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Biomedical subjects

B P Riley

Publications and source records attributed to B P Riley.

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

Genomewide linkage study in the Irish affected sib pair study of alcohol dependence: evidence for a susceptibility region for symptoms of alcohol dependence on chromosome 4.

Alcoholism is a relatively common, chronic, disabling and often treatment-resistant disorder. Evidence from twin and adoption studies indicates a substantial genetic influence, with heritability estimates of 50-60%. We conducted a genome scan in the Irish Affected Sib Pair Study of Alcohol Dependence (IASPSAD). Most probands were ascertained through alcoholism treatment settings and were severely affected. Probands, affected siblings and parents were evaluated by structured interview. A 4 cM genome scan was conducted using 474 families of which most (96%) were comprised by affected sib pairs. Nonparametric and quantitative linkage analyses were conducted using DSM-IV alcohol dependence (AD) and number of DSM-IV AD symptoms (ADSX). Quantitative results indicate strong linkage for number of AD criteria to a broad region of chromosome 4, ranging from 4q22 to 4q32 (peak multipoint LOD=4.59, P=2.1 x 10(-6), at D4S1611). Follow-up analyses suggest that the linkage may be due to variation in the symptoms of tolerance and out of control drinking. There was evidence of weak linkage (LODs of 1.0-2.0) to several other regions, including 1q44, 13q31, and 22q11 for AD along with 2q37, 9q21, 9q34 and 18p11 for ADSX. The location of the chromosome 4 peak is consistent with results from prior linkage studies and includes the alcohol dehydrogenase gene cluster. The results of this study suggest the importance of genetic variation in chromosome 4 in the etiology and severity of alcoholism in Caucasian populations.

Aged↗
PubMed2004

No evidence for linkage or association of neuregulin-1 (NRG1) with disease in the Irish study of high-density schizophrenia families (ISHDSF).

The neuregulin-1 gene (NRG1) at chromosome 8p21-22 has been implicated as a schizophrenia susceptibility gene in Icelandic, Scottish, Irish and mixed UK populations. The shared ancestry between these populations led us to investigate the NRG1 polymorphisms and appropriate marker haplotypes for linkage and/or association to schizophrenia in the Irish study of high-density schizophrenia families (ISHDSF). Neither single-point nor multi-point linkage analysis of NRG1 markers gave evidence for linkage independent of our pre-existing findings telomeric on 8p. Analysis of linkage disequilibrium (LD) across the 252 kb interval encompassing the 7 marker core Icelandic/Scottish NRG1 haplotype revealed two separate regions of modest LD, comprising markers SNP8NRG255133, SNP8NRG249130 and SNP8NRG243177 (telomeric) and microsatellites 478B14-428, 420M9-1395, D8S1810 and 420M9-116I12 (centromeric). From single marker analysis by TRANSMIT and FBAT we found no evidence for association with schizophrenia for any marker. Haplotype analysis for the three SNPs in LD region 1 and, separately, the four microsatellites in LD region 2 (analyzed in overlapping 2-marker windows), showed no evidence for overtransmission of specific haplotypes to affected individuals. We therefore conclude that if NRG1 does contain susceptibility alleles for schizophrenia, they impact quite weakly on risk in the ISHDSF.

Chromosome Mapping↗
PubMed2003

Identification of a high-risk haplotype for the dystrobrevin binding protein 1 (DTNBP1) gene in the Irish study of high-density schizophrenia families.

