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G Kalsi

Publications and source records attributed to G Kalsi.

At least 19 recordsLinked to original sources
PubMed2006

Alcohol dependence is associated with the ZNF699 gene, a human locus related to Drosophila hangover, in the Irish Affected Sib Pair Study of Alcohol Dependence (IASPSAD) sample.

Because tolerance is an important aspect of alcohol dependence (AD) in humans, recent evidence showing that the Drosophila gene hang is critically involved in the development of alcohol tolerance in the fly suggests that variation in related human loci might be important in the etiology of alcohol-related disorders. The orthology of hang in mammals is complex, but a number of human gene products (including ZNF699) with similar levels of amino-acid identity (18-26%) and similarity (30-41%), are consistently identified as the best matches with the translated hang sequence. We tested for association between the dichotomous clinical phenotype of alcohol dependence and seven single nucleotide polymorphisms (SNPs) in ZNF699 in our sample of 565 genetically independent cases and 496 siblings diagnosed with AD, and 609 controls. In analyses of genetically independent cases and controls, four of the seven single markers show strong evidence for association with AD (0.00003<Fisher's exact P<0.001), and the most significant single marker, rs7254880, tags an associated haplotype with frequency 0.071 in cases compared to 0.034 in controls (chi2 15.563, P<0.00008, 5000 permutation P<0.001, OR 2.17); inclusion of affected siblings gives similar results. Expression analyses conducted in independent postmortem brain samples show that expression of ZNF699 mRNA is significantly reduced in the dorsolateral prefrontal cortex of individuals carrying this haplotype compared with other observed haplotype combinations.

Alcohol-Related Disorders↗
PubMed2006

Fine mapping of a susceptibility locus for bipolar and genetically related unipolar affective disorders, to a region containing the C21ORF29 and TRPM2 genes on chromosome 21q22.3.

Linkage analyses of bipolar families have confirmed that there is a susceptibility locus near the telomere on chromosome 21q. To fine map this locus we carried out tests of allelic association using 30 genetic markers near the telomere at 21q22.3 in 600 bipolar research subjects and 450 ancestrally matched supernormal control subjects. We found significant allelic association with the microsatellite markers D21S171 (P=0.016) and two closely linked single-nucleotide polymorphisms, rs1556314 (P=0.008) and rs1785467 (P=0.025). A test of association with a three locus haplotype across the susceptibility region was significant with a permutation test of P=0.011. A two SNP haplotype was also significantly associated with bipolar disorder (P=0.01). Only two brain expressed genes, TRPM2 and C21ORF29 (TSPEAR), are present in the associated region. TRPM2 encodes a calcium channel receptor and TSPEAR encodes a peptide with repeats associated with epilepsy in the mouse. DNA from subjects who had inherited the associated marker alleles was sequenced. A base pair change (rs1556314) in exon 11 of TRPM2, which caused a change from an aspartic acid to a glutamic acid at peptide position 543 was found. This SNP showed the strongest association with bipolar disorder (P=0.008). Deletion of exon 11 of TRPM2 is known to cause dysregulation of cellular calcium homeostasis in response to oxidative stress. A second nonconservative change from arginine to cysteine at position 755 in TRPM2 (ss48297761) was also detected. A third nonconservative change from histidine to glutamic acid was found in exon 8 of TSPEAR. These changes need further investigation to establish any aetiological role in bipolar disorder.

Amino Acid Substitution↗
PubMed2004

Genome scan of Tourette syndrome in a single large pedigree shows some support for linkage to regions of chromosomes 5, 10 and 13.

OBJECTIVES: To localize genes influencing the susceptibility to Gilles de la Tourette syndrome (GTS) and associated chronic multiple tics (CMT). METHOD: A single, large, multiple affected pedigree containing 35 subjects diagnosed with GTS and a further 14 with CMT was genotyped for markers spanning the autosomes. Linkage analysis was carried out using classical lod score analysis and model-free lod score analysis. All markers were subjected to two-point analysis, and markers producing a two-point result significant at P<0.005 were subjected to three-point analysis using adjacent markers. RESULTS: The following markers produced at least one result significant at 0.005 using two-point analysis: D5S1981, D5S2050, D10S591, D10S189, D13S217, and D14S288. Three-point analysis with D5S2050 and D5S400 produced a lod of 2.9 with CMT. Three-point analysis of D10S591 and D10S189 produced lods of 1.9 with GTS and CMT. Three-point analysis of D13S217 and D13S171 produced a lod of 2.7 with GTS. No single haplotype appeared to account for the majority of cases within the pedigree. CONCLUSIONS: It seems likely that more than one susceptibility allele is present in the pedigree. Although none of the three positive regions is conclusively implicated, it seems probable that at least one contains a susceptibility locus. We recommend that association-based studies be carried out in these three regions to produce further evidence for a localization and to carry out fine-mapping.

