Genome-wide association study reveals susceptibility loci for self-reported headache in a large community-based Asian population.

BACKGROUND: The genetic substrate for headache in the general population has not been identified in Asians. We investigated susceptible genetic variants for self-reported headache in a large community-based Asian population. METHODS: We conducted a genome-wide association study in participants recruited from a community-based cohort to identify the genetic variants associated with headache in Taiwanese. All participants received a structured questionnaire for self-reported headache. A total of 2084 patients with "self-reported headache" and 11,822 age- and sex-matched controls were enrolled. Gene enrichment analysis using the Genotype-Tissue Expression version 6 database was performed to explore the potential function of the identified variants. RESULTS: We identified two novel loci, rs10493859 in TGFBR3 and rs13312779 in FGF23, that are functionally relevant to vascular function and migraine to be significantly associated with self-reported headache after adjusting age, sex and top 10 principal components (p = 8.53 × 10-11 and p = 1.07 × 10-8, respectively). Gene enrichment analysis for genes with GWAS suggestive significance (p < 10-6) demonstrated that the expression of these genes was significantly enriched in the artery (p = 8.18 × 10-4) and adipose tissue (p = 8.95 × 10-4). CONCLUSION: Our results suggest that vascular dysfunction might play important roles in the pathogenesis of self-reported headache in Asian populations.

Genome-wide analyses identify novel risk loci for cluster headache in Han Chinese residing in Taiwan.

BACKGROUND: Cluster headache is a highly debilitating neurological disorder with considerable inter-ethnic differences. Genome-wide association studies (GWAS) recently identified replicable genomic loci for cluster headache in Europeans, but the genetic underpinnings for cluster headache in Asians remain unclear. The objective of this study is to investigate the genetic architecture and susceptibility loci of cluster headache in Han Chinese resided in Taiwan. METHODS: We conducted a two-stage genome-wide association study in a Taiwanese cohort enrolled from 2007 through 2022 to identify the genetic variants associated with cluster headache. Diagnosis of cluster headache was retrospectively ascertained with the criteria of International Classification of Headache Disorders, third edition. Control subjects were enrolled from the Taiwan Biobank. Genotyping was conducted with the Axiom Genome-Wide Array TWB chip, followed by whole genome imputation. A polygenic risk score was developed to differentiate patients from controls. Downstream analyses including gene-set and tissue enrichment, linkage disequilibrium score regression, and pathway analyses were performed. RESULTS: We enrolled 734 patients with cluster headache and 9,846 population-based controls. We identified three replicable loci, with the lead SNPs being rs1556780 in CAPN2 (odds ratio = 1.59, 95% CI 1.42‒1.78, p = 7.61 × 10-16), rs10188640 in MERTK (odds ratio = 1.52, 95% CI 1.33‒1.73, p = 8.58 × 10-13), and rs13028839 in STAB2 (odds ratio = 0.63, 95% CI 0.52‒0.78, p = 2.81 × 10-8), with the latter two replicating the findings in European populations. Several previously reported genes also showed significant associations with cluster headache in our samples. Polygenic risk score differentiated patients from controls with an area under the receiver operating characteristic curve of 0.77. Downstream analyses implicated circadian regulation and immunological processes in the pathogenesis of cluster headache. CONCLUSIONS: This study revealed the genetic architecture and novel susceptible loci of cluster headache in Han Chinese residing in Taiwan. Our findings support the common genetic contributions of cluster headache across ethnicities and provide novel mechanistic insights into the pathogenesis of cluster headache.

Genome-wide analysis identified novel susceptible genes of restless legs syndrome in migraineurs.

