Wen-Chen Ou-Yang

Genome-wide association study of bipolar I disorder in the Han Chinese population

We report the first genome-wide association study in 1000 bipolar I patients and 1000 controls, with a replication of the top hits in another 409 cases and 1000 controls in the Han Chinese population. Four regions with most strongly associated single-nucleotide polymorphisms (SNPs) were detected, of which three were not found in previous GWA studies in the Caucasian populations. Among them, SNPs close to specificity protein 8 (SP8) and ST8 α-N-acetyl- neuraminide α-2,8-sialyltransferase (ST8SIA2) are associated with Bipolar I, with P-values of 4.87 × 10−7 (rs2709736) and 6.05 × 10−6 (rs8040009), respectively. We have also identified SNPs in potassium channel tetramerization domain containing 12 gene (KCTD12) (rs2073831, P=9.74 × 10−6) and in CACNB2 (Calcium channel, voltage-dependent, β-2 subunit) gene (rs11013860, P=5.15 × 10−5), One SNP nearby the rs1938526 SNP of ANK3 gene and another SNP nearby the SNP rs11720452 in chromosome 3 reported in previous GWA studies also showed suggestive association in this study (P=6.55 × 10−5 and P=1.48 × 10−5, respectively). This may suggest that there are common and population-specific susceptibility genes for bipolar I disorder.

Survey of quality of life and related risk factors for a Taiwanese village population 3 years post-earthquake

OBJECTIVE To investigate quality of life (QOL) and related risk factors in Taiwanese earthquake survivors diagnosed with different psychiatric disorders 3 years after the 1999 Chi-Chi earthquake. METHOD This study was a population survey. Trained assistants used the Medical Outcomes Study Short Form-36 (MOS SF-36) and questionnaires to interview 405 respondents (189 men and 216 women) aged 16 years or older, who had been exposed to the earthquake. Psychiatrists interviewed the same respondents using the Mini-International Neuropsychiatric Interview, with an adjusted response rate of 70.2%. RESULTS The prevalence range for psychiatric disorders in the earthquake survivors was 0.2-7.2% 3 years after the Chi-Chi earthquake, with rates for major depression (MD) and posttraumatic stress disorder (PTSD) of 6.4% and 4.4%, respectively. The QOL scores for the PTSD/MD group were lower than for the other two diagnostic groups, as determined by assessment of physical and mental aspects of functional integrity from MOS SF-36 scores. The predictors for poor QOL were age, female gender, economic problems, physical illness, subjective assessment of memory and social-activity decline and diagnosis of PTSD or MD. CONCLUSION The QOL for earthquake survivors with psychiatric disorders, especially PTSD or MD, was inferior compared with the mentally healthy analogues, with contemporaneous decreases in mental and physical function scores across the QOL subscales. The persistence of long-term economic problems was one of many important factors affecting QOL.

Variant GADL1 and response to lithium therapy in bipolar I disorder.

BACKGROUND Lithium has been a first-line choice for maintenance treatment of bipolar disorders to prevent relapse of mania and depression, but many patients do not have a response to lithium treatment. METHODS We selected subgroups from a sample of 1761 patients of Han Chinese descent with bipolar I disorder who were recruited by the Taiwan Bipolar Consortium. We assessed their response to lithium treatment using the Alda scale and performed a genomewide association study on samples from one subgroup of 294 patients with bipolar I disorder who were receiving lithium treatment. We then tested the single-nucleotide polymorphisms (SNPs) that showed the strongest association with a response to lithium for association in a replication sample of 100 patients and tested them further in a follow-up sample of 24 patients. We sequenced the exons, exon-intron boundaries, and part of the promoter of the gene encoding glutamate decarboxylase-like protein 1 (GADL1) in 94 patients who had a response to lithium and in 94 patients who did not have a response in the genomewide association sample. RESULTS Two SNPs in high linkage disequilibrium, rs17026688 and rs17026651, that are located in the introns of GADL1 showed the strongest associations in the genomewide association study (P=5.50×10(-37) and P=2.52×10(-37), respectively) and in the replication sample of 100 patients (P=9.19×10(-15) for each SNP). These two SNPs had a sensitivity of 93% for predicting a response to lithium and differentiated between patients with a good response and those with a poor response in the follow-up cohort. Resequencing of GADL1 revealed a novel variant, IVS8+48delG, which lies in intron 8 of the gene, is in complete linkage disequilibrium with rs17026688 and is predicted to affect splicing. CONCLUSIONS Genetic variations in GADL1 are associated with the response to lithium maintenance treatment for bipolar I disorder in patients of Han Chinese descent. (Funded by Academia Sinica and others.).

