1Am. J. Med. Genet. B Neuropsychiatr. Genet. 2007 Mar 144B: 129-58
PMID17266109
TitleTowards understanding the schizophrenia code: an expanded convergent functional genomics approach.
AbstractIdentifying genes for schizophrenia through classical genetic approaches has proven arduous. Here, we present a comprehensive convergent analysis that translationally integrates brain gene expression data from a relevant pharmacogenomic mouse model (involving treatments with a psychomimetic agent - phencyclidine (PCP), and an anti-psychotic - clozapine), with human genetic linkage data and human postmortem brain data, as a Bayesian strategy of cross validating findings. Topping the list of candidate genes, we have three genes involved in GABA neurotransmission (GABRA1, GABBR1, and GAD2), one gene involved in glutamate neurotransmission (GRIA2), one gene involved in neuropeptide signaling (TAC1), two genes involved in synaptic function (SYN2 and KCNJ4), six genes involved in myelin/glial function (CNP, MAL, MBP, PLP1, MOBP and GFAP), and one gene involved in lipid metabolism (LPL). These data suggest that schizophrenia is primarily a disorder of brain functional and structural connectivity, with GABA neurotransmission playing a prominent role. These findings may explain the EEG gamma band abnormalities detected in schizophrenia. The analysis also revealed other high probability candidates genes (neurotransmitter signaling, other structural proteins, ion channels, signal transduction, regulatory enzymes, neuronal migration/neurite outgrowth, clock genes, transcription factors, RNA regulatory genes), pathways and mechanisms of likely importance in pathophysiology. Some of the pathways identified suggest possible avenues for augmentation pharmacotherapy of schizophrenia with other existing agents, such as benzodiazepines, anticonvulsants and lipid modulating agents. Other pathways are new potential targets for drug development. Lastly, a comparison with our earlier work on bipolar disorder illuminates the significant molecular overlap between schizophrenia and bipolar disorder.
SCZ Keywordsschizophrenia, schizophrenic
2Pharmacogenomics J. 2008 Jun 8: 228-36
PMID17726453
TitleAllelic variation in ApoC3, ApoA5 and LPL genes and first and second generation antipsychotic effects on serum lipids in patients with schizophrenia.
Abstractschizophrenic patients who are treated with antipsychotics, especially second generation antipsychotics, such as clozapine and olanzapine, manifest an increase in cholesterol and triglycerides as well as other changes associated with diabetes or the metabolic syndrome. Previous studies have shown that polymorphisms in several genes that regulate lipid metabolism can influence the levels of these lipids and response to drug treatment. We have investigated in an exploratory study whether polymorphisms in the apolipoprotein C-III (ApoC3), apolipoprotein A-V gene (ApoA5) and lipoprotein lipase genes influence differential lipid response to treatment with three second generation antipsychotics-olanzapine, clozapine and risperidone-or treatment with a first generation antipsychotic. A total of 189 patients with schizophrenia or schizoaffective disorder who were being treated with a single antipsychotic were studied in a cross-sectional study design in which fasting serum cholesterol and triglycerides and selected single-nucleotide polymorphosms (SNPs) in the three lipid metabolism genes were assessed. The treatment with antipsychotic monotherapy makes drug haplotype ascertainment less complex. Our analyses showed several nominally significant drug x gene and drug x haplotype interactions. The rarer C allele or the ApoA5_1131 (T/C) SNP was associated with higher cholesterol levels in patients treated with first generation antipsychotics and lower cholesterol levels in patients treated with olanzapine or clozapine. The rarer C allele of the ApoA5_SW19 (G/C) SNP was associated with higher cholesterol in risperidone-treated patients. An ApoA5 CG haplotype was associated with decreased cholesterol in olanzapine- or clozapine-treated patients and higher cholesterol in patients treated with first generation antipsychotics. The presence of the rarer T allele of the ApoC3_1100 (C/T) SNP or the presence of the ApoC3 TG haplotype was associated with decreased triglyceride levels in patients treated with olanzapine or clozapine and a nonsignificant trend for increased triglycerides in patients treated with first generation antipsychotics. The presence of the ApoC3 CC haplotype was associated with increased triglycerides in patients treated with olanzapine or clozapine. The overall magnitude of the effects was not large. These results provide a potential initial step toward a pharmacogenetic approach to selection of antipsychotic treatment which may help minimize the side effect of increases in serum lipids.