BACKGROUND: Restless legs syndrome is a highly prevalent comorbidity of migraine; however, its genetic contributions remain unclear. OBJECTIVES: To identify the genetic variants of restless legs syndrome in migraineurs and to investigate their potential pathogenic roles. METHODS: We conducted a two-stage genome-wide association study (GWAS) to identify susceptible genes for restless legs syndrome in 1,647 patients with migraine, including 264 with and 1,383 without restless legs syndrome, and also validated the association of lead variants in normal controls unaffected with restless legs syndrome (n = 1,053). We used morpholino translational knockdown (morphants), CRISPR/dCas9 transcriptional knockdown, transient CRISPR/Cas9 knockout (crispants) and gene rescue in one-cell stage embryos of zebrafish to study the function of the identified genes. RESULTS: We identified two novel susceptibility loci rs6021854 (in VSTM2L) and rs79823654 (in CCDC141) to be associated with restless legs syndrome in migraineurs, which remained significant when compared to normal controls. Two different morpholinos targeting vstm2l and ccdc141 in zebrafish demonstrated behavioural and cytochemical phenotypes relevant to restless legs syndrome, including hyperkinetic movements of pectoral fins and decreased number in dopaminergic amacrine cells. These phenotypes could be partially reversed with gene rescue, suggesting the specificity of translational knockdown. Transcriptional CRISPR/dCas9 knockdown and transient CRISPR/Cas9 knockout of vstm2l and ccdc141 replicated the findings observed in translationally knocked-down morphants. CONCLUSIONS: Our GWAS and functional analysis suggest VSTM2L and CCDC141 are highly relevant to the pathogenesis of restless legs syndrome in migraineurs.

Analysis of site-specific glycan profiles of serum proteins in patients with multiple sclerosis or neuromyelitis optica spectrum disorder-a pilot study.

Glycosylation is important for biological functions of proteins and greatly affected by diseases. Exploring the glycosylation profile of the protein-specific glycosylation and/or the site-specific glycosylation may help understand disease etiology, differentiate diseases and ultimately develop therapeutics. Patients with multiple sclerosis (MS) and patients with neuromyelitis optica spectrum disorder (NMOSD) are sometimes difficult to differentiate due to the similarity in their clinical symptoms. The disease-related glycosylation profiles of MS and NMOSD have not yet been well studied. Here, we analyzed site-specific glycan profiles of serum proteins of these patients by using a recently developed mass spectrometry technique. A total of 286 glycopeptides from 49 serum glycoproteins were quantified and compared between healthy controls (n = 6), remitting MS (n = 45) and remitting NMOSD (n = 23) patients. Significant differences in the levels of site-specific N-glycans on inflammation-associated components [IgM, IgG1, IgG2, complement components 8b (CO8B) and attractin], central nerve system-damage-related serum proteins [apolipoprotein D (APOD), alpha-1-antitrypsin, plasma kallikrein and ADAMTS-like protein 3] were observed among three study groups. We furthered demonstrated that site-specific N-glycans on APOD on site 98, CO8B on sites 243 and 553 are potential markers to differentiate MS from NMOSD with an area under receiver operating curve value > 0.75. All these observations indicate that remitting MS or NMOSD patients possess a unique disease-associated glyco-signature in their serum proteins. We conclude that monitoring one's serum protein glycan profile using this high-throughput analysis may provide an additional diagnostic criterion for differentiating diseases, monitoring disease status and estimating response-to-treatment effect.

Genetic associations and expression of extra-short isoforms of disrupted-in-schizophrenia 1 in a neurocognitive subgroup of schizophrenia.

Disrupted-in-schizophrenia 1 (DISC1) was reported to be associated with schizophrenia. In a previous study, we found significant association with schizophrenia patients with deficient sustained attention assessed by continuous performance test (CPT). This study aimed to identify risk polymorphisms in this specific neurocognitive subgroup and investigate the expression of different isoforms of DISC1. A total of 83 genetic variants were identified through direct sequencing in 50 controls and 100 schizophrenia patients. Fourteen variants were genotyped in 600 controls and 912 patients. Patients were subgrouped by familial loading (multiplex or simplex) and performance on CPT. The frequency of AA genotype of rs11122324 at the 3'-UTR of Es and Esv1 isoforms and of rs2793091 at intron 4 were significantly higher in multiplex schizophrenia patients than those in controls (corrected p < 0.05). In further subgrouping, the frequency of AA genotype of the two SNPs were significantly higher in multiplex schizophrenia patients with deficient sustained attention than those in controls (corrected p < 0.005). The mRNA expression levels of two extra-short isoforms (Es and Esv1) in the EBV-transformed lymphocytes of schizophrenia were significantly higher than those of controls. Luciferase reporter assays demonstrated that the A-allele of rs11122324 significantly upregulated DISC1 extra-short isoforms transcription compared with the G-allele. We found two SNPs (rs11122324 and rs2793091) of DISC1 may be specifically associated with multiplex schizophrenia patients with deficient sustained attention. The SNP rs11122324 may be a risk polymorphism, which may have functional influence on the transcription of Es and Esv1 through increasing their expression.

