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1.
J Prev Alzheimers Dis ; 9(3): 556-560, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-35841257

RESUMEN

Improving the prevention, detection, and treatment of Alzheimer's disease and Alzheimer's disease related dementias (AD/ADRD) across racial, ethnic, and other diverse populations is a national priority. To this end, this paper proposes the development of the Standard Health Record for Dementia (SHRD, pronounced "shared") for collecting and sharing AD/ADRD real-world data (RWD). SHRD would replace the current unstandardized, fragmented, or missing state of key RWD with an open source, consensus-based, and interoperable common data standard. This paper describes how SHRD could leverage the best practices of the Minimal Common Oncology Data Elements (mCODETM) initiative to advance prevention, detection, and treatment; gain adoption by clinicians and electronic health record (EHR) vendors; and establish sustainable business and governance models. It describes a range of potential use cases to advance equity, including strengthening public health surveillance by facilitating AD/ADRD registry reporting; improving case detection and staging; and diversifying participation in clinical trials.


Asunto(s)
Enfermedad de Alzheimer , Equidad en Salud , Enfermedad de Alzheimer/diagnóstico , Enfermedad de Alzheimer/prevención & control , Registros Electrónicos de Salud , Humanos
2.
Mol Psychiatry ; 23(2): 467-475, 2018 02.
Artículo en Inglés | MEDLINE | ID: mdl-27752079

RESUMEN

Mice lacking DIX domain containing-1 (DIXDC1), an intracellular Wnt/ß-catenin signal pathway protein, have abnormal measures of anxiety, depression and social behavior. Pyramidal neurons in these animals' brains have reduced dendritic spines and glutamatergic synapses. Treatment with lithium or a glycogen synthase kinase-3 (GSK3) inhibitor corrects behavioral and neurodevelopmental phenotypes in these animals. Analysis of DIXDC1 in over 9000 cases of autism, bipolar disorder and schizophrenia reveals higher rates of rare inherited sequence-disrupting single-nucleotide variants (SNVs) in these individuals compared with psychiatrically unaffected controls. Many of these SNVs alter Wnt/ß-catenin signaling activity of the neurally predominant DIXDC1 isoform; a subset that hyperactivate this pathway cause dominant neurodevelopmental effects. We propose that rare missense SNVs in DIXDC1 contribute to psychiatric pathogenesis by reducing spine and glutamatergic synapse density downstream of GSK3 in the Wnt/ß-catenin pathway.


Asunto(s)
Espinas Dendríticas/genética , Péptidos y Proteínas de Señalización Intracelular/genética , Péptidos y Proteínas de Señalización Intracelular/fisiología , Animales , Ansiedad , Trastornos de Ansiedad , Espinas Dendríticas/metabolismo , Depresión , Trastorno Depresivo , Proteínas de Transporte de Glutamato en la Membrana Plasmática/metabolismo , Glucógeno Sintasa Quinasa 3/metabolismo , Trastornos Mentales/genética , Ratones , Ratones Noqueados , Polimorfismo de Nucleótido Simple/genética , Células Piramidales/fisiología , Conducta Social , Sinapsis/metabolismo , Vía de Señalización Wnt/fisiología , beta Catenina/metabolismo
3.
Mol Psychiatry ; 21(5): 650-5, 2016 May.
Artículo en Inglés | MEDLINE | ID: mdl-26216301

RESUMEN

Major depressive disorder (MDD) is among the leading causes of worldwide disability. Despite its significant heritability, large-scale genome-wide association studies (GWASs) of MDD have yet to identify robustly associated common variants. Although increased sample sizes are being amassed for the next wave of GWAS, few studies have as yet focused on rare genetic variants in the study of MDD. We sequenced the exons of 1742 synaptic genes previously identified by proteomic experiments. PLINK/SEQ was used to perform single variant, gene burden and gene set analyses. The GeneMANIA interaction database was used to identify protein-protein interaction-based networks. Cases were selected from a familial collection of early-onset, recurrent depression and were compared with screened controls. After extensive quality control, we analyzed 259 cases with familial, early-onset MDD and 334 controls. The distribution of association test statistics for the single variant and gene burden analyses were consistent with the null hypothesis. However, analysis of prioritized gene sets showed a significant association with damaging singleton variants in a Cav2-adaptor gene set (odds ratio=2.6; P=0.0008) that survived correction for all gene sets and annotation categories tested (empirical P=0.049). In addition, we also found statistically significant evidence for an enrichment of rare variants in a protein-based network of 14 genes involved in actin polymerization and dendritic spine formation (nominal P=0.0031). In conclusion, we have identified a statistically significant gene set and gene network of rare variants that are over-represented in MDD, providing initial evidence that calcium signaling and dendrite regulation may be involved in the etiology of depression.


