Hung-Yu Chan

A single nucleotide polymorphism fine mapping study of chromosome 1q42.1 reveals the vulnerability genes for schizophrenia, GNPAT and DISC1 : Association with impairment of sustained attention

BACKGROUND The marker D1S251 of chromosome 1q42.1 showed significant association with schizophrenia in a Taiwanese sample. We used single nucleotide polymorphism (SNP) fine mapping to search for the vulnerability genes of schizophrenia. METHODS We selected 120 SNPs covering 1 Mb around D1S251 from the public database. These selected SNPs were initially validated if allele frequency was >10%. Forty-seven validated SNPs were genotyped in 102 families with at least 2 siblings affected with schizophrenia. RESULTS Two SNP blocks showed significant association with schizophrenia. Block 1 (five-SNP), located between intron 2 and intron 13 of the glyceronephosphate O-acyltransferase (GNPAT) gene, showed the most significant associations using single-locus TDT (z = -2.07, p = .038, df = 1) and haplotype association analyses (z = -1.99, p = .046, df = 1). Block 2 (two-SNP), located between intron 4 and intron 5 of the disrupted-in-schizophrenia 1 (DISC1) gene, also showed the most significant results in both the single-locus (z = -3.22, p = .0013, df = 1) and haplotype association analyses (z = 3.35, p = .0008, df = 1). The association of the DISC1 gene with schizophrenia was mainly in the patient group with sustained attention deficits as assessed by the Continuous Performance Test. CONCLUSIONS Chromosome 1q42.1 harbors GNPAT and DISC1 as candidate genes for schizophrenia, and DISC1 is associated with sustained attention deficits.

Psychiatric comorbidity and gender difference among treatment-seeking heroin abusers in Taiwan

Abstract  The objectives of the present study were to estimate the psychiatric comorbidity of Taiwanese heroin users seeking treatment and to identify the gender differences in psychiatric comorbidity and drug use behavior. Subjects were interviewed using a structured questionnaire on drug use behavior and the Mini International Neuropsychiatric Interview for psychiatric disorders. Of the subjects, 58.5% of the male and 62.5% of the female subjects had at least one non‐substance‐use axis I psychiatric disorder or antisocial personality disorder. Compared to male subjects, female subjects were younger, were less educated, had higher rates of unemployment and had earlier onset of illicit drug use. Female subjects were 11‐fold more likely than male subjects to exhibit suicidal behavior. Among heroin abusers in the present study, female subjects were more widely exposed to unfavorable social factors and had substantially higher incidence of suicidal behavior than male subjects. Drug treatment centers should be aware of these gender differences and pay particular attention to comorbid depressive disorders and suicidal behavior of female heroin abusers.

No association of G72 and d-amino acid oxidase genes with schizophrenia

The genes of D-amino acid oxidase (DAAO) activator (DAOA or G72; 13q34) and DAAO (12q24) have been suggested as candidate genes and involved in the N-methyl-D-aspartate receptor regulation pathway for schizophrenia. In order to evaluate the potential association of these two genes with schizophrenia in a Taiwanese sample, three single nucleotide polymorphisms (SNPs) for DAAO (rs2111902, rs3918346, rs3741775) and eleven SNPs for G72 (rs3916965, rs3916966, rs3916967, rs2391191, rs3916968, rs947267, rs778294, rs3916970, rs3916971, rs778293, rs3918342) were genotyped by the MALDI-TOF mass spectrometry method in 218 families (864 individuals) containing at least two siblings affected with schizophrenia. In SNP-based single locus association analyses, neither G72 nor DAAO showed significant association with schizophrenia. Additionally, a three-SNP haplotype in DAAO, and a four-SNP as well as a two-SNP haplotype in G72, showed no significant associations with schizophrenia. These results suggest that the DAAO and G72 genes are not susceptibility genes for schizophrenia in a Taiwanese sample.

