RESUMEN
BACKGROUND: Few rare variants have been identified in genetic loci from genome wide association studies of Alzheimer's disease (AD), limiting understanding of mechanisms and risk assessment, and genetic counseling. METHODS: Using genome sequencing data from 197 families in The NIA Alzheimer's Disease Family Based Study, and 214 Caribbean Hispanic families, we searched for rare coding variants within known GWAS loci from the largest published study. RESULTS: Eighty-six rare missense or loss of function (LoF) variants completely segregated in 17.5% of families, but in 91 (22.1%) of families APOE-e4 was the only variant segregating. However, in 60.3% of families neither APOE-e4 nor missense or LoF variants were found within the GWAS loci. DISCUSSION: Although APOE-ε4 and several rare variants were found to segregate in both family datasets, many families had no variant accounting for their disease. This suggests that familial AD may be the result of unidentified rare variants.
RESUMEN
INTRODUCTION: Clinical research in Alzheimer's disease (AD) lacks cohort diversity despite being a global health crisis. The Asian Cohort for Alzheimer's Disease (ACAD) was formed to address underrepresentation of Asians in research, and limited understanding of how genetics and non-genetic/lifestyle factors impact this multi-ethnic population. METHODS: The ACAD started fully recruiting in October 2021 with one central coordination site, eight recruitment sites, and two analysis sites. We developed a comprehensive study protocol for outreach and recruitment, an extensive data collection packet, and a centralized data management system, in English, Chinese, Korean, and Vietnamese. RESULTS: ACAD has recruited 606 participants with an additional 900 expressing interest in enrollment since program inception. DISCUSSION: ACAD's traction indicates the feasibility of recruiting Asians for clinical research to enhance understanding of AD risk factors. ACAD will recruit > 5000 participants to identify genetic and non-genetic/lifestyle AD risk factors, establish blood biomarker levels for AD diagnosis, and facilitate clinical trial readiness. HIGHLIGHTS: The Asian Cohort for Alzheimer's Disease (ACAD) promotes awareness of under-investment in clinical research for Asians. We are recruiting Asian Americans and Canadians for novel insights into Alzheimer's disease. We describe culturally appropriate recruitment strategies and data collection protocol. ACAD addresses challenges of recruitment from heterogeneous Asian subcommunities. We aim to implement a successful recruitment program that enrolls across three Asian subcommunities.
Asunto(s)
Enfermedad de Alzheimer , Pueblos de América del Norte , Humanos , Enfermedad de Alzheimer/genética , Proyectos Piloto , Asiático/genética , Canadá , Factores de RiesgoRESUMEN
INTRODUCTION: One goal of the Longitudinal Early-onset Alzheimer's Disease Study (LEADS) is to investigate the genetic etiology of early onset (40-64 years) cognitive impairment. Toward this goal, LEADS participants are screened for known pathogenic variants. METHODS: LEADS amyloid-positive early-onset Alzheimer's disease (EOAD) or negative early-onset non-AD (EOnonAD) cases were whole exome sequenced (N = 299). Pathogenic variant frequency in APP, PSEN1, PSEN2, GRN, MAPT, and C9ORF72 was assessed for EOAD and EOnonAD. Gene burden testing was performed in cases compared to similar-age cognitively normal controls in the Parkinson's Progression Markers Initiative (PPMI) study. RESULTS: Previously reported pathogenic variants in the six genes were identified in 1.35% of EOAD (3/223) and 6.58% of EOnonAD (5/76). No genes showed enrichment for carriers of rare functional variants in LEADS cases. DISCUSSION: Results suggest that LEADS is enriched for novel genetic causative variants, as previously reported variants are not observed in most cases. HIGHLIGHTS: Sequencing identified eight cognitively impaired pathogenic variant carriers. Pathogenic variants were identified in PSEN1, GRN, MAPT, and C9ORF72. Rare variants were not enriched in APP, PSEN1/2, GRN, and MAPT. The Longitudinal Early-onset Alzheimer's Disease Study (LEADS) is a key resource for early-onset Alzheimer's genetic research.
