RESUMEN
A recent genome-wide association meta-analysis for Alzheimer's disease (AD) identified 19 risk loci (in addition to APOE) in which the functional genes are unknown. Using Drosophila, we screened 296 constructs targeting orthologs of 54 candidate risk genes within these loci for their ability to modify Tau neurotoxicity by quantifying the size of >6000 eyes. Besides Drosophila Amph (ortholog of BIN1), which we previously implicated in Tau pathology, we identified p130CAS (CASS4), Eph (EPHA1), Fak (PTK2B) and Rab3-GEF (MADD) as Tau toxicity modulators. Of these, the focal adhesion kinase Fak behaved as a strong Tau toxicity suppressor in both the eye and an independent focal adhesion-related wing blister assay. Accordingly, the human Tau and PTK2B proteins biochemically interacted in vitro and PTK2B co-localized with hyperphosphorylated and oligomeric Tau in progressive pathological stages in the brains of AD patients and transgenic Tau mice. These data indicate that PTK2B acts as an early marker and in vivo modulator of Tau toxicity.
Asunto(s)
Quinasa 2 de Adhesión Focal/genética , Proteínas tau/metabolismo , Enfermedad de Alzheimer/genética , Animales , Biomarcadores , Modelos Animales de Enfermedad , Drosophila/genética , Quinasa 2 de Adhesión Focal/metabolismo , Sitios Genéticos/genética , Predisposición Genética a la Enfermedad/genética , Estudio de Asociación del Genoma Completo , Humanos , Factores de Riesgo , Proteínas tau/genéticaRESUMEN
To assess the role of rare copy number variations in Alzheimer's disease (AD), we conducted a case-control study using whole-exome sequencing data from 522 early-onset cases and 584 controls. The most recurrent rearrangement was a 17q21.31 microduplication, overlapping the CRHR1, MAPT, STH and KANSL1 genes that was found in four cases, including one de novo rearrangement, and was absent in controls. The increased MAPT gene dosage led to a 1.6-1.9-fold expression of the MAPT messenger RNA. Clinical signs, neuroimaging and cerebrospinal fluid biomarker profiles were consistent with an AD diagnosis in MAPT duplication carriers. However, amyloid positon emission tomography (PET) imaging, performed in three patients, was negative. Analysis of an additional case with neuropathological examination confirmed that the MAPT duplication causes a complex tauopathy, including prominent neurofibrillary tangle pathology in the medial temporal lobe without amyloid-ß deposits. 17q21.31 duplication is the genetic basis of a novel entity marked by prominent tauopathy, leading to early-onset dementia with an AD clinical phenotype. This entity could account for a proportion of probable AD cases with negative amyloid PET imaging recently identified in large clinical series.
Asunto(s)
Enfermedad de Alzheimer/genética , Cromosomas Humanos Par 17/genética , Demencia/genética , Anciano , Encéfalo/metabolismo , Estudios de Casos y Controles , Variaciones en el Número de Copia de ADN/genética , Femenino , Dosificación de Gen , Duplicación de Gen/genética , Humanos , Masculino , Persona de Mediana Edad , Ovillos Neurofibrilares/patología , Neuroimagen , Tauopatías/genética , Proteínas tau/genética , Proteínas tau/metabolismoRESUMEN
The SORL1 protein plays a protective role against the secretion of the amyloid ß peptide, a key event in the pathogeny of Alzheimer's disease. We assessed the impact of SORL1 rare variants in early-onset Alzheimer's disease (EOAD) in a case-control setting. We conducted a whole exome analysis among 484 French EOAD patients and 498 ethnically matched controls. After collapsing rare variants (minor allele frequency ≤1%), we detected an enrichment of disruptive and predicted damaging missense SORL1 variants in cases (odds radio (OR)=5.03, 95% confidence interval (CI)=(2.02-14.99), P=7.49.10(-5)). This enrichment was even stronger when restricting the analysis to the 205 cases with a positive family history (OR=8.86, 95% CI=(3.35-27.31), P=3.82.10(-7)). We conclude that predicted damaging rare SORL1 variants are a strong risk factor for EOAD and that the association signal is mainly driven by cases with positive family history.
