Biomedical subjects

J R Gilbert

Publications and source records attributed to J R Gilbert.

At least 19 recordsLinked to original sources

PubMed2007

Genotype-phenotype study in an FSHD family with a proximal deletion encompassing p13E-11 and D4Z4.

BACKGROUND: In the majority of facioscapulohumeral muscular dystrophy (FSHD) cases, the molecular basis of the disease is due to loss of subtelomeric D4Z4 repeat units at 4q35. Occasionally, an apparent absence of the contracted D4Z4 repeat is associated with FSHD. One explanation for this finding is a deletion in the region proximal to the D4Z4 repeat array that encompasses the p13E-11 (D4F104S1) probe-binding site used in the DNA diagnosis. The frequency of such proximally extended deletions is unknown, and to date, few patients have been described due to the difficulties in the molecular identification of such cases. METHODS: We describe a family (DUK 2531) in which a contracted D4Z4 allele and a large proximal deletion of approximately 75 kb are segregating to 11 individuals. This is the largest deletion identified to date. Family DUK 2531 was initially thought to have normal D4Z4 fragment size and therefore unlinked to the 4q35 region (FSHD1B). RESULTS: Further molecular analysis of DUK 2531 reveals the presence of 10 repeat units (33 kb). The extended deletion includes the probe p13E-11 and B31 binding sites, the inverted repeat D4S2463, and genes FRG2 and TUBB4Q. CONCLUSION: Despite the length of the proximal deletion in this family, the range and severity of the clinical manifestations are typical for the disorder. Because such deletions can lead to misinterpretation in the diagnostic setting, this suggests the need for additional diagnostic tests in facioscapulohumeral muscular dystrophy.

Adult↗

PubMed2006

Dissecting the locus heterogeneity of autism: significant linkage to chromosome 12q14.

Autism is a common neurodevelopmental disorder with a significant genetic component and locus heterogeneity. To date, 12 microsatellite genome screens have been performed using various data sets of sib-pair families (parents and affected children) resulting in numerous regions of potential linkage across the genome. However, no universal region or consistent candidate gene from these regions has emerged. The use of large, extended pedigrees is a recognized powerful approach to identify significant linkage results, as these families potentially contain more potential linkage information than sib-pair families. A genome-wide linkage analysis was performed on 26 extended autism families (65 affected, 184 total individuals). Each family had two to four affected individuals comprised of either avuncular or cousin pairs. For analysis, we used a high-density single-nucleotide polymorphism genotyping assay, the Affymetrix GeneChip Human Mapping 10K array. Two-point analysis gave peak heterogeneity limit of detection (HLOD) of 2.82 at rs2877739 on chromosome 14q. Suggestive linkage evidence (HLOD>2) from a two-point analysis was also found on chromosomes 1q, 2q, 5q, 6p,11q and 12q. Chromosome 12q was the only region showing significant linkage evidence by multipoint analysis with a peak HLOD=3.02 at rs1445442. In addition, this linkage evidence was enhanced significantly in the families with only male affected (multipoint HLOD=4.51), suggesting a significant gender-specific effect in the etiology of autism. Chromosome-wide haplotype analyses on chromosome 12 localized the potential autism gene to a 4 cM region shared among the affected individuals across linked families. This novel linkage peak on chromosome 12q further supports the hypothesis of substantial locus heterogeneity in autism.

Autistic Disorder↗

PubMed2006

Exploring the association of glyceraldehyde-3-phosphate dehydrogenase gene and Alzheimer disease.

BACKGROUND: Previous linkage studies have shown that chromosome 12 harbors susceptibility genes for late-onset Alzheimer disease (LOAD). However, association studies of several candidate genes on this chromosome region have produced ambiguous results. A recent study reported the association between the glyceraldehyde-3-phosphate dehydrogenase (GAPD) gene on chromosome 12p and the risk of LOAD. METHODS: The authors conducted family-based and case-control association studies in two independent LOAD data sets on 12 single-nucleotide polymorphisms (SNPs) in the GAPD gene and its paralogs. RESULTS: No association was found of the GAPD gene with LOAD in the family-based data set, but marginal evidence of association was seen in the later-onset subgroup when age at onset was stratified. The SNP rs2029721 in one GAPD pseudogene was also found to be associated with risk for LOAD in the unrelated case-control data set (p = 0.003). CONCLUSIONS: The GAPD gene and its pseudogene may play a role in the development of late-onset Alzheimer disease. However, the effect, if any, is likely to be limited.

