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Biomedical subjects

G P Hemmings

Publications and source records attributed to G P Hemmings.

At least 19 recordsLinked to original sources
PubMed2004

TNXB locus may be a candidate gene predisposing to schizophrenia.

We report here on the detection of nine single nucleotide polymorphisms (SNPs) near to the NOTCH4 locus in the search for schizophrenia susceptibility genes in the class III region of the human major histocompatibility complex (MHC). We totally analyzed 122 family trios recruited in the UK. The TDT analysis demonstrated that of the nine SNPs, three were associated with schizophrenia, including rs1009382 (P = 0.00047), rs204887 (P = 0.007), and rs8283 (P = 0.015). Both rs1009382 and rs204887 are present in the TNXB locus. The rs1009382 is a non-synonymous SNP located in exon 23 of the gene and its A to G base change causes a Glu2578Gly substitution. The goodness-of-fit test showed that genotypic distribution of rs1009382 was deviated from Hardy-Weinberg equilibrium due to homozygote excess in the patient group (P = 0.01), suggesting that a double dose of a genetic risk may be involved. Possibly, rs1009382 is a candidate SNP predisposing to a schizophrenic illness. Moreover, the test for linkage disequilibrium (LD) between paired SNPs showed that the nine SNPs studied may be in the same LD block with an unexpected pattern as the strength of LD was not correlated with the distance between paired SNPs. The haplotype analysis suggested that there might be more than one disease-related allele located in the class III region of the MHC, and that these alleles possibly confer either susceptibility or resistance to schizophrenia.

Alleles↗
PubMed2004

The CLDN5 locus may be involved in the vulnerability to schizophrenia.

The present study was designed to detect three single nucleotide polymorphisms (SNPs) located on 22q11 that was thought as being of particularly importance for genetic research into schizophrenia. We recruited a total of 176 Chinese family trios of Han descent, consisting of mothers, fathers and affected offspring with schizophrenia for the genetic analysis. The transmission disequilibrium test (TDT) showed that of three SNPs, rs10314 in the 3'-untranslated region of the CLDN5 locus was associated with schizophrenia (chi(2) = 4.75, P = 0.029). The other two SNPs, rs1548359 present in the CDC45L locus centromeric of rs10314 and rs739371 in the 5'-flanking region of the CLDN5 locus, did not show such an association. The global chi-square (chi(2)) test showed that the 3-SNP haplotype system was not associated with schizophrenia although the 1-df test for individual haplotypes showed that the rs1548359(C)-rs10314(G)-rs739371(C) haplotype was excessively non-transmitted (chi(2) = 5.32, P = 0.02). Because the claudin proteins are a major component for barrier-forming tight junctions that could play a crucial role in response to changing natural, physiological and pathological conditions, the CLDN5 association with schizophrenia may be an important clue leading to look into a meeting point of genetic and environmental factors.

Cell Cycle Proteins↗
PubMed2004

A study of a genetic association between the PTGS2/PLA2G4A locus and schizophrenia.

Six single nucleotide polymorphisms (SNPs) present in the PTGS2/PLA2G4A locus were detected among 118 British family trios of schizophrenia patients. The transmission disequilibrium test showed that SNP4 located in the 5'-flanking region of the PLA2G4A gene was associated with schizophrenia and that the haplotype analysis also showed a genetic association between the PTGS2 gene and schizophrenia. Because these two genes are arranged in a head-to-head configuration and separated by just about 149kb of DNA, they may have a combined effect on susceptibility to schizophrenia in some cases.

Adult↗
PubMed2000

Searching for a locus for schizophrenia within chromosome Xp11.

Three gene-rich loci-HS212G6, HSU93305, and HS884M20-within the short arm of the X chromosome have been examined for allelic association with schizophrenia by the transmission disequilibrium test in 70 families of male individuals affected with schizophrenia. Neither the HS212G6 nor HS884M20 was found to be associated with schizophrenia. The HSU93305 locus, however, was significantly associated with schizophrenia (X(2)=17.92, df=3, P<0.001). The HSU93305 locus contains four distinct genes. They code, respectively, for A4 differentiation-dependent protein, triple LIM domain protein, synaptophysin, and calcium channel alpha-1 subunit. It is possible that one of these genes or some loci near to it may predispose a vulnerability to schizophrenia. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:4-7, 2000.