Epidemiologic psychiatric studies on post-disaster impact among Chi-Chi earthquake survivors in Yu-Chi, Taiwan.

Abstract  The aim of the present study was to survey a cohort population for the risk factors of post‐traumatic stress disorder (PTSD) and major depression, and the prevalence of different psychiatric disorders at 6 months and 2 and 3 years after a major earthquake. The Disaster‐Related Psychological Screening Test (DRPST), part I, and the Mini‐International Neuropsychiatric Interview (MINI) were, respectively, administered by trained interviewers and psychiatrists in this community‐interview program. The prevalence of PTSD decreased from 8.3% at 6 months to 4.2% at 3 years after the earthquake. Suicidality increased from 4.2% at 6 months and 5.6% at 2 years to 6.0% at 3 years after the earthquake; drug abuse/dependence increased from 2.3% at 6 months to 5.1% at 3 years after the disaster. The risk factors for PTSD and major depression in various post‐disaster stages were determined. Earthquake survivors had a high percentage of psychiatric disorders in the first 2 years, and then the prevalence declined. Following the devastation caused by the Chi‐Chi earthquake, it is important to focus on treating symptoms of major depression and PTSD and eliminating the risk factors for both of these disorders in survivors to avoid the increase in suicidality.

Quality of life and related risk factors in a Taiwanese Village population 21 months after an earthquake

OBJECTIVE To investigate quality of life and related risk factors of Taiwanese earthquake survivors with different psychiatric disorders 21 months after the earthquake. METHOD This was a population survey. Trained assistants used the Medical Outcomes Study Short Form-36 (MOS SF-36) and questionnaires to interview 461 respondents (209 males and 252 females) 16 years or older who were equally exposed to the earthquake. Psychiatrists interviewed the same respondents using the Mini-International Neuropsychiatric Interview (MINI), with an adjusted response rate of 79.9%. RESULTS The prevalence of varied psychiatric disorders in earthquake survivors ranged from 3.3% to 18%. However, there was almost a positive trend in quality of life in survivors among the following groups: posttraumatic stress disorder combined with major depressive episode; major depressive episode; posttraumatic stress disorder; other psychiatric diseases; and healthy mentality groups on the physical aspect or mental aspect of the MOS SF-36. When survivors were elderly or female and had experienced prominent financial loss immediately after the earthquake, social network change, and mental impairment, their quality of life tended to be worse. CONCLUSION The earthquake survivors had a higher percentage of psychiatric disorders. The risk factors that affected quality of life in survivors were age, female sex, financial loss, social network change, and mental impairment.

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.

The relationship between quality of life and psychiatric impairment for a Taiwanese community post-earthquake

This purpose of this study was to investigate the relationship between quality of life and psychiatric impairment in a Taiwanese community located near the epicenter of the 1999 earthquake, as assessed four to six months after the natural catastrophe. Trained assistants interviewed the 4223 respondents using the disaster-related psychological screening test (DRPST), an instrument specifically designed and validated by senior psychiatrists for assessment of psychiatric impairment after natural catastrophe. Additionally, the 36-Item Short-Form Health Survey (SF-36) was used to evaluate quality of life. The collected results were analyzed using Windows SPSS 10.0 software. Psychiatric impairment rated moderate to severe was assessed for 1448 (34.3%) of the responding residents. The 4223 respondents were divided into 4 psychiatric-impairment groups based on DPRST score: healthy (n = 952); mild impairment (n = 1823); moderate impairment (n = 1126); and, severe impairment (n = 322). The four groups were compared for a number of salient factors, including gender, age, current marital status and psychiatric-impairment score, to determine impact on quality of life. Respondents assessed as psychiatrically impaired tended to be older, female, divorced/widowed, and less educated, and they were more likely to have experienced major familial financial loss as an immediate consequence of the earthquake. Further, the greater the severity of the psychiatric impairment, the lower the scores for quality of life, for both the physical and mental aspects of this important general indicator.