Chromosome Mapping↗
PubMed2003

Variation in the DCP1 gene, encoding the angiotensin converting enzyme ACE, is not associated with increased susceptibility to Alzheimer's disease.

OBJECTIVES: To attempt to replicate previous reports that polymorphic variation in the DCP1 gene causes increased susceptibility to the development of Alzheimer's disease, either on its own or in interaction with the effects of the gene for apolipoprotein E (APOE). METHOD: Subjects older than 65 years of age consisting of 81 dementia patients diagnosed as having possible or probable Alzheimer's disease and 68 controls were obtained from Camden, Islington and Harlow psychiatric services. Subjects were genotyped for APOE alleles e2, e3 and e4, and the common insertion/deletion polymorphisms for DCP1* I/D were genotyped. RESULTS: There was no statistically significant difference in the frequency of the DCP1* insertion/deletion alleles between the cases and controls (X2 =0.04, 1 degree of freedom, not significant). When subjects were subdivided according to whether they possessed at least one copy of the APOE e4 allele, there were still no differences in DCP1 allele frequencies between cases and controls. CONCLUSIONS: Further research is needed to elucidate any role that the DCP1 polymorphism may play in relation to Alzheimer's disease. Previous studies may be false positive, or inconsistency in replication may be due to heterogeneity.

Aged↗
PubMed2001

Genetic association studies of schizophrenia using the 8p21-22 genes: prepronociceptin (PNOC), neuronal nicotinic cholinergic receptor alpha polypeptide 2 (CHRNA2) and arylamine N-acetyltransferase 1 (NAT1).

Schizophrenia is a common, genetically heterogeneous disorder with a lifetime prevalence of approximately 1% in the general population. Linkage studies of affected families have now strongly implicated a susceptibility locus on chromosome 8p21-22. Tests of allelic association with markers on 8p21-22 should be able to localise any quantitative trait nucleotides (QTN's) or susceptibility mutations to within a few hundred kilobases. Three brain expressed candidate susceptibility genes, prepronociceptin (PNOC), neuronal cholinergic receptor, nicotinic, alpha polypeptide 2 (CHRNA2) and arylamine N-acetyltransferase 1 (NAT1) have been mapped to chromosome 8p21-22. A case-control, allelic association study was performed using a novel highly polymorphic dinucleotide repeat, D8S2611 near the PNOC gene, two previously characterised dinucleotide repeats, D8S131 and D8S131P at the CHRNA2 locus and an RFLP at the 3'UTR of the arylamine N-acetyltransferase 1 (NAT1) gene. No differences were found in allele frequencies between the patient and control groups. DNA variations or mutations at or near the three genes under study are unlikely to increase susceptibility to schizophrenia in our population sample.

3' Untranslated Regions↗
PubMed2001

Genomewide genetic linkage analysis confirms the presence of susceptibility loci for schizophrenia, on chromosomes 1q32.2, 5q33.2, and 8p21-22 and provides support for linkage to schizophrenia, on chromosomes 11q23.3-24 and 20q12.1-11.23.

We have performed genetic linkage analysis in 13 large multiply affected families, to test the hypothesis that there is extensive heterogeneity of linkage for genetic subtypes of schizophrenia. Our strategy consisted of selecting 13 kindreds containing multiple affected cases in three or more generations, an absence of bipolar affective disorder, and a single progenitor source of schizophrenia with unilineal transmission into the branch of the kindred sampled. DNA samples from these families were genotyped with 365 microsatellite markers spaced at approximately 10-cM intervals across the whole genome. We observed LOD scores >3.0 at five distinct loci, either in the sample as a whole or within single families, strongly suggesting etiological heterogeneity. Heterogeneity LOD scores >3.0 in the sample as a whole were found at 1q33.2 (LOD score 3.2; P=.0003), 5q33.2 (LOD score 3.6; P=.0001), 8p22.1-22 (LOD score 3.6; P=.0001), and 11q21 (LOD score 3.1; P=.0004). LOD scores >3.0 within single pedigrees were found at 4q13-31 (LOD score 3.2; P=.0003) and at 11q23.3-24 (LOD score 3.2; P=.0003). A LOD score of 2.9 was also found at 20q12.1-11.23 within in a single family. The fact that other studies have also detected LOD scores >3.0 at 1q33.2, 5q33.2, 8p21-22 and 11q21 suggests that these regions do indeed harbor schizophrenia-susceptibility loci. We believe that the weight of evidence for linkage to the chromosome 1q22, 5q33.2, and 8p21-22 loci is now sufficient to justify intensive investigation of these regions by methods based on linkage disequilibrium. Such studies will soon allow the identification of mutations having a direct effect on susceptibility to schizophrenia.

