A splicing-regulatory polymorphism in DRD2 disrupts ZRANB2 binding, impairs cognitive functioning and increases risk for schizophrenia in six Han Chinese samples.

The rs1076560 polymorphism of DRD2 (encoding dopamine receptor D2) is associated with alternative splicing and cognitive functioning; however, a mechanistic relationship to schizophrenia has not been shown. Here, we demonstrate that rs1076560(T) imparts a small but reliable risk for schizophrenia in a sample of 616 affected families and five independent replication samples totaling 4017 affected and 4704 unaffected individuals (odds ratio=1.1; P=0.004). rs1076560(T) was associated with impaired verbal fluency and comprehension in schizophrenia but improved performance among healthy comparison subjects. rs1076560(T) also associated with lower D2 short isoform expression in postmortem brain. rs1076560(T) disrupted a binding site for the splicing factor ZRANB2, diminished binding affinity between DRD2 pre-mRNA and ZRANB2 and abolished the ability of ZRANB2 to modulate short:long isoform-expression ratios of DRD2 minigenes in cell culture. Collectively, this work implicates rs1076560(T) as one possible risk factor for schizophrenia in the Han Chinese population, and suggests molecular mechanisms by which it may exert such influence.

Minor physical anomalies and craniofacial measures in patients with treatment-resistant schizophrenia.

BACKGROUND: Schizophrenia patients have higher rates of minor physical anomalies (MPAs) than controls, particularly in the craniofacial region; this difference lends support to the neurodevelopmental model of schizophrenia. Whether MPAs are associated with treatment response in schizophrenia remains unknown. The aim of this case-control study was to investigate whether more MPAs and specific quantitative craniofacial features in patients with schizophrenia are associated with operationally defined treatment resistance. METHOD: A comprehensive scale, consisting of both qualitatively measured MPAs and quantitative measurements of the head and face, was applied in 108 patients with treatment-resistant schizophrenia (TRS) and in 104 non-TRS patients. Treatment resistance was determined according to the criteria proposed by Conley & Kelly (2001; Biological Psychiatry 50, 898-911). RESULTS: Our results revealed that patients with TRS had higher MPA scores in the mouth region than non-TRS patients, and the two groups also differed in four quantitative measurements (facial width, lower facial height, facial height, and length of the philtrum), after controlling for multiple comparisons using the false discovery rate. Among these dysmorphological measurements, three MPA item types (mouth MPA score, facial width, and lower facial height) and earlier disease onset were further demonstrated to have good discriminant validity in distinguishing TRS from non-TRS patients in a multivariable logistic regression analysis, with an area under the curve of 0.84 and a generalized R 2 of 0.32. CONCLUSIONS: These findings suggest that certain MPAs and craniofacial features may serve as useful markers for identifying TRS at early stages of the illness.

Association of older paternal age with earlier onset among co-affected schizophrenia sib-pairs.

BACKGROUND: Advanced paternal age is associated with increased risk of schizophrenia. This study aimed to explore whether older paternal age is associated with earlier onset among co-affected schizophrenia sib-pairs with the same familial predisposition. METHOD: A total of 1297 patients with schizophrenia from 630 families, which were ascertained to have at least two siblings affected, throughout Taiwan were interviewed using the Diagnostic Interview for Genetic Studies. Both inter-family comparisons, a hierarchical regression model allowing for familial dependence and adjusting for confounders, and within-family comparisons, examining the consistency between onset order and birth order, were performed. RESULTS: An inverted U shape was observed between paternal age and onset of schizophrenia. Affected offspring with paternal age of 20-24 years had the oldest onset. As paternal age increased over 25 years, older paternal age exhibited a linear decrease in the onset of schizophrenia. On average, the onset was lowered by 1.5 years for paternal age of 25-29 years and by 5.5 years for paternal age ⩾50 years (p = 0.04; trend test). The proportion of younger siblings with earlier onset (58%) was larger than that of older siblings with earlier onset (42%) (p = 0.0002). CONCLUSIONS: These findings indicate that paternal age older than 25 years and younger than 20 years were both associated with earlier onset among familial schizophrenia cases. The associations of advanced paternal age with both increased susceptibility to schizophrenia and earlier onset of schizophrenia are consistent with the rate of increases in spontaneous mutations in sperm as men age.