Asunto(s)
Enfermedad de Alzheimer , Humanos , Enfermedad de Alzheimer/genética , Precursor de Proteína beta-Amiloide/genética , Proteína C9orf72/genética , Pruebas Genéticas , Estudios Longitudinales , Mutación , Presenilina-1/genética , Presenilina-2/genéticaRESUMEN
INTRODUCTION: One goal of the Longitudinal Early Onset Alzheimer's Disease Study (LEADS) is to define the fluid biomarker characteristics of early-onset Alzheimer's disease (EOAD). METHODS: Cerebrospinal fluid (CSF) concentrations of Aß1-40, Aß1-42, total tau (tTau), pTau181, VILIP-1, SNAP-25, neurogranin (Ng), neurofilament light chain (NfL), and YKL-40 were measured by immunoassay in 165 LEADS participants. The associations of biomarker concentrations with diagnostic group and standard cognitive tests were evaluated. RESULTS: Biomarkers were correlated with one another. Levels of CSF Aß42/40, pTau181, tTau, SNAP-25, and Ng in EOAD differed significantly from cognitively normal and early-onset non-AD dementia; NfL, YKL-40, and VILIP-1 did not. Across groups, all biomarkers except SNAP-25 were correlated with cognition. Within the EOAD group, Aß42/40, NfL, Ng, and SNAP-25 were correlated with at least one cognitive measure. DISCUSSION: This study provides a comprehensive analysis of CSF biomarkers in sporadic EOAD that can inform EOAD clinical trial design.
Asunto(s)
Enfermedad de Alzheimer , Humanos , Enfermedad de Alzheimer/diagnóstico , Enfermedad de Alzheimer/líquido cefalorraquídeo , Proteína 1 Similar a Quitinasa-3 , Péptidos beta-Amiloides/líquido cefalorraquídeo , Proteínas tau/líquido cefalorraquídeo , Estudios Longitudinales , Biomarcadores/líquido cefalorraquídeo , Neurogranina/líquido cefalorraquídeoRESUMEN
With improved healthcare, the Down syndrome (DS) population is both growing and aging rapidly. However, with longevity comes a very high risk of Alzheimer's disease (AD). The LIFE-DSR study (NCT04149197) is a longitudinal natural history study recruiting 270 adults with DS over the age of 25. The study is designed to characterize trajectories of change in DS-associated AD (DS-AD). The current study reports its cross-sectional analysis of the first 90 subjects enrolled. Plasma biomarkers phosphorylated tau protein (p-tau), neurofilament light chain (NfL), amyloid ß peptides (Aß1-40, Aß1-42), and glial fibrillary acidic protein (GFAP) were undertaken with previously published methods. The clinical data from the baseline visit include demographics as well as the cognitive measures under the Severe Impairment Battery (SIB) and Down Syndrome Mental Status Examination (DS-MSE). Biomarker distributions are described with strong statistical associations observed with participant age. The biomarker data contributes to understanding DS-AD across the spectrum of disease. Collectively, the biomarker data show evidence of DS-AD progression beginning at approximately 40 years of age. Exploring these data across the full LIFE-DSR longitudinal study population will be an important resource in understanding the onset, progression, and clinical profiles of DS-AD pathophysiology.
RESUMEN
INTRODUCTION: Abnormal gene expression patterns may contribute to the onset and progression of late-onset Alzheimer's disease (LOAD). METHODS: We performed transcriptome-wide meta-analysis (N = 1440) of blood-based microarray gene expression profiles as well as neuroimaging and cerebrospinal fluid (CSF) endophenotype analysis. RESULTS: We identified and replicated five genes (CREB5, CD46, TMBIM6, IRAK3, and RPAIN) as significantly dysregulated in LOAD. The most significantly altered gene, CREB5, was also associated with brain atrophy and increased amyloid beta (Aß) accumulation, especially in the entorhinal cortex region. cis-expression quantitative trait loci mapping analysis of CREB5 detected five significant associations (P < 5 × 10-8 ), where rs56388170 (most significant) was also significantly associated with global cortical Aß deposition measured by [18 F]Florbetapir positron emission tomography and CSF Aß1-42 . DISCUSSION: RNA from peripheral blood indicated a differential gene expression pattern in LOAD. Genes identified have been implicated in biological processes relevant to Alzheimer's disease. CREB, in particular, plays a key role in nervous system development, cell survival, plasticity, and learning and memory.
