RESUMEN
We conducted a 9-cM genome scan in a large bipolar pedigree sample from the National Institute of Mental Health genetics initiative (1060 individuals from 154 multiplex families). We performed parametric and nonparametric analyses using both standard diagnostic models and comorbid conditions thought to identify phenotypic subtypes: psychosis, suicidal behavior, and panic disorder. Our strongest linkage signals (genome-wide significance) were observed on chromosomes 10q25, 10p12, 16q24, 16p13, and 16p12 using standard diagnostic models, and on 6q25 (suicidal behavior), 7q21 (panic disorder) and 16p12 (psychosis) using phenotypic subtypes. Several other regions were suggestive of linkage, including 1p13 (psychosis), 1p21 (psychosis), 1q44, 2q24 (suicidal behavior), 2p25 (psychosis), 4p16 (psychosis, suicidal behavior), 5p15, 6p25 (psychosis), 8p22 (psychosis), 8q24, 10q21, 10q25 (suicidal behavior), 10p11 (psychosis), 13q32 and 19p13 (psychosis). Over half the implicated regions were identified using phenotypic subtypes. Several regions - 1p, 1q, 6q, 8p, 13q and 16p - have been previously reported to be linked to bipolar disorder. Our results suggest that dissection of the disease phenotype can enrich the harvest of linkage signals and expedite the search for susceptibility genes. This is the first large-scale linkage scan of bipolar disorder to analyze simultaneously bipolar disorder, psychosis, suicidal behavior, and panic disorder.
Asunto(s)
Trastorno Bipolar/genética , Mapeo Cromosómico , Ligamiento Genético , Genoma Humano , Trastorno de Pánico/genética , Trastornos Psicóticos/genética , Suicidio , Marcadores Genéticos , Humanos , National Institutes of Health (U.S.) , Estados UnidosRESUMEN
We report on the development and the initial testing of a new microbial-based caries model. Specimens were fixed on a rotating mount within a reaction chamber hermetically surrounded by a sterilised glove box. A cariogenic environment was obtained by inoculation with Streptococcus mutans (ATCC 25175) combined with a continuously repeating supply of sucrose solution, trypticase soy broth and artificial saliva applied by dripping. Twenty-five caries-free upper premolars were used. The mesial parts of the occlusal fissures had been sealed with a resin-based fissure sealant (test group 1). To produce marginal gaps, the distal parts had been moistened with saliva before resin application (test group 2). Five teeth served as control and were exposed to all fluids under sterile conditions before being removed from the system after 7 days. Test specimens were infected with S. mutans and were incubated for another 14 days. No unintentional contamination occurred during the 3-week period of operation. Demineralizations were evaluated by using confocal laser scanning microscopy. Only the test specimens showed clearly visible signs of biofilm formation and caries-like lesions. The mean primary lesion depth did not differ significantly between test groups. Wall lesion depths and surface areas of demineralizations underneath the fissure sealants were significantly higher in test group 2. Thus, our model allows the simultaneous production of primary and secondary caries-like enamel lesions in a considerable number of specimens and facilitates the possibility to manipulate and transfer them without necessarily terminating the experiment, opening new possibilities for in vitro caries research.