Risperidone and olanzapine versus another first generation antipsychotic in patients with schizophrenia inadequately responsive to first generation antipsychotics.

OBJECTIVE: This study compares the efficacy of risperidone and olanzapine to that of first-generation antipsychotics (FGAs) in patients with schizophrenia, who failed to show a response to initial trials of FGAs. METHOD: This study was an 8-week treatment, randomized, rater-blind, active-control study with 3 treatment arms. 48 patients, who showed inadequate response to 1 FGA, were enrolled and randomized into risperidone, olanzapine, or FGA (haloperidol or trifluoperazine) groups. They were blindly assessed with the Positive and Negative Syndrome Scale (PANSS), the Clinical Global Impression Scale-Severity, and the Extrapyramidal Symptom Rating Scale (ESRS) at baseline and biweekly. RESULTS: All 3 groups demonstrated a significant decrease in the PANSS total, positive, and general scores from baseline to endpoint (p-values range from 0.003 to 0.021). There were no significant differences among the 3 groups in score changes. The olanzapine group had significant score reductions than the risperidone and FGAs groups in terms of the ESRS subjective total score and did not experience a significant increase in the dose of anticholinergics. The FGA group demonstrated that extrapyramidal syndrome (EPS) worsened under an increased dosage of anti-EPS drugs. Olanzapine was associated with significant body weight gain (2.69 ± 4.0 kg, p=0.026), but there were no significant group differences on weight gain. CONCLUSIONS: Haloperidol or trifluoperazine demonstrated similar efficacy as risperidone or olanzapine for patients with schizophrenia who had failed their first trial with a FGA. Related double-blind, fixed dose studies with a larger sample size are needed to confirm the results of our study.

Family-based association testing strongly implicates DRD2 as a risk gene for schizophrenia in Han Chinese from Taiwan.

The gene that codes for dopamine receptor D2 (DRD2 on chromosome 11q23) has long been a prime functional and positional candidate risk gene for schizophrenia. Collectively, prior case-control studies found a reliable effect of the Ser311Cys DRD2 polymorphism (rs1801028) on risk for schizophrenia, but few other polymorphisms in the gene had ever been evaluated and no adequately powered family-based association study has been performed to date. Our objective was to test 21 haplotype-tagging and all three known nonsynonymous single-nucleotide polymorphisms (SNPs) in DRD2 for association with schizophrenia in a family-based study of 2408 Han Chinese, including 1214 affected individuals from 616 families. We did not find a significant effect of rs1801028, but we did find significant evidence for association of schizophrenia with two multi-marker haplotypes spanning blocks of strong linkage disequilibrium (LD) and nine individual SNPs (Ps<0.05). Importantly, two SNPs (rs1079727 and rs2283265) and both multi-marker haplotypes spanning entire LD blocks (including one that contained rs1801028) remained significant after correcting for multiple testing. These results further add to the body of data implicating DRD2 as a schizophrenia risk gene; however, a causal variant(s) in DRD2 remains to be elucidated by further fine mapping of the gene, with particular attention given to the area surrounding the third through fifth exons.

Meta-analysis of 32 genome-wide linkage studies of schizophrenia.