Asunto(s)
Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/patología , Proteína de Unión al Elemento de Respuesta al AMP Cíclico/genética , Perfilación de la Expresión Génica , Anciano , Enfermedad de Alzheimer/sangre , Péptidos beta-Amiloides/líquido cefalorraquídeo , Péptidos beta-Amiloides/metabolismo , Compuestos de Anilina , Atrofia/patología , Encéfalo/patología , Corteza Entorrinal/patología , Glicoles de Etileno , Femenino , Técnicas de Genotipaje , Humanos , Masculino , Tomografía de Emisión de PositronesRESUMEN
BACKGROUND: Although shorter telomeres have been associated with Alzheimer's disease (AD), it is unclear whether longitudinal change in telomere length is associated with AD progression. OBJECTIVE: To investigate the association of telomere length change with AD diagnosis and progression. METHODS: In 653 individuals from the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort, T/S ratio (telomere versus single copy gene), a proxy of telomere length, was measured for up to five visits per participant (Nâ=â1918 samples post-QC) using quantitative PCR (qPCR). T/S ratio was adjusted for batch effects and DNA storage time. A mixed effects model was used to evaluate association of telomere length with AD diagnostic group and interaction of age and diagnosis. Another mixed effects model was used to compare T/S ratio changes pre- to post-conversion to MCI or AD to telomere change in participants with stable diagnoses. RESULTS: Shorter telomeres were associated with older age (Effect Size (ES)â=â-0.23) and male sex (ESâ=â-0.26). Neither baseline T/S ratio (ESâ=â-0.036) nor T/S ratio change (ESâ=â0.046) differed significantly between AD diagnostic groups. MCI/AD converters showed greater, but non-significant, telomere shortening compared to non-converters (ESâ=â-0.186). CONCLUSIONS: Although AD compared to controls showed small, non-significant effects for baseline T/S ratio and T/S ratio shortening, we did observe a larger, though still non-significant effect for greater telomere shortening in converters compared to non-converters. Although our results do not support telomere shortening as a robust biomarker of AD progression, further investigation in larger samples and for subgroups of participants may be informative.
Asunto(s)
Enfermedad de Alzheimer , Neuroimagen/métodos , Acortamiento del Telómero , Factores de Edad , Anciano , Enfermedad de Alzheimer/diagnóstico , Enfermedad de Alzheimer/genética , Bases de Datos Factuales , Progresión de la Enfermedad , Femenino , Humanos , Masculino , Factores Sexuales , Homeostasis del Telómero/fisiologíaRESUMEN
Psychotic symptoms are frequent in late-onset Alzheimer's disease (LOAD) patients. Although the risk for psychosis in LOAD is genetically mediated, no genes have been identified. To identify loci potentially containing genetic variants associated with risk of psychosis in LOAD, a total of 263 families from the National Institute of Aging-LOAD cohort were classified into psychotic (LOAD+P, n = 215) and nonpsychotic (LOAD-P, n = 48) families based on the presence/absence of psychosis during the course of LOAD. The LOAD+P families yielded strong evidence of linkage on chromosome 19q13 (two-point [2-pt] âlogarithm of odds [LOD] = 3.8, rs2285513 and multipoint LOD = 2.7, rs541169). Joint linkage and association in 19q13 region detected strong association with rs2945988 (p = 8.7 × 10(-7)). Linkage results for the LOAD-P families yielded nonsignificant 19q13 LOD scores. Several 19q13 single-nucleotide polymorphisms generalized the association of LOAD+P in a Caribbean Hispanic (CH) cohort, and the strongest signal was rs10410711 (pmeta = 5.1 × 10(-5)). A variant located 24 kb upstream of rs10410711 and rs10421862 was strongly associated with LOAD+P (pmeta = 1.0 × 10(-5)) in a meta-analysis of the CH cohort and an additional non-Hispanic Caucasian dataset. Identified variants rs2945988 and rs10421862 affect brain gene expression levels. Our results suggest that genetic variants in genes on 19q13, some of which are involved in brain development and neurodegeneration, may influence the susceptibility to psychosis in LOAD patients.