Aged↗

PubMed2006

Lack of association between UBQLN1 and Alzheimer disease.

Alzheimer disease (AD) is heterogeneous and complex with a strong genetic diathesis. It is the most common cause of dementia affecting the elderly. Linkage studies [Kehoe et al., 1999; Hum Mol Genet 8: 237-245]; [Pericak-Vance et al., 2000; Exp Gerontol 35: 1343-1352]; [Myers et al., 2002; Am J Med Genet 114: 235-244]; [Blacker et al., 2003; Hum Mol Genet 12: 23-32] identified chromosome 9q as a region containing a possible AD candidate gene. Functional protein studies [Mah et al., 2000; J Cell Biol 151: 847-862]; [Ko et al., 2002; J Biol Chem 277: 35386-35392] identified the UBQLN1 gene on chromosome 9q that encodes ubiquilin as a likely candidate for a role in late-onset AD pathogenesis. A recent family-based study by [Bertram et al., 2005; N Engl J 352: 884-894] reported genetic association and expression evidence for a putative AD risk allele of an intronic single nucleotide polymorphism (SNP) within the UBQLN1 gene. In this study, we comprehensively assessed whether any of seven polymorphisms located across the UBQLN1 gene are associated with AD in another large family-based data set and an independent case-control data set. We found no significant association of AD risk with any of the seven SNPs genotyped (including those SNPs previously reported by Bertram et al.) in either the family-based or case-control data set. Age-specific analyses and analyses conditional on Apolipoprotein E (ApoE) genotype and sex also revealed no significant associations to AD risk in either data set. Using age at onset (AAO) as a quantitative trait revealed a modest age modifying association; however, the results were inconsistent between the data sets. Our results suggest that UBQLN1 variants do not increase risk for AD in these data.

Adaptor Proteins, Signal Transducing↗

PubMed2006

Covariate analysis of late-onset Alzheimer disease refines the chromosome 12 locus.

Alzheimer disease (AD) is a progressive neurodegenerative disorder of later life with a complex etiology and a strong genetic component. Several genomic screens have suggested that a region between chromosome 12p13 and 12q22 contains at least one additional locus underlying the susceptibility of AD. However, localization of this locus has been difficult. We performed a 5 cM microsatellite marker screen across 74 cM on chromosome 12 with 15 markers in 585 multiplex families consisting of 994 affected sibpairs and 213 other affected relative pairs. Analyses across the entire data set did not reveal significant evidence of linkage. However, suggestive linkage was observed in several subsets. In the 91 families where no affected individuals carry an ApoE varepsilon4 allele, an HLOD score of 1.55 was generated at D12S1042. We further examined the linkage data considering the proposed linkages to chromosome 9 (D9S741) and chromosome 10 (alpha-catenin gene). There was a modest (P=0.20) increase in the LOD score for D12S368 (MLOD=1.70) when using the D9S741 LOD scores as a covariate and a highly significant (P<0.001) increase in the MLOD score (4.19) for D12S1701 in autopsy-confirmed families (n=228) when using alpha-catenin LOD scores as a covariate. In both cases, families with no evidence of linkage to D9S741 or alpha-catenin demonstrated most of the evidence of linkage to chromosome 12, suggesting locus heterogeneity. Taken together, our data suggest that the 16 cM region between D12S1042 and D12S368 should be the subject of further detailed genomic efforts for the disease.

Age of Onset↗

PubMed2006

An analysis paradigm for investigating multi-locus effects in complex disease: examination of three GABA receptor subunit genes on 15q11-q13 as risk factors for autistic disorder.