A genome scan meta-analysis (GSMA) was carried out on 32 independent genome-wide linkage scan analyses that included 3255 pedigrees with 7413 genotyped cases affected with schizophrenia (SCZ) or related disorders. The primary GSMA divided the autosomes into 120 bins, rank-ordered the bins within each study according to the most positive linkage result in each bin, summed these ranks (weighted for study size) for each bin across studies and determined the empirical probability of a given summed rank (P(SR)) by simulation. Suggestive evidence for linkage was observed in two single bins, on chromosomes 5q (142-168 Mb) and 2q (103-134 Mb). Genome-wide evidence for linkage was detected on chromosome 2q (119-152 Mb) when bin boundaries were shifted to the middle of the previous bins. The primary analysis met empirical criteria for 'aggregate' genome-wide significance, indicating that some or all of 10 bins are likely to contain loci linked to SCZ, including regions of chromosomes 1, 2q, 3q, 4q, 5q, 8p and 10q. In a secondary analysis of 22 studies of European-ancestry samples, suggestive evidence for linkage was observed on chromosome 8p (16-33 Mb). Although the newer genome-wide association methodology has greater power to detect weak associations to single common DNA sequence variants, linkage analysis can detect diverse genetic effects that segregate in families, including multiple rare variants within one locus or several weakly associated loci in the same region. Therefore, the regions supported by this meta-analysis deserve close attention in future studies.

Polygenic risk for schizophrenia and neurocognitive performance in patients with schizophrenia.

Both neurocognitive deficits and schizophrenia are highly heritable. Genetic overlap between neurocognitive deficits and schizophrenia has been observed in both the general population and in the clinical samples. This study aimed to examine if the polygenic architecture of susceptibility to schizophrenia modified neurocognitive performance in schizophrenia patients. Schizophrenia polygenic risk scores (PRSs) were first derived from the Psychiatric Genomics Consortium (PGC) on schizophrenia, and then the scores were calculated in our independent sample of 1130 schizophrenia trios, who had PsychChip data and were part of the Schizophrenia Families from Taiwan project. Pseudocontrols generated from the nontransmitted parental alleles of the parents in these trios were compared with alleles in schizophrenia patients in assessing the replicability of PGC-derived susceptibility variants. Schizophrenia PRS at the P-value threshold (PT) of 0.1 explained 0.2% in the variance of disease status in this Han-Taiwanese samples, and the score itself had a P-value 0.05 for the association test with the disorder. Each patient underwent neurocognitive evaluation on sustained attention using the continuous performance test and executive function using the Wisconsin Card Sorting Test. We applied a structural equation model to construct the neurocognitive latent variable estimated from multiple measured indices in these 2 tests, and then tested the association between the PRS and the neurocognitive latent variable. Higher schizophrenia PRS generated at the PT of 0.1 was significantly associated with poorer neurocognitive performance with explained variance 0.5%. Our findings indicated that schizophrenia susceptibility variants modify the neurocognitive performance in schizophrenia patients.

Association evidence of schizophrenia with distal genomic region of NOTCH4 in Taiwanese families.

Evidence for association with schizophrenia has been reported for NOTCH4, although results have been inconsistent. Previous studies have focused on polymorphisms in the 5' promoter region and first exon of NOTCH4. Our aim was to test the association of the entire genomic region of NOTCH4 in 218 families with at least two siblings affected by schizophrenia in Taiwan. We genotyped seven single nucleotide polymorphisms (SNPs) of this gene, with average intermarker distances of 5.3 kb. Intermarker linkage disequilibrium (LD) was calculated using gold software, and single-locus and haplotype association analyses were performed using transmit software. We found that the T allele of SNP rs2071285 (P= 0.035) and the G allele of SNP rs204993 (P= 0.0097) were significantly preferentially transmitted to the affected individuals in the single-locus association analysis. The two SNPs were in high LD (D' > 0.8). Trend for overtransmission was shown for the T-G haplotype of the two SNPs to affected individuals (P= 0.053), with the A-A haplotype significantly undertransmitted (P= 0.034). The associated region distributed across the distal portion of the NOTCH4 gene and overlapped with the genomic region of the G-protein signaling modulator 3 and pre-B-cell leukemia transcription factor 2. In summary, we found modest association evidence between schizophrenia and the distal genomic region of NOTCH4 in this Taiwanese family sample. Further replication for association with the distal genomic region of NOTCH4 is warranted.

Aberrant expression of microRNAs as biomarker for schizophrenia: from acute state to partial remission, and from peripheral blood to cortical tissue.