Base Sequence↗
PubMed2000

The NOTCH4 locus is associated with susceptibility to schizophrenia.

Linkage disequilibrium mapping of the MHC region in 80 British parent-offspring trios showed that NOTCH4 was highly associated with schizophrenia. The A-->G substitution in the promoter region and the (CTG)n repeat in exon 1 of NOTCH4 may be candidate sites conferring susceptibility to schizophrenia.

Exons↗
PubMed1999

The CCK-A receptor gene possibly associated with auditory hallucinations in schizophrenia.

In this study, a PstI polymorphic site with two individual alleles, namely A1 and A2, was identified withinthe boundary between intron 1 and exon 2 of the cholecystokinin (CCK) type A receptor gene. The PstI polymorphic site was used as a genetic marker to study its association with psychotic symptoms in schizophrenia. A significant difference in allelic frequency was found between schizophrenic patients with and without auditory hallucinations(chi(2) = 6.26, df = 1, P = 0.012), and the odds ratio for the allelic association was 2.21 (95% CI 1.18-4.15) with an attributable fraction of 0.1. The frequency of A1-A1 and A1-A2 genotypes showed a significant excess in schizophrenic patients with auditory hallucinations as compared to those without such symptoms (chi(2) = 5.45, df = 1, P = 0.02), and the odds ratio for the genotypic association was 2.27 (95% CI 1. 13-4.57) with an attributable fraction of 0.177. The haplotype-based haplotype relative risk (HHRR) test revealed a significant difference between transmitted and non-transmitted alleles in nuclear families of schizophrenic patients with auditory hallucinations (chi(2) = 4.54, df = 1,P = 0.033) but not in those of schizophrenic patients without them. The present study suggests that the CCK-A receptor gene may be associated with auditory hallucinations in schizophrenia.

Adult↗
PubMed1999

A study of linkage disequilibrium between polymorphic loci for monamine oxidases A and B in schizophrenia.

Two X-linked microsatellites, (AC) n repeats at the monoamine oxidase (MAO)-A locus and (TG)n repeats at the MAO-B locus, were studied in 140 unrelated Caucasian male patients with schizophrenia and 91 unrelated Caucasian male controls. Among these subjects, we totally typed out nine alleles for the (AC) n repeats and eight alleles for the (TG) n repeats by using a PCR-based procedure. Allelic frequencies of either (AC) n repeats or (TG) n repeats were not found to be significantly different between patients and controls. However, a significant excess of the (AC)18/(TG)23 haplotype with a relative risk of 4.05 (95%; CI 1.15-14.26) was observed in patients with schizophrenia (Fisher's P = 0.011). The coefficient of linkage disequilibrium (delta) for the (AC)18/(TG)23 haplotype was 0.019 in schizophrenic patients and -0.046 in control subjects, respectively. The latter reached statistical significance (chi 2 = 6.02; df = 1; P < 0.02). The present findings suggest that linkage disequilibrium between polymorphic loci for human MAO-A and MAO-B may be associated with schizophrenia, and the (AC)18/(TG)23 haplotype may render an individual more vulnerable to such an illness.

Case-Control Studies↗
PubMed1999

Lack of evidence for association between the COMT locus and schizophrenia.

Family-based studies have been conducted with restriction fragment length polymorphism (RFLP) analysis for testing association between polymorphisms for the catechol-O-methyltransferase (COMT) locus and schizophrenia in 49 Caucasian nuclear families consisting of fathers, mothers and offspring affected with schizophrenia. The present results did not support the hypothesis that the COMT gene might play an important role in predisposing an individual to a genetic risk for schizophrenia. Neither did we find a significant association of the COMT locus with violent behaviour in schizophrenia. Nevertheless, there may be a susceptibility gene for schizophrenia in a distinct region from the COMT locus on chromosome 22q, as a genome scan has suggested recently.

Catechol O-Methyltransferase↗
PubMed1998

TaqI polymorphic sites at the human dopamine beta-hydroxylase gene possibly associated with biochemical alterations of the catecholamine pathway in schizophrenia.