A recent report showed significant associations between several SNPs in a previously unknown EST cluster with schizophrenia. (1). The cluster was identified as the human dystrobrevin binding protein 1 gene (DTNBP1) by sequence database comparisons and homology with mouse DTNBP1. (2). However, the linkage disequilibrium (LD) among the SNPs in DTNBP1 as well as the pattern of significant SNP-schizophrenia association was complex. This raised several questions such as the number of susceptibility alleles that may be involved and the size of the region where the actual disease mutation(s) could be located. To address these questions, we performed different single-marker tests on the 12 previously studied and 2 new SNPs in DTNBP1 that were re-scored using an improved procedure, and performed a variety of haplotype analyses. The sample consisted of 268 Irish multiplex families selected for high density of schizophrenia. Results suggested a simple structure where the LD in the target region could be explained by 6 haplotypes that together accounted for 96% of haplotype diversity in the whole sample. From these six, a single high-risk haplotype was identified that showed a significant association with schizophrenia and explained the pattern of significant findings in the analyses with individual markers. This haplotype was 30 kb long, had a large effect, could be measured with two tag SNPs only, had a frequency of 6% in our sample, seemed to be of relatively recent origin in evolutionary terms, and was equally distributed over Ireland. Implications of these findings for follow-up and replication studies are discussed.

Carrier Proteins↗
PubMed2003

FP-TDI SNP scoring by manual and statistical procedures: a study of error rates and types.

For technologies that are commonly used in ordinary laboratories such as fluorescence-polarization detection with template-directed, dye-terminator incorporation (FP-TDI), SNP genotype scoring is usually done manually. Here we study rates of errors and missing genotypes obtained with this procedure. We also introduce three statistical genotype scoring methods to examine whether they form a viable alternative. Data consisted of eight SNPs typed in about 1400 individuals from 268 pedigrees. The statistical procedures performed better on several internal criteria, such as the number of Mendelian errors, and showed much higher agreement with discrepant genotypes re-scored by two raters. The best results were obtained with the statistical procedure that incorporated information about regularities in the error structure of the FP-TDI data. We estimated that there were about 1.6% more errors if genotypes were scored manually. About 0.6% of these errors could be explained by data manipulation errors, leaving 1% as the result of possible incorrect scoring. There were 3.3% more missing genotypes in the manual scoring due to errors in data manipulation (1.7%) and conservative scoring (1.6%).

Algorithms↗
PubMed2000

Haplotype transmission disequilibrium and evidence for linkage of the CHRNA7 gene region to schizophrenia in Southern African Bantu families.

Recent reports have strongly linked markers near the alpha-7 nicotinic cholinergic receptor subunit gene on human chromosome 15q13-q14 to a sensory gating deficit common in schizophrenics, and have shown positive though non-significant results linking this region to the primary phenotype of schizophrenia in a sample of North American families. We therefore tested for linkage between markers in this region of chromosome 15q and schizophrenia in a sample of 15 multiply affected and 5 single case families with schizophrenia drawn from the Bantu-speaking black population of South Africa. An initial replication using markers from the original study gave an affected-only LOD score maximum of 1.08 under a recessive model at Theta=0.00 for D15S1360, a dinucleotide polymorphism found on the same YAC as the alpha-7 receptor gene. Nonparametric affected-only multipoint analysis gave a Z-score of 1. 29, P=0.098, for D15S1360, and Z=1.45, p=0.075 for D15S118. We then increased the resolution of the map with an extended set of 20 markers. Again, two peaks were observed, with NPL scores of 1.81, p=0.037, at D15S1043 and 1.79 at D15S1360 and 1.80 at D15S1010, both p=0.037. Transmission disequilibrium testing of data from D15S1360 gave an allele-wise and genotype-wise chi(2) of 6.59, 2 df, p=0.037. Haplotype transmission disequilibrium testing using a restricted allele and haplotype set from D15S1043 and D15S1360 gave a global chi(2) of 10.647, 4 df, P=0.007, and a maximum chi(2) of 6.567, 1 df, P=0.004 for excess transmission of the 1.2 haplotype into affected offspring. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:196-201, 2000.

Bungarotoxins↗
PubMed2000

Linkage and associated studies of schizophrenia.

