall, 9 markers cover a 95 kb region, including the 5¢ and 3¢ flanking regions of the DAOA locus, constituting the region of interest for linkage disequilibrium (LD) mapping. In total, 1,619 UK and 697 Canadian samples were genotyped. An 80% threshold was applied for the call rate across the SNP set. The call rate for each SNP varied between 94.5% and 99.7%. A total of 176 samples were regenotyped with 100% consistency. For statistical analysis, 1,408 UK and 644 Canadian samples were available. Genotype and allele frequencies were assessed for association with BD using chi-squared tests. Risk magnitudes were estimated by calculating odds ratios (OR) with 95% confidence intervals. Haplotype analysis was conducted using UNPHASED (16). Interaction analysis was performed using the Genetic Association Interaction Analysis (GAIA) application (17). We applied the Bonferroni correction for the number of genes and the number of samples investigated, and assumed that four independent tests were applied (a = 0.013). Allele frequencies of the SNPs are shown in Table 1. All genotype distributions were consistent with Hardy-Weinberg equilibrium (p > 0.05). There were no significant differences in allele or genotype frequency between cases and controls in either the UK or Canadian sample, or in the combined sample. The analysis in the subgroup with psychotic traits did not show any significant differences either (data not shown). No significant differences in global haplotype distribution or individual haplotype frequency were revealed between cases and controls in the investigated samples (Table 2). The pattern of intermarker LD of the DAOA in the two samples was similar to each other and to that in a HapMap Centre d Etude du Polymorphisme Humain (CEPH) sample (http://www.hapmap.org). Bipolar Disorders 2010: 12: 579–581 a 2010 The Authors Journal compilation a 2010 Blackwell Munksgaard

NRG1 gene in recurrent major depression: no association in a large-scale case-control association study.

The Neuregulin 1 (NRG1) gene was initially implicated in schizophrenia (SZ) and has recently been associated with bipolar disorder (BPD) in two studies. An association with major depressive disorder (MDD) has not yet been investigated but is warranted in view of the genetic overlap between MDD and BPD. We have performed a large‐scale case–control study investigating the association between NRG1 polymorphisms and MDD, genotyping a selection of 14 single nucleotide polymorphisms (SNPs) spanning the NRG1 gene in a sample of 1,398 patients of White European ancestry with a diagnosis of MDD and 1,304 ethnically matched controls from three clinical sites in the UK. We found no single marker or haplotype associations that withstood correction for multiple testing. Our findings do not provide evidence that NRG1 plays a role in MDD or that this gene explains part of the genetic overlap with BPD.

The DAOA gene is associated with schizophrenia in the Taiwanese population

The gene D-amino acid oxidase activator (DAOA), which has a former name of G72, and the D-amino acid oxidase (DAO) gene have been suggested as candidate genes of schizophrenia. However, association studies have so far yielded equivocal results. We analyzed one single nucleotide polymorphism (SNP) for DAO (rs3741775) and seven SNPs for G72 (rs3916956, rs2391191, rs9558562, rs947267, rs778292, rs3918342, and rs1421292) in this study enrolling 248 schizophrenia cases and 267 controls in the Taiwanese samples. In SNP-based single locus association analyses, the rs778292 in the DAOA gene showed significant association with schizophrenia. The rs3741775 in the DAO gene could not withstand statistically significant after multiple corrections. Additionally, a three-SNP haplotype (rs778292-rs3918342-rs1421292) in the DAOA gene were observed to be significantly associated with schizophrenia. Among them, the TCT haplotype presented higher prevalence in controls than in cases whereas the TTT and CTT haplotype were significantly more frequent in cases than in controls. The study also provides significant evidence for epistatic interactions among DAOA and DAO gene in the development of schizophrenia. These results provide additional evidence and indicate that the DAOA gene and DAOA-DAO gene-gene interactions might play a role for schizophrenia in a Taiwanese sample.

Association between Polymorphisms in Dopamine-Related Genes and Orthopedic Pain Expression in Chinese Elderly Population

The dopaminergic pathway plays a vital role in pain expression. Here, our aim was to investigate the effects of polymorphisms in genes encoding the dopamine active transporter (SLC6A3) and dopamine receptor D2 (DRD2) on preoperative pain expression among patients preparing for orthopedic surgery.

Allergic Skin Reactions to Multiple Antiepileptic Drugs

Objective: We report a case of bipolar disorder patient who was allergic to multiple newer anti-epileptic drugs (AEDs). Case report: This 67-year-old woman patient was diagnosed as bipolar disorder for more than 20 years. At first she received valproic acid (VPA) and lamotrigine (LTG) for her mixed episode of bipolar disorder. After a three-week-combined treatment, she was diagnosed as Stevens-Johnson syndrome (SJS). We stopped all psychiatric medications and prescribed steroid. Few days later, her dermatologic symptoms were improved. When we tried to reload VPA, her dermatologic lesion was exacerbated. Therefore, we stopped VPA for one month and her dermatologic symptoms got remitted. Because of her hypomania, we prescribed topiramate (TPM) and gradually titrated to 200 mg/d. After few days, she developed intolerant general pruritus, therefore, olanzapine was given to substitute for TPM. Then, her allergic symptoms were relieved and her mental status had become stable. Conclusion: LTG has been most associated with rash of the nine newer AEDs introduced in the past decade. When prescribed with VPA, lamotrigins initial dose and the subsequent rate of dose escalation must be lower and slower than usual, respectively. In addition, if patients have a history of allergic reaction to multiple AEDs, secondary generation antipsychotic medication may be an alternative choice.