Chromosome Aberrations↗
PubMed2000

Localization of a Nod factor-binding protein in legume roots and factors influencing its distribution and expression.

The roots of the legume Dolichos biflorus contain a lectin/nucleotide phosphohydrolase (Db-LNP) that binds to the Nod factor signals produced by rhizobia that nodulate this plant. In this study we show that Db-LNP is differentially distributed along the surface of the root axis in a pattern that correlates with the zone of nodulation of the root. Db-LNP is present on the surface of young and emerging root hairs and redistributes to the tips of the root hairs in response to treatment of the roots with a rhizobial symbiont or with a carbohydrate ligand. This redistribution does not occur in response to a non-symbiotic rhizobial strain or a root pathogen. Db-LNP is also present in the root pericycle where its level decreases upon initiation of nodule formation. Maximum levels of Db-LNP are found in 2-d-old roots, and the expression of this root protein is increased when the plants are grown in the absence of NO(3)(-) and NH(4)(+). These results support the possibility that Db-LNP is involved in the initiation of the Rhizobium legume symbiosis.

Bradyrhizobium↗
PubMed1999

A nod factor binding lectin with apyrase activity from legume roots.

A lectin isolated from the roots of the legume, Dolichos biflorus, binds to Nod factors produced by rhizobial strains that nodulate this plant and has a deduced amino acid sequence with no significant homology to any lectin reported to date. This lectin also is an enzyme that catalyzes the hydrolysis of phosphoanhydride bonds of nucleoside di- and triphosphates; the enzyme activity is increased in the presence of carbohydrate ligands. This lectin-nucleotide phosphohydrolase (LNP) has a substrate specificity characteristic of the apyrase category of phosphohydrolases, and its sequence contains four motifs characteristic of this category of enzymes. LNP is present on the surface of the root hairs, and treatment of roots with antiserum to LNP inhibits their ability to undergo root hair deformation and to form nodules on exposure to rhizobia. These properties suggest that this protein may play a role in the rhizobium-legume symbiosis and/or in a related carbohydrate recognition event endogenous to the plant.

Amino Acid Sequence↗
PubMed1999

Adjacent genetic markers on chromosome 11p15.5 at or near the tyrosine hydroxylase locus that show population linkage disequilibrium with each other do not show allelic association with bipolar affective disorder.

BACKGROUND: Linkage and association studies have suggested genetic susceptibility to bipolar affective disorder in a region of chromosome 11 around the tyrosine hydroxylase locus. We attempted to test the hypothesis that there was allelic association between polymorphisms around the tyrosine hydroxylase locus and bipolar affective disorder. METHODS: A case-control association study was employed using four polymorphic markers, which span a region of approximately 2 cM across the tyrosine hydroxylase locus. RESULTS: No evidence for allelic association between bipolar affective disorder and any of these markers was found. However, linkage disequilibrium between the markers was detected. CONCLUSIONS: This finding diminishes the probability that genes in this region influence susceptibility to bipolar affective disorder, at least in our sample.

Alleles↗
PubMed1999

New DNA markers with increased informativeness show diminished support for a chromosome 5q11-13 schizophrenia susceptibility locus and exclude linkage in two new cohorts of British and Icelandic families.

Genetic linkage of schizophrenia to markers at 5q11.2-13.3 had been reported previously in five Icelandic and two British families, but attempts at replication in independent samples have been unsuccessful. We report here an update on the diagnoses and results of linkage analyses using newer highly polymorphic microsatellite markers at or near the loci D5S76 and D5S39 in the original sample of pedigrees and in two new family samples from Iceland and from Britain. The new results show a reduction in evidence for linkage in the original sample and evidence against linkage in the two new family samples. Although it is possible that a rare locus is present, perhaps in the region 5p14.1-13.1 rather than 5q11.2-13.3, it appears most likely that the original positive lod scores represent an exaggeration of the 'true' lod scores due to random effects and that the small lod scores we now obtain could have arisen by chance.

Chromosomes, Human, Pair 5↗
PubMed1999

No evidence for linkage of schizophrenia to DXS7 at chromosome Xp11.