Asunto(s)
Enfermedad de Alzheimer/genética , Cromosomas Humanos Par 19/genética , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad/genética , Variación Genética/genética , Trastornos Psicóticos/genética , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/complicaciones , Estudios de Cohortes , Conjuntos de Datos como Asunto , Femenino , Humanos , Masculino , Metaanálisis como Asunto , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple , Trastornos Psicóticos/etiología , Población BlancaRESUMEN
INTRODUCTION: Genetic data from the Alzheimer's Disease Neuroimaging Initiative (ADNI) have been crucial in advancing the understanding of Alzheimer's disease (AD) pathophysiology. Here, we provide an update on sample collection, scientific progress and opportunities, conceptual issues, and future plans. METHODS: Lymphoblastoid cell lines and DNA and RNA samples from blood have been collected and banked, and data and biosamples have been widely disseminated. To date, APOE genotyping, genome-wide association study (GWAS), and whole exome and whole genome sequencing data have been obtained and disseminated. RESULTS: ADNI genetic data have been downloaded thousands of times, and >300 publications have resulted, including reports of large-scale GWAS by consortia to which ADNI contributed. Many of the first applications of quantitative endophenotype association studies used ADNI data, including some of the earliest GWAS and pathway-based studies of biospecimen and imaging biomarkers, as well as memory and other clinical/cognitive variables. Other contributions include some of the first whole exome and whole genome sequencing data sets and reports in healthy controls, mild cognitive impairment, and AD. DISCUSSION: Numerous genetic susceptibility and protective markers for AD and disease biomarkers have been identified and replicated using ADNI data and have heavily implicated immune, mitochondrial, cell cycle/fate, and other biological processes. Early sequencing studies suggest that rare and structural variants are likely to account for significant additional phenotypic variation. Longitudinal analyses of transcriptomic, proteomic, metabolomic, and epigenomic changes will also further elucidate dynamic processes underlying preclinical and prodromal stages of disease. Integration of this unique collection of multiomics data within a systems biology framework will help to separate truly informative markers of early disease mechanisms and potential novel therapeutic targets from the vast background of less relevant biological processes. Fortunately, a broad swath of the scientific community has accepted this grand challenge.
Asunto(s)
Enfermedad de Alzheimer/diagnóstico , Enfermedad de Alzheimer/genética , Biomarcadores/metabolismo , Disfunción Cognitiva/genética , Apolipoproteínas E/genética , Bases de Datos Bibliográficas/estadística & datos numéricos , Progresión de la Enfermedad , Estudios de Asociación Genética , Humanos , Proteínas de Transporte de Membrana/genética , Proteínas del Complejo de Importación de Proteínas Precursoras Mitocondriales , NeuroimagenRESUMEN
IMPORTANCE: Previous studies have indicated a heritable component of the etiology of neurodegenerative diseases such as Alzheimer disease (AD), frontotemporal dementia (FTD), and progressive supranuclear palsy (PSP). However, few have examined the contribution of low-frequency coding variants on a genome-wide level. OBJECTIVE: To identify low-frequency coding variants that affect susceptibility to AD, FTD, and PSP. DESIGN, SETTING, AND PARTICIPANTS: We used the Illumina HumanExome BeadChip array to genotype a large number of variants (most of which are low-frequency coding variants) in a cohort of patients with neurodegenerative disease (224 with AD, 168 with FTD, and 48 with PSP) and in 224 control individuals without dementia enrolled between 2005-2012 from multiple centers participating in the Genetic Investigation in Frontotemporal Dementia and Alzheimer's Disease (GIFT) Study. An additional multiancestral replication cohort of 240 patients with AD and 240 controls without dementia was used to validate suggestive findings. Variant-level association testing and gene-based testing were performed. MAIN OUTCOMES AND MEASURES: Statistical association of genetic variants with clinical diagnosis of AD, FTD, and PSP. RESULTS: Genetic variants typed by the exome array explained 44%, 53%, and 57% of the total phenotypic variance of AD, FTD, and PSP, respectively. An association with the known AD gene ABCA7 was replicated in several ancestries (discovery P=.0049, European P=.041, African American P=.043, and Asian P=.027), suggesting that exonic variants within this gene modify AD susceptibility. In addition, 2 suggestive candidate genes, DYSF (P=5.53×10(-5)) and PAXIP1 (P=2.26×10(-4)), were highlighted in patients with AD and differentially expressed in AD brain. Corroborating evidence from other exome array studies and gene expression data points toward potential involvement of these genes in the pathogenesis of AD. CONCLUSIONS AND RELEVANCE: Low-frequency coding variants with intermediate effect size may account for a significant fraction of the genetic susceptibility to AD and FTD. Furthermore, we found evidence that coding variants in the known susceptibility gene ABCA7, as well as candidate genes DYSF and PAXIP1, confer risk for AD.