Gene-gene interactions are likely involved in many complex genetic disorders and new statistical approaches for detecting such interactions are needed. We propose a multi-analytic paradigm, relying on convergence of evidence across multiple analysis tools. Our paradigm tests for main and interactive effects, through allele, genotype and haplotype association. We applied our paradigm to genotype data from three GABAA receptor subunit genes (GABRB3, GABRA5, and GABRG3) on chromosome 15 in 470 Caucasian autism families. Previously implicated in autism, we hypothesized these genes interact to contribute to risk. We detected no evidence of main effects by allelic (PDT, FBAT) or genotypic (genotype-PDT) association at individual markers. However, three two-marker haplotypes in GABRG3 were significant (HBAT). We detected no significant multi-locus associations using genotype-PDT analysis or the EMDR data reduction program. However, consistent with the haplotype findings, the best single locus EMDR model selected a GABRG3 marker. Further, the best pairwise genotype-PDT result involved GABRB3 and GABRG3, and all multi-locus EMDR models also selected GABRB3 and GABRG3 markers. GABA receptor subunit genes do not significantly interact to contribute to autism risk in our overall data set. However, the consistency of results across analyses suggests that we have defined a useful framework for evaluating gene-gene interactions.

Autistic Disorder↗

PubMed2005

Identification of significant association and gene-gene interaction of GABA receptor subunit genes in autism.

Autism is a common neurodevelopmental disorder with a significant genetic component. Existing research suggests that multiple genes contribute to autism and that epigenetic effects or gene-gene interactions are likely contributors to autism risk. However, these effects have not yet been identified. Gamma-aminobutyric acid (GABA), the primary inhibitory neurotransmitter in the adult brain, has been implicated in autism etiology. Fourteen known autosomal GABA receptor subunit genes were studied to look for the genes associated with autism and their possible interactions. Single-nucleotide polymorphisms (SNPs) were screened in the following genes: GABRG1, GABRA2, GABRA4, and GABRB1 on chromosome 4p12; GABRB2, GABRA6, GABRA1, GABRG2, and GABRP on 5q34-q35.1; GABRR1 and GABRR2 on 6q15; and GABRA5, GABRB3, and GABRG3 on 15q12. Intronic and/or silent mutation SNPs within each gene were analyzed in 470 white families with autism. Initially, SNPs were used in a family-based study for allelic association analysis--with the pedigree disequilibrium test and the family-based association test--and for genotypic and haplotypic association analysis--with the genotype-pedigree disequilibrium test (geno-PDT), the association in the presence of linkage (APL) test, and the haplotype family-based association test. Next, with the use of five refined independent marker sets, extended multifactor-dimensionality reduction (EMDR) analysis was employed to identify the models with locus joint effects, and interaction was further verified by conditional logistic regression. Significant allelic association was found for markers RS1912960 (in GABRA4; P = .01) and HCV9866022 (in GABRR2; P = .04). The geno-PDT found significant genotypic association for HCV8262334 (in GABRA2), RS1912960 and RS2280073 (in GABRA4), and RS2617503 and RS12187676 (in GABRB2). Consistent with the allelic and genotypic association results, EMDR confirmed the main effect at RS1912960 (in GABRA4). EMDR also identified a significant two-locus gene-gene effect model involving RS1912960 in GABRA4 and RS2351299 in GABRB1. Further support for this two-locus model came from both the multilocus geno-PDT and the APL test, which indicated a common genotype and haplotype combination positively associated with disease. Finally, these results were also consistent with the results from the conditional logistic regression, which confirmed the interaction between GABRA4 and GABRB1 (odds ratio = 2.9 for interaction term; P = .002). Through the convergence of all analyses, we conclude that GABRA4 is involved in the etiology of autism and potentially increases autism risk through interaction with GABRB1. These results support the hypothesis that GABA receptor subunit genes are involved in autism, most likely via complex gene-gene interactions.

Autistic Disorder↗

PubMed2005

Ordered-subset analysis of savant skills in autism for 15q11-q13.

Autism is a complex disorder characterized by genetic and phenotypic heterogeneity. Analysis of phenotypically homogeneous subtypes has been used to both confirm and narrow potential autism linkage regions such as the chromosomal region 15q11-q13. Increased evidence for linkage in this region had been found in a subgroup of 21 autism families (total families = 94) stratified based on a savant skill factor (SSF) from the Autism Diagnostic Interview, Revised (ADI-R). We examined the savant phenotypic finding in our sample of 91 multiplex autism families. Using two-point parametric analysis in stratification with a cutoff point of a savant skill score of 0.16, our families failed to demonstrate linkage to 15q11-q13. In addition, ordered subset analysis (OSA) using SSF as a covariate also failed to show evidence for linkage. Our findings do not support savant skills as an informative phenotypic subset for linkage in our sample.

