Search PubMed⌕ Search

Biomedical subjects

E R Martin

Publications and source records attributed to E R Martin.

At least 37 records · Page 2Linked to original sources
PubMed2001

Association of single-nucleotide polymorphisms of the tau gene with late-onset Parkinson disease.

CONTEXT: The human tau gene, which promotes assembly of neuronal microtubules, has been associated with several rare neurologic diseases that clinically include parkinsonian features. We recently observed linkage in idiopathic Parkinson disease (PD) to a region on chromosome 17q21 that contains the tau gene. These factors make tau a good candidate for investigation as a susceptibility gene for idiopathic PD, the most common form of the disease. OBJECTIVE: To investigate whether the tau gene is involved in idiopathic PD. DESIGN, SETTING, AND PARTICIPANTS: Among a sample of 1056 individuals from 235 families selected from 13 clinical centers in the United States and Australia and from a family ascertainment core center, we tested 5 single-nucleotide polymorphisms (SNPs) within the tau gene for association with PD, using family-based tests of association. Both affected (n = 426) and unaffected (n = 579) family members were included; 51 individuals had unclear PD status. Analyses were conducted to test individual SNPs and SNP haplotypes within the tau gene. MAIN OUTCOME MEASURE: Family-based tests of association, calculated using asymptotic distributions. RESULTS: Analysis of association between the SNPs and PD yielded significant evidence of association for 3 of the 5 SNPs tested: SNP 3, P =.03; SNP 9i, P =.04; and SNP 11, P =.04. The 2 other SNPs did not show evidence of significant association (SNP 9ii, P =.11, and SNP 9iii, P =.87). Strong evidence of association was found with haplotype analysis, with a positive association with one haplotype (P =.009) and a negative association with another haplotype (P =.007). Substantial linkage disequilibrium (P<.001) was detected between 4 of the 5 SNPs (SNPs 3, 9i, 9ii, and 11). CONCLUSIONS: This integrated approach of genetic linkage and positional association analyses implicates tau as a susceptibility gene for idiopathic PD.

Age of Onset↗
PubMed2001

Strong association of a novel Tau promoter haplotype in progressive supranuclear palsy.

The microtubule associated protein, tau, is found in fibrillar lesions that characterise progressive supranuclear palsy (PSP) and related tauopathies. Mutations in the tau gene in frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17) and genetic association of the H1 haplotype of the tau gene with PSP has firmly established a direct role for tau in disease pathogenesis. However, the functional significance of the tau genetic association in PSP is unknown. We analysed the tau gene promoter sequence and identified two novel single nucleotide polymorphisms. Here we report the genetic association of a novel tau promoter haplotype with PSP which may influence tau transcription.

DNA Mutational Analysis↗
PubMed2001

Applying data mining techniques to the mapping of complex disease genes.

The simulated sequence data for the Genetic Analysis Workshop 12 were analyzed using data mining techniques provided by SAS ENTERPRISE MINER Release 4.0 in addition to traditional statistical tests for linkage and association of genetic markers with disease status. We examined two ways of combining these approaches to make use of the covariate data along with the genotypic data. The result of incorporating data mining techniques with more classical methods is an improvement in the analysis, both by correctly classifying the affection status of more individuals and by locating more single nucleotide polymorphisms related to the disease, relative to analyses that use classical methods alone.

Chromosome Mapping↗
PubMed2001

Analysis of single nucleotide polymorphisms in candidate genes using the pedigree disequilibrium test.

The pedigree disequilibrium test (PDT) has been proposed recently as a test for association in general pedigrees [Martin et al., Am J Hum Genet 67:146-54, 2000]. The Genetic Analysis Workshop (GAW) 12 simulated data, with many extended pedigrees, is an example the type of data to which the PDT is ideally suited. In replicate 42 from the general population the PDT correctly identifies candidate genes 1, 2, and 6 as containing single nucleotide polymorphisms (SNPs) that are significantly associated with the disease. We also applied the truncated product method (TPM) [Zaykin et al., Genet Epidemiol, in press] to combine p-values in overlapping windows across the genes. Our results show that the TPM is helpful in identifying significant SNPs as well as removing spurious false positives. Our results indicate that, using the PDT, functional disease-associated SNPs can be successfully identified with a dense map of moderately polymorphic SNPs.

