Chien-Ching Chang

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.

Diverse Associations between ESR1 Polymorphism and Breast Cancer Development and Progression

Purpose: To test the hypothesis that polymorphisms of ESR1, the gene encoding estrogen receptor α (ERα), are associated with susceptibility, clinical phenotype, and progression of breast cancer. Patients and Methods: A case-control study was done on 940 patients with incident breast cancer and 1,547 healthy female controls. Fifteen single-nucleotide polymorphisms (SNP) selected from chr6:152,170,379-152,466,100 (exons 1–8 of the ESR1 gene, excluding flanking sequences), reflecting major polymorphisms of this gene, were genotyped. Frequencies of SNPs were compared between cases and controls to identify SNPs associated with cancer susceptibility and between cases with different clinical phenotypes to determine the role of ESR1 polymorphism in cancer progression. Results: SNPs located in one cluster in intron 1 and one haplotype, based on these SNPs, showed a significant association with breast cancer susceptibility. The tumorigenic contribution of these intron 1 SNPs was more obvious in combination with reproductive risk factors (P for interaction <0.05). One of these intron 1 SNPs was also significantly associated with low ERα expression in tumors. Interestingly, the same intron 1 SNPs showed a correlation with worse clinical phenotypes, including poor differentiation of tumor cells and a late stage. These intron 1 SNPs also showed a significant association with the 5-year breast cancer–specific survival rate of patients, but had opposite effects in ERα-negative and ERα-positive early-stage patients. Conclusions: Our findings provide support for diverse roles of ESR1 polymorphism in determining susceptibility in different stages of breast cancer. The differences between the important ESR1 SNPs identified in Chinese women in this study and those identified in studies on Western women with breast cancer suggest different roles of ERα in these two populations. Clin Cancer Res; 16(13); 3473–84. ©2010 AACR.

DRD2 haplotype associated with negative symptoms and sustained attention deficits in Han Chinese with schizophrenia in Taiwan

Previous studies have reported significant associations between schizophrenia and the dopamine receptor D2 gene (DRD2) variants. The relationships between DRD2 and clinical phenotypes are of particular interest because DRD2 has been shown to associate with treatment response and prefrontal dopamine transmission. Glatt et al. reported significant associations between schizophrenia and DRD2 variants (two single-nucleotide polymorphisms (SNPs) rs1079727 and rs2283265, and two haplotypes, block 3 (rs1079727(A)–rs2440390(C)–rs2283265(G)) and block 4 (rs1801028(G)–rs1110977(A)–rs1124492(C)–rs2734841 (T))) in 2408 Han Chinese individuals in Taiwan. To further investigate the relationships between the SNPs/haplotypes of DRD2 and clinical symptoms and neuropsychological function, we compared the quantitative phenotypes in patients with risk alleles/haplotypes and those without. The results showed that the A allele of rs1079727, G allele of rs2283265, A allele of rs1124492 and the risk haplotype (A–C–G) of block 3 were associated with more severe negative symptoms. With regard to neuropsychological performance, the risk haplotype (G–A–C–T) of block 4 was associated with poorer performance in the sustained attention task. Our results imply that the genetic variants of DRD2 might not only have a role in susceptibility to schizophrenia, but also influence the phenotypes of negative symptoms and sustained attention in schizophrenia. This association warrants further validation.

A genome-wide scanning and fine mapping study of COGA data

A thorough genetic mapping study was performed to identify predisposing genes for alcoholism dependence using the Collaborative Study on the Genetics of Alcoholism (COGA) data. The procedure comprised whole-genome linkage and confirmation analyses, single locus and haplotype fine mapping analyses, and gene × environment haplotype regression. Stratified analysis was considered to reduce the ethnic heterogeneity and simultaneously family-based and case-control study designs were applied to detect potential genetic signals. By using different methods and markers, we found high linkage signals at D1S225 (253.7 cM), D1S547 (279.2 cM), D2S1356 (64.6 cM), and D7S2846 (56.8 cM) with nonparametric linkage scores of 3.92, 4.10, 4.44, and 3.55, respectively. We also conducted haplotype and odds ratio analyses, where the response was the dichotomous status of alcohol dependence, explanatory variables were the inferred individual haplotypes and the three statistically significant covariates were age, gender, and max drink (the maximum number of drinks consumed in a 24-hr period). The final model identified important AD-related haplotypes within a candidate region of NRXN1 at 2p21 and a few others in the inter-gene regions. The relative magnitude of risks to the identified risky/protective haplotypes was elucidated.

ANXA7, PPP3CB, DNAJC9, and ZMYND17 genes at chromosome 10q22 associated with the subgroup of schizophrenia with deficits in attention and executive function.

