Complement factor H and susceptibility to major depressive disorder in Han Chinese.

BACKGROUND: Accumulating evidence suggests that altered immunity contributes to the development of major depressive disorder (MDD). AIMS: To examine whether complement factor H (CFH), a regulator of activation of the alternative pathway of the complement cascade, confers susceptibility to MDD. METHOD: Expression analyses were tested in 53 unmedicated people with MDD and 55 healthy controls. A two-stage genetic association analysis was performed in 3323 Han Chinese with or without MDD. Potential associations between CFH single nucleotide polymorphisms and age at MDD onset were evaluated. RESULTS: CFH levels were significantly lower in the MDD group at both protein and mRNA levels (P = 0.009 and P = 0.014 respectively). A regulatory variant in the CFH gene, rs1061170, showed statistically significant genotypic and allelic differences between the MDD and control groups (genotypic P = 0.0005, allelic P = 0.0001). Kaplan-Meier survival analysis showed that age at onset of MDD was significantly associated with the C allele of rs1061170 (log rank statistic χ(2) = 6.82, P = 0.009). The C-allele carriers had a younger age at onset of MDD (22.2 years, s.d. = 4.0) than those without the C allele (23.6 years, s.d. = 4.3). CONCLUSIONS: CFH is likely to play an important role in the development of MDD. rs1061170 has an important effect on age at onset of MDD in Han Chinese and may therefore be related to early pathogenesis of MDD, although further study is needed.

Genetic variant in NDUFS1 gene is associated with schizophrenia and negative symptoms in Han Chinese.

Abnormalities in mitochondrial complex I, which is responsible for controlling mitochondrial function, have been implicated in a variety of diseases associated with mitochondrial dysfunction, potentially including schizophrenia. The NADH dehydrogenase Fe-S protein 1 (NDUFS1) is the largest subunit of complex I. To explore whether the encoding NDUFS1 gene confers susceptibility to schizophrenia or is associated with the severity of typical symptoms of schizophrenia, we recruited 519 stable schizophrenia patients receiving clozapine treatment and 594 healthy controls for genotyping to investigate the association of four selected tagging single-nucleotide polymorphisms (SNPs) of NDUFS1 and both schizophrenia risk and symptom severity. The severity of psychotic symptoms was evaluated using the Positive and Negative Syndrome Scale and then tested for association with the four SNPs. The SNP rs1044120 showed significant association with schizophrenia (adjusted P=0.032). The frequency of the G allele of rs1044120 was significantly higher in patients than among the healthy controls (adjusted P=0.008). Stratification by sex revealed a significant association between the rs1044120 polymorphism and schizophrenia among males (adjusted P=0.036 and 0.008 in genotypic and allelic comparisons, respectively). We also observed a significant difference in the negative symptom scores among the three genotypes among these males (adjusted P=0.036). Post hoc comparisons showed that rs1044120 G/G carriers had higher negative symptom scores than those with G/T and T/T carriers (raw P=0.035 and 0.005, respectively). Our findings suggest that NDUFS1 may confer susceptibility to schizophrenia in male subjects, acting as a causative factor for the severity of negative symptoms in schizophrenia.

A Comprehensive Analysis of the CaMK2A Gene and Susceptibility to Alzheimer's Disease in the Han Chinese Population.

There is ample evidence suggesting that calcium/calmodulin-dependent protein kinase II alpha (CaMK2A) may play an important role in the pathophysiology of Alzheimer's disease (AD). This genetic study aimed to investigate whether CaMK2A confers susceptibility to the development of AD in the Han Chinese population. A total of seven single nucleotide polymorphisms (SNPs) within CaMK2A were screened in two independent cohorts from southwestern China (333 AD patients and 334 controls) and eastern China (382 AD patients and 426 controls) to discern the potential association between this gene and AD. In addition, a cross-platform normalized expression resource was used to investigate whether CaMK2A is differentially expressed in the brain between individuals with AD and the controls. In addition, expression quantitative trait loci (eQTL) analysis was used to explore the differences in CaMK2A expression in the brain among different genotypes. The cross-platform normalized data showed significant differences in CaMK2A expression in the hippocampus, entorhinal cortex and temporal cortex between the AD patients and the control subjects (|log FC| > 0.1, P < 0.05); however, only the differences in the hippocampus and temporal cortex remained after the multiple comparisons correction [false discovery rate (FDR)-corrected, P < 0.05]. The frequency of the rs4958445 genotype was significantly different between the AD subjects and the controls from southwestern China (P = 0.013, P = 0.034 after FDR correction). When the two samples were combined, rs4958445 still showed a significant association with AD (P = 0.044). Haplotype analysis indicated that the T-A-C-A-T-C-C and T-G-C-A-T-C-C haplotypes in the southwestern cohort and the T-G-C-G-C-T-C haplotype in the eastern cohort, consisting of rs10051644, rs6869634, rs3797617, rs3756577, rs4958445, rs10515639 and rs6881743, showed a significant association with AD (P = 0.037, P = 0.026 and P = 0.045, respectively). Furthermore, the brain eQTL analysis revealed a significant association between the rs4958445 polymorphism and CaMK2A expression in the inferior olivary nucleus (P = 0.029). Our results suggest an important role for CaMK2A in the pathophysiology of AD in the Han Chinese population, especially the southwestern population.

