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Nigel M Williams

Publications and source records attributed to Nigel M Williams.

At least 19 recordsLinked to original sources
PubMed2006

Evaluation of a susceptibility gene for schizophrenia: genotype based meta-analysis of RGS4 polymorphisms from thirteen independent samples.

BACKGROUND: Associations between schizophrenia (SCZ) and polymorphisms at the regulator of G-protein signaling 4 (RGS4) gene have been reported (single nucleotide polymorphisms [SNPs] 1, 4, 7, and 18). Yet, similar to other SCZ candidate genes, studies have been inconsistent with respect to the associated alleles. METHODS: In an effort to resolve the role for RGS4 in SCZ susceptibility, we undertook a genotype-based meta-analysis using both published and unpublished family-based and case-control samples (total n = 13,807). RESULTS: The family-based dataset consisted of 10 samples (2160 families). Significant associations with individual SNPs/haplotypes were not observed. In contrast, global analysis revealed significant transmission distortion (p = .0009). Specifically, analyses suggested overtransmission of two common haplotypes that account for the vast majority of all haplotypes. Separate analyses of 3486 cases and 3755 control samples (eight samples) detected a significant association with SNP 4 (p = .01). Individual haplotype analyses were not significant, but evaluation of test statistics from individual samples suggested significant associations. CONCLUSIONS: Our collaborative meta-analysis represents one of the largest SCZ association studies to date. No individual risk factor arose from our analyses, but interpretation of these results is not straightforward. Our analyses suggest risk due to at least two common haplotypes in the presence of heterogeneity. Similar analysis for other putative susceptibility genes is warranted.

Case-Control Studies↗
PubMed2006

Evidence that interaction between neuregulin 1 and its receptor erbB4 increases susceptibility to schizophrenia.

There is now strong evidence that Neuregulin 1 (NRG1) is a susceptibility gene for schizophrenia. NRG1 mediates some of its effects through the tyrosine kinase receptor erbB4, and analysis of gene knock-out animals suggests that the functional interaction of NRG1 and erbB4 mediates behaviors that may model some aspects of the schizophrenia phenotype in mice. Given these findings, we have sought evidence for association between schizophrenia and erbB4. Mutation screening of erbB4 in 14 DSMIV schizophrenics revealed 15 SNPs, none of which were nonsynonymous. Analysis of the allele frequencies of each SNP in pools of 368 DSMIV schizophrenics and 368 controls provided modest evidence for association with two of the SNPs, although individual genotyping in an extended sample of 680 cases did not confirm this. However, we did find evidence for a significant interaction between the NRG1 "Icelandic" schizophrenia risk haplotype and erbB4 (P = 0.019). The NRG1 and erbB4 interacting marker was further genotyped in an independent sample of 290 cases and 634 controls from Dublin. Interaction between NRG1 and erbB4 remained significant in the combined sample of 970 cases and 1,341 controls, OR = 2.98 (CI: 1.16-7.64), P = 0.01, although it only showed a trend in the Dublin sample alone (P = 0.11, two tailed). Our data require independent replication, but tentatively suggest that NRG1 may mediate its effects on schizophrenia susceptibility through functional interaction with erbB4, and that genetic interaction between variants at the two loci increases susceptibility to schizophrenia.

Adult↗
PubMed2006

Convergent evidence for 2',3'-cyclic nucleotide 3'-phosphodiesterase as a possible susceptibility gene for schizophrenia.