Adolescent↗

PubMed2005

Whole genomewide linkage screen for neural tube defects reveals regions of interest on chromosomes 7 and 10.

Neural tube defects (NTDs) are the second most common birth defects (1 in 1000 live births) in the world. Periconceptional maternal folate supplementation reduces NTD risk by 50-70%; however, studies of folate related and other developmental genes in humans have failed to definitively identify a major causal gene for NTD. The aetiology of NTDs remains unknown and both genetic and environmental factors are implicated. We present findings from a microsatellite based screen of 44 multiplex pedigrees ascertained through the NTD Collaborative Group. For the linkage analysis, we defined our phenotype narrowly by considering individuals with a lumbosacral level myelomeningocele as affected, then we expanded the phenotype to include all types of NTDs. Two point parametric analyses were performed using VITESSE and HOMOG. Multipoint parametric and nonparametric analyses were performed using ALLEGRO. Initial results identified chromosomes 7 and 10, both with maximum parametric multipoint lod scores (Mlod) >2.0. Chromosome 7 produced the highest score in the 24 cM interval between D7S3056 and D7S3051 (parametric Mlod 2.45; nonparametric Mlod 1.89). Further investigation demonstrated that results on chromosome 7 were being primarily driven by a single large pedigree (parametric Mlod 2.40). When this family was removed from analysis, chromosome 10 was the most interesting region, with a peak Mlod of 2.25 at D10S1731. Based on mouse human synteny, two candidate genes (Meox2, Twist1) were identified on chromosome 7. A review of public databases revealed three biologically plausible candidates (FGFR2, GFRA1, Pax2) on chromosome 10. The results from this screen provide valuable positional data for prioritisation of candidate gene assessment in future studies of NTDs.

Chromosomes, Human, Pair 10↗

PubMed2005

The genes encoding for D4Z4 binding proteins HMGB2, YY1, NCL, and MYOD1 are excluded as candidate genes for FSHD1B.

Facioscapulohumeral muscular dystrophy is a disease of skeletal muscle, with symptoms including both facial and shoulder girdle weakness and progression to involve the pelvic girdle and extremities in the majority of cases. For most cases of FSHD, the molecular basis of the disease can be identified as a partial deletion of the D4Z4 repeat array on the end of the long arm of chromosome 4. However, in up to 5% of FSHD families there is no linkage to 4q35. These cases are designated as FSHD1B. Proteins have been identified that bind to the D4Z4 repeats of chromosome 4q35. The genes encoding D4Z4 binding proteins YY1, HMGB2, NCL, and MYOD1 were investigated as candidate genes for FSHD1B. Coding sequences and promoter region were analyzed for HMBG2 and no sequence variations were detected. For YY1, all five exons were analyzed and a polymorphism was detected in both the unaffected and affected populations. In nucleolin (NCL), several SNPs were identified, including a SNP causing the non-synonymous change P515H; however, all polymorphisms either occurred in control samples or were previously reported. A novel polymorphism was also detected in MYOD1, but did not represent a disease-specific variation. These results suggest that HMBG2, YY1, NCL, and MYOD1 are unlikely to represent the genes responsible for FSHD in these families.

Chromatography, High Pressure Liquid↗

PubMed2005

Analysis of the RELN gene as a genetic risk factor for autism.

Several genome-wide screens have indicated the presence of an autism susceptibility locus within the distal long arm of chromosome 7 (7q). Mapping at 7q22 within this region is the candidate gene reelin (RELN). RELN encodes a signaling protein that plays a pivotal role in the migration of several neuronal cell types and in the development of neural connections. Given these neurodevelopmental functions, recent reports that RELN influences genetic risk for autism are of significant interest. The total data set consists of 218 Caucasian families collected by our group, 85 Caucasian families collected by AGRE, and 68 Caucasian families collected at Tufts University were tested for genetic association of RELN variants to autism. Markers included five single-nucleotide polymorphisms (SNPs) and a repeat in the 5'-untranslated region (5'-UTR). Tests for association in Duke and AGRE families were also performed on four additional SNPs in the genes PSMC2 and ORC5L, which flank RELN. Family-based association analyses (PDT, Geno-PDT, and FBAT) were used to test for association of single-locus markers and multilocus haplotypes with autism. The most significant association identified from this combined data set was for the 5'-UTR repeat (PDT P-value=0.002). These analyses show the potential of RELN as an important contributor to genetic risk in autism.

