RESUMEN
Genome-wide association studies (GWAS) of late-onset Alzheimer disease (LOAD) have consistently observed strong evidence of association with polymorphisms in APOE. However, until recently, variants at few other loci with statistically significant associations have replicated across studies. The present study combines data on 483,399 single nucleotide polymorphisms (SNPs) from a previously reported GWAS of 492 LOAD cases and 496 controls and from an independent set of 439 LOAD cases and 608 controls to strengthen power to identify novel genetic association signals. Associations exceeding the experiment-wide significance threshold (alpha=1.03x10(-7)) were replicated in an additional 1,338 cases and 2,003 controls. As expected, these analyses unequivocally confirmed APOE's risk effect (rs2075650, P=1.9x10(-36)). Additionally, the SNP rs11754661 at 151.2 Mb of chromosome 6q25.1 in the gene MTHFD1L (which encodes the methylenetetrahydrofolate dehydrogenase (NADP+ dependent) 1-like protein) was significantly associated with LOAD (P=4.70x10(-8); Bonferroni-corrected P=0.022). Subsequent genotyping of SNPs in high linkage disequilibrium (r2>0.8) with rs11754661 identified statistically significant associations in multiple SNPs (rs803424, P=0.016; rs2073067, P=0.03; rs2072064, P=0.035), reducing the likelihood of association due to genotyping error. In the replication case-control set, we observed an association of rs11754661 in the same direction as the previous association at P=0.002 (P=1.90x10(-10) in combined analysis of discovery and replication sets), with associations of similar statistical significance at several adjacent SNPs (rs17349743, P=0.005; rs803422, P=0.004). In summary, we observed and replicated a novel statistically significant association in MTHFD1L, a gene involved in the tetrahydrofolate synthesis pathway. This finding is noteworthy, as MTHFD1L may play a role in the generation of methionine from homocysteine and influence homocysteine-related pathways and as levels of homocysteine are a significant risk factor for LOAD development.
Asunto(s)
Enfermedad de Alzheimer/genética , Cromosomas Humanos Par 6/genética , Demencia/genética , Ácido Fólico/metabolismo , Sitios Genéticos/genética , Redes y Vías Metabólicas/genética , Anciano , Aminohidrolasas/genética , Emparejamiento Base/genética , Bases de Datos Genéticas , Demografía , Femenino , Formiato-Tetrahidrofolato Ligasa/genética , Estudio de Asociación del Genoma Completo , Humanos , Masculino , Metilenotetrahidrofolato Deshidrogenasa (NADP)/genética , Complejos Multienzimáticos/genética , Polimorfismo de Nucleótido Simple/genética , Reproducibilidad de los ResultadosRESUMEN
Only Apolipoprotein E polymorphisms have been consistently associated with the risk of late-onset Alzheimer disease (LOAD), but they represent only a minority of the underlying genetic effect. To identify additional LOAD risk loci, we performed a genome-wide association study (GWAS) on 492 LOAD cases and 498 cognitive controls using Illumina's HumanHap550 beadchip. An additional 238 cases and 220 controls were used as a validation data set for single-nucleotide polymorphisms (SNPs) that met genome-wide significance. To validate additional associated SNPs (p < 0.0001) and nominally associated candidate genes, we imputed SNPs from our GWAS using a previously published LOAD GWAS(1) and the IMPUTE program. Association testing was performed with the Cochran-Armitage trend test and logistic regression, and genome-wide significance was determined with the False Discovery Rate-Beta Uniform Mixture method. Extensive quality-control methods were performed at both the sample and the SNP level. The GWAS confirmed the known APOE association and identified association with a 12q13 locus at genome-wide significance; the 12q13 locus was confirmed in our validation data set. Four additional highly associated signals (1q42, 4q28, 6q14, 19q13) were replicated with the use of the imputed data set, and six candidate genes had SNPs with nominal association in both the GWAS and the joint imputated data set. These results help to further define the genetic architecture of LOAD.
Asunto(s)
Enfermedad de Alzheimer/genética , Cromosomas Humanos Par 12/genética , Predisposición Genética a la Enfermedad , Genoma Humano , Estudio de Asociación del Genoma Completo , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple , RiesgoAsunto(s)
Enfermedad de Alzheimer/genética , Proteínas Portadoras/genética , Proteínas de Ciclo Celular/genética , Polimorfismo de Nucleótido Simple , Proteínas Adaptadoras Transductoras de Señales , Edad de Inicio , Proteínas Relacionadas con la Autofagia , Cromosomas Humanos Par 9 , Ligamiento Genético , Humanos , Factores de RiesgoRESUMEN
Genetic studies on late-onset Alzheimer's disease (AD) have repeatedly mapped susceptibility loci onto chromosome 12q13, encompassing the vitamin D receptor (VDR) gene. Epidemiology studies have indicated vitamin D insufficiency as a risk factor for AD. Given that VDR is the major mediator for vitamin D's actions, we sought to clarify the role of VDR in late-onset AD. We conducted an association study in 492 late-onset AD cases and 496 controls with 80 tagging single nucleotide polymorphisms (SNPs). The strongest association was found at a promoter SNP rs11568820 (P = 9.1 × 10(-6), odds ratio (OR) = 1.69), which resides within the transcription factor Cdx-2 binding site and the SNP has been also known as CDX2. The risk-allele at rs11568820 is associated with lower VDR promoter activity (p < 10(-11)). The overexpression of VDR or vitamin D treatment suppressed amyloid precursor protein (APP) transcription in neuroblastoma cells (p < 0.001). We provide both statistical evidence and functional data suggesting VDR confers genetic risk for AD. Our findings are consistent with epidemiology studies suggesting that vitamin D insufficiency increases the risk of developing AD.
Asunto(s)
Enfermedad de Alzheimer/epidemiología , Enfermedad de Alzheimer/genética , Proteínas de Homeodominio/genética , Receptores de Calcitriol/genética , Transactivadores/genética , Deficiencia de Vitamina D/epidemiología , Deficiencia de Vitamina D/genética , Anciano , Factor de Transcripción CDX2 , Comorbilidad , Femenino , Predisposición Genética a la Enfermedad/epidemiología , Predisposición Genética a la Enfermedad/genética , Humanos , Masculino , Prevalencia , Medición de Riesgo , Estados Unidos/epidemiologíaRESUMEN
Several studies have reported an association between the ApolipoproteinE-epsilon4 (APOE4) allele and depression among elders. However others have failed to find an association. Since APOE4 is a well recognized risk factor for Alzheimer dementia, cognitive status may represent an important confounder between APOE4 and depression. In this investigation, we examined the relationship between the ApolipoproteinE-epsilon4 allele and depression among elders accounting for cognitive status. Using a case-control design (n=1052), we investigated the association between ApolipoproteinE-epsilon4 and depression in Alzheimer disease patients (n=528) and in cognitively intact controls (n=524). We demonstrated an apparent association between the APOE4 allele and depression in the combined dataset (p=0.001) when not controlling for cognitive status. However, once stratified by the presence of Alzheimer disease, there was no association in either the Alzheimer group (p=0.290) or the cognitively intact controls (p=0.494). In this dataset there is no association between the ApolipoproteinE-epsilon4 allele and depression among those with Alzheimer disease or among cognitively intact elders. However there is a significant association between female gender and depression in the cognitively intact (p=0.003) but not among those with Alzheimer disease. Additionally, individuals with Alzheimer disease and depression had a significantly younger age of onset for their Alzheimer disease than those without depression (p=0.017).