Asunto(s)
Trastorno Depresivo Mayor/genética , Predisposición Genética a la Enfermedad , Proteínas del Tejido Nervioso/genética , Proteoma/genética , Sinapsis/genética , Redes Reguladoras de Genes , Variación Genética , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Proteómica/métodos
4.
Psychol Med ; 45(13): 2781-91, 2015 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-25920726

RESUMEN

BACKGROUND: Depression is known to run in families, but the effects of parental history of other psychiatric diagnoses on depression rates are less well studied. Few studies have examined the impact of parental psychopathology on depression rates in older age groups. METHOD: We established a population-based cohort including all individuals born in Denmark after 1954 and alive on their 10th birthday (N = 29 76 264). Exposure variables were maternal and paternal history of schizophrenia, bipolar disorder, depression, anxiety or 'other' psychiatric diagnoses. Incidence rate ratios (IRRs) were estimated using Poisson regressions. RESULTS: Parental history of any psychiatric diagnosis increased incidence rates of outpatient (maternal: IRR 1.88, p < 0.0001; paternal: IRR 1.68, p < 0.0001) and inpatient (maternal: IRR 1.99, p < 0.0001; paternal: IRR 1.83, p < 0.0001) depression relative to no parental history. IRRs for parental history of non-affective disorders remained relatively stable across age groups, while IRRs for parental affective disorders (unipolar or bipolar) decreased with age from 2.29-3.96 in the youngest age group to 1.53-1.90 in the oldest group. IRR estimates for all parental diagnoses were similar among individuals aged ⩾41 years (IRR range 1.51-1.90). CONCLUSIONS: Parental history of any psychiatric diagnosis is associated with increased incidence rates of unipolar depression. In younger age groups, parental history of affective diagnoses is more strongly associated with rates of unipolar depression than non-affective diagnoses; however, this distinction disappears after age 40, suggesting that parental psychopathology in general, rather than any one disorder, confers risk for depression in middle life.


Asunto(s)
Depresión/diagnóstico , Depresión/epidemiología , Trastorno Depresivo/diagnóstico , Trastorno Depresivo/epidemiología , Padres/psicología , Adulto , Estudios de Cohortes , Dinamarca/epidemiología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Escalas de Valoración Psiquiátrica , Sistema de Registros , Índice de Severidad de la Enfermedad , Análisis de Supervivencia , Adulto Joven
5.
Psychol Med ; 45(11): 2437-46, 2015 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-25851411

RESUMEN

BACKGROUND: Distinguishing bipolar disorder (BP) from major depressive disorder (MDD) has important relevance for prognosis and treatment. Prior studies have identified clinical features that differ between these two diseases but have been limited by heterogeneity and lack of replication. We sought to identify depression-related features that distinguish BP from MDD in large samples with replication. METHOD: Using a large, opportunistically ascertained collection of subjects with BP and MDD we selected 34 depression-related clinical features to test across the diagnostic categories in an initial discovery dataset consisting of 1228 subjects (386 BPI, 158 BPII and 684 MDD). Features significantly associated with BP were tested in an independent sample of 1000 BPI cases and 1000 MDD cases for classifying ability in receiver operating characteristic (ROC) analysis. RESULTS: Seven clinical features showed significant association with BPI compared with MDD: delusions, psychomotor retardation, incapacitation, greater number of mixed symptoms, greater number of episodes, shorter episode length, and a history of experiencing a high after depression treatment. ROC analyses of a model including these seven factors showed significant evidence for discrimination between BPI and MDD in an independent dataset (area under the curve = 0.83). Only two features (number of mixed symptoms, and feeling high after an antidepressant) showed an association with BPII versus MDD. CONCLUSIONS: Our study suggests that clinical features distinguishing depression in BPI versus MDD have important classification potential for clinical practice, and should also be incorporated as 'baseline' features in the evaluation of novel diagnostic biomarkers.


