RESUMEN
We assessed the role of rare copy number variants (CNVs) in Alzheimer's disease (AD) using intensity data from 3260 AD cases and 1290 age-matched controls from the genome-wide association study (GWAS) conducted by the Genetic and Environmental Risk for Alzheimer's disease Consortium (GERAD). We did not observe a significant excess of rare CNVs in cases, although we did identify duplications overlapping APP and CR1 which may be pathogenic. We looked for an excess of CNVs in loci which have been highlighted in previous AD CNV studies, but did not replicate previous findings. Through pathway analyses, we observed suggestive evidence for biological overlap between single nucleotide polymorphisms and CNVs in AD susceptibility. We also identified that our sample of elderly controls harbours significantly fewer deletions >1 Mb than younger control sets in previous CNV studies on schizophrenia and bipolar disorder (P = 8.9 × 10(-4) and 0.024, respectively), raising the possibility that healthy elderly individuals have a reduced rate of large deletions. Thus, in contrast to diseases such as schizophrenia, autism and attention deficit/hyperactivity disorder, CNVs do not appear to make a significant contribution to the development of AD.
Asunto(s)
Enfermedad de Alzheimer/genética , Variaciones en el Número de Copia de ADN , Duplicación de Gen , Anciano , Precursor de Proteína beta-Amiloide/genética , Estudios de Casos y Controles , Sitios Genéticos , Predisposición Genética a la Enfermedad , Genoma Humano , Estudio de Asociación del Genoma Completo , Genotipo , Humanos , Polimorfismo de Nucleótido Simple , Receptores de Complemento 3b/genética , Factores de RiesgoRESUMEN
We sought to investigate the contribution of extended runs of homozygosity in a genome-wide association dataset of 1,955 Alzheimer's disease cases and 955 elderly screened controls genotyped for 529,205 autosomal single nucleotide polymorphisms. Tracts of homozygosity may mark regions inherited from a common ancestor and could reflect disease loci if observed more frequently in cases than controls. We found no excess of homozygous tracts in Alzheimer's disease cases compared to controls and no individual run of homozygosity showed association to Alzheimer's disease.
Asunto(s)
Enfermedad de Alzheimer/genética , Predisposición Genética a la Enfermedad , Homocigoto , Anciano , Anciano de 80 o más Años , Estudios de Casos y Controles , Cromosomas Humanos Par 8/genética , Femenino , Genes/genética , Estudio de Asociación del Genoma Completo , Humanos , MasculinoRESUMEN
Rare mutations in AßPP, PSEN1, and PSEN2 cause uncommon early onset forms of Alzheimer's disease (AD), and common variants in MAPT are associated with risk of other neurodegenerative disorders. We sought to establish whether common genetic variation in these genes confer risk to the common form of AD which occurs later in life (>65 years). We therefore tested single-nucleotide polymorphisms at these loci for association with late-onset AD (LOAD) in a large case-control sample consisting of 3,940 cases and 13,373 controls. Single-marker analysis did not identify any variants that reached genome-wide significance, a result which is supported by other recent genome-wide association studies. However, we did observe a significant association at the MAPT locus using a gene-wide approach (p = 0.009). We also observed suggestive association between AD and the marker rs9468, which defines the H1 haplotype, an extended haplotype that spans the MAPT gene and has previously been implicated in other neurodegenerative disorders including Parkinson's disease, progressive supranuclear palsy, and corticobasal degeneration. In summary common variants at AßPP, PSEN1, and PSEN2 and MAPT are unlikely to make strong contributions to susceptibility for LOAD. However, the gene-wide effect observed at MAPT indicates a possible contribution to disease risk which requires further study.