Based on our previous finding of a seven-miRNA (hsa-miR-34a, miR-449a, miR-564, miR-432, miR-548d, miR-572 and miR-652) signature as a potential biomarker for schizophrenia, this study aimed to examine if hospitalization could affect expressions of these miRNAs. We compared their expression levels between acute state and partial remission state in people with schizophrenia (n=48) using quantitative PCR method. Further, to examine whether the blood and brain show similar expression patterns, the expressions of two miRNAs (hsa-miR-34a and hsa-miR-548d) were examined in the postmortem brain tissue of people with schizophrenia (n=25) and controls (n=27). The expression level of the seven miRNAs did not alter after ~2 months of hospitalization with significant improvement in clinical symptoms, suggesting the miRNAs could be traits rather than state-dependent markers. The aberrant expression seen in the blood of hsa-miR-34a and hsa-miR-548d were not present in the brain samples, but this does not discount the possibility that the peripheral miRNAs could be clinically useful biomarkers for schizophrenia. Unexpectedly, we found an age-dependent increase in hsa-miR-34a expressions in human cortical (Brodmann area 46 (BA46)) but not subcortical region (caudate putamen). The correlation between hsa-miR-34a expression level in BA46 and age was much stronger in the controls than in the cases, and the corresponding correlation in the blood was only seen in the cases. The association between the miRNA dysregulations, the disease predisposition and aging warrants further investigation. Taken together, this study provides further insight on the candidate peripheral miRNAs as stable biomarkers for the diagnostics of schizophrenia.

Alcoholism--North America and Asia. A comparison of population surveys with the Diagnostic Interview Schedule.

The Diagnostic Interview Schedule (DIS) is a highly structured instrument that enables lay examiners to gather the clinical information necessary to generate psychiatric disorders according to the DSM-III, Feighner, and Research Diagnostic Criteria. It was developed originally as the diagnostic interview for the Epidemiologic Catchment Area (ECA) survey. Because it adheres to DSM-III and can be used by lay interviewers, thus making it practical for studies involving large samples, it has been used for other population surveys in North and South America, Europe, and Asia. This investigation compares the epidemiology of DSM-III-defined alcohol abuse and addiction in DIS-based population surveys cross-nationally (in St Louis, Mo; Edmonton, Canada; Puerto Rico; Taipei City, Taiwan; and South Korea). We found considerable variation in the lifetime prevalence of alcoholism but a similarity in the age of onset, the symptomatic expression, and the associated risk factors. We also found an inverse correlation between the prevalence of alcoholism and the strength of the association of the risk factors we examined. The work described herein demonstrates the utility of consistent definition and method in cross-cultural psychiatric research. The substantive findings have implications for the definition of alcoholism and for a better understanding of genetic and environmental interactions in its etiology.

The cross-national epidemiology of panic disorder.

BACKGROUND: Epidemiological data on panic disorder from community studies from 10 countries around the world are presented to determine the consistency of findings across diverse cultures. METHOD: Data from independently conducted community surveys from 10 countries (the United States, Canada, Puerto Rico, France, West Germany, Italy, Lebanon, Taiwan, Korea, and New Zealand), using the Diagnostic Interview Schedule and DSM-III criteria and including over 40,000 subjects, were analyzed with appropriate standardization for age and sex differences among subjects from different countries. RESULTS: The lifetime prevalence rates for panic disorder ranged from 1.4 per 100 in Edmonton, Alberta, to 2.9 per 100 in Florence, Italy, with the exception of that in Taiwan, 0.4 per 100, where rates for most psychiatric disorders are low. Mean age at first onset was usually in early to middle adulthood. The rates were higher in female than male subjects in all countries. Panic disorder was associated with an increased risk of agoraphobia and major depression in all countries. CONCLUSIONS: Panic disorder is relatively consistent, with a few exceptions, in rates and patterns across different countries. It is unclear why the rates of panic and other psychiatric disorders are lower in Taiwan.

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.