Asunto(s)
Síntomas Afectivos/diagnóstico , Trastorno Bipolar/diagnóstico , Trastorno Depresivo Mayor/diagnóstico , Adulto , Diagnóstico Diferencial , Manual Diagnóstico y Estadístico de los Trastornos Mentales , Femenino , Humanos , Modelos Logísticos , Masculino , Persona de Mediana Edad , Análisis Multivariante , Curva ROC
6.
Psychol Med ; 45(8): 1709-20, 2015 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-25488392

RESUMEN

BACKGROUND: Previous studies suggest that the relationship between genetic risk and depression may be moderated by stressful life events (SLEs). The goal of this study was to assess whether SLEs moderate the association between polygenic risk of major depressive disorder (MDD) and depressive symptoms in older adults. METHOD: We used logistic and negative binomial regressions to assess the associations between polygenic risk, SLEs and depressive symptoms in a sample of 8761 participants from the Health and Retirement Study. Polygenic scores were derived from the Psychiatric Genomics Consortium genome-wide association study of MDD. SLEs were operationalized as a dichotomous variable indicating whether participants had experienced at least one stressful event during the previous 2 years. Depressive symptoms were measured using an eight-item Center for Epidemiologic Studies Depression Scale subscale and operationalized as both a dichotomous and a count variable. RESULTS: The odds of reporting four or more depressive symptoms were over twice as high among individuals who experienced at least one SLE (odds ratio 2.19, 95% confidence interval 1.86-2.58). Polygenic scores were significantly associated with depressive symptoms (ß = 0.21, p ⩽ 0.0001), although the variance explained was modest (pseudo r 2 = 0.0095). None of the interaction terms for polygenic scores and SLEs was statistically significant. CONCLUSIONS: Polygenic risk and SLEs are robust, independent predictors of depressive symptoms in older adults. Consistent with an additive model, we found no evidence that SLEs moderated the association between common variant polygenic risk and depressive symptoms.


Asunto(s)
Trastorno Depresivo Mayor/epidemiología , Trastorno Depresivo Mayor/genética , Predisposición Genética a la Enfermedad/epidemiología , Predisposición Genética a la Enfermedad/genética , Acontecimientos que Cambian la Vida , Herencia Multifactorial , Depresión/epidemiología , Depresión/genética , Femenino , Humanos , Masculino , Persona de Mediana Edad , Oportunidad Relativa , Factores de Riesgo , Estados Unidos/epidemiología
8.
Mol Psychiatry ; 18(3): 340-6, 2013 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-22212596

RESUMEN

We conducted a systematic study of top susceptibility variants from a genome-wide association (GWA) study of bipolar disorder to gain insight into the functional consequences of genetic variation influencing disease risk. We report here the results of experiments to explore the effects of these susceptibility variants on DNA methylation and mRNA expression in human cerebellum samples. Among the top susceptibility variants, we identified an enrichment of cis regulatory loci on mRNA expression (eQTLs), and a significant excess of quantitative trait loci for DNA CpG methylation, hereafter referred to as methylation quantitative trait loci (mQTLs). Bipolar disorder susceptibility variants that cis regulate both cerebellar expression and methylation of the same gene are a very small proportion of bipolar disorder susceptibility variants. This finding suggests that mQTLs and eQTLs provide orthogonal ways of functionally annotating genetic variation within the context of studies of pathophysiology in brain. No lymphocyte mQTL enrichment was found, suggesting that mQTL enrichment was specific to the cerebellum, in contrast to eQTLs. Separately, we found that using mQTL information to restrict the number of single-nucleotide polymorphisms studied enhances our ability to detect a significant association. With this restriction a priori informed by the observed functional enrichment, we identified a significant association (rs12618769, P(bonferroni)<0.05) from two other GWA studies (TGen+GAIN; 2191 cases and 1434 controls) of bipolar disorder, which we replicated in an independent GWA study (WTCCC). Collectively, our findings highlight the importance of integrating functional annotation of genetic variants for gene expression and DNA methylation to advance the biological understanding of bipolar disorder.


Asunto(s)
Trastorno Bipolar/genética , Metilación de ADN/genética , Regulación de la Expresión Génica/genética , Predisposición Genética a la Enfermedad/genética , Sitios de Carácter Cuantitativo/genética , Cerebelo/metabolismo , Estudio de Asociación del Genoma Completo , Humanos , Metilación , Polimorfismo de Nucleótido Simple/genética
10.
Transl Psychiatry ; 2: e180, 2012 Oct 23.
Artículo en Inglés | MEDLINE | ID: mdl-23092984