5' Untranslated Regions↗

PubMed2005

Interaction between the alpha-T catenin gene (VR22) and APOE in Alzheimer's disease.

BACKGROUND: APOE is the only gene that has been consistently replicated as a risk factor for late onset Alzheimer's disease. Several recent studies have identified linkage to chromosome 10 for both risk and age of onset, suggesting that this region harbours genes that influence the development of the disease. A recent study reported association between single nucleotide polymorphisms (SNPs) in the VR22 gene (CTNNA3) on chromosome 10 and plasma levels of Abeta42, an endophenotype related to Alzheimer's disease. OBJECTIVE: To assess whether polymorphisms in the VR22 gene are associated with Alzheimer's disease in a large sample of Alzheimer's disease families and an independent set of unrelated cases and controls. RESULTS: Several SNPs showed association in either the family based or case-control analyses (p<0.05). The most consistent findings were with SNP6, for which there was significant evidence of association in both the families and the unrelated cases and controls. Furthermore, there was evidence of significant interaction between APOE-4 and two of the VR22 SNPs, with the strongest evidence of association being concentrated in individuals carrying APOE-4. CONCLUSIONS: This study suggests that VR22 or a nearby gene influences susceptibility to Alzheimer's disease, and the effect is dependent on APOE status.

Aged↗

PubMed2004

No association between the APOE gene and autism.

Autism is a neurodevelopmental disorder characterized by stereotypic and repetitive behavior and interests, together with social and communicative deficiencies. The results of several genomic screens suggest the presence of an autism susceptibility locus on chromosome 19p13.2-q13.4. The apolipoprotein E (APOE) gene on chromosome 19 encodes for a protein, apoE, whose different isoforms (E2, E3, E4) influence neuronal growth. APOE participates in lipid transport and metabolism, repair, growth, and maintenance of axons and myelin during neuronal development. The APOE protein competes with the Reelin protein for VLDL/APOER2 receptor binding. Several studies have reported evidence for an association between autism and the Reelin gene. Based on these data we tested for association between APOE and autism using family-based association methods in a data set of 322 autism families. Three promoter, one intronic, and one 3' UTR single nucleotide polymorphisms (SNPs) in the APOE gene (-491a/t, -427c/t, -219g/t, 113c/g, and 5361c/t) as well as the APOE functional polymorphism (E2, E3, E4) were examined and failed to reveal significant evidence that autism is associated with APOE.

Apolipoproteins E↗

PubMed2003

Fine mapping of autistic disorder to chromosome 15q11-q13 by use of phenotypic subtypes.

Autistic disorder (AutD) is a complex genetic disease. Available evidence suggests that several genes contribute to the underlying genetic risk for the development of AutD. However, both etiologic heterogeneity and genetic heterogeneity confound the discovery of AutD-susceptibility genes. Chromosome 15q11-q13 has been identified as a strong candidate region on the basis of both the frequent occurrence of chromosomal abnormalities in that region and numerous suggestive linkage and association findings. Ordered-subset analysis (OSA) is a novel statistical method to identify a homogeneous subset of families that contribute to overall linkage at a given chromosomal location and thus to potentially help in the fine mapping and localization of the susceptibility gene within a chromosomal area. For the present analysis, a factor that represents insistence on sameness (IS)--derived from a principal-component factor analysis using data on 221 patients with AutD from the repetitive behaviors/stereotyped patterns domain in the Autism Diagnostic Interview-Revised--was used as a covariate in OSA. Analysis of families sharing high scores on the IS factor increased linkage evidence for the 15q11-q13 region, at the GABRB3 locus, from a LOD score of 1.45 to a LOD score of 4.71. These results narrow our region of interest on chromosome 15 to an area surrounding the gamma-aminobutyric acid-receptor subunit genes, in AutD, and support the hypothesis that the analysis of phenotypic homogeneous subtypes may be a powerful tool for the mapping of disease-susceptibility genes in complex traits.