TRPM8 genetic variant is associated with chronic migraine and allodynia.

BACKGROUND: Many single nucleotide polymorphisms (SNPs) have been reported to be associated with migraine susceptibility. However, evidences for their associations with migraine endophenotypes or subtypes are scarce. We aimed to investigate the associations of pre-identified migraine susceptibility loci in Taiwanese with migraine endophenotypes or subtypes, including chronic migraine and allodynia. METHODS: The associations of six SNPs identified from our previous study, including TRPM8 rs10166942, LRP1 rs1172113, DLG2 rs655484, GFRA1 rs3781545, UPP2 rs7565931, and GPR39 rs10803531, and migraine endophenotypes, including chronic migraine and allodynia were tested. Significant associations in the discovery cohort were validated in the replication cohort. The adjusted odds ratios (aOR) were calculated after controlling for confounders. RESULTS: In total, 1904 patients (mean age 37.5 ± 12.2 years old, female ratio: 77.7%) including 1077 in the discovery cohort and 827 in the replication cohort were recruited. Of them, 584 (30.7%) had chronic migraine. Of the 6 investigated SNPs, TRPM8 rs10166942 T allele-carrying patients were more likely to have chronic migraine than non-T allele carriers in both discovery and replication cohorts and combined samples (33.7% vs. 25.8%, p = 0.004, aOR = 1.62). In addition, T allele carriers reported more allodynic symptoms than non-T allele carriers (3.5 ± 3.7 vs. 2.6 ± 2.8, p < 0.001). However, allodynia severity did not differ between episodic and chronic migraine patients. No further correlations between genetic variants and endophenotypes were noted for the other SNPs. CONCLUSIONS: TRPM8 may contribute to the pathogenesis of chronic migraine. However, our study did not support allodynia as a link between them. The underlying mechanisms deserve further investigations.

Unsupervised clustering identified clinically relevant metabolic syndrome endotypes in UK and Taiwan Biobanks.

Metabolic syndrome (MetS) is a collection of cardiovascular risk factors; however, the high prevalence and heterogeneity impede effective clinical management. We conducted unsupervised clustering on individuals from UK Biobank to reveal endotypes. Five MetS subgroups were identified: Cluster 1 (C1): non-descriptive, Cluster 2 (C2): hypertensive, Cluster 3 (C3): obese, Cluster 4 (C4): lipodystrophy-like, and Cluster 5 (C5): hyperglycemic. For all of the endotypes, we identified the corresponding cardiometabolic traits and their associations with clinical outcomes. Genome-wide association studies (GWASs) were conducted to identify associated genotypic traits. We then determined endotype-specific genotypic traits and constructed polygenic risk score (PRS) models specific to each endotype. GWAS of each MetS clusters revealed different genotypic traits. C1 GWAS revealed novel findings of TRIM63, MYBPC3, MYLPF, and RAPSN. Intriguingly, C1, C3, and C4 were associated with genes highly expressed in brain tissues. MetS clusters with comparable phenotypic and genotypic traits were identified in Taiwan Biobank.

A genome-wide association study identifies novel loci of vertigo in an Asian population-based cohort.

The contributing genetic factors of vertigo remain poorly characterized, particularly in individuals of non-European ancestries. Here we show the genetic landscape of vertigo in an Asian population-based cohort. In a two-stage genome-wide association study (Ncase = 6199; Ncontrol = 54,587), we identify vertigo-associated genomic loci in DROSHA and ZNF91/LINC01224, with the latter replicating the findings in European ancestries. Gene-based association testing corroborates these findings. Interestingly, both genes are enriched in cerebellum, a key structure receiving sensory input from the vestibular system. Subjects carrying risk alleles from lead SNPs of DROSHA and ZNF91 incur a 1.74-fold risk of vertigo than those without. Moreover, composite clinical-polygenic risk scores allow differentiation between patients and controls, yielding an area under receiver operating characteristic curve of 0.69. This study identified novel genomic loci for vertigo in an Asian population-based cohort, which may help identifying high risk subjects and provide mechanistic insight in understanding the pathogenesis of vertigo.