CONTEXT: Convergent data make 2',3'-cyclic nucleotide 3'-phosphodiesterase (CNP) a candidate gene for schizophrenia. Reduced expression has been reported in the schizophrenic brain. The CNP gene maps to a region to which we have reported linkage to schizophrenia. Mice in which the CNP gene has been knocked out display central nervous system pathological characteristics reminiscent of some features observed in schizophrenia. 2',3'-Cyclic nucleotide 3'-phosphodiesterase is used as a marker of myelin-forming cells and is detectable in cells of oligodendrocyte lineage throughout life. Because CNP is thought to be important for oligodendrocyte function, altered expression has been interpreted as supportive of the hypothesis that altered oligodendrocyte function may be an etiological factor in schizophrenia. However, it is unclear whether the observed changes in the schizophrenic brain are primary or secondary. OBJECTIVES: To determine if CNP expression is influenced by DNA polymorphisms and to verify if these polymorphisms are associated with schizophrenia. DESIGN: Allele-specific messenger RNA expression assay and genetic association studies. SETTING: Unrelated subjects were ascertained from secondary psychiatric inpatient and outpatient services. PARTICIPANTS: We used brain tissue from 60 anonymous individuals with no known psychiatric disorder; a case-control sample of 708 white individuals from the United Kingdom meeting DSM-IV criteria for schizophrenia matched for age, sex, and ethnicity to 711 blood donor controls; and a pedigree with DNA from 6 affected siblings and 1 parent, showing evidence for linkage to CNP. MAIN OUTCOME MEASURES: Association between allele and gene expression. Association between allele and schizophrenia. RESULTS: The exonic single nucleotide polymorphism rs2070106 was associated with CNP expression (P<.001). Compatible with underexpression of CNP messenger RNA in schizophrenia, the lower-expressing A allele was significantly associated with schizophrenia (P = .04) in the case-control sample. All affected individuals in the linked pedigree were homozygous for the lower-expression allele, providing independent support for the association (P = .03). CONCLUSIONS: Our data support the hypothesis that reduced CNP expression in the schizophrenic brain is relevant to disease etiology and therefore provide support for the general hypothesis that altered oligodendrocyte function is an etiological factor in schizophrenia.

2',3'-Cyclic-Nucleotide Phosphodiesterases↗
PubMed2006

Variation at the DAOA/G30 locus influences susceptibility to major mood episodes but not psychosis in schizophrenia and bipolar disorder.

CONTEXT: Variation at the DAOA/G30 locus has been described to be associated with both schizophrenia and bipolar disorder, but there is little consistency between studies of the tested polymorphisms or variants showing association. OBJECTIVES: To obtain a stringent replication of association in large samples of both disorders using consistent clinical and laboratory methods, and to test the hypothesis that association at DAOA/G30 identifies an underlying domain of psychopathological abnormalities that cuts across traditional diagnostic categories. DESIGN: A systematic study of polymorphisms at DAOA/G30 using genetic case-control association analysis. SETTING: Subjects were unrelated and ascertained from general psychiatric inpatient and outpatient services. PARTICIPANTS: White persons from the United Kingdom meeting criteria for DSM-IV schizophrenia (n = 709) or bipolar I disorder (n = 706) and 1416 ethnically matched controls. METHODS: Nine polymorphisms that tag common genetic variations at DAOA/G30 were genotyped in all of the individuals, and comparisons were made between affected and unaffected individuals. RESULTS: We identified significant association (P = .01-.047) between 3 single-nucleotide polymorphisms and bipolar disorder but failed to find association with schizophrenia. Analyses across the traditional diagnostic categories revealed significant evidence (P = .002-.02) for association with 4 single-nucleotide polymorphisms in the subset of cases (n = 818) in which episodes of major mood disorder had occurred (gene-wide P = .009). We found a similar pattern of association in bipolar cases and in schizophrenia cases in which individuals had experienced major mood disorder. In contrast, we found no evidence for association in the subset of cases (n = 1153) in which psychotic features occurred (all P>.08). CONCLUSIONS: Despite being originally described as a schizophrenia susceptibility locus, our data suggest that variation at the DAOA/G30 locus does not primarily increase susceptibility for prototypical schizophrenia or psychosis. Instead, our results imply that variation at the DAOA/G30 locus influences susceptibility to episodes of mood disorder across the traditional bipolar and schizophrenia categories.

Bipolar Disorder↗
PubMed2005

Is the dysbindin gene (DTNBP1) a susceptibility gene for schizophrenia?

Over recent years the gene DTNBP1 (chromosome 6p24-22) has emerged as one of the most promising candidate genes for schizophrenia. In this article, we review the current genetic evidence that implicates DTNBP1 as a schizophrenia-susceptibility gene. While there is now impressive support from genetic association studies, it is important to remain aware that the actual DTNBP1 susceptibility variants have not been identified. While functional analyses have allowed us to speculate their likely function, only when they are identified will we be able to confidently specify the type of altered gene function that is relevant to schizophrenia pathogenesis. This we hope will then open up new vistas for neurobiological research, allowing us to study the exact contribution of DTNBP1 in schizophrenia, its relationships with various aspects of the phenotype, and the potential of epistatic interactions with other genes, as well as functional interactions between the gene products.