Autistic Disorder↗

PubMed2003

Genotype-based association test for general pedigrees: the genotype-PDT.

Many family-based tests of linkage disequilibrium (LD) are based on counts of alleles rather than genotypes. However, allele-based tests may not detect interactions among alleles at a single locus that are apparent when examining associations with genotypes. Family-based tests of LD based on genotypes have been developed, but they are typically valid as tests of association only in families with a single affected individual. To take advantage of families with multiple affected individuals, we propose the genotype-pedigree disequilibrium test (geno-PDT) to test for LD between marker locus genotypes and disease. Unlike previous tests for genotypic association, the geno-PDT is valid in general pedigrees. Simulations to compare the power of the allele-based PDT and geno-PDT reveal that under an additive model, the allele-based PDT is more powerful, but that the geno-PDT can have greater power when the genetic model is recessive or dominant. Perhaps the most important property of the geno-PDT is the ability to test for association with particular genotypes, which can reveal underlying patterns of association at the genotypic level. These genotype-specific tests can be used to suggest possible underlying genetic models that are consistent with the pattern of genotypic association. This is illustrated through an application to a candidate gene analysis of the MLLT3 gene in families with Alzheimer disease. The geno-PDT approach for testing genotypes in general family data provides a useful tool for identifying genes in complex disease, and partitioning individual genotype contributions will help to dissect the influence of genotype on risk.

Alzheimer Disease↗

PubMed2002

Defective neuronal sprouting by human apolipoprotein E4 is a gain-of-negative function.

The apolipoprotein E (apoE) epsilon 4 allele (apoE4) is a major risk factor for neurodegenerative conditions, including Alzheimer's disease (AD). A role for apoE in regeneration of synaptic circuitry after neural injury has been shown in several in vitro studies in which apoE3 supports neuronal sprouting better than apoE4. We evaluated sprouting in an in vitro mouse organotypic hippocampal slice culture system derived from transgenic mice expressing apoE3 or apoE4, in which apoE-dependent granule cell mossy fiber sprouting in the presence of apoE4 is only 51% of the level of apoE3. Sprouting supported by apoE4 had a dose response opposite that by supported by apoE3: although increasing E3 expression increased sprouting, increasing E4 expression decreased sprouting, suggesting that the defect in E4 in supporting neuronal sprouting is a gain-of-negative activity. These results may have important pharmacogenomic implications for AD therapies that modulate apoE expression levels.

Alzheimer Disease↗

PubMed2001

De novo partial duplication of chromosome 7p in a male with autistic disorder.

We describe a de novo partial duplication of 7p in a 25-year-old male with autistic disorder (AD). High-resolution chromosome analysis revealed an extra segment added to the proximal short arm of chromosome 7. The G-band pattern was consistent with an inverted duplication of 7p11.2-p14.1. Fluorescent in situ hybridization (FISH), using a whole chromosome 7 DNA probe (Cytocell, Inc., UK), confirmed that the extra chromosome material is derived from chromosome 7, indicating that the patient is partially trisomic for a region of the short arm of chromosome 7. Partial duplication of the short arm of chromosome 7 is uncommon with little more than 30 cases in the literature. This is the first report of an individual with a 7p duplication who also has AD.

Adult↗

PubMed2001

Linkage disequilibrium at the Angelman syndrome gene UBE3A in autism families.

Autistic disorder is a neurodevelopmental disorder with a complex genetic etiology. Observations of maternal duplications affecting chromosome 15q11-q13 in patients with autism and evidence for linkage and linkage disequilibrium to markers in this region in chromosomally normal autism families indicate the existence of a susceptibility locus. We have screened the families of the Collaborative Linkage Study of Autism for several markers spanning a candidate region covering approximately 2 Mb and including the Angelman syndrome gene (UBE3A) and a cluster of gamma-aminobutyric acid (GABA(A)) receptor subunit genes (GABRB3, GABRA5, and GABRG3). We found significant evidence for linkage disequilibrium at marker D15S122, located at the 5' end of UBE3A. This is the first report, to our knowledge, of linkage disequilibrium at UBE3A in autism families. Characterization of null alleles detected at D15S822 in the course of genetic studies of this region showed a small (approximately 5-kb) genomic deletion, which was present at somewhat higher frequencies in autism families than in controls.

Alleles↗