Genotype-phenotype correlation in Taiwanese children with diazoxide-unresponsive congenital hyperinsulinism.

Objective: Congenital hyperinsulinism (CHI) is a group of clinically and genetically heterogeneous disorders characterized by dysregulated insulin secretion. The aim of the study was to elucidate genetic etiologies of Taiwanese children with the most severe diazoxide-unresponsive CHI and analyze their genotype-phenotype correlations. Methods: We combined Sanger with whole exome sequencing (WES) to analyze CHI-related genes. The allele frequency of the most common variant was estimated by single-nucleotide polymorphism haplotype analysis. The functional effects of the ATP-sensitive potassium (KATP) channel variants were assessed using patch clamp recording and Western blot. Results: Nine of 13 (69%) patients with ten different pathogenic variants (7 in ABCC8, 2 in KCNJ11 and 1 in GCK) were identified by the combined sequencing. The variant ABCC8 p.T1042QfsX75 identified in three probands was located in a specific haplotype. Functional study revealed the human SUR1 (hSUR1)-L366F KATP channels failed to respond to intracellular MgADP and diazoxide while hSUR1-R797Q and hSUR1-R1393C KATP channels were defective in trafficking. One patient had a de novo dominant mutation in the GCK gene (p.I211F), and WES revealed mosaicism of this variant from another patient. Conclusion: Pathogenic variants in KATP channels are the most common underlying cause of diazoxide-unresponsive CHI in the Taiwanese cohort. The p.T1042QfsX75 variant in the ABCC8 gene is highly suggestive of a founder effect. The I211F mutation in the GCK gene and three rare SUR1 variants associated with defective gating (p.L366F) or traffic (p.R797Q and p.R1393C) KATP channels are also associated with the diazoxide-unresponsive phenotype.

Cost-effectiveness analysis of pneumococcal conjugate vaccine in Taiwan: a transmission dynamic modeling approach.

OBJECTIVES: Streptococcus pneumoniae causes significant morbidity and mortality worldwide. Static pharmacoeconomic models have been used to conduct pharmacoeconomic analyses of pediatric pneumococcal conjugate vaccination programs. The objective of this study was to develop a transmission dynamic model to evaluate the cost-effectiveness of a 13-valent pneumococcal conjugate vaccine (PCV13) in Taiwan. METHODS: An age-structured transmission dynamic model was populated with parameters from the Taiwanese National Health Insurance Research Database and publicly available sources to evaluate the clinical and economic impact of PCV13. Sensitivity analyses were performed to explore model uncertainties. RESULTS: In the base-case analysis, four-dose scheduled universal infant PCV13 vaccination will prevent 5112 cases of invasive pneumococcal diseases, 535,607 cases of all-cause hospitalized pneumonia, 726,986 cases of acute otitis media, and 420 deaths over a 10-year time horizon since 2009. The four-dose vaccination program is estimated to yield an incremental cost-effectiveness ratio of US$38,045 and US$18,299 from payer and societal perspectives. One-way sensitivity analyses indicated that the incremental cost-effectiveness ratio is most sensitive to vaccine price. The 95% confidence interval of the incremental cost-effectiveness ratio was US$10,186 to US$34,563 by multivariate probabilistic sensitivity analyses in the societal perspective. CONCLUSIONS: With a World Health Organization-recommended cost-effectiveness threshold, the PCV13 vaccination program would be cost-effective in Taiwan. To circumvent the lack of long-term real data, a transmission dynamic model is informative to decision makers on evaluating the long-term cost-effectiveness of PCV13.

Genome-wide association study of early-onset bipolar I disorder in the Han Taiwanese population.