Serial dexamethasone suppression test in psychiatric inpatients.

A sample of 100 consecutively admitted cases were recruited to test the hypothesis that an abnormal dexamethasone suppression test (AbDST) is associated with decreasing clinical severity during the course of hospitalization in various diagnostic categories. Serial DSTs and psychopathological ratings were done at the end of the first and the third week postadmission, and 1 week before discharge. DST was also done at 1-year follow-up after discharge. The results of this study strongly suggest that a dual mechanism is responsible for the prevalence of AbDST. One is related to the global psychopathology of a nonspecific quantitative mechanism in various diagnostic categories. The other is a specific qualitative mechanism relating to the depressive state, as reflected in the higher prevalence of AbDST and more consistent AbDST results across different study time points in melancholia, and also in higher AbDST rates in disorders with higher depressive scores.

Dexamethasone suppression test in primary depression: significance of family history and psychosis.

The overnight dexamethasone suppression test (DST) was administered to 31 inpatients with endogenous depression. DST results were abnormal in 42% of the group and in 67% of those patients with psychotic depression. Division of the sample into genetic subtypes based on family history criteria of Winokur et al. failed to replicate his group's DST findings. Subjects with sporadic depressive disorder, especially delusional patients, had a higher rate of dexamethasone nonsuppression than the others. Familial pure depressive patients did not show the expected greater frequency of DST abnormality compared to the depression spectrum disorder group.

Dopamine D4 receptor gene polymorphisms and neuroleptic response in schizophrenia.

BACKGROUND: Dopamine D4 receptor (DRD4) gene polymorphisms are associated with various pharmacologic activities. This study investigated whether polymorphisms of 48-bp tandem repeats in the exon 3 of the DRD4 gene are related to neuroleptic response. METHODS: The neuroleptic response at the acute stage of schizophrenia was assessed in 80 (48 men, 32 women) schizophrenic patients. The negative symptoms at remission were also rated. DRD4 genotype was established using the polymerase chain reaction. Patients with genotypes containing an allele with only two repeats (2-2, 2-3, 2-4, 2-6) were assigned to group I (n = 38). Those homozygous for four 48-bp repeats were assigned to group II (n = 42). RESULTS: Thirteen (34.2%) of the 38 group I subjects and 26 (61.9%) of the 42 group II subjects had good neuroleptic response during acute stage treatment (chi 2 6.12, df = 1, p < .02). In remission, the rates of negative symptoms of blunt affect, avolition, and global negative rating were higher in group I than in group II. This was more prominent in men than in women. CONCLUSIONS: The presence of homozygous four 48-bp repeats in both alleles in exon 3 of the DRD4 gene is associated with good neuroleptic response during acute treatment, and with a lower prevalence of negative symptoms at remission, especially in male schizophrenic patients.

New methods in cross-cultural psychiatry: psychiatric illness in Taiwan and the United States.

OBJECTIVE: Cross-cultural psychiatric research has suffered from many methodological shortcomings. To answer some of these shortcomings, the present study compared rates of psychiatric disorders in Taiwan and the United States by combining data from both countries into a single data set. METHOD: Results from large, community-based surveys in the United States and Taiwan, the National Institute of Mental Health (NIMH) Epidemiologic Catchment Area survey and the Taiwan Psychiatric Epidemiological Project, were combined into a single data set. This integration of the data sets was possible because both surveys used the NIMH Diagnostic Interview Schedule to ascertain cases. The integrated data sets were then analyzed with identical algorithms to generate lifetime prevalence rates of psychiatric disorders according to DSM-III criteria for both the United States and Taiwan. RESULTS: Lifetime prevalence rates of psychiatric illness in Taiwan were generally lower than U.S. rates. The rates of any disorder were 21.56% in Taiwan and 35.55% in the United States (Z = 22.34, p less than 10(-109]. The rates of most specific disorders were lower in Taiwan, and none of the rates was higher in Taiwan. CONCLUSIONS: While a culturally determined response bias may have lowered the rates in Taiwan somewhat, the results appear to be valid. Implications for the future use of structured diagnostic interviews in cross-cultural research are discussed.