Genetic Predisposition to Disease↗
PubMed2001

Life after the screen: making sense of many P-values.

A multiple analytic approach may be useful for analyzing complex traits since different methods extract both similar and distinct, but complementary pieces of information from genome screen data on extended pedigrees. We examined the usefulness of combining p-values both across methods and across adjacent markers, taking into account the observed correlation structure among these p-values. To this end, we employed the recently proposed truncated product method [Zaykin et al., Genet Epidemiol, in press]. It appears that this approach is helpful for visualizing priority regions for follow-up analysis and reducing the number of false-positive linkage signals.

Chromosome Mapping↗
PubMed2001

Power calculations for a general class of tests of linkage and association that use nuclear families with affected and unaffected sibs.

Family-based tests of association are now often used when trying to fine-map a disease susceptibility locus. Recently, several tests of linkage and association have been proposed that use nuclear families with multiple affected and unaffected sibs rather than just case-parent triads. In this paper we propose a test that generalizes these previous tests. Formulae are derived to calculate the power of the test for a randomly mating population. These power calculations are used to determine conditions under which it is advantageous to include unaffected sibs in the analysis.

Alleles↗
PubMed2001

Linkage and association analysis of chromosome 19q13 in multiple sclerosis.

Multiple sclerosis (MS) is an autoimmune neurological disorder with a complex etiology. Sibling risk, twin, and adoption studies have demonstrated that genes play a vital role in susceptibility to MS. Numerous association and linkage studies have implicated the major histocompatibility complex (MHC) as one component of the genetic etiology, but additional loci remain to be identified. Genomic screens have suggested over 50 regions that might harbor these genes, but there has been little agreement between studies. The one region suggested by all four screens resides within chromosome 19q13. Allelic associations with several markers in this region have also been described. This region has now been examined in detail in an expanded dataset of MS families from the United States. Genetic linkage and association were tested with multiple markers in this region using both parametric and non-parametric analyses. Additional support for an MS susceptibility locus was observed, primarily in families with the MS-associated HLA-DR2 allele. While consistent, this effect appears to be modest with a maximum lambda(s) = 1.47, probably representing no more than 10% of the overall genetic effect in MS.

Chromosomes, Human, Pair 19↗
PubMed2001

Association analysis of chromosome 15 gabaa receptor subunit genes in autistic disorder.

Gamma-aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the brain, acting via the GABAA receptors. The GABAA receptors are comprised of several different homologous subunits, forming a group of receptors that are both structurally and functionally diverse. Three of the GABAA receptor subunit genes (GABRB3, GABRA5 and GABRG3) form a cluster on chromosome 15q11-q13, in a region that has been genetically associated with autistic disorder (AutD). Based on these data, we examined 16 single nucleotide polymorphisms (SNPs) located within GABRB3, GABRA5 and GABRG3 for linkage disequilibrium (LD) in 226 AutD families (AutD patients and parents). Genotyping was performed using either OLA (oligonucleotide ligation assay), or SSCP (single strand conformation polymorphism) followed by DNA sequencing. We tested for LD using the Pedigree Disequilibrium Test (PDT). PDT results gave significant evidence that AutD is associated with two SNPs located within the GABRG3 gene (exon5_539T/C, p=0.02 and intron5_687T/C, p=0.03), suggesting that the GABRG3 gene or a gene nearby contributes to genetic risk in AutD.

Autistic Disorder↗
PubMed2000

SNPing away at complex diseases: analysis of single-nucleotide polymorphisms around APOE in Alzheimer disease.