Asunto(s)
Enfermedad de Alzheimer/genética , Exoma , Demencia Frontotemporal/genética , Predisposición Genética a la Enfermedad , Parálisis Supranuclear Progresiva/genética , Adulto , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/diagnóstico , Femenino , Demencia Frontotemporal/diagnóstico , Pruebas Genéticas/métodos , Variación Genética/genética , Estudio de Asociación del Genoma Completo , Genotipo , Humanos , Masculino , Análisis por Micromatrices , Persona de Mediana Edad , RiesgoRESUMEN
IMPORTANCE: Recently, a rare variant in the amyloid precursor protein gene (APP) was described in a population from Iceland. This variant, in which alanine is replaced by threonine at position 673 (A673T), appears to protect against late-onset Alzheimer disease (AD). We evaluated the frequency of this variant in AD cases and cognitively normal controls to determine whether this variant will significantly contribute to risk assessment in individuals in the United States. OBJECTIVE: To determine the frequency of the APP A673T variant in a large group of elderly cognitively normal controls and AD cases from the United States and in 2 case-control cohorts from Sweden. DESIGN, SETTING, AND PARTICIPANTS: Case-control association analysis of variant APP A673T in US and Swedish white individuals comparing AD cases with cognitively intact elderly controls. Participants were ascertained at multiple university-associated medical centers and clinics across the United States and Sweden by study-specific sampling methods. They were from case-control studies, community-based prospective cohort studies, and studies that ascertained multiplex families from multiple sources. MAIN OUTCOMES AND MEASURES: Genotypes for the APP A673T variant were determined using the Infinium HumanExome V1 Beadchip (Illumina, Inc) and by TaqMan genotyping (Life Technologies). RESULTS: The A673T variant genotypes were evaluated in 8943 US AD cases, 10 480 US cognitively normal controls, 862 Swedish AD cases, and 707 Swedish cognitively normal controls. We identified 3 US individuals heterozygous for A673T, including 1 AD case (age at onset, 89 years) and 2 controls (age at last examination, 82 and 77 years). The remaining US samples were homozygous for the alanine (A673) allele. In the Swedish samples, 3 controls were heterozygous for A673T and all AD cases were homozygous for the A673 allele. We also genotyped a US family previously reported to harbor the A673T variant and found a mother-daughter pair, both cognitively normal at ages 72 and 84 years, respectively, who were both heterozygous for A673T; however, all individuals with AD in the family were homozygous for A673. CONCLUSIONS AND RELEVANCE: The A673T variant is extremely rare in US cohorts and does not play a substantial role in risk for AD in this population. This variant may be primarily restricted to Icelandic and Scandinavian populations.