Asunto(s)
Diente Premolar , Caries Dental/microbiología , Streptococcus mutans , Cariogénicos/efectos adversos , Caseínas/efectos adversos , Caries Dental/inducido químicamente , Esmalte Dental , Técnicas In Vitro , Hidrolisados de Proteína/efectos adversos , Saliva Artificial/efectos adversos , Estadísticas no Paramétricas , Sacarosa/efectos adversos , Desmineralización Dental/inducido químicamenteRESUMEN
The low-to-moderate resolution of linkage analysis in complex traits has underscored the need to identify disease phenotypes with presumed genetic homogeneity. Bipolar disorder (BP) accompanied by psychosis (psychotic BP) may be one such phenotype. We previously reported a genome-wide screen in a large bipolar pedigree sample. In this follow-up study, we reclassified the disease phenotype based on the presence or absence of psychotic features and subgrouped pedigrees according to familial load of psychosis. Evidence for significant linkage to psychotic BP (genome-wide P<0.05) was obtained on chromosomes 9q31 (lod=3.55) and 8p21 (lod=3.46). Several other sites were supportive of linkage, including 5q33 (lod=1.78), 6q21 (lod=1.81), 8p12 (lod=2.06), 8q24 (lod=2.01), 13q32 (lod=1.96), 15q26 (lod=1.96), 17p12 (lod=2.42), 18q21 (lod=2.4), and 20q13 (lod=1.98). For most loci, the highest lod scores, including those with genome-wide significance (at 9q31 and 8p21), occurred in the subgroup of families with the largest concentration of psychotic individuals (> or =3 in a family). Interestingly, all regions but six--5q33, 6q21, 8p21, 8q24, 13q32 and 18q21--appear to be novel; namely, they did not show notable linkage to BP in other genome scans, which did not employ psychosis for disease classification. Also of interest is possible overlap with schizophrenia, another major psychotic disorder: seven of the regions presumed linked in this study--5q, 6q, 8p, 13q, 15q, 17p, and 18q--are also implicated in schizophrenia, as are 2p13 and 10q26, which showed more modest support for linkage. Our results suggest that BP in conjunction with psychosis is a potentially useful phenotype that may: (1) expedite the detection of susceptibility loci for BP and (2) cast light on the genetic relationship between BP and schizophrenia.
Asunto(s)
Trastorno Bipolar/genética , Predisposición Genética a la Enfermedad/genética , Escala de Lod , Esquizofrenia/genética , Cromosomas Humanos Par 8/genética , Cromosomas Humanos Par 9/genética , Humanos , LinajeRESUMEN
Bipolar disorder (BP) is a severe and common psychiatric disorder characterized by extreme mood swings. Family, twin and adoption studies strongly support a genetic component. The mode of inheritance is complex and likely involves multiple, as yet unidentified genes. To identify susceptibility loci, we conducted a genome-wide scan with 343 microsatellite markers in one of the largest, well-characterized pedigree samples assembled to date (373 individuals in 40 pedigrees). To increase power to detect linkage, scan statistics were used to examine the logarithm of odds (lod) scores based on evidence at adjacent chromosomal loci. This analysis yielded significant evidence of linkage (genome-wide P&<0.05) for markers on 2p13-16. Standard linkage analysis was also supportive of linkage to 2p13-16 (lod=3.20), and identified several other interesting regions: 4q31 (lod=3.16), 7q34 (lod=2.78), 8q13 (lod=2.06), 9q31 (lod=2.07), 10q24 (lod=2.79), 13q32 (lod=2.2), 14q21 (lod=2.36) and 17q11-12 (lod=2.75). In this systematic, large-scale study, we identified novel putative loci for BP (on 2p13-16, 8q13 and 14q21) and found support for previously proposed loci (on 4q31, 7q34, 9q31, 10q21-24, 13q32 and 17q11-12). Two of the regions implicated in our study, 2p13-14 and 13q32, have also been linked to schizophrenia, suggesting that the two disorders may have susceptibility genes in common.
Asunto(s)
Trastorno Bipolar/genética , Cromosomas Humanos Par 2 , Escala de Lod , Adolescente , Adulto , Cromosomas Humanos Par 10 , Cromosomas Humanos Par 13 , Cromosomas Humanos Par 14 , Cromosomas Humanos Par 17 , Cromosomas Humanos Par 4 , Cromosomas Humanos Par 7 , Cromosomas Humanos Par 8 , Cromosomas Humanos Par 9 , Predisposición Genética a la Enfermedad/genética , HumanosRESUMEN
Evidence for linkage between bipolar affective disorder (BP) and 21q22 was first reported by our group in a single large pedigree with a lod score of 3.41 with the PFKL locus. In a subsequent study, with denser marker coverage in 40 multiplex BP pedigrees, we reported supporting evidence with a two-point lod score of 2.76 at the D21S1260 locus, about 6 cM proximal to PFKL. For cost-efficiency, the individuals genotyped in that study comprised a subset of our large pedigree sample. To augment our previous analysis, we now report a follow-up study including a larger sample set with an additional 331 typed individuals from the original 40 families, improved marker coverage, and an additional 16 pedigrees. The analysis of all 56 pedigrees (a total of 862 genotyped individuals vs. the 372 genotyped previously), the largest multigenerational BP pedigree sample reportedly analyzed to date, supports our previous results, with a two-point lod score of 3.56 with D21S1260. The 16 new pedigrees analyzed separately gave a maximum two-point lod score of 1.89 at D21S266, less than 1 cM proximal to D21S1260. Our results are consistent with a putative BP locus on 21q22.