Carrier Proteins↗
PubMed2005

No association between the putative functional ZDHHC8 single nucleotide polymorphism rs175174 and schizophrenia in large European samples.

BACKGROUND: It has been recently reported that a functional variant in the ZDHHC8 gene encoding a putative palmitoyltransferase directly confers susceptibility to schizophrenia in females (). METHODS: We investigated the putative risk allele (rs175174) in four schizophrenia association samples including a Bulgarian proband and parent sample (474 trios) and three case-control panels of European origin (1028 patients/1253 control subjects) in an attempt to replicate these findings. RESULTS: Our results do not support the hypothesis that genetic variation at rs175174 is associated with increased risk for schizophrenia nor do they suggest the presence of gender-specific differences. CONCLUSIONS: Our data suggest that the reported genetic association by either represents type I error resulting from sampling variance or that rs175174 is in linkage disequilibrium (LD) with the functional variant for schizophrenia and different LD patterns obscure the detection of association.

Acyltransferases↗
PubMed2005

A family based study implicates solute carrier family 1-member 3 (SLC1A3) gene in attention-deficit/hyperactivity disorder.

BACKGROUND: The glutamatergic system, the major excitatory neurotransmitter system in the central nervous system (CNS) has been proposed as contributing a possible role in the etiology of attention deficit hyperactivity disorder (ADHD). This is based upon observations from animal, neuroimaging, neuroanatomical and neuropsychological studies. Genes related to glutamate function are therefore good functional candidates for this disorder. The SLC1A3 (Solute Carrier Family 1, member 3) gene encodes a glial glutamate transporter which maps to chromosome 5p12, a region of linkage that coincides in two published ADHD genome scans so far. SLC1A3 is thus both a functional and positional candidate gene for ADHD. METHODS: We have undertaken detailed association analysis of SLC1A3 using a multi-stage approach for candidate gene analysis. RESULTS: In a family-based sample (n = 299) we found a significant association between marker rs2269272 (p = .007) and ADHD. Two, two-marker haplotypes, rs2269272/rs3776581 (p = .016) and rs2269272/rs2032893 (p = .013) also yielded evidence of association. CONCLUSIONS: The results of our study suggest that genetic variation in SLC1A3 may contribute to susceptibility to ADHD.

Adolescent↗
PubMed2005

Haplotypes at the dystrobrevin binding protein 1 (DTNBP1) gene locus mediate risk for schizophrenia through reduced DTNBP1 expression.

The DTNBP1 gene, encoding dysbindin, is now generally considered to be a susceptibility gene for schizophrenia. However, the confidence with which this hypothesis can be held has to be tempered by the poor reproducibility between studies in terms of the exact nature of the associated haplotypes, by the failure so far to identify any specific susceptibility variants and by the absence of any demonstrated function associated with any of the risk haplotypes. In the present study, we show that a defined schizophrenia risk haplotype tags one or more cis-acting variants that results in a relative reduction in DTNBP1 mRNA expression in human cerebral cortex. Subsidiary analyses suggest that risk haplotypes identified in other sample groups of white European ancestry also index lower DTNBP1 expression, whereas putative 'protective' haplotypes index high DTNBP1 expression. Our data indicate that variation in the DTNBP1 gene confers susceptibility to schizophrenia through reduced expression, and that this, therefore, represents a primary aetiological mechanism in the disorder.

Adult↗
PubMed2005

No evidence for association between polymorphisms in GRM3 and schizophrenia.

BACKGROUND: Three studies have previously reported data that were interpreted by the authors as supportive of association between schizophrenia and polymorphisms in the gene encoding the metabotropic glutamate receptor GRM3. METHODS: In a bid to examine this hypothesis, we examined seven SNPs spanning GRM3 in a UK case-control sample (schizophrenic cases n = 674, controls n = 716). These included all SNPs previously reported to be associated, alone or in haplotypes, with schizophrenia in European or European American samples. RESULTS: Our data showed no evidence for association with single markers, or 2, 3, 4 and 5 marker haplotypes, nor did any specific haplotypes show evidence for association according to previously observed patterns. CONCLUSION: Examination of our own data and those of other groups leads us to conclude that at present, GRM3 should not be viewed as a gene for which there is replicated evidence for association with schizophrenia.