Asunto(s)
Enfermedad de Alzheimer/genética , Precursor de Proteína beta-Amiloide/genética , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/epidemiología , Estudios de Casos y Controles , Femenino , Genotipo , Humanos , Masculino , Linaje , Factores Protectores , Suecia/epidemiología , Estados Unidos/epidemiologíaRESUMEN
IMPORTANCE: Late-onset Alzheimer disease (LOAD), defined as onset of symptoms after age 65 years, is the most common form of dementia. Few reports investigate incidence rates in large family-based studies in which the participants were selected for family history of LOAD. OBJECTIVE: To determine the incidence rates of dementia and LOAD in unaffected members in the National Institute on Aging Genetics Initiative for Late-Onset Alzheimer Disease/National Cell Repository for Alzheimer Disease (NIA-LOAD/NCRAD) and Estudio Familiar de Influencia Genetica en Alzheimer (EFIGA) family studies. DESIGN, SETTING, AND PARTICIPANTS: Families with 2 or more affected siblings who had a clinical or pathological diagnosis of LOAD were recruited as a part of the NIA-LOAD/NCRAD Family Study. A cohort of Caribbean Hispanics with familial LOAD was recruited in a different study at the Taub Institute for Research on Alzheimer's Disease and the Aging Brain in New York and from clinics in the Dominican Republic as part of the EFIGA study. MAIN OUTCOMES AND MEASURES: Age-specific incidence rates of LOAD were estimated in the unaffected family members in the NIA-LOAD/NCRAD and EFIGA data sets. We restricted analyses to families with follow-up and complete phenotype information, including 396 NIA-LOAD/NCRAD and 242 EFIGA families. Among the 943 at-risk family members in the NIA-LOAD/NCRAD families, 126 (13.4%) developed dementia, of whom 109 (86.5%) met criteria for LOAD. Among 683 at-risk family members in the EFIGA families, 174 (25.5%) developed dementia during the study period, of whom 145 (83.3%) had LOAD. RESULTS: The annual incidence rates of dementia and LOAD in the NIA-LOAD/NCRAD families per person-year were 0.03 and 0.03, respectively, in participants aged 65 to 74 years; 0.07 and 0.06, respectively, in those aged 75 to 84 years; and 0.08 and 0.07, respectively, in those 85 years or older. Incidence rates in the EFIGA families were slightly higher, at 0.03 and 0.02, 0.06 and 0.05, 0.10 and 0.08, and 0.10 and 0.07, respectively, in the same age groups. Contrasting these results with the population-based estimates, the incidence was increased by 3-fold for NIA-LOAD/NCRAD families (standardized incidence ratio, 3.44) and 2-fold among the EFIGA compared with the NIA-LOAD/NCRAD families (1.71). CONCLUSIONS AND RELEVANCE: The incidence rates for familial dementia and LOAD in the NIA-LOAD/NCRAD and EFIGA families are significantly higher than population-based estimates. The incidence rates in all groups increase with age. The higher incidence of LOAD can be explained by segregation of Alzheimer disease-related genes in these families or shared environmental risks.
Asunto(s)
Enfermedad de Alzheimer/epidemiología , Factores de Edad , Edad de Inicio , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/genética , Apolipoproteína E4/genética , República Dominicana/epidemiología , Femenino , Estudios de Seguimiento , Predisposición Genética a la Enfermedad , Humanos , Incidencia , Masculino , National Institute on Aging (U.S.) , New York/epidemiología , Estados Unidos/epidemiologíaRESUMEN
Copy number variations (CNVs) are genomic regions that have added (duplications) or deleted (deletions) genetic material. They may overlap genes affecting their function and have been shown to be associated with disease. We previously investigated the role of CNVs in late-onset Alzheimer's disease (AD) and mild cognitive impairment using Alzheimer's Disease Neuroimaging Initiative (ADNI) and National Institute of Aging-Late Onset AD/National Cell Repository for AD (NIA-LOAD/NCRAD) Family Study participants, and identified a number of genes overlapped by CNV calls. To confirm the findings and identify other potential candidate regions, we analyzed array data from a unique cohort of 1617 Caucasian participants (1022 AD cases and 595 controls) who were clinically characterized and whose diagnosis was neuropathologically verified. All DNA samples were extracted from brain tissue. CNV calls were generated and subjected to quality control (QC). 728 cases and 438 controls who passed all QC measures were included in case/control association analyses including candidate gene and genome-wide approaches. Rates of deletions and duplications did not significantly differ between cases and controls. Case-control association identified a number of previously reported regions (CHRFAM7A, RELN and DOPEY2) as well as a new gene (HLA-DRA). Meta-analysis of CHRFAM7A indicated a significant association of the gene with AD and/or MCI risk (P = 0.006, odds ratio = 3.986 (95% confidence interval 1.490-10.667)). A novel APP gene duplication was observed in one case sample. Further investigation of the identified genes in independent and larger samples is warranted.