Antipsychotic discontinuation in patients with dementia: a systematic review and meta-analysis of published randomized controlled studies.

Background: There is a lack of clarity in the literature on the impact of antipsychotic discontinuation in dementia. Method: We conducted a systematic review and meta-analysis of published randomized controlled studies comparing the effects of antipsychotic discontinuation versus continuation in dementia. MEDLINE, EMBASE, PsycInfo, Cochrane Library and CINAHL were searched. Severity change of behavioral and psychological symptoms of dementia (BPSD) was the primary outcome. Results: Ten studies were included in the systematic review and 9 studies in the meta-analysis. The results showed that the antipsychotic discontinuation group had no statistically significant difference in BPSD severity change compared to the continuation group (n = 214, standardized mean difference: 0.19, 95% CI: -0.20 to 0.58). Secondary outcome analyses revealed that the discontinuation group included a statistically significantly higher proportion of subjects whose BPSD severity worsened (n = 366, risk ratio: 1.78, 95% CI: 1.31-2.41). Although not statistically significant, the discontinuation group appeared to have higher early study termination rates and a lower mortality during follow-up. Conclusions: This meta-analysis showed that antipsychotic discontinuation resulted in no statistically significant difference in BPSD severity change, early study terminations and mortality. However, a statistically significantly higher proportion of subjects with BPSD worsened in this group compared to the continuation group. Further studies are needed to explore the effects of antipsychotic discontinuation on BPSD.

Heroin Use among Youths Incarcerated for Illicit Drug Use: Psychosocial Environment, Substance Use History, Psychiatric Comorbidity, and Route of Administration

This study examines differences in psychosocial characteristics, substance use history, and psychiatric comorbidity in relation to heroin use among youths aged 15 to 22 incarcerated in 2003 for illicit drug use in northern Taiwan. Factors associated with heroin use included experiences of child abuse, having friends with illicit drug use, poor school attendance, polydrug use, and early age of drug initiation. Heroin users were found to have more severe clinical manifestation and experiences of conduct and anxiety disorders than non-heroin users; injection users tended to have a longer heroin history. This information may help guide future prevention programs to reduce heroin problems in youth.

Utilization of antidepressants in Taiwan: a nationwide population-based survey from 2000 to 2009

This study examined trends in antidepressant utilization in Taiwan between 2000 and 2009.

Evaluation of RGS4 as a candidate gene for schizophrenia

Several studies have suggested that the regulator of G‐protein signaling 4 (RGS4) may be a positional and functional candidate gene for schizophrenia. Three single nucleotide polymorphisms (SNP) located at the promoter region (SNP4 and SNP7) and the intron 1 (SNP18) of RGS4 have been verified in different ethnic groups. Positive results have been reported in these SNPs with different numbers of SNP combinatory haplotypes. In this study, these three SNP markers were genotyped in 218 schizophrenia pedigrees of Taiwan (864 individuals) for association analysis. Among these three SNPs, neither SNP4, SNP7, SNP18 has shown significant association with schizophrenia in single locus association analysis, nor any compositions of the three SNP haplotypes has shown significantly associations with the DSM‐IV diagnosed schizophrenia. Our results fail to support the RGS4 as a candidate gene for schizophrenia when evaluated from these three SNP markers.

Genetic variants of IL-6 and its receptor are not associated with schizophrenia in Taiwan.