BACKGROUND A genome scan of Taiwanese schizophrenia families suggested linkage to chromosome 10q22.3. We aimed to find the candidate genes in this region. METHODS A total of 476 schizophrenia families were included. Hierarchical clustering method was used for clustering families to homogeneous subgroups according to their performances of sustained attention and executive function. Association analysis was performed using family-based association testing and TRANSMIT. Candidate associated regions were identified using the longest significance run method. The relative messenger RNA expression level was determined using real-time reverse transcriptase polymerase chain reaction. RESULTS First, we genotyped 18 microsatellite markers between D10S1432 and D10S1239. The maximum nonparametric linkage score was 2.79 on D10S195. Through family clustering, we found the maximum nonparametric linkage score was 3.70 on D10S195 in the family cluster with deficits in attention and executive function. Second, we genotyped 79 single nucleotide polymorphisms between D10S1432 and D10S580 in 90 attention deficit and execution deficit families. Association analysis indicated significant transmission distortion for nine single nucleotide polymorphisms. Using the longest significance run method, we identified a 427-kilobase region as a significant candidate region, which encompasses nine genes. Third, we studied messenger RNA expression of these nine genes in Epstein-Barr virus-transformed lymphoblastic cells. In schizophrenic patients, there was significantly lower expression of ANXA7, PPP3CB, and DNAJC9 and significantly higher expression of ZMYND17. CONCLUSIONS ANXA7, PPP3CB, DNAJC9, and ZMYND17 genes are potential candidate genes for schizophrenia, especially in patients with deficits in sustained attention and executive function. The responsible functional variants remained to be clarified.

Linkage of Graves' disease to the human leucocyte antigen region in the Chinese-Han population in Taiwan.

Objective  To investigate whether markers in the candidate chromosome regions, including the human leucocyte antigen (HLA) region, are linked to Graves’ disease (GD).

Haplotypes of the D-Amino Acid Oxidase Gene Are Significantly Associated with Schizophrenia and Its Neurocognitive Deficits

D-amino acid oxidase (DAO) has been reported to be associated with schizophrenia. This study aimed to search for genetic variants associated with this gene. The genomic regions of all exons, highly conserved regions of introns, and promoters of this gene were sequenced. Potentially meaningful single-nucleotide polymorphisms (SNPs) obtained from direct sequencing were selected for genotyping in 600 controls and 912 patients with schizophrenia and in a replicated sample consisting of 388 patients with schizophrenia. Genetic associations were examined using single-locus and haplotype association analyses. In single-locus analyses, the frequency of the C allele of a novel SNP rs55944529 located at intron 8 was found to be significantly higher in the original large patient sample (p = 0.016). This allele was associated with a higher level of DAO mRNA expression in the Epstein-Barr virus-transformed lymphocytes. The haplotype distribution of a haplotype block composed of rs11114083-rs2070586-rs2070587-rs55944529 across intron 1 and intron 8 was significantly different between the patients and controls and the haplotype frequencies of AAGC were significantly higher in patients, in both the original (corrected p < 0.0001) and replicated samples (corrected p = 0.0003). The CGTC haplotype was specifically associated with the subgroup with deficits in sustained attention and executive function and the AAGC haplotype was associated with the subgroup without such deficits. The DAO gene was a susceptibility gene for schizophrenia and the genomic region between intron 1 and intron 8 may harbor functional genetic variants, which may influence the mRNA expression of DAO and neurocognitive functions in schizophrenia.

Comprehensive human leukocyte antigen genotyping of patients with type 1 diabetes mellitus in Taiwan

Type 1 diabetes (T1D) mellitus is an autoimmune disorder involving both complex genetic and environmental factors. The incidence rates are low in Asian countries, and the specific, explanatory genetic factors underlying this have been investigated. The aim of this study was to elucidate the association of human leukocyte antigen (HLA) alleles/haplotypes with T1D in Taiwan.

Differentiation of remitting neuromyelitis optica spectrum disorders from multiple sclerosis by integrating parameters from serum proteins and lymphocyte subsets

Differential diagnosis for neuromyelitis optica spectrum disorder (NMOSD) and multiple sclerosis (MS) is always doubtful. To differentiate these diseases, we studied the immune status in the blood of patients with MS (n = 45) or NMOSD (n = 23) at remission phase. Remitting NMOSD patients had increased levels of CXCL13 and memory B cells, while remitting MS patients had elevated levels of galectin-9 and Th1 cells. A diagnostic model with these four variables is built to distinguish remitting NMOSD from MS with a sensitivity of 91.30%. Our diagnostic model may help to improve the differentiation of remitting NMOSD from MS.

A non-threshold region-specific method for detecting rare variants in complex diseases

A region-specific method, NTR (non-threshold rare) variant detection method, was developed—it does not use the threshold for defining rare variants and accounts for directions of effects. NTR also considers linkage disequilibrium within the region and accommodates common and rare variants simultaneously. NTR weighs variants according to minor allele frequency and odds ratio to combine the effects of common and rare variants on disease occurrence into a single score and provides a test statistic to assess the significance of the score. In the simulations, under different effect sizes, the power of NTR increased as the effect size increased, and the type I error of our method was controlled well. Moreover, NTR was compared with several other existing methods, including the combined multivariate and collapsing method (CMC), weighted sum statistic method (WSS), sequence kernel association test (SKAT), and its modification, SKAT-O. NTR yields comparable or better power in simulations, especially when the effects of linkage disequilibrium between variants were at least moderate. In an analysis of diabetic nephropathy data, NTR detected more confirmed disease-related genes than the other aforementioned methods. NTR can thus be used as a complementary tool to help in dissecting the etiology of complex diseases.