Adult↗
PubMed2005

No association between schizophrenia and polymorphisms in COMT in two large samples.

OBJECTIVE: A valine/methionine polymorphism in the catechol O-methyltransferase (COMT) gene has been proposed to influence susceptibility to schizophrenia, as has a COMT haplotype in Ashkenazi Jewish and Irish subjects. The authors examined these hypotheses. METHOD: They reviewed data from more than 2,800 individuals, including almost 1,200 with schizophrenia, from case-control and family-based European association samples. RESULTS: The authors found no support for the hypothesis that a valine/methionine polymorphism in the COMT gene influences susceptibility to schizophrenia or the hypothesis that a COMT haplotype influences susceptibility to schizophrenia in Ashkenazi Jewish and Irish subjects. CONCLUSIONS: The data suggest that the valine allele of COMT does not increase susceptibility to schizophrenia in Europeans and that the Ashkenazi or Irish haplotype does not increase susceptibility. Ethnic variation in the linkage disequilibrium structure at COMT means that the haplotype data may not generalize across populations. However, the authors' examination of the hypothesis that the valine allele confers susceptibility, with a particularly strong effect in Europeans, reveals that no such caveat applies.

Case-Control Studies↗
PubMed2004

Strong evidence for association between the dystrobrevin binding protein 1 gene (DTNBP1) and schizophrenia in 488 parent-offspring trios from Bulgaria.

BACKGROUND: The gene encoding the dystrobrevin binding protein (DTNBP1) has been implicated in the pathogenesis of schizophrenia by several association studies. We tried to replicate these findings in a sample of 488 parent-proband trios recruited in Bulgaria. Probands had a diagnosis of schizophrenia (n = 441) or schizoaffective disorder (n = 47). METHODS: We genotyped eight single nucleotide polymorphisms within the gene, four of which had been reported in previous studies, and four identified as informative by our group through direct screening of the gene and genotyping in a sample of cases and control subjects. RESULTS: A significant excess of transmissions was observed for two of the markers, p1635 and p1757, (p =.0009 and.0013, respectively). Analysis of two-, three-, and four-marker haplotypes produced numerous positive results, with six (4% of the total combinations) at p <.001. CONCLUSIONS: These results provide strong support for DTNBP1 as a susceptibility gene for schizophrenia; however, different haplotypes seem to be associated in different studies.

Bulgaria↗
PubMed2004

Identification and analysis of the promoter region of the human hyaluronan synthase 2 gene.

Hyaluronan (HA) is a linear glycosaminoglycan of the vertebrate extracellular matrix that is synthesized at the plasma membrane by the HA synthase (HAS) enzymes HAS1, -2 and -3. The regulation of HA synthesis has been implicated in a variety of extracellular matrix-mediated and pathological processes, including renal fibrosis. We have recently described the genomic structures of each of the human HAS genes. In the present study, we analyzed the HAS2 promoter region. In 5'-rapid amplification of cDNA ends analysis of purified mRNA from human renal epithelial proximal tubular cells, we detected an extended sequence for HAS2 exon 1, relocating the transcription initiation site 130 nucleotides upstream of the reference HAS2 mRNA sequence, GenBank accession number NM_005328. A luciferase reporter gene assay of nested fragments spanning the 5' terminus of NM_005328 demonstrated the constitutive promoter activity of sequences directly upstream of the repositioned transcription initiation site but not of the newly designated exonic nucleotides. Using reverse transcription-PCR, expression of this extended HAS2 mRNA was demonstrated in a variety of human cell types, and orthologous sequences were detected in mouse and rat kidney. Alignment of human, murine, and equine genomic DNA sequences upstream of the repositioned HAS2 exon 1 provided evidence for the evolutionary conservation of specific transcription factor binding sites. The location of the HAS2 promoter will facilitate analysis of the transcriptional regulation of this gene in a variety of pathological contexts as well as in developmental models in which HAS2 null animals have an embryonic lethal phenotype.