Downregulation of blood serum microRNA 29 family in patients with Parkinson's disease.

There is currently no reliable and easily applicable diagnostic marker for Parkinson's disease (PD). The aims of the present study were to compare the expression profiles of the microRNA29 family (miR-29s) in blood serum from patients with PD with healthy controls and to clarify whether the expression of miR-29s is correlated with disease severity, duration or L-dopa therapy and whether expression depends on the gender and age of patients. The levels of blood serum miR-29s in 80 patients with PD and 80 unaffected controls were assessed by reverse transcription-quantitative real-time PCR. The PCR products were confirmed by cloning and sequencing. Additionally, the expression of miR-7 in the blood serum from PD patients and control subjects was assessed. Serum miR-29 levels were significantly downregulated in PD patients compared to healthy controls. The serum miR-29 levels in female PD patients were markedly higher than in male PD patients. The expression of serum miR-29a and miR-29c expression tended to decrease with disease severity. Moreover, we found that serum miR-7 levels did not differ between PD patients and control subjects. Therefore, the reduction of serum miR-29 levels, particularly miR-29a and miR-29c, warrants further investigation of its potential serving as biomarkers for PD.

The NCAN gene: schizophrenia susceptibility and cognitive dysfunction.

BACKGROUND: Cognitive dysfunction has been recognized as a cardinal feature of schizophrenia. Elucidating the neurobiological substrates of cognitive dysfunction in schizophrenia would help identify the underlying mechanism of this disorder. The rs1064395 single nucleotide polymorphism, within the gene encoding neurocan (NCAN), is reported to be associated with schizophrenia in European populations and may influence brain structure in patients with schizophrenia. METHODS: In this study, we aimed to explore whether NCAN rs1064395 confers some risk for schizophrenia and cognitive dysfunction in Han Chinese. We recruited 681 patients with schizophrenia and 699 healthy subjects. Two hundred and fifty-four patients were evaluated according to Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). RESULTS: There were no significant differences in genotype or allele distributions of the rs1064395 polymorphism between the schizophrenia and control groups. Patients showed significantly poorer performance than controls on immediate memory, visuospatial skill, language, attention, delayed memory, and total RBANS score. Patients with the A/A or A/G genotype of rs1064395 had lower scores of immediate memory, visuospatial skill, attention, and total RBANS score than those with the G/G genotype. We performed an expression quantitative trait loci analysis and observed a significant association between rs1064395 and NCAN expression in the frontal (P=0.0022, P=0.022 after Bonferroni correction) and cerebellar cortex (P=0.0032, P=0.032 after Bonferroni correction). CONCLUSION: Our findings indicate that this single nucleotide polymorphism may be a risk factor for cognitive dysfunction in patients with schizophrenia. Further investigations are warranted for validation purposes and to identify the precise mechanism by which rs1064395 influences cognitive performance in patients with schizophrenia.

A haplotype in the 5'-upstream region of the NDUFV2 gene is associated with major depressive disorder in Han Chinese.

BACKGROUND: There is ample evidence supporting the idea that mitochondrial dysfunction and altered expression of complex I subunits play important roles in the pathophysiology of mental disorders. Early literature reports have implicated NDUFV2, a nuclear-encoded mitochondrial complex I subunit gene, in bipolar disorder and schizophrenia. There has been no genetic study to investigate whether there is an association between NDUFV2 and major depressive disorder (MDD). METHODS: This study recruited 744 patients with MDD and 767 well-matched healthy controls in a Chinese Han population, and genotyped 9 SNPs within NDUFV2. RESULTS: Initial analysis showed statistically significant differences for 2 SNPs (rs4798765 and rs12964485) in the genotypic distribution and for 1 SNP (rs4797356) in the allelic distribution between the case and control groups. Nevertheless, no significance was demonstrated following multiple testing corrections. Haplotype analysis showed that the T-C haplotype, consisting of rs12457810 and rs12964485, was significantly associated with MDD (P=0.005, corrected P=0.04 after a 10,000 permutation test). We performed an eQTL analysis and found that rs12964485 was significantly associated with NDUFV2 expression in the occipital cortex (P=0.036), albeit this significance did not survive after Bonferroni correction. LIMITATION: This is a preliminary investigation with a relatively modest sample size. CONCLUSION: Our findings provided preliminary evidence that a haplotype T-C consisting of rs12457810 and rs12964485 in the 5'-upstream region of NDUFV2 may be a protective factor for the development of MDD in Han Chinese.

