RESUMO
BACKGROUND: Herpes virus infections can cause cognitive impairment during and after acute encephalitis. Although chronic, latent/persistent infection is considered to be relatively benign, some studies have documented cognitive impairment in exposed persons that is untraceable to encephalitis. These studies were conducted among schizophrenia (SZ) patients or older community dwellers, among whom it is difficult to control for the effects of co-morbid illness and medications. To determine whether the associations can be generalized to other groups, we examined a large sample of younger control individuals, SZ patients and their non-psychotic relatives (n=1852). Method Using multivariate models, cognitive performance was evaluated in relation to exposures to herpes simplex virus type 1 (HSV-1), herpes simplex virus type 2 (HSV-2) and cytomegalovirus (CMV), controlling for familial and diagnostic status and sociodemographic variables, including occupation and educational status. Composite cognitive measures were derived from nine cognitive domains using principal components of heritability (PCH). Exposure was indexed by antibodies to viral antigens. RESULTS: PCH1, the most heritable component of cognitive performance, declines with exposure to CMV or HSV-1 regardless of case/relative/control group status (p = 1.09 × 10-5 and 0.01 respectively), with stronger association with exposure to multiple herpes viruses (ß = -0.25, p = 7.28 × 10-10). There were no significant interactions between exposure and group status. CONCLUSIONS: Latent/persistent herpes virus infections can be associated with cognitive impairments regardless of other health status.
Assuntos
Transtornos Cognitivos/epidemiologia , Infecções por Citomegalovirus/epidemiologia , Herpes Simples/epidemiologia , Modelos Estatísticos , Testes Neuropsicológicos/estatística & dados numéricos , Esquizofrenia/epidemiologia , Adulto , Negro ou Afro-Americano/genética , Negro ou Afro-Americano/psicologia , Anticorpos Antivirais/sangue , Encéfalo/virologia , Estudos de Casos e Controles , Doença Crônica , Transtornos Cognitivos/genética , Transtornos Cognitivos/virologia , Citomegalovirus/imunologia , Infecções por Citomegalovirus/sangue , Escolaridade , Emprego , Feminino , Predisposição Genética para Doença , Herpes Simples/sangue , Humanos , Masculino , Análise Multivariada , Fenótipo , Análise de Componente Principal , Esquizofrenia/genética , Esquizofrenia/virologia , Simplexvirus/imunologiaRESUMO
UNLABELLED: The role of daily functioning is an integral part of the schizophrenia (SZ) phenotype and deficits in this trait appear to be present in both affected persons and some unaffected relatives; hence we have examined its heritability in our cohort of African American schizophrenia families. There is now ample evidence that deficits in cognitive function can impact family members who are not themselves diagnosed with SZ; there is some, but less evidence that role function behaves likewise. We evaluate whether role function tends to "run in families" who were ascertained because they contain an African American proband diagnosed with SZ. METHODS: We analyzed heritability for selected traits related to daily function, employment, living situation, marital status, and Global Assessment Scale (GAS) score; modeling age, gender, along with neurocognition and diagnosis as covariates in a family based African-American sample (N=2488 individuals including 979 probands). RESULTS: Measures of role function were heritable in models including neurocognitive domains and factor analytically derived neurocognitive summary scores and demographics as covariates; the most heritable estimate was obtained from the current GAS scores (h2=0.72). Neurocognition was not a significant contributor to heritability of role function. CONCLUSIONS: Commonly assessed demographic and clinical indicators of functioning are heritable with a global rating of functioning being the most heritable. Measures of neurocognition had little impact on heritability of functioning overall. The family covariance for functioning, reflected in its heritability, supports the concept that interventions at the family level, such as evidenced-based family psychoeducation may be beneficial in schizophrenia.
