RESUMEN
Recent genome-wide association studies have identified 5 loci (BIN1, CLU, CR1, EXOC3L2, and PICALM) as genetic determinants of Alzheimer's disease (AD). We attempted to confirm the association between these genes and the AD risk in 3 contrasting European populations (from Finland, Italy, and Spain). Because CLU and CR1 had already been analyzed in these populations, we restricted our investigation to BIN1, EXO2CL3, and PICALM. In a total of 2816 AD cases and 2706 controls, we unambiguously replicated the association of rs744373 (for BIN1) and rs541458 (for PICALM) polymorphisms with the AD risk (odds ratio [OR] = 1.26, 95% confidence interval [CI] [1.15-1.38], p = 2.9 × 10(-7), and OR = 0.80, 95% CI [0.74-0.88], p = 4.6 × 10(-7), respectively). In a meta-analysis, rs597668 (EXOC3L2) was also associated with the AD risk, albeit to a lesser extent (OR = 1.19, 95% CI [1.06-1.32], p = 2.0 × 10(-3)). However, this signal did not appear to be independent of APOE. In conclusion, we confirmed that BIN1 and PICALM are genetic determinants of AD, whereas the potential involvement of EXOC3L2 requires further investigation.
Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/genética , Enfermedad de Alzheimer/genética , Proteínas de Ensamble de Clatrina Monoméricas/genética , Proteínas Nucleares/genética , Proteínas Supresoras de Tumor/genética , Finlandia , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Genotipo , Humanos , Italia , Polimorfismo de Nucleótido Simple , España , Población Blanca/genéticaRESUMEN
For more than half a decade, lithium has been successfully used to treat bipolar disorder. Worldwide, it is considered the first-line mood stabilizer. Apart from its proven antimanic and prophylactic effects, considerable evidence also suggests an antisuicidal effect in affective disorders. Lithium is also effectively used to augment antidepressant drugs in the treatment of refractory major depressive episodes and prevent relapses in recurrent unipolar depression. In contrast to many psychiatric drugs, lithium has outlasted various pharmacotherapeutic 'fashions', and remains an indispensable element in contemporary psychopharmacology. Nevertheless, data from pharmacogenetic studies of lithium are comparatively sparse, and these studies are generally characterized by small sample sizes and varying definitions of response. Here, we present an international effort to elucidate the genetic underpinnings of lithium response in bipolar disorder. Following an initiative by the International Group for the Study of Lithium-Treated Patients (www.IGSLI.org) and the Unit on the Genetic Basis of Mood and Anxiety Disorders at the National Institute of Mental Health,lithium researchers from around the world have formed the Consortium on Lithium Genetics (www.ConLiGen.org) to establish the largest sample to date for genome-wide studies of lithium response in bipolar disorder, currently comprising more than 1,200 patients characterized for response to lithium treatment. A stringent phenotype definition of response is one of the hallmarks of this collaboration. ConLiGen invites all lithium researchers to join its efforts.
Asunto(s)
Antimaníacos/farmacología , Trastorno Bipolar/tratamiento farmacológico , Trastorno Bipolar/genética , Compuestos de Litio/farmacología , National Institute of Mental Health (U.S.) , Antimaníacos/efectos adversos , Antimaníacos/uso terapéutico , Humanos , Cooperación Internacional , Compuestos de Litio/efectos adversos , Compuestos de Litio/uso terapéutico , Farmacogenética , Fenotipo , Estados UnidosRESUMEN
We tested for associations between five single nucleotide polymorphisms (SNPs) located in the area containing the Neuregulin 1 gene (NRG1) and three SNPs within the brain-derived neutrophic factor gene (BDNF) in an Italian sample consisting of 171 schizophrenia subjects and 349 controls. No association was found for any of the polymorphisms tested, either in single locus or in haplotype analysis.