Animals↗
PubMed2004

Support for RGS4 as a susceptibility gene for schizophrenia.

BACKGROUND: The gene encoding the regulator of G-protein signaling 4 has recently been associated with susceptibility to schizophrenia. This finding is particularly interesting, because it was replicated within the same study and also because there are functional, positional, and expression data to support the regulator of G-protein signaling 4 as a schizophrenia candidate gene. Although the original report was highly suggestive, a limitation was that the study was conducted on rather small samples. METHODS: We have examined a large case (n = 709) control (n = 710) sample for association between schizophrenia using four markers investigated in the earlier study, denoted single nucleotide polymorphisms 1, 4, 7, and 18. RESULTS: We were able to replicate the associations with single nucleotide polymorphisms 4 and 18 that had previously been reported individually and have also identified significant association with haplotypes constructed from single nucleotide polymorphisms 1 and 4. CONCLUSIONS: Our data give modest support for the hypothesis that the regulator of G-protein signaling 4 is a susceptibility gene for schizophrenia.

Adult↗
PubMed2004

Genetic abnormalities of chromosome 22 and the development of psychosis.

A microdeletion at chromosome 22q11 is the most frequently known interstitial deletion found in humans, occurring in approximately one of every 4000 live births. Its occurrence is associated with a characteristic facial dysmorphology, a range of congenital abnormalities, and psychiatric problems, especially schizophrenia. The prevalence of psychosis in those with 22q11 deletion syndrome is high (30%), suggesting that haploinsufficiency of a gene or genes in this region may confer a substantially increased risk. In addition, several studies provide evidence for linkage to schizophrenia on 22q, suggesting that a gene in this region could confer susceptibility to schizophrenia in nondeleted cases. Recent studies have provided compelling evidence that haploinsufficiency of TBX1 is likely to be responsible for many of the physical features associated with the deletion. However, although a number of genes have been implicated as possible schizophrenia susceptibility loci, further confirmatory studies are required.

Animals↗
PubMed2004

DNA pooling as a tool for large-scale association studies in complex traits.

Pooled genotyping is a powerful and efficient tool for high throughput association analysis, both case-control and family-based. The use of pooling designs can significantly reduce the consumable and labour costs of a study. At the same time, since it is also extremely efficient with DNA resources, pooling can be an extremely effective method for conserving DNA. Here, we consider the main points in study design, and illustrate the application of pooling using psychiatric phenotypes as an example.

DNA↗
PubMed2004

Dysbindin-1 and schizophrenia: from genetics to neuropathology.

The gene encoding dysbindin-1 has recently been implicated in susceptibility to schizophrenia. In this issue of the JCI, Talbot et al. show that, contrary to expectations, dysbindin-1 is located presynaptically in glutamatergic neurons and is reduced at these locations in schizophrenia. Further studies of dysbindin-1 and the proteins with which it interacts can be expected to throw light on the pathogenesis of schizophrenia.

Brain↗
PubMed2003

Recent advances in the genetics of schizophrenia.

The high heritability of schizophrenia has stimulated much work aimed at identifying susceptibility genes using positional genetics. As a result, several strong and well-established linkages have emerged. Three of the best-supported regions are 6p24-22, 1q21-22 and 13q32-34 where single studies have achieved genome-wide significance at P<0.05 and suggestive positive findings have also been reported in other samples. Other promising regions include 8p21-22, 6q21-25, 22q11-12, 5q21-q33, 10p15-p11 and 1q42. Recently, evidence implicating individual genes within some of the linked regions has been reported and more importantly replicated. Currently, the weight of evidence supports NRG1 and DTNBP1 as schizophrenia susceptibility loci, though work remains before we understand precisely how genetic variation at each locus confers susceptibility and protection. The evidence for COMT, RGS4 and G72 is promising but not yet persuasive. While it is essential that further replications are established, the respective contributions of each gene, relationships with aspects of the phenotype, the possibility of epistatic interactions between genes and functional interactions between the gene products will all need investigation. The ability of positional genetics to implicate novel genes and pathways will open up new vistas for neurobiological research, and all the signs are that genetic research is poised to deliver crucial insights into the nature of schizophrenia.

Carrier Proteins↗