Assuntos
Transtornos Cognitivos/etiologia , Saúde da Família , Esquizofrenia/complicações , Esquizofrenia/genética , Psicologia do Esquizofrênico , Atividades Cotidianas , Adolescente , Adulto , Negro ou Afro-Americano , Idoso , Idoso de 80 Anos ou mais , Transtornos Cognitivos/genética , Emprego , Análise Fatorial , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos , Fenótipo , Escalas de Graduação Psiquiátrica , Índice de Gravidade de Doença , Adulto JovemRESUMO
BACKGROUND: We evaluated the cross-sectional relationship of blood pressure (BP) components with cognitive impairment after adjusting for potential confounders. METHODS: Reasons for Geographic and Racial Differences in Stroke (REGARDS) is a national, longitudinal population cohort evaluating stroke risk in 30,228 black and white men and women >or=45 years old. During the in-home visit, BP measurements were taken as the average of 2 measurements using a standard aneroid sphygmomanometer. Excluding participants with prior stroke or TIA, the present analysis included 19,836 participants (enrolled from December 2003 to March 2007) with complete baseline physical and cognitive evaluations. Incremental logistic models examined baseline relationships between BP components (systolic blood pressure [SBP], diastolic blood pressure [DBP], and pulse pressure [PP]) and impaired cognitive status (score of Assuntos
Pressão Sanguínea/fisiologia
, Transtornos Cognitivos/fisiopatologia
, Hipertensão/fisiopatologia
, Idoso
, Transtornos Cognitivos/epidemiologia
, Transtornos Cognitivos/etiologia
, Estudos de Coortes
, Estudos Transversais
, Feminino
, Humanos
, Hipertensão/complicações
, Hipertensão/epidemiologia
, Estudos Longitudinais
, Masculino
, Pessoa de Meia-Idade
, Fatores de Risco
RESUMO
An increased prevalence of type 2 diabetes (T2D) in schizophrenia (SCZ) patients has been observed. Exposure to antipsychotics (APs) has been shown to induce metabolic dysregulation in some patients but not all treated patients. We hypothesized that important candidate genes for T2D may increase risk for T2D in African-American patients with SCZ or schizoaffective disorder. The PAARTNERS study comprises African-American families with at least one proband with SCZ or schizoaffective disorder. The current study of PAARTNERS SCZ and schizoaffective disorder cases (N=820) examined single nucleotide polymorphisms (SNPs) within select T2D candidate genes including transcription factor 7-like 2 (TCF7L2), calpain 10 (CAPN10), and ectoenzyme nucleotide pyrophosphatase phosphodiesterase 1 (ENNP1) for association with prevalent T2D. We report the association of TCF7L2 (rs7903146) with T2D under both additive and recessive models for the risk allele T. Specifically, the odds ratio (OR) for having T2D was 1.4 (p=0.03) under an additive model and 2.4 (p=0.004) under a recessive model. We also report a marginally significant TCF7L2 by AP treatment interaction that should be investigated in future studies. CAPN10 (rs3792267) was marginally associated with T2D with OR=1.5 (p=0.08) when considering the model GG vs. AG/AA with risk allele G. ENPP1 (rs1044498) was not associated with T2D. We conclude TCF7L2, a risk factor for T2D in the general population, is also a risk factor for T2D in African-American patients with SCZ or schizoaffective disorder. Research is needed to determine if T2D associated polymorphisms are of interest in the pharmacogenetics and future treatment choices of antipsychotics in African-American patients.
Assuntos
Antipsicóticos/efeitos adversos , Antipsicóticos/uso terapêutico , Negro ou Afro-Americano/genética , Diabetes Mellitus Tipo 2 , Predisposição Genética para Doença , Transtornos Psicóticos/tratamento farmacológico , Esquizofrenia/tratamento farmacológico , Adulto , Idoso , Calpaína/genética , Diabetes Mellitus Tipo 2/induzido quimicamente , Diabetes Mellitus Tipo 2/genética , Saúde da Família , Feminino , Genética Populacional , Estudo de Associação Genômica Ampla , Humanos , Masculino , Pessoa de Meia-Idade , Razão de Chances , Farmacogenética , Diester Fosfórico Hidrolases/genética , Polimorfismo de Nucleotídeo Único/genética , Transtornos Psicóticos/genética , Pirofosfatases/genética , Fatores de Risco , Esquizofrenia/genética , Fatores de Transcrição TCF/genética , Proteína 2 Semelhante ao Fator 7 de TranscriçãoRESUMO
While many studies have sought a window into the genetics of schizophrenia, few have focused on African-American families. An exception is the Project among African-Americans to Explore Risks for Schizophrenia (PAARTNERS), which seeks to identify novel and known risk variation for schizophrenia by genetic analyses of African-American families. We report a linkage study of diagnostic status in 217 African-American families using the Illumina Linkage Panel. Due to assumed incomplete and time-dependent penetrance, we performed linkage analysis using two different treatments of diagnosis: (1) treating both affected and unaffected individuals as informative for linkage (using the program SIBPAL) and (2) treating only affected individuals as informative (using the program MERLIN). We also explore three definitions of affected status: narrowly defined schizophrenia; one broadened to include schizoaffective disorder; and another including all diagnoses indicating psychosis. Several regions show a decrease in the evidence for linkage as the definition broadens 8q22.1 (rs911, 99.26 cM; SIBPAL p-value [p] goes from 0.006 to 0.02), 16q24.3 (rs1006547, 130.48 cM; p from 0.00095 to 0.0085), and 20q13.2 (rs1022689, 81.73 cM; p from 0.00015 to 0.032). One region shows a substantial increase in evidence for linkage, 11p15.2 (rs722317, 24.27 cM; p from 0.0022 to 0.0000003); MERLIN results support the significance of the SIBPAL results (p=0.00001). Our linkage results overlap two broad, previously-reported linkage regions: 8p23.3-p12 found in studies sampling largely families of European ancestry; and 11p11.2-q22.3 reported by a study of African-American families. These results should prove quite useful for uncovering loci affecting risk for schizophrenia.
