RESUMO
We previously reported linkage of bipolar disorder to 5q33-q34 in families from two closely related population isolates, the Central Valley of Costa Rica (CVCR) and Antioquia, Colombia (CO). Here we present follow up results from fine-scale mapping in large CVCR and CO families segregating severe bipolar disorder, BP-I, and in 343 population trios/duos from CVCR and CO. Employing densely spaced SNPs to fine map the prior linkage peak region increases linkage evidence and clarifies the position of the putative BP-I locus. We performed two-point linkage analysis with 1134 SNPs in an approximately 9 Mb region between markers D5S410 and D5S422. Combining pedigrees from CVCR and CO yields a LOD score of 4.9 at SNP rs10035961. Two other SNPs (rs7721142 and rs1422795) within the same 94 kb region also displayed LOD scores greater than 4. This linkage peak coincides with our prior microsatellite results and suggests a narrowed BP-I susceptibility regions in these families. To investigate if the locus implicated in the familial form of BP-I also contributes to disease risk in the population, we followed up the family results with association analysis in duo and trio samples, obtaining signals within 2 Mb of the peak linkage signal in the pedigrees; rs12523547 and rs267015 (P = 0.00004 and 0.00016, respectively) in the CO sample and rs244960 in the CVCR sample and the combined sample, with P = 0.00032 and 0.00016, respectively. It remains unclear whether these association results reflect the same locus contributing to BP susceptibility within the extended pedigrees.
Assuntos
Indígena Americano ou Nativo do Alasca/genética , Transtorno Bipolar/genética , Cromossomos Humanos Par 5/genética , Ligação Genética , Linhagem , Colômbia , Costa Rica , Família , Feminino , Frequência do Gene , Marcadores Genéticos , Predisposição Genética para Doença , Humanos , América Latina , Escore Lod , Masculino , Polimorfismo de Nucleotídeo Único/genéticaRESUMO
This work presents the experience developed by the Radioisotope Metrology Laboratory (LMR), of the Argentine National Atomic Energy Commission (CNEA), as result of the accreditation process of the Quality System by ISO 17025 Standard. Considering the LMR as a calibration laboratory, services of secondary activity determinations and calibration of activimeters used in Nuclear Medicine were accredited. A peer review of the (alpha/beta)-gamma coincidence system was also carried out. This work shows in detail the structure of the quality system, the results of the accrediting audit and gives the number of non-conformities detected and of observations made which have all been resolved.
Assuntos
Acreditação/organização & administração , Laboratórios/normas , Medicina Nuclear/organização & administração , Garantia da Qualidade dos Cuidados de Saúde/organização & administração , Monitoramento de Radiação/normas , Proteção Radiológica/normas , Compostos Radiofarmacêuticos/análise , Acreditação/métodos , Argentina , Doses de Radiação , Compostos Radiofarmacêuticos/normasRESUMO
We have searched for genes predisposing to bipolar disorder (BP) by studying individuals with the most extreme form of the affected phenotype, BP-I, ascertained from the genetically isolated population of the Central Valley of Costa Rica (CVCR). The results of a previous linkage analysis on two extended CVCR BP-I pedigrees, CR001 and CR004, and of linkage disequilibrium (LD) analyses of a CVCR population sample of BP-I patients implicated a candidate region on 18p11.3. We further investigated this region by creating a physical map and developing 4 new microsatellite and 26 single-nucleotide polymorphism markers for typing in the pedigree and population samples. We report the results of fine-scale association analyses in the population sample, as well as evaluation of haplotypes in pedigree CR001. Our results suggest a candidate region containing six genes but also highlight the complexities of LD mapping of common disorders.
Assuntos
Transtorno Bipolar/genética , Mapeamento Cromossômico , Cromossomos Humanos Par 18 , Transtornos do Humor/genética , Alelos , Costa Rica , Feminino , Marcadores Genéticos , Predisposição Genética para Doença , Humanos , Masculino , Repetições de Microssatélites/genética , LinhagemRESUMO
Linkage disequilibrium (LD) methods offer great promise for mapping complex traits, but have thus far been applied sparingly. In this paper we describe an LD mapping study of severe bipolar disorder (BP-I) in the genetically isolated population of the Central Valley of Costa Rica. This study provides the first complete screen of a chromosome for a complex trait using LD mapping and presents the first application of a new LD mapping statistic (ancestral haplotype reconstruction (AHR)) that evaluates haplotype sharing among affected individuals. The results of this chromosome-wide analysis are instructive for genome-wide LD mapping in isolated populations. Furthermore, the analysis continues to support a possible BP-I locus on 18pter, suggested by previous analyses in this population. Evidence for a possible BP-I locus on 18q12.2 is also described.