RESUMEN

Mood-incongruent psychotic features (MICP) are familial symptoms of bipolar disorder (BP) that also occur in schizophrenia (SZ), and may represent manifestations of shared etiology between the major psychoses. In this study we have analyzed three large samples of BP with imputed genome-wide association data and have performed a meta-analysis of 2196 cases with MICP and 8148 controls. We found several regions with suggestive evidence of association (P<10(-6)), although no marker met genome-wide significance criteria. The top associations were on chromosomes: 6q14.2 within the PRSS35/SNAP91 gene complex (rs1171113, P=9.67 × 10(-8)); 3p22.2 downstream of TRANK/LBA1 (rs9834970, P=9.71 × 10(-8)); and 14q24.2 in an intron of NUMB (rs2333194, P=7.03 × 10(-7)). These associations were present in all three samples, and both rs1171113 and rs2333194 were found to be overrepresented in an analysis of MICP cases compared with all other BP cases. To test the relationship of MICP with SZ, we performed polygenic analysis using the Psychiatric GWAS Consortium SZ results and found evidence of association between SZ polygenes and the presence of MICP in BP cases (meta-analysis P=0.003). In summary, our analysis of the MICP phenotype in BP has provided suggestive evidence for association of common variants in several genes expressed in the nervous system. The results of our polygenic analysis provides support for a modest degree of genetic overlap between BP with MICP and SZ, highlighting that phenotypic correlations across syndromes may be due to the influence of polygenic risk factors.


Asunto(s)
Trastorno Bipolar/genética , Antígenos/genética , Estudios de Casos y Controles , Cromosomas Humanos Par 14/genética , Cromosomas Humanos Par 3/genética , Cromosomas Humanos Par 6/genética , Estudio de Asociación del Genoma Completo , Humanos , Proteínas de la Membrana/genética , Proteínas de Ensamble de Clatrina Monoméricas/genética , Proteínas del Tejido Nervioso/genética , Esquizofrenia/genética , Serina Proteasas/genética
11.
Int J Geriatr Psychiatry ; 27(12): 1248-57, 2012 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-22374884

RESUMEN

OBJECTIVE: The use of psychotropic medications in Alzheimer's disease (AD) has been associated with both deleterious and potentially beneficial outcomes. We examined the longitudinal association of psychotropic medication use with cognitive, functional, and neuropsychiatric symptom (NPS) trajectories among community-ascertained incident AD cases from the Cache County Dementia Progression Study. METHODS: A total of 230 participants were followed for a mean of 3.7 years. Persistency index (PI) was calculated for all antidepressants, selective serotonin reuptake inhibitors (SSRIs), antipsychotics (atypical and typical), and benzodiazepines as the proportion of observed time of medication exposure. Mixed-effects models were used to examine the association between PI for each medication class and Mini-Mental State Exam (MMSE), Clinical Dementia Rating Sum of Boxes (CDR-Sum), and Neuropsychiatric Inventory - Total (NPI-Total) trajectories, controlling for appropriate demographic and clinical covariates. RESULTS: At baseline, psychotropic medication use was associated with greater severity of dementia and poorer medical status. Higher PI for all medication classes was associated with a more rapid decline in MMSE. For antidepressant, SSRI, benzodiazepine, and typical antipsychotic use, a higher PI was associated with a more rapid increase in CDR-Sum. For SSRIs, antipsychotics, and typical antipsychotics, a higher PI was associated with more rapid increase in NPI-Total. CONCLUSIONS: Psychotropic medication use was associated with more rapid cognitive and functional decline in AD, and not with improved NPS. Clinicians may tend to prescribe psychotropic medications to AD patients at risk of poorer outcomes, but one cannot rule out the possibility of poorer outcomes being caused by psychotropic medications.


Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Antidepresivos/uso terapéutico , Antipsicóticos/uso terapéutico , Benzodiazepinas/uso terapéutico , Cognición/efectos de los fármacos , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/psicología , Trastornos del Conocimiento/tratamiento farmacológico , Trastornos del Conocimiento/psicología , Progresión de la Enfermedad , Femenino , Humanos , Estudios Longitudinales , Masculino , Pruebas Neuropsicológicas , Escalas de Valoración Psiquiátrica
12.
Mol Psychiatry ; 17(4): 433-44, 2012 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-21423239