Assuntos
Negro ou Afro-Americano/genética , Família , Ligação Genética , Esquizofrenia/genética , Mapeamento Cromossômico , Feminino , Predisposição Genética para Doença/genética , Genótipo , Humanos , Masculino , Linhagem , Polimorfismo de Nucleotídeo Único/genética , Fatores de RiscoRESUMO
OBJECTIVES: In preparation for the development of an educational intervention on Alzheimer disease (AD) genetics, we undertook a pilot survey of knowledge in this area and attitudes toward genetic testing for AD among individuals with a family history of AD. METHODS: For the pilot study, we administered a 30-min questionnaire to 57 unaffected individuals from a genetic linkage study. For the focus groups, we interviewed two groups of subjects, ages 44-70 years, with a family history of AD, one of 10 Caucasians and the other of 6 African-Americans. RESULTS: The pilot study showed that there was limited knowledge of genetics overall and AD genetics in particular, considerable concern about personal risk, and little knowledge of or interest in genetic testing for the disease. The focus groups reinforced and fleshed out these impressions and highlighted the importance of caregiving experience in the attitudes toward personal risk for AD. CONCLUSIONS: These results underscore the value of genetics education for this and other complex diseases and suggest specific foci for educational interventions.
Assuntos
Doença de Alzheimer/genética , Testes Genéticos , Conhecimentos, Atitudes e Prática em Saúde , Adulto , Idoso , Idoso de 80 Anos ou mais , Apolipoproteínas E/genética , Coleta de Dados , Feminino , Grupos Focais , Testes Genéticos/psicologia , Humanos , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Inquéritos e QuestionáriosRESUMO
Genes involved in cellular mechanisms to repair oxidative damage are strong candidates as etiologic factors for Alzheimer's disease (AD). One important enzyme involved in this mechanism is superoxide dismutase 2 (SOD2). The gene for this enzyme lies within a single haplotype block at 6q25.3, a region showing evidence for linkage to AD in a genome scan. We genotyped four single nucleotide polymorphisms (SNPs) in SOD2 in families of the National Institute of Mental Health-AD Genetics Initiative (ADGI): rs2758346 in the 5' untranslated region (UTR), rs4880 in exon 2, rs2855116 in intron 3 and rs5746136 in the 3'UTR. Under a dominant model, family-based association tests showed significant evidence for association of AD with the first three loci in a candidate gene set of families with individuals having age of onset of at least 50 years and two affected and one unaffected sibling, and in a late-onset subset of families (families with all affected individuals having age of onset of at least 65 years) from the full ADGI sample. The alleles transmitted more frequently to cases than expected under the null hypothesis were T, C, G, and G. Global tests of the transmission of haplotypes indicate that the first two loci have the most consistent association with risk of AD. Because of the high linkage disequilibrium in this small (14 kb) gene, and the presence of 100 SNPs in this gene, 26 of which may have functional significance, additional genotyping and sequencing are needed to identify the functionally relevant SNP. We discuss the importance of our findings and the relevance of SOD2 to AD risk.
Assuntos
Doença de Alzheimer/genética , Predisposição Genética para Doença , Desequilíbrio de Ligação/genética , Superóxido Dismutase/genética , Idade de Início , Doença de Alzheimer/enzimologia , Família , Frequência do Gene , Genes Dominantes , Ligação Genética , Haplótipos , Humanos , Linhagem , Polimorfismo de Nucleotídeo Único , Superóxido Dismutase/metabolismoRESUMO
Substantial laboratory evidence suggests Transforming Growth Factor-beta1 (TGFB1) is linked to Alzheimer's Disease (AD) pathology. The purpose of the study was to estimate the genetic association of TGFB1 with AD while controlling for apolipoprotein E4 allele (APOE4) status, the only well-established genetic risk factor for AD. Two study populations were genotyped for the TGFB1-509 and +869 single nucleotide polymorphisms (SNPs) that have been associated with TGFB1 levels. Constituting these populations were 203 families from the NIMH AD Genetic Initiative with at least two affected siblings and a normal sibling, and a population of 126 African-American (AA) AD cases versus 93 age matched controls. Results from family-based analyses showed a significant association between the TGFB1 -509 SNP and AD for the entire set of 203 families (P = 0.007), and a subset of these families without a homozygous APOE4 family member (P = 0.026). Results from family-based analyses on the TGFB1 +869 SNP were not significant in the 203 families. While associations for the main effects of the TGFB1 +869 and -509 SNP with AD in the AA case-control study were also not significant, results did indicate that TGFB1 may function as an effect modifier of APOE4 risk. Specifically, the odds of AD associated with having at least one APOE4 allele increased in an additive fashion with one or two copies of the higher producer allele when stratified by TGFB1 -509 genotype and by TGFB1 +869 genotype. Results support a role for TGFB1 in AD pathogenesis.