Biomedical subjects

Y Bradford

Publications and source records attributed to Y Bradford.

5 recordsLinked to original sources

PubMed2006

Examination of seven candidate regions for multiple sclerosis: strong evidence of linkage to chromosome 1q44.

Multiple sclerosis (MS) is a debilitating neuroimmunological and neurodegenerative disease with a strong genetic component. Numerous studies have failed to consistently identify genes that confer disease susceptibility except for association with HLA-DR. Seven non-HLA regions (1q, 2q, 9q, 13q, 16q, 18p and 19q) identified in a recent genomic screen were investigated by genotyping approximately 20 single-nucleotide polymorphisms (SNPs) at approximately 1 Mb intervals. Non-parametric multipoint analyses identified a peak LOD* score of 2.99 for the 1q44 region and substantially narrowed the linkage peak to approximately 7 Mb. Ordered subset analyses (OSA) identified significant LOD score increases for 2q35 and 18p11 when ranking families by HLA-DR status and identified a significant LOD score increase in region 2q35 when ranking families by linkage to chromosome 1q44. 1q44 is particularly interesting because of linkage evidence for this region in studies of both rheumatoid arthritis and systemic lupus erythematosus.

Chromosomes, Human, Pair 1↗

PubMed2004

A second-generation genomic screen for multiple sclerosis.

Multiple sclerosis (MS) is a debilitating neuroimmunological and neurodegenerative disorder. Despite substantial evidence for polygenic inheritance of the disease, the major histocompatibility complex is the only region that clearly and consistently demonstrates linkage and association in MS studies. The goal of this study was to identify additional chromosomal regions that harbor susceptibility genes for MS. With a panel of 390 microsatellite markers genotyped in 245 U.S. and French multiplex families (456 affected relative pairs), this is the largest genomic screen for MS conducted to date. Four regions met both of our primary criteria for further interest (heterogeneity LOD [HLOD] and Z scores >2.0): 1q (HLOD=2.17; Z=3.38), 6p (HLOD=4.21; Z=2.26), 9q (HLOD; Z=2.71), and 16p (HLOD=2.64; Z=2.05). Two additional regions met only the Z score criterion: 3q (Z=2.39) and 5q (Z=2.17). Further examination of the data by country (United States vs. France) identified one additional region demonstrating suggestive linkage in the U.S. subset (18p [HLOD=2.39]) and two additional regions generating suggestive linkage in the French subset (1p [HLOD=2.08] and 22q [HLOD=2.06]). Examination of the data by human leukocyte antigen (HLA)-DR2 stratification identified four additional regions demonstrating suggestive linkage: 2q (HLOD=3.09 in the U.S. DR2- families), 6q (HLOD=3.10 in the French DR2- families), 13q (HLOD=2.32 in all DR2+ families and HLOD=2.17 in the U.S. DR2+ families), and 16q (HLOD=2.32 in all DR2+ families and HLOD=2.13 in the U.S. DR2+ families). These data suggest several regions that warrant further investigation in the search for MS susceptibility genes.

Chromosome Mapping↗

PubMed2003

Defining the autism minimum candidate gene region on chromosome 7.

Previous genetic and cytogenetic studies provide evidence that points to one or more autism susceptibility genes residing on chromosome 7q (AUTS1, 115-149 cM on the Marshfield map). However, further localization using linkage analysis has proven difficult. To overcome this problem, we examined the Collaborative Linkage Study of Autism (CLSA) data-set to identify only the families potentially linked to chromosome 7. Out of 94, 47 families were identified and 17 markers were used to generate chromosomal haplotypes. We performed recombination breakpoint analysis to determine if any portion of the chromosome was predominately shared across families. The most commonly shared region spanned a 6 cM interval between D7S501 and D7S2847. Additional markers at 1 cM intervals within this region were genotyped and association and recombination breakpoint analysis was again performed. Although no significant allelic association was found, the recombination breakpoint data points to a shared region between D7S496-D7S2418 (120-123 cM) encompassing about 4.5 Mb of genomic DNA containing over 50 genes.

Autistic Disorder↗

PubMed2001

Incorporating language phenotypes strengthens evidence of linkage to autism.

We investigated the effect of incorporating information about proband and parental structural language phenotypes into linkage analyses in the two regions for which we found the highest signals in our first-stage affected sibling pair genome screen: chromosomes 13q and 7q. We were particularly interested in following up on our chromosome 7q finding in light of two prior reports of linkage of this region to developmental language disorder, since one of the diagnostic criteria for autism is absent or abnormal language development. We hypothesized that if the language phenotype were genetically relevant to linkage at the chromosome 7q locus, then incorporating parents phenotypes would increase the signal at that locus, and most of the signal would originate from the subset of families in which both probands had severe language delay. The results support these hypotheses. The linkage signals we obtained on chromosome 7q as well as at least one signal on chromosome 13q are mainly attributable to the subgroup of families in which both probands had language delay. This became apparent only when the parents' history of language-related difficulties was also incorporated into the analyses. Although based on our data, we were not able to distinguish between epistasis or heterogeneity models, we tentatively concluded that there may be more than one autism susceptibility locus related to language development.

Autistic Disorder↗

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↗