RESUMEN
Bipolar-related subphenotypes that cluster within families may help identify subsets of patients that are more genetically homogeneous. Environmental or assessment factors that segregate by family may influence estimates of familiality. We aimed to determine familiality of subphenotypes of bipolar disorder (BP), accounting for effects of age, sex, diagnosis, and site/wave of ascertainment. We studied 589 sibships with 1416 siblings affected with bipolar I (BPI), schizoaffective disorder, bipolar type (SAB), bipolar II (BPII), or recurrent unipolar depression (RUDD). Sibships were from families with > or =2 BPI cases collected by the NIMH Bipolar Genetics Initiative (NIMHBGI). Rapid cycling showed the strongest evidence for familiality [odds ratio (OR) (95%CI) = 2.02 (1.43, 2.85), P = 6.0 x 10(-5)] in a model including age, sex, diagnosis, and site/wave of ascertainment. Additional significantly familial traits were comorbid alcohol abuse/dependence (P = 2 x 10(-4)) and comorbid panic disorder (P = 8 x 10(-3)), as well as psychosis, suicidal thoughts, and rapid mood switching (P = 6 x 10(-3) - 0.03). Omission of the effect of site/wave of ascertainment from the model inflated the significance level of the apparent familial association of almost all subphenotypes from one to four orders of magnitude. We have found evidence of familiality for subphenotypes of BP. In multicenter samples, familiality may be overestimated if variability in diagnosis of subphenotypes between site/wave of ascertainment is not considered.
Asunto(s)
Trastorno Bipolar/diagnóstico , Fenotipo , Adulto , Edad de Inicio , Trastorno Bipolar/clasificación , Trastorno Bipolar/genética , Familia , Femenino , Ligamiento Genético , Predisposición Genética a la Enfermedad , Genotipo , Humanos , Masculino , Persona de Mediana Edad , National Institute of Mental Health (U.S.) , Estados UnidosRESUMEN
Infection with HIV-1, SIV, or simian HIV is associated with abnormalities in the number, size, and structure of germinal centers (GCs). To determine whether these histopathologic abnormalities are associated with abnormalities in Ab development, we analyzed nucleotide sequences of Igs from splenic GCs of simian HIV-infected macaques. Virus-specific GCs were identified in frozen splenic tissue sections by inverse immunohistochemistry using rHIV-1 gp120 as a probe. B cells from envelope-specific GCs were isolated from these sections using laser capture microdissection. Their Igs were amplified from cDNA using nested PCR, then cloned and sequenced. Nucleotide sequences were recovered from nine multimember clonal lineages. Within each lineage, sequences had similar V-D-J or V-J junctions but differed by somatic mutations distributed throughout the variable domain. The clones were highly mutated, similar to that previously reported for HIV-1-specific human IgG Abs. The average clone had 37 mutations in the V region, for a frequency of 0.11 mutations/base. The mutational pattern was strikingly nonrandom, with somatic mutations occurring preferentially at RGYW/WRCY hotspots. Transition mutations were favored over transversions, with C-->T and G-->A replacements together accounting for almost one-third of all mutations. Analysis of replacement and silent mutations in the framework and CDRs suggests that the Igs were subjected to affinity selection. These data demonstrate that the process of Ab maturation is not seriously disrupted in GCs during the early stages of immunodeficiency virus infection, and that Env-specific Igs developing in GCs are subject to extensive somatic mutation and profound selection pressures.