Biomedical subjects

Shannon J Kenealy

Publications and source records attributed to Shannon J Kenealy.

5 recordsLinked to original sources

PubMed2006

Functional candidate genes in age-related macular degeneration: significant association with VEGF, VLDLR, and LRP6.

PURPOSE: Age-related macular degeneration (AMD) is a retinal degenerative disease that is the leading cause of blindness worldwide for individuals over the age of 60. Although the etiology of AMD remains largely unknown, numerous studies have suggested that both genes and environmental risk factors significantly influence the risk of developing AMD. Identification of the underlying genes has been difficult, with both genomic screen (locational) and candidate gene (functional) approaches being used. The present study tested candidate genes for association with AMD. METHODS: Eight genes (alpha-2-macroglobulin [A2M], creatine kinase [CKB], angiotensin-converting enzyme [DCP1], interleukin-1alpha [IL1A], low-density lipoprotein receptor-related protein 6 [LRP6], microsomal glutathione-S-transferase 1 [MGST1], vascular entothelial growth factor [VEGF], and very low density lipoprotein receptor [VLDLR]) were tested for genetic linkage and allelic association, using two independent datasets: a family-based association dataset including 162 families and an independent case-control dataset with 399 cases and 159 fully evaluated controls. RESULTS: Test results suggested that genetic variation in five of these genes (IL1A, CKB, A2M, MGST1, and DCP1) is unlikely to explain a significant fraction of the risk of developing AMD in this population. LRP6 showed evidence both for linkage (heterogeneity lod [HLOD] = 1.14) in the family-based dataset and for association (P = 0.004) in the case-control dataset. VEGF showed evidence of linkage (HLOD = 1.32) and demonstrated significant independent allelic association in both the family-based (P = 0.001) and case-control (P = 0.02) datasets. VLDLR showed evidence of association in both the family based (P = 0.03) and case-control (P = 0.01) datasets. CONCLUSIONS: These data suggest that LRP6, VEGF, and VLDLR may play a role in the risk of developing AMD.

Aged↗

PubMed2005

A high-density screen for linkage in multiple sclerosis.

To provide a definitive linkage map for multiple sclerosis, we have genotyped the Illumina BeadArray linkage mapping panel (version 4) in a data set of 730 multiplex families of Northern European descent. After the application of stringent quality thresholds, data from 4,506 markers in 2,692 individuals were included in the analysis. Multipoint nonparametric linkage analysis revealed highly significant linkage in the major histocompatibility complex (MHC) on chromosome 6p21 (maximum LOD score [MLS] 11.66) and suggestive linkage on chromosomes 17q23 (MLS 2.45) and 5q33 (MLS 2.18). This set of markers achieved a mean information extraction of 79.3% across the genome, with a Mendelian inconsistency rate of only 0.002%. Stratification based on carriage of the multiple sclerosis-associated DRB1*1501 allele failed to identify any other region of linkage with genomewide significance. However, ordered-subset analysis suggested that there may be an additional locus on chromosome 19p13 that acts independent of the main MHC locus. These data illustrate the substantial increase in power that can be achieved with use of the latest tools emerging from the Human Genome Project and indicate that future attempts to systematically identify susceptibility genes for multiple sclerosis will have to involve large sample sizes and an association-based methodology.

Australia↗

PubMed2004

Enhancing linkage analysis of complex disorders: an evaluation of high-density genotyping.

To explore the potential value of recently developed high-density linkage mapping methods in the analysis of complex disease we have regenotyped five nuclear families first studied in the 1996 UK multiple sclerosis linkage genome screen, using Applied Biosystems high-density microsatellite linkage mapping set, the Illumina BeadArray linkage mapping panel (version 3) and the Affymetrix GeneChip Human Mapping 10K array. We found that genotyping success, information extraction and genotyping accuracy were improved with all systems. These improvements were particularly marked with the SNP-based methods (Illumina and Affymetrix), with little difference between these. The extent of additional information extracted is considerable, indicating that reanalysis of existing multiplex families using these newer systems would substantially increase power.

Chromosome Mapping↗

PubMed2004

Linkage analysis for age-related macular degeneration supports a gene on chromosome 10q26.

PURPOSE: Age-related macular degeneration (AMD) is a retinal degenerative disease that is the leading cause of blindness worldwide in individuals over the age of 60. Although the etiology of AMD remains largely unknown, numerous studies have suggested both genetic and environmental influences. A previous study of affected multiplex families identified four chromosomal regions that potentially harbor AMD susceptibility genes. The purpose of our study was to further investigate these regions with additional microsatellite marker coverage in our independent data set. METHODS: We examined regions on chromosomes 1q, 9p, 10q, and 17q for genetic linkage in our 70 multiplex families (consisting of 133 affected sibpairs). Two point heterogeneity LOD score (HLOD) and nonparametric LOD score (MLS) analyses were performed for disease models defined by the most severe status in either eye. Conditional analyses were performed using apolipoprotein E (APOE) alleles as covariates in semiparametric LOD (LOD*) score calculations. RESULTS: Regions on chromosomes 1q, 9p, and 17q did not provide evidence of linkage in our data set. However, markers D10S1230 and D10S1656 on chromosome 10q26 generated maximum HLOD scores of 1.52 and 1.13, respectively. Marker D10S1230 also generated an MLS score of 1.56 in stage 4 and 5 individuals. Controlling for the potential effect of the APOE-epsilon4 allele did not substantially alter these scores. CONCLUSIONS: With the inclusion of this study, at least five AMD data sets provide support of genetic linkage to 10q26. Such consistency and confirmation of evidence strongly suggests that this region should be the subject of further detailed genomic efforts for the disease.

Chromosome Mapping↗

PubMed2003

The genetic epidemiology of multiple sclerosis.

Multiple sclerosis (MS) is a debilitating immunological and neurodegenerative disorder. Epidemiological studies have provided overwhelming evidence of complex genetic susceptibility to MS. However, with the exception of the human leukocyte antigen (HLA) locus, genetic studies have failed to consistently identify significant linkage or association with genes that modulate MS disease expression. Numerous functional candidate gene studies, linkage genomic screens, and locational candidate gene studies have been performed in an attempt to identify additional loci. However, these methods have demonstrated insufficient power to consistently identify genes or epigenetic factors for MS. More current approaches integrate information from a variety of sources (e.g. consistent linkage data, gene expression profiling, and functional characterization studies) and utilize high throughput methods (e.g. genotyping high density markers, utilizing pooling schemes and performing new statistical analyses) in an attempt to overcome power issues. The following article presents a review of MS genetics research and a brief overview of methods that are currently being developed and utilized for fine localization of MS loci, such as the method employed in the Genetic Analysis of Multiple sclerosis in EuropeanS (GAMES) study that is presented elsewhere in this journal. It is the hope of researchers that these methods will lead to the identification of susceptibility genes for MS that aid in elucidating pathogenic mechanisms and potential therapeutic strategies for this debilitating disease.

Genetic Testing↗