Genetic epidemiology has provided consistent evidence over many years that schizophrenia has a genetic component, and that this genetic component is complex, polygenic, and involves epistatic interaction between loci. Molecular genetics studies have, however, so far failed to identify any DNA variant that can be demonstrated to contribute to either liability to schizophrenia or to any identifiable part of the underlying pathology. Replication studies of positive findings have been difficult to interpret for a variety of reasons. First, few have reproduced the initial findings, which may be due either to random variation between two samples in the genetic inputs involved, or to a lack of power to replicate an effect at a given alpha level. Where positive data have been found in replication studies, the positioning of the locus has been unreliable, leading no closer to positional cloning of genes involved. However, an assessment of all the linkage studies performed over the past ten years does suggest a number of regions where positive results are found numerous times. These include regions on chromosomes 1, 2, 4, 5, 6, 7, 8, 9, 10, 13, 15, 18, 22 and the X. All of these data are critically reviewed and their locations compared. Reasons for the difficulty in obtaining consistent results and possible strategies for overcoming them are discussed. Am. J. Med. Genet. (Semin. Med. Genet.) 97:23-44, 2000.

Chromosome Mapping↗
PubMed1998

Failure to exclude a possible schizophrenia susceptibility locus on chromosome 13q14.1-q32 in southern African Bantu-speaking families.

Several recent reports have provided evidence suggesting linkage of markers on chromosome 13q14.1-q32 to schizophrenia in families from England, Wales, Japan and the USA, but not in Chinese families. We tested for linkage between markers in this region and schizophrenia in a sample of 16 families multiply affected with schizophrenia drawn from the Bantu-speaking black population of South Africa. Twelve markers spanning 76 cM of chromosome 13q were examined in these analyses, including 10 markers covering the most positive region in the studies of the English, Welsh and Chinese families, and two additional markers yielding the largest positive LOD scores in the American study. The map of markers used was D13S126-14.6cM-D13S119-12.2cM-D13S144-10.+ ++2cM-D13S160-7.9cM-D13S121-6.3cM -D13S71-1.6cM-D13S122- 4.9cM-D13S128-8.9cM-D13S770-1.4cM-D13S7 79-2.2cM-D13S64-7.4cM-D13S173. Parametric two-point analysis yields strongly negative LOD scores across the region D13S71-D13S64 under all models, and D13S71-D13S173 under a recessive model, when analysing either the whole sample or affected individuals only. ALOD maxima are 0.0 when allowing for heterogeneity for all markers in this subset. Under recessive modelling, the ALOD maximum is 0.717, theta = 0.0, alpha = 0.45, for D13S126 when analysing all samples. Affected-only analysis of this marker yields a maximum LOD score of 0.645, theta = 0.1, and an ALOD maximum of 0.697, theta = 0.0, alpha = 0.55. Non-parametric multipoint analysis of these markers provides no support for excess sharing of alleles identical by descent, although D13S119 and D13S770 show some evidence for excess sharing of alleles identical by state.

Black People↗
PubMed1997

A linkage study of the N-methyl-D-aspartate receptor subunit gene loci and schizophrenia in southern African Bantu-speaking families.

Both direct and indirect evidence implicate excitatory amino acid neurotransmission in the aetiology of schizophrenia. The data are particularly suggestive for N-methyl-D-aspartate (NMDA) neurotransmission. Four of the six genes coding for subunits of the neural NMDA receptor have been mapped. We have studied segregation and allele sharing of markers in these four regions in a sample of southern African Bantu-speaking families multiply affected with DSM-III-R schizophrenia. This population was chosen because anthropological and linguistic data suggest that it has diverged from a small initial population within the past 1000 years, making shared genetic aetiology more likely. We find positive LOD score maxima of 0.876 at a marker D9S1838 on chromosome 9q34.3 near the NMDAR1 central subunit gene, 0.758 at marker D17S784 on chromosome 17q25 near the NMDAR2C potentiating subunit gene, and 0.453 at marker D12S77 near the NMDAR2B gene on chromosome 12p12 when analysing affected samples only. Only the region of NMDAR2A, on chromosome 16p13, can be excluded in this population. There is evidence of increased allele sharing on chromosomes 9p34.3 and 17q25 using APM. Multipoint allele-sharing analysis using GENEHUNTER does not reject possible effects on chromosome 9q34.3, but does not support any involvement of chromosome 17q25. We propose that the NMDA receptor may be involved in the genetic predisposition to schizophrenia in this population through covariation in several of the subunits, which is consistent with the genetic models of the inheritance of the disease.