RESUMEN

The heritable component to attempted and completed suicide is partly related to psychiatric disorders and also partly independent of them. Although attempted suicide linkage regions have been identified on 2p11-12 and 6q25-26, there are likely many more such loci, the discovery of which will require a much higher resolution approach, such as the genome-wide association study (GWAS). With this in mind, we conducted an attempted suicide GWAS that compared the single-nucleotide polymorphism (SNP) genotypes of 1201 bipolar (BP) subjects with a history of suicide attempts to the genotypes of 1497 BP subjects without a history of suicide attempts. In all, 2507 SNPs with evidence for association at P<0.001 were identified. These associated SNPs were subsequently tested for association in a large and independent BP sample set. None of these SNPs were significantly associated in the replication sample after correcting for multiple testing, but the combined analysis of the two sample sets produced an association signal on 2p25 (rs300774) at the threshold of genome-wide significance (P=5.07 × 10(-8)). The associated SNPs on 2p25 fall in a large linkage disequilibrium block containing the ACP1 (acid phosphatase 1) gene, a gene whose expression is significantly elevated in BP subjects who have completed suicide. Furthermore, the ACP1 protein is a tyrosine phosphatase that influences Wnt signaling, a pathway regulated by lithium, making ACP1 a functional candidate for involvement in the phenotype. Larger GWAS sample sets will be required to confirm the signal on 2p25 and to identify additional genetic risk factors increasing susceptibility for attempted suicide.


Asunto(s)
Trastorno Bipolar/genética , Trastorno Bipolar/psicología , Predisposición Genética a la Enfermedad/genética , Estudio de Asociación del Genoma Completo/estadística & datos numéricos , Proteínas Tirosina Fosfatasas/genética , Proteínas Proto-Oncogénicas/genética , Intento de Suicidio/psicología , Encéfalo/metabolismo , Estudios de Casos y Controles , Femenino , Estudio de Asociación del Genoma Completo/métodos , Genotipo , Humanos , Masculino , Polimorfismo de Nucleótido Simple , Proteínas Tirosina Fosfatasas/metabolismo , Proteínas Proto-Oncogénicas/metabolismo
13.
Mol Psychiatry ; 17(8): 818-26, 2012 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-21769101

RESUMEN

Because of the high costs associated with ascertainment of families, most linkage studies of Bipolar I disorder (BPI) have used relatively small samples. Moreover, the genetic information content reported in most studies has been less than 0.6. Although microsatellite markers spaced every 10 cM typically extract most of the genetic information content for larger multiplex families, they can be less informative for smaller pedigrees especially for affected sib pair kindreds. For these reasons we collaborated to pool family resources and carried out higher density genotyping. Approximately 1100 pedigrees of European ancestry were initially selected for study and were genotyped by the Center for Inherited Disease Research using the Illumina Linkage Panel 12 set of 6090 single-nucleotide polymorphisms. Of the ~1100 families, 972 were informative for further analyses, and mean information content was 0.86 after pruning for linkage disequilibrium. The 972 kindreds include 2284 cases of BPI disorder, 498 individuals with bipolar II disorder (BPII) and 702 subjects with recurrent major depression. Three affection status models (ASMs) were considered: ASM1 (BPI and schizoaffective disorder, BP cases (SABP) only), ASM2 (ASM1 cases plus BPII) and ASM3 (ASM2 cases plus recurrent major depression). Both parametric and non-parametric linkage methods were carried out. The strongest findings occurred at 6q21 (non-parametric pairs LOD 3.4 for rs1046943 at 119 cM) and 9q21 (non-parametric pairs logarithm of odds (LOD) 3.4 for rs722642 at 78 cM) using only BPI and schizoaffective (SA), BP cases. Both results met genome-wide significant criteria, although neither was significant after correction for multiple analyses. We also inspected parametric scores for the larger multiplex families to identify possible rare susceptibility loci. In this analysis, we observed 59 parametric LODs of 2 or greater, many of which are likely to be close to maximum possible scores. Although some linkage findings may be false positives, the results could help prioritize the search for rare variants using whole exome or genome sequencing.


Asunto(s)
Trastorno Bipolar/genética , Ligamiento Genético/genética , Predisposición Genética a la Enfermedad/genética , Estudio de Asociación del Genoma Completo/estadística & datos numéricos , Trastornos Psicóticos/genética , Trastorno Bipolar/complicaciones , Trastorno Depresivo Mayor/genética , Estudio de Asociación del Genoma Completo/métodos , Genotipo , Humanos , Linaje , Polimorfismo de Nucleótido Simple/genética , Trastornos Psicóticos/complicaciones , Población Blanca/genética
14.
Neurology ; 75(21): 1888-95, 2010 Nov 23.
Artículo en Inglés | MEDLINE | ID: mdl-21068429