Sustained attention deficit and schizotypal personality features in nonpsychotic relatives of schizophrenic patients.

OBJECTIVE: The authors investigated whether nonpsychotic relatives of schizophrenic probands have an elevated risk of deficits in sustained attention as measured by the Continuous Performance Test (CPT), whether such deficits are associated with specific factors of schizotypy, and whether poor CPT performance by probands predicts poor performance by their relatives. In addition, the heritability of CPT performance in the families of schizophrenic probands was estimated. METHOD: The study subjects were 60 schizophrenic probands, 148 of their first-degree relatives, 20 normal comparison probands, and 42 of the comparison probands' first-degree relatives. Subjects completed undegraded and 25% degraded sessions of the CPT and were interviewed with use of the Chinese version of the Diagnostic Interview for Genetic Studies. Subjects' CPT sensitivity indexes, d', were standardized against those of a community sample of 345 subjects, with adjustment for age, sex, and level of education. RESULTS: On average, the d' values of the relatives of schizophrenic probands were lower than those of the relatives of comparison probands but higher than those of schizophrenic probands. Lower sensitivity indexes among the relatives of schizophrenic patients were associated with the interpersonal dysfunction and disorganization factors of schizotypy but not the cognitive/perceptual factor. When schizophrenic probands were divided into two subgroups by a cutoff of -3.0 for adjusted z score on the CPT, the d' values of relatives of probands with CPT deficits were lower than those of relatives of probands without deficits. The estimated heritability of performance on the CPT ranged from 0.48 to 0.62. CONCLUSIONS: Sustained attention deficit may be a genetic vulnerability marker for schizophrenia, and it may be more useful in linkage analysis than traditional phenotype definitions of schizophrenia.

Association of 5HT2A receptor gene polymorphism and alcohol abuse with behavior problems.

This study investigated the association between T/C polymorphism, at position 102, of the 5-hydroxytryptamine 2A receptor gene and alcoholism with and without behavior problems. Eighty-five subjects (45 men, 40 women) with alcohol abuse, 75 subjects (51 men, 24 women) with alcohol dependence, and 70 normal control subjects (21 men, 49 women) participated in the study. The results show that the frequency of the homozygous T102 genotype was significantly lower in the group of male alcohol abuse with behavior problems than in the female group (chi(2) = 4.072, df = 1, P < 0.05) and the allele frequency of T102 was also lower in the male group than in the female group (chi(2) = 4.187, df = 1, P < 0.05). Of the male alcohol abuse subjects, the group with behavior problems was found to have lower frequencies of the T102 allele than the group without behavior problems (chi(2) = 4.328, df = 1, P < 0.05). In conclusion, this study demonstrates that alcoholism is heterogeneous and male alcohol abuse with behavioral problems was associated with T/C 102 polymorphism of the 5HT2A receptor gene. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:797-800, 2000.

No association of dopamine D2 receptor molecular variant Cys311 and schizophrenia in Chinese patients.

A serine-to-cysteine mutation of dopamine D2 receptor at codon 311 (Cys311) was found to have higher frequency in schizophrenic patients than in normal controls in Japanese by Arinami et al. [1994: Lancet 343: 703-704]. The Cys311 allele was found to be associated with patients with younger age-of-onset, positive family history, and more positive symptoms. To investigate the possible involvement of Cys311 in schizophrenia in the Chinese population, 114 unrelated Taiwanese Chinese schizophrenic patients with positive family history and 88 normal controls were genotyped for Cys311. Four patients and 5 normal controls were heterozygotes of Ser311/Cys311; no homozygotes of Cys311 were identified in either group. The allele frequencies of Cys311 in Chinese schizophrenic patients and normal controls were 2% and 3%, respectively. No significant difference was detected between the two groups. Our results do not support the argument that the Cys311 allele of DRD2 poses a genetic risk for certain types of schizophrenia in Chinese populations.