Asunto(s)
Enfermedad de Alzheimer/genética , Precursor de Proteína beta-Amiloide/genética , Predisposición Genética a la Enfermedad , Polimorfismo de Nucleótido Simple/genética , Presenilina-1/genética , Presenilina-2/genética , Proteínas tau/genética , Anciano , Anciano de 80 o más Años , Femenino , Estudio de Asociación del Genoma Completo , Genotipo , Humanos , Masculino , Metaanálisis como Asunto , Oportunidad RelativaRESUMEN
We sought to identify new susceptibility loci for Alzheimer's disease through a staged association study (GERAD+) and by testing suggestive loci reported by the Alzheimer's Disease Genetic Consortium (ADGC) in a companion paper. We undertook a combined analysis of four genome-wide association datasets (stage 1) and identified ten newly associated variants with P ≤ 1 × 10(-5). We tested these variants for association in an independent sample (stage 2). Three SNPs at two loci replicated and showed evidence for association in a further sample (stage 3). Meta-analyses of all data provided compelling evidence that ABCA7 (rs3764650, meta P = 4.5 × 10(-17); including ADGC data, meta P = 5.0 × 10(-21)) and the MS4A gene cluster (rs610932, meta P = 1.8 × 10(-14); including ADGC data, meta P = 1.2 × 10(-16)) are new Alzheimer's disease susceptibility loci. We also found independent evidence for association for three loci reported by the ADGC, which, when combined, showed genome-wide significance: CD2AP (GERAD+, P = 8.0 × 10(-4); including ADGC data, meta P = 8.6 × 10(-9)), CD33 (GERAD+, P = 2.2 × 10(-4); including ADGC data, meta P = 1.6 × 10(-9)) and EPHA1 (GERAD+, P = 3.4 × 10(-4); including ADGC data, meta P = 6.0 × 10(-10)).
Asunto(s)
Transportadoras de Casetes de Unión a ATP/genética , Proteínas Adaptadoras Transductoras de Señales/genética , Enfermedad de Alzheimer/genética , Antígenos CD/genética , Antígenos de Diferenciación Mielomonocítica/genética , Proteínas del Citoesqueleto/genética , Proteínas de la Membrana/genética , Receptor EphA1/genética , Anciano , Anciano de 80 o más Años , Estudios de Casos y Controles , Bases de Datos Genéticas , Femenino , Predisposición Genética a la Enfermedad , Variación Genética , Estudio de Asociación del Genoma Completo , Humanos , Masculino , Familia de Multigenes , Polimorfismo de Nucleótido Simple , Lectina 3 Similar a Ig de Unión al Ácido SiálicoRESUMEN
BACKGROUND: Late Onset Alzheimer's disease (LOAD) is the leading cause of dementia. Recent large genome-wide association studies (GWAS) identified the first strongly supported LOAD susceptibility genes since the discovery of the involvement of APOE in the early 1990s. We have now exploited these GWAS datasets to uncover key LOAD pathophysiological processes. METHODOLOGY: We applied a recently developed tool for mining GWAS data for biologically meaningful information to a LOAD GWAS dataset. The principal findings were then tested in an independent GWAS dataset. PRINCIPAL FINDINGS: We found a significant overrepresentation of association signals in pathways related to cholesterol metabolism and the immune response in both of the two largest genome-wide association studies for LOAD. SIGNIFICANCE: Processes related to cholesterol metabolism and the innate immune response have previously been implicated by pathological and epidemiological studies of Alzheimer's disease, but it has been unclear whether those findings reflected primary aetiological events or consequences of the disease process. Our independent evidence from two large studies now demonstrates that these processes are aetiologically relevant, and suggests that they may be suitable targets for novel and existing therapeutic approaches.
Asunto(s)
Enfermedad de Alzheimer/genética , Colesterol/metabolismo , Estudio de Asociación del Genoma Completo , Sistema Inmunológico/metabolismo , Enfermedad de Alzheimer/inmunología , Enfermedad de Alzheimer/metabolismo , Apolipoproteínas E/genética , Apolipoproteínas E/metabolismo , Mapeo Cromosómico , Predisposición Genética a la Enfermedad/genética , Genoma Humano , Humanos , Polimorfismo de Nucleótido SimpleRESUMEN
We undertook a two-stage genome-wide association study (GWAS) of Alzheimer's disease (AD) involving over 16,000 individuals, the most powerful AD GWAS to date. In stage 1 (3,941 cases and 7,848 controls), we replicated the established association with the apolipoprotein E (APOE) locus (most significant SNP, rs2075650, P = 1.8 x 10(-157)) and observed genome-wide significant association with SNPs at two loci not previously associated with the disease: at the CLU (also known as APOJ) gene (rs11136000, P = 1.4 x 10(-9)) and 5' to the PICALM gene (rs3851179, P = 1.9 x 10(-8)). These associations were replicated in stage 2 (2,023 cases and 2,340 controls), producing compelling evidence for association with Alzheimer's disease in the combined dataset (rs11136000, P = 8.5 x 10(-10), odds ratio = 0.86; rs3851179, P = 1.3 x 10(-9), odds ratio = 0.86).