The search for susceptibility genes underlying the heterogeneous bipolar disorder has been inconclusive, often with irreproducible results. There is a hope that narrowing the phenotypes will increase the power of genetic analysis. Early-onset bipolar disorder is thought to be a genetically homogeneous subtype with greater symptom severity. We conducted a genome-wide association study (GWAS) for this subtype in bipolar I (BPI) disorder. Study participants included 1779 patients of Han Chinese descent with BPI disorder recruited by the Taiwan Bipolar Consortium. We conducted phenotype assessment using the Chinese version of the Schedules for Clinical Assessment in Neuropsychiatry and prepared a life chart with graphic depiction of lifetime clinical course for each of the BPI patient recruited. The assessment of onset age was based on this life chart with early onset defined as ≤20 years of age. We performed GWAS in a discovery group of 516 early-onset and 790 non-early-onset BPI patients, followed by a replication study in an independent group of 153 early-onset and 320 non-early-onset BPI patients and a meta-analysis with these two groups. The SNP rs11127876, located in the intron of CADM2, showed association with early-onset BPI in the discovery cohort (P = 7.04 × 10-8) and in the test of replication (P = 0.0354). After meta-analysis, this SNP was demonstrated to be a new genetic locus in CADM2 gene associated with early-onset BPI disorder (P = 5.19 × 10-8).

Genome-Wide Association Study of Lithium-Induced Dry Mouth in Bipolar I Disorder.

Dry mouth is a rather common unpleasant adverse drug reaction (ADR) to lithium treatment in bipolar disorders that often lead to poor adherence or early dropout. The aim of this study was to identify the genetic variants of dry mouth associated with lithium treatment in patients with bipolar I (BPI) disorder. In total, 1242 BPI patients who had ever received lithium treatment were identified by the Taiwan Bipolar Consortium for this study. The proportions of patients who experienced impaired drug compliance during lithium medication were comparable between those only with dry mouth and those with any other ADR (86% and 93%, respectively). Dry mouth appeared to be the most prevalent (47.3%) ADR induced by lithium treatment. From the study patients, 921 were included in a genome-wide association study (GWAS), and replication was conducted in the remaining 321 patients. The SNP rs10135918, located in the immunoglobulin heavy chain locus (IGH), showed the strongest associations in the GWAS (p = 2.12 × 10-37) and replication groups (p = 6.36 × 10-13) (dominant model) for dry mouth with a sensitivity of 84.9% in predicting dry mouth induced by lithium. Our results may be translated into clinical recommendation to help identify at-risk individuals for early identification and management of dry mouth, which will improve medication adherence.

Association of the 3' region of COMT with schizophrenia in Taiwan.

BACKGROUND/PURPOSE: The Val108/158Met (rs4680) single nucleotide polymorphism (SNP) in the catechol-O-methyltransferase (COMT) gene contributes to genetic susceptibility to schizophrenia, which is specifically related to impairments in executive functioning. A different genomic region composed of three SNPs (rs737865, rs4680, rs165599) within the COMT gene has been reported to be significantly associated with schizophrenia in Ashkenazi Jews. This study aims to clarify the association between these three SNPs and their haplotypes with schizophrenia and neurocognitive functioning, using both case-control and family-based designs. METHODS: The case-control study included 124 schizophrenia patients and 112 healthy controls, while the family samples included 83 families with at least two affected siblings. The neurocognitive functioning was assessed by the Continuous Performance Test (CPT) and Wisconsin Card Sorting Test. The association analysis was performed using TRANSMIT and FBAT. RESULTS: There was no significant association between the three SNPs and schizophrenia in the case-control study. In the family study, the A allele of rs165599 was transmitted preferentially to the affected individuals (p = 0.023), and significantly associated with a later age of onset (p = 0.018), more severe delusion/hallucination symptom dimension (p = 0.027), and poorer performance in the CPT (p = 0.04). The triple SNP haplotypes did not reveal any significant association with schizophrenia or neurocognitive function. CONCLUSION: The SNP rs165599, which has been mapped to the 3'-UTR region of the COMT gene, was significantly associated with schizophrenia in our family study, and possibly associated with the age of onset, delusion/hallucination symptom dimension, and CPT performance. Therefore, COMT may contribute to the genetic risk for schizophrenia not through the Val108/158Met polymorphism, but through other variants that are situated 3' to this region, in the Taiwanese population. Nevertheless, the true associated functional variants in our subjects remain to be elucidated.

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.

Thyrotropin receptor antibodies and a genetic hint in antithyroid drug-induced adverse drug reactions.