There has been great interest in the prospects of using single-nucleotide polymorphisms (SNPs) in the search for complex disease genes, and several initiatives devoted to the identification and mapping of SNPs throughout the human genome are currently underway. However, actual data investigating the use of SNPs for identification of complex disease genes are scarce. To begin to look at issues surrounding the use of SNPs in complex disease studies, we have initiated a collaborative SNP mapping study around APOE, the well-established susceptibility gene for late-onset Alzheimer disease (AD). Sixty SNPs in a 1.5-Mb region surrounding APOE were genotyped in samples of unrelated cases of AD, in controls, and in families with AD. Standard tests were conducted to look for association of SNP alleles with AD, in cases and controls. We also used family-based association analyses, including recently developed methods to look for haplotype association. Evidence of association (P</=.05) was identified for 7 of 13 SNPs, including the APOE-4 polymorphism, spanning 40 kb on either side of APOE. As expected, very strong evidence for association with AD was seen for the APOE-4 polymorphism, as well as for two other SNPs that lie <16 kb from APOE. Haplotype analysis using family data increased significance over that seen in single-locus tests for some of the markers, and, for these data, improved localization of the gene. Our results demonstrate that associations can be detected at SNPs near a complex disease gene. We found that a high density of markers will be necessary in order to have a good chance of including SNPs with detectable levels of allelic association with the disease mutation, and statistical analysis based on haplotypes can provide additional information with respect to tests of significance and fine localization of complex disease genes.

Age of Onset↗
PubMed2000

A test for linkage and association in general pedigrees: the pedigree disequilibrium test.

Family-based tests of linkage disequilibrium typically are based on nuclear-family data including affected individuals and their parents or their unaffected siblings. A limitation of such tests is that they generally are not valid tests of association when data from related nuclear families from larger pedigrees are used. Standard methods require selection of a single nuclear family from any extended pedigrees when testing for linkage disequilibrium. Often data are available for larger pedigrees, and it would be desirable to have a valid test of linkage disequilibrium that can use all potentially informative data. In this study, we present the pedigree disequilibrium test (PDT) for analysis of linkage disequilibrium in general pedigrees. The PDT can use data from related nuclear families from extended pedigrees and is valid even when there is population substructure. Using computer simulations, we demonstrated validity of the test when the asymptotic distribution is used to assess the significance, and examined statistical power. Power simulations demonstrate that, when extended pedigree data are available, substantial gains in power can be attained by use of the PDT rather than existing methods that use only a subset of the data. Furthermore, the PDT remains more powerful even when there is misclassification of unaffected individuals. Our simulations suggest that there may be advantages to using the PDT even if the data consist of independent families without extended family information. Thus, the PDT provides a general test of linkage disequilibrium that can be widely applied to different data structures.

Alleles↗
PubMed2000

Analysis of linkage disequilibrium in gamma-aminobutyric acid receptor subunit genes in autistic disorder.

Autistic disorder (AD) is a neurodevelopmental disorder characterized by abnormalities in behavior, communication, and social interactions and functioning. Recently, Cook et al. reported significant linkage disequilibrium with an AD susceptibility locus and a marker, GABRB3 155CA-2, in the gamma-aminobutyric acid(A) (GABA(A)) receptor beta3-subunit gene on chromosome 15q11-q13. This linkage disequilibrium was detected using a multiallelic version of the transmission/disequilibrium test (TDT) in a sample of nuclear families having at least one child with autistic disorder. In an attempt to replicate this finding we tested for linkage disequilibrium with this marker, as well as with three additional markers in and around the GABA(A) receptor beta3-subunit gene, in an independent, clinically comparable set of AD families. Unlike Cook et al., we failed to detect significant linkage disequilibrium between GABRB3 155CA-2 and AD in our sample. We did, however, find suggestive evidence for linkage disequilibrium with a marker, GABRB3, approximately 60 kb beyond the 3' end of beta3-subunit gene. This finding lends support for previous reports implicating the involvement of genes in this region with AD. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:43-48, 2000

Autistic Disorder↗
PubMed2000

Analysis of association at single nucleotide polymorphisms in the APOE region.

The discussion of the prospects of using a dense map of single nucleotide polymorphisms (SNPs) to identify disease genes with association analysis has been extensive. However, there is little empiric evidence to support this strategy. To begin to examine the practical issues surrounding this methodology, we identified 10 SNPs in the region immediately surrounding the apolipoprotein E locus (APOE), an established susceptibility gene for Alzheimer disease. Our goal was to examine patterns of allelic association to begin to investigate the question of whether APOE could have been identified using SNPs. Our strongest evidence of association was at the 2 SNPs immediately flanking APOE.