Two parts of the dopamine beta-hydroxylase (DBH) gene, one a 7.5-kb single copy fragment (F1) spanning the 5'-flanking region to exon 3 and the second a 9.0-kb single copy fragment (F2) spanning exon 3 to exon 7, were amplified by a long PCR procedure in 161 unrelated patients with schizophrenia and 67 unrelated control subjects. The PCR products were completely digested with the restriction enzyme TaqI. These subjects were classified into genetic subgroups according to the TaqI restriction fragment length polymorphisms (RFLPs) for the human DBH gene, and the association of the TaqI RFLPs with biochemical alterations of the catecholamine pathway in schizophrenia was then examined. The frequencies of the two TaqI polymorphic sites did not show significant differences between the patients and control subjects, but the TaqI RFLPs were found to be associated with biochemical alterations of the catecholamine pathway in schizophrenia.

Adult↗
PubMed1997

Is the polymorphic microsatellite repeat of the dopamine beta-hydroxylase gene associated with biochemical variability of the catecholamine pathway in schizophrenia?

Six allelic fragments were typed by a polymerase chain reaction process with a pair of primers specific for a sequence containing the polymorphic (GT)n repeat, a microsatellite repeat, in the human dopamine beta-hydroxylase (DBH) gene. Their frequencies in unrelated patients with schizophrenia were 0.003 (A1), 0.114 (A2), 0.343 (A3), 0.526 (A4), 0.006 (A5), and 0.009 (A6), and in unrelated control subjects, 0.012 (A1), 0.086 (A2), 0.309 (A3), 0.574 (A4), 0.006 (A5), and 0.012 (A6). Kruskal-Wallis analysis revealed significant differences among the three groups, the drug-free and drug-treated patients, and the control subjects, in serum DBH activity of the subjects whose genotype was A2/A3 (H = 6.0, p < .05) or A3/A3 (H = 9.8, p < .01), in serum homovanillic acid concentration of those whose genotype was A3/A4 (H = 7.7, p < .025), and in serum tyrosine concentration of those whose genotype was A4/A4 (H = 8.3, p < .02). Mann-Whitney U test showed that in the subjects carrying the A3/A4 genotype, serum noradrenaline concentration of drug-treated patients was significantly higher than that of control subjects (N = 58, p < .02). These results suggest that genotypic polymorphism of the human DBH is likely to be associated with biochemical variability of the catecholamine pathway in schizophrenia.

Adult↗
PubMed1997

Possible control of dopamine beta-hydroxylase via a codominant mechanism associated with the polymorphic (GT)n repeat at its gene locus in healthy individuals.

Six allelic fragments were typed by a PCR-based process with a pair of primers specific for a sequence containing the polymorphic (GT)n repeat at the human dopamine beta-hydroxylase (DBH) locus in 125 unrelated healthy individuals. Their frequencies among these individuals were 0.012 (A1), 0.08 (A2), 0.344 (A3), 0.548 (A4), 0.004 (A5) and 0.012 (A6); the two major alleles, A3 and A4, made up nearly 90% of the alleles. These individuals were divided into four groups according to the genotype they possessed, i.e. A3/A3, A4/A4, A3/A4 and others (mixed group). Kruskal-Wallis analysis revealed a significant difference in serum DBH activity among these four genetic groups (H = 32.7, P < 0.0001). The homozygotic genotypes, A3/A3 and A4/A4, were associated with low and high DBH activity, respectively, and the heterozygotic genotype, A3/A4, seemed to play a role in keeping the DBH activity at a moderate level. The present work suggests that the human DBH is likely to be controlled via a codominant mechanism associated with the dinucleotide repeat polymorphism at its gene locus.

Alleles↗
PubMed1997

Possible association of catecholamine turnover with the polymorphic (TCAT)n repeat in the first intron of the human tyrosine hydroxylase gene.