There have been claims that a gene on the X chromosome may contribute to susceptibility to schizophrenia. Crow (1988) initially proposed that such a gene might lie in the pseudoautosomal region, but when evidence that weakened this hypothesis accumulated, he proposed that a susceptibility locus might be present elsewhere on the sex chromosomes instead. DeLisi et al. (1994) found a small nonsignificant positive lod score between the marker DXS7 and schizophrenia, but other failed to replicate this finding. Another study reported by Crow and DeLisi's group was also weakly positive for this marker (Dann et al., 1997). This locus was then investigated in a collaborative study by Laval et al. (1997), which produced a nonparametric lod score of 2.44. Using a sample of 17 pedigrees from Britain and Iceland, we have also tested the hypothesis of linkage between DXS7 and schizophrenia. The 17 families were selected from a larger sample on the basis of an absence of male-to-male transmission for schizophrenia. These families were originally selected for having multiple cases of schizophrenia within them and for having no cases of bipolar affective disorder. We genotyped subjects for a marker at DXS7 and performed classical lod score and model-free linkage analysis using broad and narrow definitions of affection with schizophrenia. We found strongly negative lod scores and no evidence for linkage using model-free analysis. Therefore, this study does not support the hypothesis of linkage of schizophrenia to DXS7, and the evidence for a susceptibility locus on this part of the X chromosome is weakened.

Chromosome Mapping↗
PubMed1998

No evidence of expansion of CAG or GAA repeats in schizophrenia families and monozygotic twins.

Many diseases caused by trinucleotide expansion exhibit increased severity and decreased age of onset (genetic anticipation) in successive generations. Apparent evidence of genetic anticipation in schizophrenia has led to a search for trinucleotide repeat expansions. We have used several techniques, including Southern blot hybridization, repeat expansion detection (RED) and locus-specific PCR to search for expanded CAG/CTG repeats in 12 families from the United Kingdom and 11 from Iceland that are multiplex for schizophrenia and demonstrate anticipation. The unstable DNA theory could also explain discordance of phenotype for schizophrenia in pairs of monozygotic twins, where the affected twin has a greater number of repeats than the unaffected twin. We used these techniques to look for evidence of different CAG/CTG repeat size in 27 pairs of monozygotic twins who are either concordant or discordant for schizophrenia. We have found no evidence of an increase in CAG/CTG repeat size for affected members in the families, or for the affected twins in the MZ twin sample. Southern hybridization and RED analysis were also performed for the twin and family samples to look for evidence of expansion of GAA/TTC repeats. However, no evidence of expansion was found in either sample. Whilst these results suggest that these repeats are not involved in the etiology of schizophrenia, the techniques used for detecting repeat expansions have limits to their sensitivity. The involvement of other trinucleotide repeats or other expandable repeat sequences cannot be ruled out.

Base Sequence↗
PubMed1997

Exclusion of linkage between schizophrenia and the gene encoding a neutral amino acid glutamate/aspartate transporter, SLC1A5.

An abnormality in glutamatergic function has been hypothesized as being of etiological importance in schizophrenia. Twenty-three multiplex English and Icelandic schizophrenia families were genotyped with a polymorphic dinucleotide repeat sequence in the 3'-untranslated region of the glutamate/aspartate transporter gene called SLC1A5. Using the lod and a model-free method of linkage analysis (MFLINK), no evidence of linkage between SLC1A5 and schizophrenia was found. Our results do not support the hypothesis that SLC1A5 gene mutations or allelic variants provide a major gene contribution to the etiology of schizophrenia. However, because of the likelihood of heterogeneity of linkage in schizophrenia, there is a case for testing other pedigrees for linkage to the SLC1A5 locus. The SLC1A5 locus is one of a complex family of genes encoding neutral amino acid transporter proteins and the genetic relation between these other loci and schizophrenia has not yet been established.

Alleles↗
PubMed1997

Two-locus admixture linkage analysis of bipolar and unipolar affective disorder supports the presence of susceptibility loci on chromosomes 11p15 and 21q22.

Following a report of a linkage study that yielded evidence for a susceptibility locus for bipolar affective disorder on the long arm of chromosome 21, we studied 23 multiply affected pedigrees collected from Iceland and the UK, using the markers PFKL, D21S171, and D21S49. Counting only bipolar cases as affected, a two-point LOD of 1.28 was obtained using D21S171 (theta = 0.01, alpha = 0.35), with three Icelandic families producing LODs of 0.63, 0.62, and 1.74 (all at theta = 0.0). Affected sib pair analysis demonstrated increased allele sharing at D21S171 (P = 0.001) when unipolar cases were also considered affected. The same set of pedigrees had previously been typed for a tyrosine hydroxylase gene (TH) polymorphism at 11p15 and had shown some moderate evidence for linkage. When information from TH and the 21q markers was combined in a two-locus admixture analysis, an overall admixture LOD of 3.87 was obtained using the bipolar affection model. Thus the data are compatible with the hypothesis that a locus at or near TH influences susceptibility in some pedigrees, while a locus near D21S171 is active in others. Similar analyses in other datasets should be carried out to confirm or refute our tentative finding.

Bipolar Disorder↗