RESUMEN

BACKGROUND: Cellular and animal studies suggest that hypercholesterolemia contributes to Alzheimer disease (AD). However, the relationship between cholesterol and dementia at the population level is less clear and may vary over the lifespan. METHODS: The Prospective Population Study of Women, consisting of 1,462 women without dementia aged 38-60 years, was initiated in 1968-1969 in Gothenburg, Sweden. Follow-ups were conducted in 1974-1975, 1980-1981, 1992-1993, and 2000-2001. All-cause dementia was diagnosed according to DSM-III-R criteria and AD according to National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer's Disease and Related Disorders Association criteria. Cox proportional hazards regression examined baseline, time-dependent, and change in cholesterol levels in relation to incident dementia and AD among all participants. Analyses were repeated among participants who survived to the age of 70 years or older and participated in the 2000-2001 examination. RESULTS: Higher cholesterol level in 1968 was not associated with an increased risk of AD (highest vs lowest quartile: hazard ratio [HR] 2.82, 95% confidence interval [CI] 0.94-8.43) among those who survived to and participated in the 2000-2001 examination. While there was no association between cholesterol level and dementia when considering all participants over 32 years, a time-dependent decrease in cholesterol over the follow-up was associated with an increased risk of dementia (HR 2.35, 95% CI 1.22-4.58). CONCLUSION: These data suggest that midlife cholesterol level is not associated with an increased risk of AD. However, there may be a slight risk among those surviving to an age at risk for dementia. Declining cholesterol levels from midlife to late life may better predict AD risk than levels obtained at one timepoint prior to dementia onset. Analytic strategies examining this and other risk factors across the lifespan may affect interpretation of results.


Asunto(s)
Envejecimiento , Colesterol/sangre , Demencia/etiología , Adulto , Intervalos de Confianza , Femenino , Estudios de Seguimiento , Humanos , Persona de Mediana Edad , Análisis Multivariante , Modelos de Riesgos Proporcionales , Estudios Prospectivos , Medición de Riesgo , Análisis de Supervivencia
15.
Neurology ; 74(19): 1524-30, 2010 May 11.
Artículo en Inglés | MEDLINE | ID: mdl-20458069

RESUMEN

BACKGROUND: Commonly used organophosphate and organochlorine pesticides inhibit acetylcholinesterase at synapses in the somatic, autonomic, and central nervous systems and may therefore have lasting effects on the nervous system. Few studies have examined the relationship of pesticide exposure and risk of dementia or Alzheimer disease (AD). We sought to examine the association of occupational pesticide exposure and the risk of incident dementia and AD in later life. METHODS: Residents of the agricultural community of Cache County, UT, who were aged 65 years and older as of January 1995, were invited to participate in the study. At baseline, participants completed detailed occupational history questionnaires that included information about exposures to various types of pesticides. Cognitive status was assessed at baseline and after 3, 7, and 10 years. Standardized methods were used for detection and diagnosis of dementia and AD. Cox proportional hazards survival analyses were used to evaluate the risk of incident dementia and AD associated with pesticide exposure. RESULTS: Among 3,084 enrollees without dementia, more men than women reported pesticide exposure (p < 0.0001). Exposed individuals (n = 572) had more years of education (p < 0.01) but did not differ from others in age. Some 500 individuals developed incident dementia, 344 with AD. After adjustment for baseline age, sex, education, APOE epsilon4 status, and baseline Modified Mini-Mental State Examination scores, Cox proportional hazards models showed increased risks among pesticide-exposed individuals for all-cause dementia, with hazard ratio (HR) 1.38 and 95% confidence interval (CI) 1.09-1.76, and for AD (HR 1.42, 95% CI 1.06-1.91). The risk of AD associated with organophosphate exposure (HR 1.53, 95% CI 1.05-2.23) was slightly higher than the risk associated with organochlorines (HR 1.49, 95% CI 0.99-2.24), which was nearly significant. CONCLUSIONS: Pesticide exposure may increase the risk of dementia and Alzheimer disease in late life.


Asunto(s)
Enfermedades de los Trabajadores Agrícolas/inducido químicamente , Enfermedad de Alzheimer/inducido químicamente , Encéfalo/efectos de los fármacos , Exposición Profesional/efectos adversos , Plaguicidas/efectos adversos , Anciano , Anciano de 80 o más Años , Enfermedades de los Trabajadores Agrícolas/epidemiología , Enfermedad de Alzheimer/epidemiología , Apolipoproteína E4/genética , Encéfalo/patología , Encéfalo/fisiopatología , Análisis Mutacional de ADN , Femenino , Pruebas Genéticas , Genotipo , Humanos , Incidencia , Masculino , Pruebas Neuropsicológicas , Modelos de Riesgos Proporcionales , Medición de Riesgo , Factores de Riesgo , Distribución por Sexo , Encuestas y Cuestionarios , Tiempo , Utah/epidemiología
16.
CNS Neurol Disord Drug Targets ; 9(2): 132-9, 2010 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-20205647