Five allelic fragments were typed by a PCR-based process with a pair of primers specific for the polymorphic sequence due to (TCAT)n tetranucleotide repeat, a microsatellite repeat, in the first intron of the human tyrosine hydroxylase gene, i.e. A1, A2, A3, A4 and A5. Comparisons of some neurochemical parameters of the catecholamine pathway were then made between the unrelated individuals genotypically classified into six subgroups, five homozygotic and one heterozygotic. Among the six subgroups, the individuals with the A2/A2 genotype had the highest levels of serum noradrenaline and those with the A4/A4 genotype had the lowest, and the individuals with the A1/A1 genotype had the highest levels of serum homovanillic acid. These findings suggest that polymorphism of the (TCAT)n repeat in the first intron of the human tyrosine hydroxylase gene may be associated with catecholamine turnover. Possibly, the two alleles, A2 and A4, may be related to the high and low excitabilities of the noradrenergic nerves, respectively, and the allele, A1, may be associated with the up-regulation of dopamine turnover.

Adult↗
PubMed1996

A study of the relationship between the DBH activity in serum and a MspI polymorphic site in intron 9 of the human DBH gene in schizophrenia.

Intron 9 of the human dopamine beta-hydroxylase (DBH) gene was amplified using a long PCR procedure in unrelated patients with schizophrenia and unrelated control subjects. MspI digestion of the PCR fragments showed a two allele polymorphism. A1 and A2 Kruskal-Wallis analysis revealed a significant difference in serum DBH activity among the three groups carrying the A1/A2 genotype, the drug-free and drug treated patients, and the control subjects (H = 12.2, df = 2, p < 0.005), and also a significant difference among the three subgroups of drug-treated patients carrying the genotype of A1/A1, A2/A2 or A1/A2 (H = 10.4, df = 2, p < 0.01). The present results suggest that the MspI polymorphic site in intron 9 of the human DBH gene may be associated with alterations of DBH activity in schizophrenia and with the influence of neuroleptic drugs on the DBH activity as well.

Adult↗
PubMed1996

A study of enzymes involved in catecholamine metabolism in parents of patients with schizophrenia.

The concentrations of serum homovanillic acid (HVA), norepinephrine (NE), tyrosine (Tyr), phenylalanine (Phe) and tryptophan (Trp), and the activities of serum dopamine-beta-hydroxylase (DBH), platelet monoamine oxidase (MAO), and erythrocyte catechol-O-methyl transferase (COMT) were measured in 68 healthy parents who had schizophrenic offspring. The results show a significant correlation between the parents of schizophrenic patients in serum HVA (r=0.38, n=34, p<0.05), NE (r=0.40, n=33, p<0.02), Phe (r=0.44, n=34, p<0.0l), Tyr (r=0.43, n = 34, p <0.02) and DBH activity (r=0.51, n = 30, p <0.005), but do not show a significant correlation in erythrocyte COMT (r=0.01, n=27), platelet MAO (r=0.04, n=23) or serum Trp (r=0.10, n=34). There were no significant correlations in these measurements between randomly matched parents. The present study suggests that both parental sides of schizophrenic patients are likely to have similar alleles associated with the catecholamine pathway, and their ill offspring may possess a double dose of the schizophrenogenic alleles.

Adult↗
PubMed1996

Decreased tyrosine transport in fibroblasts from schizophrenics: implications for membrane pathology.

Two independent studies reported recently have shown a significant decrease in Vmax of tyrosine transport in fibroblasts grown from schizophrenics' skin compared with controls. It has also been shown that tyrosine transport into the brain is decreased in schizophrenics compared with controls. In view of the importance of these findings in elucidating the biochemical mechanism(s) associated with schizophrenia, we have studied the kinetics of tyrosine transport and the levels of monoamine oxidase (MAO) activity in fibroblasts grown from the skins of schizophrenics and unrelated control subjects. Using the Lineweaver-Burk plot, the Eadie Hostee plot and the Hanes plot we have calculated the Km and Vmax for tyrosine transport. We have found a significant decrease in the Km and Vmax values for tyrosine transport in schizophrenics compared with control fibroblast samples. No changes were observed in the levels of MAO. Using Lineweaver-Burk plot (1/S Versus 1/V) it has been shown that the tyrosine transport inhibition is uncompetitive. This finding proposes that the inhibition is in the substrate transport protein complex, which may be taking place during the transit of the substrate through the cell membrane. From the observed findings and from the literature evidence we suggest that the altered metabolism of phospholipids in schizophrenics, such as deficiency of arachidonic acid and docosahexaenoic acid, may be contributing to this observed phenomena.

Adolescent↗