Africa, Southern↗
PubMed1996

No evidence for linkage of chromosome 6p markers to schizophrenia in southern African Bantu-speaking families.

Previous studies have yielded evidence for a locus conferring susceptibility to schizophrenia and schizophrenia spectrum disorders on chromosome 6p24-22 in a sample of multiply affected Irish families. We tested for linkage between highly polymorphic chromosome 6p24-22 markers and narrowly defined schizophrenia in a sample of 19 Southern African Bantu-speaking families, a population known to have diverged in the last 2000 years. There is no evidence to support the linkage of markers in this region of chromosome 6 to schizophrenia in this population.

Black People↗
PubMed1995

Schizophrenia and GABAA receptor subunit genes.

Alterations in gamma-aminobutyric acid (GABA) neurotransmission have been indirectly implicated in the pathogenesis of schizophrenia. Using nine multiplex pedigrees, we tested for linkage between schizophrenia and simple sequence repeat polymorphisms for the GABAA receptor alpha 1, alpha 2, alpha 4, alpha 5, alpha 6, beta 1 and beta 3 subunit genes. Evidence of linkage was not found when assuming either autosomal dominant or autosomal recessive inheritance. The non-parametric sib pair test also did not reveal significant evidence of deviation from expected segregation ratios.

Genes, Dominant↗
PubMed1994

Further evidence for clustering of human GABAA receptor subunit genes: localization of the alpha 6-subunit gene (GABRA6) to distal chromosome 5q by linkage analysis.

GABAA receptors are hetero-oligomeric ion-channel complexes that are composed of combinations of alpha, beta, gamma, and delta subunits and play a major role in inhibitory neuro-transmission in the mammalian brain. We report here a microsatellite polymorphism within the human alpha 6-subunit gene (GABRA6). Mapping of this marker in a human-hamster hybrid cell-line panel and typing of the repeat in the Centre d'Etude du Polymorphisme Human (CEPH) reference families enabled the localization of this gene to chromosome 5q and established its linkage to the GABAA receptor alpha 1-subunit gene (GA-BRA1) with a maximum lod score (Zmax) of 39.87 at a theta of 0.069 (males) and 0.100 (females). These results reveal the clustering of GABRA6, GABRA1, and the GABAA receptor gamma 2-subunit gene (GABRG2) on distal chromosome 5q.

Animals↗
PubMed1992

Confirmation of the localization of the human GABAA receptor alpha 1-subunit gene (GABRA1) to distal 5q by linkage analysis.

The GABAA receptor is the major inhibitory neurotransmitter receptor in the mammalian brain. To date, 14 genes that encode subunits of this receptor have been identified; these appear to be scattered throughout the human genome and are under investigation as candidate loci for a number of neurological and psychiatric disorders. We report here a highly polymorphic (dC-dA)n repeat within the human alpha 1-subunit gene (GABRA1). Typing of this marker in the Centre d'Etude du Polymorphisme Humain (CEPH) panel of families confirms the previous assignment of the GABRA1 locus to the distal portion of chromosome 5q by demonstrating linkage to the markers CRI-L45 (D5S61) (Zmax = 11.00, theta max = 0.15), CRI-V1022 (D5S54) (Zmax = 7.25, theta max = 0.20), and CRI-P148 (D5S72) (Zmax = 5.71, theta max = 0.24).

Base Sequence↗