Taiwan schizophrenia linkage study: The field study

One possible reason of the inconsistent results of linkage analyses of schizophrenia, a complex disorder, was mainly due to the small sample size of studies. This Taiwan Schizophrenia Linkage Study (TSLS) was designed to collect a large family sample with at least two affected siblings of a single ethnicity. The 17.6 millions of Taiwanese Chinese, age over 15, was the sample population, and 78 psychiatric hospitals or health centers participated in this TSLS program. Before data collection started, every study subject signed the informed consent. The ascertainment protocol for data collection included blood sample, structured Diagnostic Interview for Genetic Studies (DIGS), Structured Interview for Schizotypy (SIS), scales for assessment of positive and negative symptoms (SAPS, SANS), and continuous performance test (CPT), Wisconsin card sort test (WCST) of neuropsychological functions. We have contacted 831 families for this study and 607 families, comprised 2,490 subjects, were successfully recruited. The recruitment rate was 38.4% from the estimated total of 1,582 families with at least two affected siblings. These collected family samples were fairly evenly distributed all over Taiwan. Those 2,490 study subjects (1,283 male, 1,117 female) comprised 1,568 siblings (mean age 35.7 years old) and 922 parents (mean age 63.6 years old). Of these 1,568 siblings, 1,258 (80.2%) were affected (male 795, female 463), and the mean age of onset was 22.6 years old. Among 922 parents, 65 were affected (male 14, female 51) and the age of onset was 33.1 years old. This TSLS demonstrated a successful establishment of an efficient research infrastructure to collect a large nation‐wise sample of schizophrenic family for genetic linkage study.

Establishment of a disaster-related psychological screening test

Objective: To create a short screening scale for the detection of posttraumatic stress disorder (PTSD) and major depressive disorder (MDE) in earthquake survivors in Taiwan. Method: Trained research assistants used the Disaster-Related Psychological Screening Test (DRPST) to assess 461 residents of a village that had experienced a major earthquake. The participants were also evaluated by psychiatrists using the Mini-International Neuropsychiatric Interview (MINI). Best subset regression analysis and the receiver operating characteristics curve were used to select a subset of items and cut-off points from the DRPST. Results: A seven-symptom scale and a three-symptom analogue were selected for PTSD and MDE screening, respectively. Scores of three or more on the PTSD scale and two or more on the MDE scale were used to define a group of positive cases that provide useful information for the patient cohort and will be valuable in long-term follow-up studies of the prevalence of psychiatric diseases following a natural disaster. However, higher scores could also be used to define positive cases under limited psychiatric care resources. Conclusion: The DRPST, which was administered for phase 1 of this two-phase study, may be used for effective and rapid screening for PTSD and MDE after an earthquake, despite the usual limitations on resources following a disaster.

Linkage evidence of schizophrenia to loci near neuregulin 1 gene on chromosome 8p21 in Taiwanese families

Positive linkage of schizophrenia to chromosome 8p22‐21 loci had been reported in the Caucasian samples. This study was designed to replicate this finding by using eleven microsatellite markers on chromosome 8p22‐21 in 52 Taiwanese schizophrenic families with at least two affected siblings. Two phenotype models (narrow: DSM‐IV schizophrenia only; and broad: including schizophrenia, schizoaffective, and other non‐affective psychotic disorders) were used to define the disease phenotype. Maximum non‐parametric linkage scores (NPL score) of 2.45 (P = 0.008) and 1.89 (P = 0.02) were obtained for the marker D8S1222 under the broad and narrow models, respectively. Positive linkage was found across about a 4‐cM region. The marker D8S1222 was about 400 kbp distal to the exon 1 of glial growth factor 2 (GGF2), an isoform of Neuregulin 1 gene (NRG1), which has been highly suggested to be a candidate gene for schizophrenia. The results provide suggestive linkage evidence of schizophrenia to loci near NRG1 on chromosome 8p21 in an ethnically distinct Taiwanese sample. Further exploration of the candidate gene and nearby chromosome regions is warranted.