Asunto(s)
Trastorno Bipolar/genética , Cromosomas Humanos Par 21 , Ligamiento Genético , Femenino , Estudios de Seguimiento , Marcadores Genéticos , Genotipo , Heterocigoto , Humanos , Escala de Lod , Masculino , LinajeRESUMEN
Previously, we demonstrated evidence of linkage to bipolar affective disorder (BP) in a single large, multigenerational family with a LOD score of 3.41 at the PFKL locus on chromosome 21q22.3. Additional families showed little support for linkage to PFKL under homogeneity or heterogeneity, in that study. We have expanded on that analysis, with 31 microsatellite markers at an average marker spacing of =2 cM, in the largest multigenerational BP pedigree series reported to date. A two-point heterogeneity (alpha=0.5) LOD score of 3.35 (P<.000156) was found at the D21S1260 locus, 5 cM proximal to PFKL. Polylocus analysis with a cluster of three neighboring markers was consistent with these results (PL-HetLOD = 3.25). In the design of this study, 373 individuals from 40 families (from a total set of 1,508 individuals in 57 families) were chosen, as a cost-effective approach to genotyping this large sample set. Linkage analyses were performed with an "affecteds-only" method. As such, our results are based solely on genetic information from affected individuals, without assumptions about the disease-locus genotypes of the unaffecteds. Furthermore, for ease of comparison, this study was performed with the same approach as a 10-cM genome scan for BP loci, the results of which will be reported elsewhere.
Asunto(s)
Trastorno Bipolar/genética , Cromosomas Humanos Par 21 , Ligamiento Genético , Mapeo Cromosómico , Marcadores Genéticos , Genotipo , Humanos , Escala de LodRESUMEN
Bipolar affective disorder (BP) is a major neuropsychiatric disorder with high heritability and complex inheritance. Previously reported linkage between BP and DNA markers in the pericentromeric region of chromosome 18, with a parent-of-origin effect (linkage was present in pedigrees with paternal transmission and absent in pedigrees with exclusive maternal inheritance), has been a focus of interest in human genetics. We reexamined the evidence in one of the largest samples reported to date (1,013 genotyped individuals in 53 unilineal multiplex pedigrees), using 10 highly polymorphic markers and a range of parametric and nonparametric analyses. There was no evidence for significant linkage between BP and chromosome 18 pericentromeric markers in the sample as a whole, nor was there evidence for significant parent-of-origin effect (pedigrees with paternal transmission were not differentially linked to the implicated chromosomal region). Two-point LOD scores and single-locus sib-pair results gave some support for suggestive linkage, but this was not substantiated by multilocus analysis, and the results were further tempered by multiple test effects. We conclude that there is no compelling evidence for linkage between BP and chromosome 18 pericentromeric markers in this sample.
Asunto(s)
Trastorno Bipolar/genética , Cromosomas Humanos Par 18 , Ligamiento Genético , Adolescente , Adulto , Centrómero , Femenino , Marcadores Genéticos , Humanos , Masculino , LinajeRESUMEN
In a preliminary genome scan of 47 bipolar disorder families, we detected in one family a lod score of 3.41 at the PFKL locus on chromosome 21q22.3. The lod score is robust to marker allele frequencies, phenocopy rates and age-dependent penetrance, and remains strongly positive with changes in affection status. Fourteen other markers in 21q22.3 were tested on this family, with largely positive lod scores. Five of the other 46 families also show positive, but modest lod scores with PFKL. When all 47 families are analysed together, there is little support for linkage to PFKL under homogeneity or heterogeneity using lod score analysis, but the model-free affected-pedigree-member method yields statistically significant results (p < 0.0003). Our results are consistent with the presence of a gene in 21q22.3 predisposing at least one family to bipolar disorder.