RESUMEN

Alzheimer's disease imposes a significant public health burden that will only worsen as the population ages. Thus, there is considerable motivation to develop effective strategies to treat, or more ideally, prevent the disease. Epidemiologic evidence has suggested that non-steroidal anti-inflammatory drugs (or NSAIDs) may be neuro-protective. However, this evidence is controversial. Observational studies in humans have found that the use of NSAIDs is associated with a lower risk of developing Alzheimer's disease. By contrast, randomized trials have reported that NSAIDs are not effective in treating patients with clinically established disease nor in preventing the onset of dementia among those who are cognitively normal or have mild cognitive impairment. In this article, we review the existing epidemiologic evidence on the relationship between NSAIDs and Alzheimer's disease and discuss several hypotheses to explain the divergent findings.


Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Antiinflamatorios no Esteroideos/farmacología , Encefalitis/tratamiento farmacológico , Fármacos Neuroprotectores/farmacología , Anciano , Enfermedad de Alzheimer/epidemiología , Enfermedad de Alzheimer/fisiopatología , Péptidos beta-Amiloides/antagonistas & inhibidores , Péptidos beta-Amiloides/metabolismo , Antiinflamatorios no Esteroideos/uso terapéutico , Ensayos Clínicos como Asunto/estadística & datos numéricos , Inhibidores de la Ciclooxigenasa/farmacología , Inhibidores de la Ciclooxigenasa/uso terapéutico , Encefalitis/inmunología , Encefalitis/fisiopatología , Estudios Epidemiológicos , Humanos , Fármacos Neuroprotectores/uso terapéutico , Oportunidad Relativa , Reproducibilidad de los Resultados
17.
Am J Med Genet B Neuropsychiatr Genet ; 153B(2): 549-553, 2010 Mar 05.
Artículo en Inglés | MEDLINE | ID: mdl-19691043

RESUMEN

The Reelin gene (RELN) encodes a secretory glycoprotein critical for brain development and synaptic plasticity. Post-mortem studies have shown lower Reelin protein levels in the brains of patients with schizophrenia and bipolar disorder (BP) compared with controls. In a recent genome-wide association study of schizophrenia, the strongest association was found in a marker within RELN, although this association was seen only in women. In this study, we investigated whether genetic variation in RELN is associated with BP in a large family sample. We genotyped 75 tagSNPs and 6 coding SNPs in 1,188 individuals from 318 nuclear families, including 554 affected offspring. Quality control measures, transmission-disequilibrium tests (TDTs), and empirical simulations were performed in PLINK. We found a significant overtransmission of the C allele of rs362719 to BP offspring (OR = 1.47, P = 5.9 x 10(-4)); this withstood empirical correction for testing of multiple markers (empirical P = 0.048). In a hypothesis-driven secondary analysis, we found that the association with rs362719 was almost entirely accounted for by overtransmission of the putative risk allele to affected females (OR(Female) = 1.79, P = 8.9 x 10(-5) vs. OR(Male) = 1.12, P = 0.63). These results provide preliminary evidence that genetic variation in RELN is associated with susceptibility to BP and, in particular, to BP in females. However, our findings should be interpreted with caution until further replication and functional assays provide convergent support.


Asunto(s)
Trastorno Bipolar/genética , Moléculas de Adhesión Celular Neuronal/genética , Proteínas de la Matriz Extracelular/genética , Proteínas del Tejido Nervioso/genética , Serina Endopeptidasas/genética , Alelos , Salud de la Familia , Femenino , Marcadores Genéticos , Genotipo , Humanos , Masculino , Modelos Genéticos , Neuronas/metabolismo , Control de Calidad , Proteína Reelina , Factores de Riesgo , Esquizofrenia/genética , Factores Sexuales
18.
Mol Psychiatry ; 14(8): 755-63, 2009 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-19488044