The pathophysiological process of schizophrenia is still unclear. The levels of interleukine-6 (IL-6) and its receptor, soluble IL-6R, have been reported to be elevated in the plasma and cerebrospinal fluid of schizophrenic patients. In this study, we tested the association of genetic variants of IL-6 and IL-6R with schizophrenia. Genotyping of three single nucleotide polymorphisms (SNP) for each IL-6 (IL-6-1, IL-6-2, and IL-6-3) and IL-6R (rs4845617=IL-6R1, rs4553185=IL-6R2, and rs4379670=IL-6R3) gene was performed in 100 patients with schizophrenia and 113 normal controls. The polymorphisms of IL-6R2 were genotyped using Tetra-primer ARMS PCR. IL-6R3 polymorphisms were genotyped using restriction fragment length polymorphism (RFLP) with Apo I enzyme as the restriction enzyme. All other polymorphisms were genotyped using the direct sequencing method. We found a di-nucleotide haplotype block and a tri-nucleotide haplotype block in the genes of IL-6 and IL-6R, respectively. All six SNPs and their haplotypes failed to show a significant association with schizophrenia. The IL-6-2 SNP showed a nominally significant association with the positive symptoms of schizophrenia (p=0.0472). We conclude that the genetic variants of IL-6 and IL-6R are not associated with schizophrenia. In order to verify this result, further study using a larger sample size and exploring the association between the genotype of IL-6-2 and plasma level of IL-6 is recommended.

Persistence of antidepressant treatment for depressive disorder in Taiwan

OBJECT We sought to explore factors associated with persistence of antidepressant treatment in Taiwan and to compare persistence rates across various antidepressants. METHOD This was a retrospective cohort study using medical claims in Taiwan. We collected data of all new antidepressant users with depressive disorder, aged 18 years or older, during the study period from January 1, 1998, to July 4, 2009. Overall antidepressant treatment persistence was defined as undergoing treatment for 180 days without exceeding a 30-day gap. We also assess the cause of treatment change of initial monotherapy, including discontinuation, switching or combination. The competing risks method was used to estimate cause-specific cumulative incidence and to determine associated factors. RESULTS Only 17.4% of patients continued overall antidepressant treatment and 7.6% continued initial antidepressant monotherapy for 180 days or more. Most patients change initial monotherapy through discontinuation, followed by switching and combination. Male gender, older age, comorbidity with anxiety or sleep disorders, and more concomitant use of drugs were associated with lower discontinuation rate. In terms of antidepressant comparisons, we found that patients treated with selective serotonin reuptake inhibitors are less likely to change initial monotherapy. CONCLUSION The overall persistence of antidepressant treatment in Taiwan was lower than in other countries.

Analysis of exome sequence in 604 trios for recessive genotypes in schizophrenia.

Genetic associations involving both rare and common alleles have been reported for schizophrenia but there have been no systematic scans for rare recessive genotypes using fully phased trio data. Here, we use exome sequencing in 604 schizophrenia proband–parent trios to investigate the role of recessive (homozygous or compound heterozygous) nonsynonymous genotypes in the disorder. The burden of recessive genotypes was not significantly increased in probands at either a genome-wide level or in any individual gene after adjustment for multiple testing. At a system level, probands had an excess of nonsynonymous compound heterozygous genotypes (minor allele frequency, MAF ⩽1%) in voltage-gated sodium channels (VGSCs; eight in probands and none in parents, P=1.5 × 10−4). Previous findings of multiple de novo loss-of-function mutations in this gene family, particularly SCN2A, in autism and intellectual disability provide biological and genetic plausibility for this finding. Pointing further to the involvement of VGSCs in schizophrenia, we found that these genes were enriched for nonsynonymous mutations (MAF ⩽0.1%) in cases genotyped using an exome array, (5585 schizophrenia cases and 8103 controls), and that in the trios data, synaptic proteins interacting with VGSCs were also enriched for both compound heterozygosity (P=0.018) and de novo mutations (P=0.04). However, we were unable to replicate the specific association with compound heterozygosity at VGSCs in an independent sample of Taiwanese schizophrenia trios (N=614). We conclude that recessive genotypes do not appear to make a substantial contribution to schizophrenia at a genome-wide level. Although multiple lines of evidence, including several from this study, suggest that rare mutations in VGSCs contribute to the disorder, in the absence of replication of the original findings regarding compound heterozygosity, this conclusion requires evaluation in a larger sample of trios.