Asunto(s)
Factor Neurotrófico Derivado del Encéfalo/genética , Predisposición Genética a la Enfermedad , Neurregulina-1/genética , Polimorfismo Genético/genética , Esquizofrenia/genética , Adulto , Estudios de Casos y Controles , Femenino , Frecuencia de los Genes , Estudio de Asociación del Genoma Completo/métodos , Genotipo , Humanos , Italia , Masculino , Persona de Mediana EdadRESUMEN
The gene encoding apolipoprotein E (APOE) on chromosome 19 is the only confirmed susceptibility locus for late-onset Alzheimer's disease. To identify other risk loci, we conducted a large genome-wide association study of 2,032 individuals from France with Alzheimer's disease (cases) and 5,328 controls. Markers outside APOE with suggestive evidence of association (P < 10(-5)) were examined in collections from Belgium, Finland, Italy and Spain totaling 3,978 Alzheimer's disease cases and 3,297 controls. Two loci gave replicated evidence of association: one within CLU (also called APOJ), encoding clusterin or apolipoprotein J, on chromosome 8 (rs11136000, OR = 0.86, 95% CI 0.81-0.90, P = 7.5 x 10(-9) for combined data) and the other within CR1, encoding the complement component (3b/4b) receptor 1, on chromosome 1 (rs6656401, OR = 1.21, 95% CI 1.14-1.29, P = 3.7 x 10(-9) for combined data). Previous biological studies support roles of CLU and CR1 in the clearance of beta amyloid (Abeta) peptide, the principal constituent of amyloid plaques, which are one of the major brain lesions of individuals with Alzheimer's disease.
Asunto(s)
Enfermedad de Alzheimer/genética , Clusterina/genética , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Receptores de Complemento 3b/genética , Haplotipos , Humanos , Polimorfismo de Nucleótido Simple , Población Blanca/genéticaRESUMEN
Cognitive and motor deficits have been proposed as markers of abnormal neurodevelopment in schizophrenia and have been associated with genetic liability. In a multicenter study involving 106 subjects, 56 with deficit schizophrenia and 50 with nondeficit schizophrenia, we tested the hypothesis that the catechol-O-methyltransferase (COMT) Val(158)Met polymorphism is associated with cognitive and motor deficits either in schizophrenia as a whole or in its deficit subtype. The COMT Val(158)Met polymorphism shared 6.6% of the executive/attention dysfunction variance in patients with schizophrenia and 15.6% of the motor impairment variance in patients with deficit schizophrenia. These results support the hypothesis that the COMT Val(158)Met polymorphism influences executive functions in schizophrenia and the neuromotor performance in the deficit subtype only.
Asunto(s)
Catecol O-Metiltransferasa/genética , Trastornos del Conocimiento/complicaciones , Metionina/genética , Trastornos de la Destreza Motora/complicaciones , Polimorfismo Genético , Esquizofrenia/genética , Valina/genética , Adolescente , Adulto , Análisis de Varianza , Estudios de Casos y Controles , Distribución de Chi-Cuadrado , Intervalos de Confianza , Análisis Mutacional de ADN , Femenino , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Pruebas Neuropsicológicas/estadística & datos numéricos , Oportunidad Relativa , Escalas de Valoración Psiquiátrica/estadística & datos numéricos , ARN Mensajero/biosíntesis , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa/métodos , Esquizofrenia/complicaciones , Psicología del EsquizofrénicoRESUMEN
In a multicenter study involving 217 subjects of European ancestry [106 patients with schizophrenia and 111 healthy subjects], we tested the hypothesis that the catechol-O-methyl transferase (COMT) Val(158)Met and/or the brain-derived neurotrophic factor (BDNF) C(270)T gene polymorphisms are associated with schizophrenia. The COMT and BDNF genotype and their allele distribution did not differ between patients with schizophrenia and healthy comparison subjects. These results do not support the hypothesis that the COMT Val(158)Met or BDNF C(270)T gene polymorphisms are associated with liability to schizophrenia.