Asunto(s)
Enfermedad de Alzheimer/genética , Variaciones en el Número de Copia de ADN , Enfermedad de Alzheimer/patología , Estudios de Casos y Controles , Estudios de Cohortes , Estudio de Asociación del Genoma Completo , Humanos , Proteína ReelinaRESUMEN
Copy number variants (CNVs) are DNA regions that have gains (duplications) or losses (deletions) of genetic material. CNVs may encompass a single gene or multiple genes and can affect their function. They are hypothesized to play an important role in certain diseases. We previously examined the role of CNVs in late-onset Alzheimer's disease (AD) and mild cognitive impairment (MCI) using participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI) study and identified gene regions overlapped by CNVs only in cases (AD and/or MCI) but not in controls. Using a similar approach as ADNI, we investigated the role of CNVs using 794 AD and 196 neurologically evaluated control non-Hispanic Caucasian NIA-LOAD/NCRAD Family Study participants with DNA derived from blood/brain tissue. The controls had no family history of AD and were unrelated to AD participants. CNV calls were generated and analyzed after detailed quality review. 711 AD cases and 171 controls who passed all quality thresholds were included in case/control association analyses, focusing on candidate gene and genome-wide approaches. We identified genes overlapped by CNV calls only in AD cases but not controls. A trend for lower CNV call rate was observed for deletions as well as duplications in cases compared to controls. Gene-based association analyses confirmed previous findings in the ADNI study (ATXN1, HLA-DPB1, RELN, DOPEY2, GSTT1, CHRFAM7A, ERBB4, NRXN1) and identified a new gene (IMMP2L) that may play a role in AD susceptibility. Replication in independent samples as well as further analyses of these gene regions is warranted.
Asunto(s)
Enfermedad de Alzheimer/genética , Apolipoproteínas E/genética , Disfunción Cognitiva/genética , Anciano , Anciano de 80 o más Años , Estudios de Casos y Controles , Variaciones en el Número de Copia de ADN , Femenino , Dosificación de Gen , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Genotipo , Humanos , Masculino , Polimorfismo de Nucleótido Simple , Proteína Reelina , Población Blanca/genéticaRESUMEN
Late-onset Alzheimer's disease (LOAD) is the most common form of dementia in the elderly. The National Institute of Aging-Late Onset Alzheimer's Disease Family Study and the National Cell Repository for Alzheimer's Disease conducted a joint genome-wide association study (GWAS) of multiplex LOAD families (3,839 affected and unaffected individuals from 992 families plus additional unrelated neurologically evaluated normal subjects) using the 610 IlluminaQuad panel. This cohort represents the largest family-based GWAS of LOAD to date, with analyses limited here to the European-American subjects. SNPs near APOE gave highly significant results (e.g., rs2075650, pâ=â3.2×10(-81)), but no other genome-wide significant evidence for association was obtained in the full sample. Analyses that stratified on APOE genotypes identified SNPs on chromosome 10p14 in CUGBP2 with genome-wide significant evidence for association within APOE ε4 homozygotes (e.g., rs201119, pâ=â1.5×10(-8)). Association in this gene was replicated in an independent sample consisting of three cohorts. There was evidence of association for recently-reported LOAD risk loci, including BIN1 (rs7561528, pâ=â0.009 with, and pâ=â0.03 without, APOE adjustment) and CLU (rs11136000, pâ=â0.023 with, and pâ=â0.008 without, APOE adjustment), with weaker support for CR1. However, our results provide strong evidence that association with PICALM (rs3851179, pâ=â0.69 with, and pâ=â0.039 without, APOE adjustment) and EXOC3L2 is affected by correlation with APOE, and thus may represent spurious association. Our results indicate that genetic structure coupled with ascertainment bias resulting from the strong APOE association affect genome-wide results and interpretation of some recently reported associations. We show that a locus such as APOE, with large effects and strong association with disease, can lead to samples that require appropriate adjustment for this locus to avoid both false positive and false negative evidence of association. We suggest that similar adjustments may also be needed for many other large multi-site studies.