Showing papers by "Herbert M. Lachman published in 2003"
TL;DR: The findings provide further support that COMT is a modifying gene that plays a role in determining interindividual variability in the proclivity for outward and self‐directed aggressive behavior found in some schizophrenic patients.
Abstract: We have previously reported that increased aggressive behavior in schizophrenic patients may be associated with a polymorphism at codon 158 of the catechol O-methyltransferase (COMT) gene that encodes a low enzyme activity variant. The finding has been replicated by one group, but not others. The discordant findings could be due to statistical errors or methodological issues in the assessment of aggressive/violent behavior. Consequently, additional studies are needed. Patients with schizophrenia (SZ) were assessed for violent behavior using the Lifetime History of Aggression (LHA) scale, an 11-item questionnaire that includes Aggression, Self-Directed Aggression, and Consequences/Antisocial Behavior subscales. DNA was genotyped for the COMT 158 polymorphism, as well as a functional polymorphism in the monoamine oxidase A (MAOA) gene promoter. Similar to our previously reported findings, a statistically significant association was found between aggressive behavior in SZ and the COMT 158 polymorphism; mean LHA scores were higher in subjects homozygous for 158Met, the low enzyme activity COMT variant (F(2,105) = 5.616, P = 0.005). Analysis of the major LHA subscales revealed that the association with 158Met was due to high scores on the Aggression, and Self-Directed Aggression subscales, but not the Consequences/Antisocial Behavior subscale. No significant association was detected for the MAOA gene alone. Our findings provide further support that COMT is a modifying gene that plays a role in determining interindividual variability in the proclivity for outward and self-directed aggressive behavior found in some schizophrenic patients.
116 citations
TL;DR: Interestingly, a number of genes involved in the synthesis and dephosphorylation of PtdIns(4,5)P2 are found in regions of the genome previously mapped in bipolar disorder (BD including 10p12, 21q22, and 22q11, among others).
Abstract: Lithium is a potent noncompetitive inhibitor of inositol monophosphatases, enzymes involved in phosphoinositide (PI) and inositol phosphate metabolism. A critical component of the PI pathway is phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P2), which is hydrolyzed to second messengers and has a direct role in synaptic vesicle function. Interestingly, a number of genes involved in the synthesis and dephosphorylation of PtdIns(4,5)P2 are found in regions of the genome previously mapped in bipolar disorder (BD) including 10p12, 21q22, and 22q11, among others. Some of these regions overlap with loci mapped in schizophrenia (SZ). One gene involved in PI metabolism that maps to a region of interest is 10p12-linked PIP5K2A, a member of the phosphatidylinositol 4-phosphate 5-kinase family. Polymorphism screening revealed the existence of an imperfect CT repeat polymorphism located near the exon 9-intron 9 splice donor site. A modest difference was found in the distribution of alleles from this highly polymorphic variant when bipolar and schizophrenic subjects were compared with controls; relatively rare short repeat variants were found more commonly in patients and homozygosity for a common long repeat variant was found more commonly in controls. These data suggest that the imperfect CT repeat in PIP5K2A intron 9 should be further investigated as a possible candidate allele for 10p12-linked psychiatric disorders. © 2003 Wiley-Liss, Inc.
47 citations
TL;DR: Considering the heterogeneity of BPD and SZ and the hypothesis that BPD may be caused by abnormalities in genes that regulate PI‐mediated phenomena in the brain, the polymorphisms detected in the PIK4CA gene should be analyzed in a larger data set to help determine their significance in 22q11‐linked mental disorders.
Abstract: Lithium is potent non-competitive inhibitor of an enzyme involved in the metabolism of phosphatidylinositol 4,5-bisphosphate (PtdIns-4,5-P(2)), a critical phosphoinositide (PI) that regulates signal transduction and synaptic vesicle function. Interestingly, a number of genes involved in the regulation of PtdIns-4,5-P(2) synthesis and dephosphorylation are found in regions of the genome previously mapped in bipolar disorder (BPD) including 10p, 18q, 21q, and 22q. One is PIK4CA, a member of the phosphatidylinositol 4-kinase family that phosphorylates PtdIns at the D4 position of the inositol ring as part of the PtdIns-4,5-P(2) synthetic pathway. PIK4CA maps to 22q11 in a region believed to contain a susceptibility gene for psychiatric disorders. Screening of two functional domains of PIK4CA and the promoter region resulted in the identification of 15 different polymorphisms. Rare variants at a consensus splice donor site and the promoter region were found in a total of three patients with BPD, three with schizophrenia (SZ) and only one control. Several common non-synonymous changes and a common single nucleotide polymorphism (SNP) at position -31 in the putative promoter were identified and analyzed in patients with BPD, SZ, and controls. There was no difference in the allele distribution in mentally ill subjects and controls for two variants, R2259C and E2079Q, both located in the PIK4CA catalytic domain. There was, however, a trend toward significance in the distribution of the -31 promoter genotypes in bipolar subjects and controls. Although the results of this analysis were modest, considering the heterogeneity of BPD and SZ and the hypothesis that BPD may be caused by abnormalities in genes that regulate PI-mediated phenomena in the brain, the polymorphisms we detected in the PIK4CA gene should be analyzed in a larger data set to help determine their significance in 22q11-linked mental disorders.
33 citations