RESUMEN

To identify bipolar disorder (BD) genetic susceptibility factors, we conducted two genome-wide association (GWA) studies: one involving a sample of individuals of European ancestry (EA; n=1001 cases; n=1033 controls), and one involving a sample of individuals of African ancestry (AA; n=345 cases; n=670 controls). For the EA sample, single-nucleotide polymorphisms (SNPs) with the strongest statistical evidence for association included rs5907577 in an intergenic region at Xq27.1 (P=1.6 x 10(-6)) and rs10193871 in NAP5 at 2q21.2 (P=9.8 x 10(-6)). For the AA sample, SNPs with the strongest statistical evidence for association included rs2111504 in DPY19L3 at 19q13.11 (P=1.5 x 10(-6)) and rs2769605 in NTRK2 at 9q21.33 (P=4.5 x 10(-5)). We also investigated whether we could provide support for three regions previously associated with BD, and we showed that the ANK3 region replicates in our sample, along with some support for C15Orf53; other evidence implicates BD candidate genes such as SLITRK2. We also tested the hypothesis that BD susceptibility variants exhibit genetic background-dependent effects. SNPs with the strongest statistical evidence for genetic background effects included rs11208285 in ROR1 at 1p31.3 (P=1.4 x 10(-6)), rs4657247 in RGS5 at 1q23.3 (P=4.1 x 10(-6)), and rs7078071 in BTBD16 at 10q26.13 (P=4.5 x 10(-6)). This study is the first to conduct GWA of BD in individuals of AA and suggests that genetic variations that contribute to BD may vary as a function of ancestry.


Asunto(s)
Trastorno Bipolar/genética , Negro o Afroamericano/genética , Predisposición Genética a la Enfermedad/genética , Estudio de Asociación del Genoma Completo , Adolescente , Adulto , Trastorno Bipolar/etnología , Estudios de Casos y Controles , Estudios de Cohortes , Femenino , Genoma Humano , Haplotipos , Humanos , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple , Valores de Referencia , Población Blanca , Adulto Joven
19.
Mol Psychiatry ; 14(3): 261-8, 2009 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-18180755

RESUMEN

The FKBP5 gene product forms part of a complex with the glucocorticoid receptor and can modulate cortisol-binding affinity. Variations in the gene have been associated with increased recurrence of depression and with rapid response to antidepressant treatment. We sought to determine whether common FKBP5 variants confer risk for bipolar disorder. We genotyped seven tag single-nucleotide polymorphisms (SNPs) in FKBP5, plus two SNPs previously associated with illness, in 317 families with 554 bipolar offspring, derived primarily from two studies. Single marker and haplotypic analyses were carried out with FBAT and EATDT employing the standard bipolar phenotype. Association analyses were also conducted using 11 disease-related variables as covariates. Under an additive genetic model, rs4713902 showed significant overtransmission of the major allele (P=0.0001), which was consistent across the two sample sets (P=0.004 and 0.006). rs7757037 showed evidence of association that was strongest under the dominant model (P=0.001). This result was consistent across the two datasets (P=0.017 and 0.019). The dominant model yielded modest evidence for association (P<0.05) for three additional markers. Covariate-based analyses suggested that genetic variation within FKBP5 may influence attempted suicide and number of depressive episodes in bipolar subjects. Our results are consistent with the well-established relationship between the hypothalamic-pituitary-adrenal (HPA) axis, which mediates the stress response through regulation of cortisol, and mood disorders. Ongoing whole-genome association studies in bipolar disorder and major depression should further clarify the role of FKBP5 and other HPA genes in these illnesses.


Asunto(s)
Trastorno Bipolar/genética , Predisposición Genética a la Enfermedad , Proteínas de Unión a Tacrolimus/genética , Trastorno Bipolar/fisiopatología , Estudios de Cohortes , Haplotipos , Humanos , Sistema Hipotálamo-Hipofisario/fisiopatología , Desequilibrio de Ligamiento , Trastornos del Humor/genética , Trastornos del Humor/fisiopatología , Linaje , Sistema Hipófiso-Suprarrenal/fisiopatología , Polimorfismo de Nucleótido Simple
20.
Mol Psychiatry ; 14(4): 376-80, 2009 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-19114987

RESUMEN

An overall burden of rare structural genomic variants has not been reported in bipolar disorder (BD), although there have been reports of cases with microduplication and microdeletion. Here, we present a genome-wide copy number variant (CNV) survey of 1001 cases and 1034 controls using the Affymetrix single nucleotide polymorphism (SNP) 6.0 SNP and CNV platform. Singleton deletions (deletions that appear only once in the dataset) more than 100 kb in length are present in 16.2% of BD cases in contrast to 12.3% of controls (permutation P=0.007). This effect was more pronounced for age at onset of mania

Asunto(s)
Trastorno Bipolar/genética , Predisposición Genética a la Enfermedad , Genoma Humano/genética , Eliminación de Secuencia/genética , Estudios de Casos y Controles , Femenino , Dosificación de Gen , Estudio de Asociación del Genoma Completo , Genotipo , Humanos , Masculino , Oportunidad Relativa , Análisis de Secuencia por Matrices de Oligonucleótidos/métodos , Riesgo
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