Asunto(s)
Trastorno Bipolar/genética , Cromosomas Humanos Par 21 , Adolescente , Adulto , Anciano , Alelos , Mapeo Cromosómico , Femenino , Frecuencia de los Genes , Marcadores Genéticos , Predisposición Genética a la Enfermedad , Humanos , Escala de Lod , Masculino , Persona de Mediana Edad , LinajeRESUMEN
A series of 57 extended pedigrees with high density of bipolar affective disorder is described. Ascertainment and diagnostic procedures are documented and simulation studies to assess statistical power are carried out. The pedigrees, obtained in the US and Israel, are comprised of 1508 adult individuals with best estimate consensus diagnoses (12-71 relatives per pedigree), 490 of whom (including 401 sib pairs) meet criteria for a conservative disease definition (bipolar disorder or recurrent major depression). Cell lines have been established on 1324 of these individuals. Statistical power to detect linkage with lod score analysis, assuming autosomal dominant transmission and highly polymorphic DNA markers, is nearly 100% for alpha (proportion of linked families) = 30%, and 75% for alpha = 20%. This is the largest bipolar pedigree series reported to date; its unique features make it amenable to various gene detection techniques.
Asunto(s)
Trastorno Bipolar/genética , Mapeo Cromosómico , Linaje , Estudios de Cohortes , Simulación por Computador , Femenino , Ligamiento Genético , Humanos , Escala de Lod , Masculino , FenotipoRESUMEN
Adult male rats were fed a liquid diet providing 35% of the calories as ethanol, while pair-fed controls received the corresponding diet with alcohol replaced by an equicaloric concentration of sucrose. After 1 month, lactate/pyruvate (L/P) and beta-hydroxybutyrate/acetoacetate (beta-HB/AcAc) ratios in the livers were determined under five different conditions: (1) both diets present up to the time of sacrifice, (2) ethanol diet replaced by control diet for 24 h before sacrifice, (3) ethanol diet replaced by control diet for 48 h before sacrifice, (4) as in the preceding, followed by intraperitoneal (i.p.) injection of ethanol, 1 g/kg, 1 h before sacrifice, (5) as in the preceding, but i.p. injection 3 h before sacrifice. The L/P ratio was significantly higher in the alcohol group than in controls under the first experimental condition, but the groups did not differ under the other four conditions. The beta-HB/AcAc ratio was also significantly higher in the alcohol group under the first condition. This difference disappeared in the second and third conditions. Under the fourth and fifth conditions the beta-HB/AcAc ratio was significantly higher in the controls. The results are compatible with an adaptive increase in mitochondrial reoxidation of NADH in the chronic alcohol groups, but the possibility of a change due to alcohol withdrawal can not be excluded.
Asunto(s)
Acetoacetatos/metabolismo , Etanol/farmacología , Hidroxibutiratos/metabolismo , Lactatos/metabolismo , Hígado/metabolismo , Piruvatos/metabolismo , Animales , Dieta , Hígado/efectos de los fármacos , Masculino , Ratas , Estimulación Química , Factores de TiempoAsunto(s)
Alcoholismo/complicaciones , Hígado Graso/metabolismo , Estrés Fisiológico/metabolismo , Intoxicación Alcohólica/metabolismo , Animales , Etanol/metabolismo , Etanol/farmacología , Hígado Graso/etiología , Glucosa/farmacología , Humanos , Masculino , Ratas , Factores de Tiempo , Triglicéridos/sangreAsunto(s)
Dieta , Etanol/metabolismo , NADP/metabolismo , NAD/metabolismo , Oxidación-Reducción , Animales , Riñón/metabolismo , Hígado/metabolismo , Masculino , Piridinas/metabolismo , Ratas , Factores de TiempoRESUMEN
Pyrazole (4 millimoles per kilogram or 272 milligrams per kilogram of body weight), given to fasted rats 10 minutes before gavage with ethanol (4 grams per kilogram), completely prevented both the disappearance of ethanol from the blood over a 16-hour period and the ethanol-induced reduction in the ratio of oxidized to reduced hepatic nicotinamide-adenine dinucleotide. However, it did not affect the accumulation of triglycerides in the liver after the administration of ethanol. These results indicate that metabolism of ethanol is not required for production of fatty liver by a single, large dose of ethanol.