Asunto(s)
Enfermedad de Alzheimer/genética , Proteínas Relacionadas con Receptor de LDL/genética , Proteínas de Transporte de Membrana/genética , Alelos , Péptidos beta-Amiloides , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Estudios de Casos y Controles , Exoma , Femenino , Francia , Frecuencia de los Genes , Predisposición Genética a la Enfermedad/genética , Variación Genética , Humanos , Proteínas Relacionadas con Receptor de LDL/metabolismo , Masculino , Proteínas de Transporte de Membrana/metabolismo , Persona de Mediana Edad , Oportunidad Relativa , Factores de RiesgoRESUMEN
APOE É4, the most significant genetic risk factor for Alzheimer disease (AD), may mask effects of other loci. We re-analyzed genome-wide association study (GWAS) data from the International Genomics of Alzheimer's Project (IGAP) Consortium in APOE É4+ (10 352 cases and 9207 controls) and APOE É4- (7184 cases and 26 968 controls) subgroups as well as in the total sample testing for interaction between a single-nucleotide polymorphism (SNP) and APOE É4 status. Suggestive associations (P<1 × 10(-4)) in stage 1 were evaluated in an independent sample (stage 2) containing 4203 subjects (APOE É4+: 1250 cases and 536 controls; APOE É4-: 718 cases and 1699 controls). Among APOE É4- subjects, novel genome-wide significant (GWS) association was observed with 17 SNPs (all between KANSL1 and LRRC37A on chromosome 17 near MAPT) in a meta-analysis of the stage 1 and stage 2 data sets (best SNP, rs2732703, P=5·8 × 10(-9)). Conditional analysis revealed that rs2732703 accounted for association signals in the entire 100-kilobase region that includes MAPT. Except for previously identified AD loci showing stronger association in APOE É4+ subjects (CR1 and CLU) or APOE É4- subjects (MS4A6A/MS4A4A/MS4A6E), no other SNPs were significantly associated with AD in a specific APOE genotype subgroup. In addition, the finding in the stage 1 sample that AD risk is significantly influenced by the interaction of APOE with rs1595014 in TMEM106B (P=1·6 × 10(-7)) is noteworthy, because TMEM106B variants have previously been associated with risk of frontotemporal dementia. Expression quantitative trait locus analysis revealed that rs113986870, one of the GWS SNPs near rs2732703, is significantly associated with four KANSL1 probes that target transcription of the first translated exon and an untranslated exon in hippocampus (P ⩽ 1.3 × 10(-8)), frontal cortex (P ⩽ 1.3 × 10(-9)) and temporal cortex (P⩽1.2 × 10(-11)). Rs113986870 is also strongly associated with a MAPT probe that targets transcription of alternatively spliced exon 3 in frontal cortex (P=9.2 × 10(-6)) and temporal cortex (P=2.6 × 10(-6)). Our APOE-stratified GWAS is the first to show GWS association for AD with SNPs in the chromosome 17q21.31 region. Replication of this finding in independent samples is needed to verify that SNPs in this region have significantly stronger effects on AD risk in persons lacking APOE É4 compared with persons carrying this allele, and if this is found to hold, further examination of this region and studies aimed at deciphering the mechanism(s) are warranted.
Asunto(s)
Enfermedad de Alzheimer/genética , Polimorfismo de Nucleótido Simple , Apolipoproteína E4/genética , Cromosomas Humanos Par 17 , Estudio de Asociación del Genoma Completo , Humanos , Proteínas tau/genéticaRESUMEN
Genome-wide association studies (GWAS) have identified a region upstream the BIN1 gene as the most important genetic susceptibility locus in Alzheimer's disease (AD) after APOE. We report that BIN1 transcript levels were increased in AD brains and identified a novel 3 bp insertion allele â¼28 kb upstream of BIN1, which increased (i) transcriptional activity in vitro, (ii) BIN1 expression levels in human brain and (iii) AD risk in three independent case-control cohorts (Meta-analysed Odds ratio of 1.20 (1.14-1.26) (P=3.8 × 10(-11))). Interestingly, decreased expression of the Drosophila BIN1 ortholog Amph suppressed Tau-mediated neurotoxicity in three different assays. Accordingly, Tau and BIN1 colocalized and interacted in human neuroblastoma cells and in mouse brain. Finally, the 3 bp insertion was associated with Tau but not Amyloid loads in AD brains. We propose that BIN1 mediates AD risk by modulating Tau pathology.
Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/genética , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/patología , Predisposición Genética a la Enfermedad/genética , Proteínas Nucleares/genética , Proteínas Supresoras de Tumor/genética , Proteínas tau/metabolismo , Proteínas Adaptadoras Transductoras de Señales/biosíntesis , Enfermedad de Alzheimer/metabolismo , Animales , Encéfalo/metabolismo , Encéfalo/patología , Proteínas Portadoras/genética , Proteínas Portadoras/metabolismo , Estudios de Casos y Controles , Células Cultivadas , Proteínas de Drosophila/deficiencia , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/genética , Drosophila melanogaster/metabolismo , Endofenotipos , Expresión Génica/genética , Humanos , Ratones , Degeneración Nerviosa/genética , Degeneración Nerviosa/patología , Proteínas Nucleares/biosíntesis , Placa Amiloide/patología , Polimorfismo de Nucleótido Simple/genética , Sinaptosomas/patología , Factores de Transcripción/deficiencia , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Proteínas Supresoras de Tumor/biosíntesis , Proteínas tau/antagonistas & inhibidoresRESUMEN
The present study describes the genetic architecture of the isolated populations of Cilento, through the analysis of exome sequence data of 245 representative individuals of these populations. By annotating the exome variants and cataloguing them according to their frequency and functional effects, we identified 347,684 variants, 67.4% of which are rare and low frequency variants, and 1% of them (corresponding to 319 variants per person) are classified as high functional impact variants; also, 39,946 (11.5% of the total) are novel variants, for which we determined a significant enrichment for deleterious effects. By comparing the allele frequencies in Cilento with those from the Tuscan population from the 1000 Genomes Project Phase 3, we highlighted an increase in allele frequency in Cilento especially for variants which map to genes involved in extracellular matrix formation and organization. Furthermore, among the variants showing increased frequency we identified several known rare disease-causing variants. By different population genetics analyses, we corroborated the status of the Cilento populations as genetic isolates. Finally, we showed that exome data of Cilento represents a useful local reference panel capable of improving the accuracy of genetic imputation, thus adding power to genetic studies of human traits in these populations.
Asunto(s)
Secuenciación del Exoma , Genética de Población , Genoma Humano/genética , Exoma/genética , Femenino , Frecuencia de los Genes , Genotipo , Proyecto Genoma Humano , Humanos , Italia/epidemiología , Masculino , Polimorfismo de Nucleótido Simple/genéticaRESUMEN
To follow-up loci discovered by the International Genomics of Alzheimer's Disease Project, we attempted independent replication of 19 single nucleotide polymorphisms (SNPs) in a large Spanish sample (Fundació ACE data set; 1808 patients and 2564 controls). Our results corroborate association with four SNPs located in the genes INPP5D, MEF2C, ZCWPW1 and FERMT2, respectively. Of these, ZCWPW1 was the only SNP to withstand correction for multiple testing (P=0.000655). Furthermore, we identify TRIP4 (rs74615166) as a novel genome-wide significant locus for Alzheimer's disease risk (odds ratio=1.31; confidence interval 95% (1.19-1.44); P=9.74 × 10(-)(9)).
Asunto(s)
Enfermedad de Alzheimer/genética , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Factores de Transcripción/genética , Estudios de Seguimiento , Sitios Genéticos/genética , Humanos , Polimorfismo de Nucleótido Simple/genética , EspañaRESUMEN
Eleven susceptibility loci for late-onset Alzheimer's disease (LOAD) were identified by previous studies; however, a large portion of the genetic risk for this disease remains unexplained. We conducted a large, two-stage meta-analysis of genome-wide association studies (GWAS) in individuals of European ancestry. In stage 1, we used genotyped and imputed data (7,055,881 SNPs) to perform meta-analysis on 4 previously published GWAS data sets consisting of 17,008 Alzheimer's disease cases and 37,154 controls. In stage 2, 11,632 SNPs were genotyped and tested for association in an independent set of 8,572 Alzheimer's disease cases and 11,312 controls. In addition to the APOE locus (encoding apolipoprotein E), 19 loci reached genome-wide significance (P < 5 × 10(-8)) in the combined stage 1 and stage 2 analysis, of which 11 are newly associated with Alzheimer's disease.