A Preliminary Genetic Analysis of Complement 3 Gene and Schizophrenia.

Complement pathway activation was found to occur frequently in schizophrenia, and complement 3 (C3) plays a major role in this process. Previous studies have provided evidence for the possible role of C3 in the development of schizophrenia. In this study, we hypothesized that the gene encoding C3 (C3) may confer susceptibility to schizophrenia in Han Chinese. We analyzed 7 common single nucleotide polymorphisms (SNPs) of C3 in 647 schizophrenia patients and 687 healthy controls. Peripheral C3 mRNA expression level was measured in 23 drug-naïve patients with schizophrenia and 24 controls. Two SNPs (rs1047286 and rs2250656) that deviated from Hardy-Weinberg equilibrium were excluded for further analysis. Among the remaining 5 SNPs, there was no significant difference in allele and genotype frequencies between the patient and control groups. Logistic regression analysis showed no significant SNP-gender interaction in either dominant model or recessive model. There was no significant difference in the level of peripheral C3 expression between the drug-naïve schizophrenia patients and healthy controls. In conclusion, the results of this study do not support C3 as a major genetic susceptibility factor in schizophrenia. Other factors in AP may have critical roles in schizophrenia and be worthy of further investigation.

An evaluation of association between common variants in C4BPB/C4BPA genes and schizophrenia.

Epidemiological studies have indicated that both maternal bacterial and viral infections during pregnancy increase the risk of schizophrenia among offspring, but to date there is not clear explanation for this increased risk. Previously, the decreased C4b-binding protein (C4BP), a potent circulating soluble inhibitor of the classical and lectin pathways of complement, was reported to be associated with risk of schizophrenia. Here, we analyzed 4 common single nucleotide polymorphisms (SNPs) of C4BPB and 5 SNPs of C4BPA in a group of 556 schizophrenia patients and a matched group of 610 healthy controls to see if the genes C4BPB and C4BPA, which encode C4BP, may confer a susceptibility to schizophrenia. Comparing the genotype and allele frequencies of those SNPs between cases and controls, we found no association between the C4BPB/C4BPA variants and schizophrenia. Our results provided preliminary evidence that C4BPB/C4BPA may not confer susceptibility to schizophrenia among Han Chinese. Further genetic studies from large-scale population are required to obtain more conclusive results.

Comparison of the effectiveness of duloxetine in depressed patients with and without a family history of affective disorders in first-degree relatives.

BACKGROUND: It remains unclear whether or not a positive family history of affective disorders predicts the effectiveness of antidepressant treatment of depression. AIMS: Assess the relationship of a family history of affective disorders to the efficacy of duloxetine in the treatment of depressive disorder. METHODS: Seventy-seven patients with depressive disorder (as defined by the 10th edition of the International Classification of Diseases, ICD-10) were enrolled in the study and treated with standard doses of duloxetine for 12 weeks. Among these patients 37 had a family history of affective disorder in first-degree relatives and 40 did not. The Hamilton Depression rating scale (HAMD-17), Hamilton Anxiety rating scale (HAMA), Side Effects Rating Scale (SERS), Snaith-Hamilton Pleasure Scale (SHAPS), and Beck Depression Inventory (BDI) were assessed at baseline and at the end of the 2(nd), 4(th), 6(th), 8(th), and 12(th) week after enrollment. Repeated measures analysis of variance and logistic regression were used to analyze the association between a family history of affective disorders and the efficacy of duloxetine. RESULTS: Patients with a positive family history of affective disorders had an earlier age of onset, a longer duration of illness, a higher level of psychic anxiety, and more prominent anhedonia. Repeated measures analysis of variance showed a significant improvement in the severity of depression over the 12 weeks but no differences in the magnitude or speed of improvement between the two groups. Treatment was considered effective (i.e., drop in baseline HAMD-17 total score of ≥50%) in 75.7% of those with a family history of affective disorders and in 77.5% of those without a family history (X(2)=0.04, p=0.850). CONCLUSIONS: Family history of affective disorders is not associated with the effectiveness of duloxetine in the acute treatment of depressive disorder.