Age of Onset↗
PubMed2000

A Monte Carlo procedure for two-stage tests with correlated data.

One strategy for mapping disease loci using marker-disease associations is to test for association with case-control samples and follow up a positive result with a family-based test. Using a family-based test in the second stage can help provide protection against false-positive results that can result from use of inappropriate controls and provides assurance that association identified in the first stage is occurring between linked loci. It is crucial for this two-stage strategy that the first stage be as powerful as possible to detect association since only positive results are tested in the second stage. In certain situations, the power of the first-stage test can be increased by combining the case-control and family data. However, this introduces correlation between the first- and second-stage tests, and treating them as independent tests causes a bias. Here we propose a Monte Carlo method that accounts for the correlation and provides the correct significance level for the second-stage test. We also discuss the use of a two-stage procedure when doing a genome scan for the data presented in the Genetic Analysis Workshop 9 study.

Genetic Markers↗
PubMed2000

Circumventing multiple testing: a multilocus Monte Carlo approach to testing for association.

Advances in marker technology have made a dense marker map a reality. If each marker is considered separately, and separate tests for association with a disease gene are performed, then multiple testing becomes an issue. A common solution uses a Bonferroni correction to account for multiple tests performed. However, with dense marker maps, neighboring markers are tightly linked and may have associated alleles; thus tests at nearby marker loci may not be independent. When alleles at different marker loci are associated, the Bonferroni correction may lead to a conservative test, and hence a power loss. As an alternative, for tests of association that use family data, we propose a Monte Carlo procedure that provides a global assessment of significance. We examine the case of tightly linked markers with varying amounts of association between them. Using computer simulations, we study a family-based test for association (the transmission/disequilibrium test), and compare its power when either the Bonferroni or Monte Carlo procedure is used to determine significance. Our results show that when the alleles at different marker loci are not associated, using either procedure results in tests with similar power. However, when alleles at linked markers are associated, the test using the Monte Carlo procedure is more powerful than the test using the Bonferroni procedure. This proposed Monte Carlo procedure can be applied whenever it is suspected that markers examined have high amounts of association, or as a general approach to ensure appropriate significance levels and optimal power.

Alleles↗
PubMed2000

Outreach to public health professionals: lessons learned from a collaborative Iowa public health project.

In 1995, the National Library of Medicine (NLM) and the Public Health Service (PHS) recommended that special attention be given to the information needs of unaffiliated public health professionals. In response, the National Network of Libraries of Medicine (NN/LM) Greater Midwest Region initiated a collaborative outreach program for public health professionals working in rural east and central Iowa. Five public health agencies were provided equipment, training, and support for accessing the Internet. Key factors in the success of this project were: (1) the role of collaborating agencies in the implementation and ongoing success of information access outreach projects; (2) knowledge of the socio-cultural factors that influence the information-seeking habits of project participants (public health professionals); and (3) management of changing or varying technological infrastructures. Working with their funding, personnel from federal, state, and local governments enhanced the information-seeking skills of public health professionals in rural eastern and central Iowa communities.

Computer Communication Networks↗
PubMed1999

The gene for human transcription factor TCF11 is located telomeric to D17S1827, BTR and HP1Hsbeta on chromosome 17q22.

We report the screening of thirty-one YACs with a number of markers using polymerase chain reaction (PCR) to construct a physical map of part of human chromosome 17q21.3-q22. A contig of YACs covering about 4 Mb was constructed around the TCF11 gene at 68 cM from the most telomeric marker on the p arm, localizing TCF11 telomeric to genetic marker D17S1827. Both human and mouse P1-derived artificial chromosomes (PACs) containing TCF11 were isolated and characterized. The human heterochromatin protein 1 gene, HP1Hsbeta, and its homologue in mouse, MoMOD1, were identified centromeric to TCF11.

Animals↗