BACKGROUND: Antithyroid drugs (ATDs) are known to cause various adverse drug reactions (ADRs) that can lead to treatment complexity and unpredictable risks. With the aim of ensuring safer drug use, we assessed whether thyrotropin receptor antibody (TRAb) titers are associated with ATD-induced cutaneous reactions and/or hepatotoxicity, and examined potential genetic predisposition factors. METHODS: We compared TRAb titers of 37 Graves' disease (GD) patients who had experienced carbimazole/methimazole-induced cutaneous reactions and/or hepatotoxicity with those of 40 normal individuals, or 78 GD patients without the aforementioned ATD-induced ADRs. We performed a genome-wide association study and/or human leukocyte antigen genotyping on GD patients [first stage (chart reviews): 24 cases with ADRs and 423 controls; second stage (actively recruited): 45 cases with ADRs and 137 controls]. RESULTS: For patients with Graves' hyperthyroidism, individuals with higher TRAb titers showed a predisposition to carbimazole/methimazole-induced cutaneous reactions and/or hepatotoxicity, with an estimated odds ratio of 5.19 (cut-off value: 64%). Potential associations with the rs144542704 and rs61893841 on chromosomes 17 and 11, respectively, warrant further genetic association analysis. CONCLUSION: Our findings support the use of carbimazole/methimazole in patients with low TRAb titers to ensure safer drug use. The identified genetic associations warrant further research.

No association evidence between schizophrenia and dystrobrevin-binding protein 1 (DTNBP1) in Taiwanese families.

Several linkage studies have shown significant linkage of schizophrenia to chromosome 6p region, which includes the positional candidate genes, Dystrobrevin-binding protein 1 (DTNBP1). The aim was to examine the association evidence of the candidate gene in 693 Taiwanese families with at least two affected siblings of schizophrenia. We genotyped nine SNPs of this gene with average intermarker distance of 17 kb. Intermarker linkage disequilibrium was calculated with GOLD. Single locus and haplotype association analyses were performed with TRANSMIT program. We found no significant association between schizophrenia and DTNBP1 either through single locus or haplotype analyses. We failed to replicate the association evidence between DTNBP1 and schizophrenia and this gene may not play a major role in the etiology of schizophrenia in this Taiwanese family sample.

HTF9C gene of 22q11.21 region associates with schizophrenia having deficit-sustained attention.

OBJECTIVE: A region at chromosome 22q11.21 has been reported to potentially harbor a candidate gene for schizophrenia, ZDHHC8 (zinc finger, DHHC domain containing 8; also annotated as KIAA1292) in a number of studies. This finding has been replicated in Han Chinese, but not in other ethnicity-specific studies. For further support from within the Han Chinese ethnic group, we selected two single nucleotide polymorphisms (SNP) located at the distal 5'-end (rs1633445; intron 10 of HpaII tiny fragments locus 9C, HTF9C) and the intron 4 (rs175174) of ZDHHC8 gene to test if these were associated with schizophrenia in a study sample of Taiwan. METHODS: A total of 218 schizophrenia families with at least two affected siblings participated in this study. These two SNPs were genotyped using matrix-assisted laser desorption/localization ionization time of flight (MALDI-TOF) mass spectrometry. RESULTS: Significant associations with schizophrenia were not shown from these two SNPs. After stratifying schizophrenia according to the deficit and the nondeficit of sustained attention assessed by the Continuous Performance Test, the rs1633445 showed significant association with schizophrenia in the presence of a deficit in sustained attention (P<0.04). CONCLUSION: SNP rs1633445 of the HTF9C gene may be associated with a deficit in sustained attention within schizophrenia, in a Taiwanese cohort. The deficit of sustained attention may be an endophenotype of schizophrenia, and warrants further study.

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.

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.

Absence of significant associations between four AKT1 SNP markers and schizophrenia in the Taiwanese population.

AKT1 (V-akt murine thymoma viral oncogene homolog 1) is a protein kinase isoform of AKT. Five single-nucleotide polymorphisms, rs3803300, rs1130214, rs3730358, rs2498799 and rs2494732, at the genomic region of AKT1 have been reported to be significantly associated with schizophrenia. We tested for the presence of these five single-nucleotide polymorphisms in a Taiwanese population by genotyping 218 co-affected schizophrenia families. Both single locus and haplotypes analyses showed no association of these single-nucleotide polymorphisms with schizophrenia. These findings fail to support AKT1 as a susceptibility gene for schizophrenia in the Taiwanese population.