SCZ Keywordsschizophrenia, schizophrenic
3Pharmacogenomics J. 2008 Jun 8: 228-36
PMID17726453
TitleAllelic variation in ApoC3, ApoA5 and LPL genes and first and second generation antipsychotic effects on serum lipids in patients with schizophrenia.
Abstractschizophrenic patients who are treated with antipsychotics, especially second generation antipsychotics, such as clozapine and olanzapine, manifest an increase in cholesterol and triglycerides as well as other changes associated with diabetes or the metabolic syndrome. Previous studies have shown that polymorphisms in several genes that regulate lipid metabolism can influence the levels of these lipids and response to drug treatment. We have investigated in an exploratory study whether polymorphisms in the apolipoprotein C-III (ApoC3), apolipoprotein A-V gene (ApoA5) and lipoprotein lipase genes influence differential lipid response to treatment with three second generation antipsychotics-olanzapine, clozapine and risperidone-or treatment with a first generation antipsychotic. A total of 189 patients with schizophrenia or schizoaffective disorder who were being treated with a single antipsychotic were studied in a cross-sectional study design in which fasting serum cholesterol and triglycerides and selected single-nucleotide polymorphosms (SNPs) in the three lipid metabolism genes were assessed. The treatment with antipsychotic monotherapy makes drug haplotype ascertainment less complex. Our analyses showed several nominally significant drug x gene and drug x haplotype interactions. The rarer C allele or the ApoA5_1131 (T/C) SNP was associated with higher cholesterol levels in patients treated with first generation antipsychotics and lower cholesterol levels in patients treated with olanzapine or clozapine. The rarer C allele of the ApoA5_SW19 (G/C) SNP was associated with higher cholesterol in risperidone-treated patients. An ApoA5 CG haplotype was associated with decreased cholesterol in olanzapine- or clozapine-treated patients and higher cholesterol in patients treated with first generation antipsychotics. The presence of the rarer T allele of the ApoC3_1100 (C/T) SNP or the presence of the ApoC3 TG haplotype was associated with decreased triglyceride levels in patients treated with olanzapine or clozapine and a nonsignificant trend for increased triglycerides in patients treated with first generation antipsychotics. The presence of the ApoC3 CC haplotype was associated with increased triglycerides in patients treated with olanzapine or clozapine. The overall magnitude of the effects was not large. These results provide a potential initial step toward a pharmacogenetic approach to selection of antipsychotic treatment which may help minimize the side effect of increases in serum lipids.
SCZ Keywordsschizophrenia, schizophrenic
4Psychiatr. Genet. 2011 Dec 21: 307-14
PMID21862952
TitleAssociation between schizophrenia and single nucleotide polymorphisms in lipoprotein lipase gene in a Han Chinese population.
AbstractMany studies have suggested that certain types of lipids such as phospholipids, fatty acids, and cholesterols are involved in the pathology of nervous system diseases. Lipoprotein lipase (LPL), as the key enzyme of triglyceride hydrolysis, is expressed in the brain regions functionally relevant to learning, memory, and other cognitive functions. In addition, both genome-wide linkage and association studies in schizophrenia have implicated the chromosome 8p22 region, in which the LPL gene is located. Therefore, LPL is an attractive candidate gene for schizophrenia and we tested this hypothesis in a case-control sample.
In this study, we investigated allele and genotype frequencies distributions of nine single nucleotide polymorphisms (SNPs) within the LPL gene in Han Chinese patients with schizophrenia (n=319) and healthy controls (n=575).
Significant differences were detected between case and control groups in the frequencies of rs253 alleles [odds ratio (OR): 1.74; 95% confidence interval (CI): 1.43-2.11; P=3.2110] and genotypes (OR: 3.08; 95%CI: 2.07-4.56; global P=7.8810), respectively. Interestingly, this association was observed only in the male (P=5.8710 for allele; P=1.7910 for genotype) and not in the female samples (P>0.05). After correcting for multiple testing, the above association remains to be significant (Pc<110). These results suggest that rs253 C allele and CC genotype confer risk for schizophrenia in men.
Our study lends support to the potential role of lipid metabolism in schizophrenia and further investigations are warranted.
SCZ Keywordsschizophrenia, schizophrenic