Mitochondrial DNA haplogroup B5 confers genetic susceptibility to Alzheimer's disease in Han Chinese.

Mitochondrial dysfunction has been widely reported in psychiatric and neurodegenerative diseases. We aimed to investigate the association between matrilineal structures of Han Chinese populations and Alzheimer's disease (AD) by a 2-stage case-control study: A total of 341 AD patients and 435 normal individuals from Southwest China were analyzed for mitochondrial DNA sequence variations and were classified into respective haplogroups. A total of 371 AD patients and 470 normal individuals from East China, as validation samples, were genotyped for the variants defining the risk haplogroup. Haplogroup B5 had a significantly higher frequency in AD patients (7.33%) than in control subjects (3.68%) from Southwest China, and we found a similar pattern of higher frequency of B5 in patients in the case-control sample from East China. In the combined population, association of haplogroup B5 with AD risk was strengthened (p = 0.02; odds ratio = 1.74; 95% confidence interval = 1.10-2.76). In lymphoblastoid cell lines belonging to haplogroup B5a, we observed significantly increased reactive oxygen species and decreased mitochondrial mass. Hela cells with stable expression of the MT-ATP6 gene with B5-defining variant m.8584G>A also showed a significantly decreased mitochondrial function. Taken together, our results indicated that haplogroup B5 conferred genetic susceptibility to AD in Han Chinese, and this effect was most likely mediated by ancient variant m.8584G>A. The predisposing effect of B5 to AD is consistent with the ancestral-susceptibility model of complex diseases.

No association of the LRRK2 genetic variants with Alzheimer's disease in Han Chinese individuals.

The leucine-rich repeat kinase-2 (LRRK2) gene has been regarded as 1 of the most common genetic causes of Parkinson's disease (PD). We hypothesized that LRRK2-susceptible allele(s) for PD might pose a risk for Alzheimer's disease (AD). In this study, we screened 12 LRRK2 gene variants in 2 independent cohorts from southwestern China (341 AD patients and 435 normal individuals) and eastern China (297 AD patients and 384 normal individuals), to discern the potential association between this gene and AD. No variant was identified to be associated with AD in either case-control sample. As both of the cohorts were of Han Chinese origin, we combined the LRRK2 variant data for the 2 sample sets together (a total of 638 AD patients and 819 normal individuals) and still found no association between the LRRK2 gene and AD, suggesting that LRRK2 gene variants may not affect the development of AD in Han Chinese individuals.

T102C polymorphism of serotonin 2A type receptor gene confers susceptibility to (early onset) schizophrenia in Han Chinese: an association study and meta-analysis.

INTRODUCTION: Several lines of evidence have indicated that serotonin 2A receptor (HTR2A) may be involved in the pathophysiology of schizophrenia. One functional polymorphism in HTR2A (T102C) has been widely investigated; however, the results have been inconsistent. The purpose of this study was to evaluate the association between HTR2A T02C polymorphism and schizophrenia in a Chinese Han population. METHODS: We performed a case-control study, using an early onset sample, which may be an attractive subgroup for genetic studies. In addition, we performed a meta-analysis of the combined sample groups in Han Chinese. RESULTS: Our study, based on 385 schizophrenic patients and 399 controls, found a significant genotype-wise association of T102C and schizophrenia (P = 0.02). After applying stratified analyses, the dominant model for T allele produced significant association (OR = 1.60, 95%CI = 1.11-2.30, P = 0.01). In the meta-analysis including all of the published population-based association studies in Han Chinese and the present association study, the pooled genotype-wise result in a dominant model was statistically significant with a summary OR of 1.25 (95%CI = 1.04-1.50, P = 0.02). DISCUSSION: Our results suggest that the HTR2A T102C polymorphism may confer susceptibility to schizophrenia in Han Chinese.

Does the bipolar disorder-associated CACNA1C gene confer susceptibility to schizophrenia in Han Chinese?

The gene coding for the calcium channel, voltage-dependent, L type, alpha 1C subunit (CACNA1C) has been reported to be associated with bipolar disorder (BD) in our previous study. Broad evidence suggests some degree of shared genetic susceptibility between BD and schizophrenia. In this study, we aimed to determine whether the BD-associated gene CACNA1C confers susceptibility to schizophrenia. The association was assessed using a cross section study of 696 schizophrenia patients and 1,114 matched control subjects of Han Chinese origin. Between-group comparisons of genotypic or allelic frequencies showed no statistically significant differences. CACNA1C is unlikely to play a major role in the pathophysiology of schizophrenia in Han Chinese. Further large-scale replication studies using a haplotype-tagging single-nucleotide polymorphism selection approach are required to obtain more conclusive results of any potential association.