329 research outputs found
Genetic meta-analysis of diagnosed Alzheimer’s disease identifies new risk loci and implicates Aβ, tau, immunity and lipid processing
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Genome‐wide association analyses identify genes modifying age‐at‐onset of Alzheimer’s disease
No full textBackground
Several studies have attempted to identify genes for age‐at‐onset (AAO) of dementia symptoms in Alzheimer’s disease (AD) through genome‐wide linkage (Daw et al. 1999, Li et al. 2002, Choi et al. 2011) and genome‐wide association studies (Kamboh et al. 2012, Naj et al. 2014). Naj et al. conducted a meta‐analysis of 14 datasets from the Alzheimer’s Disease Genetics Consortium (ADGC) with genotype imputation to HapMap2. Using an expanded set of ADGC cohorts, we re‐examined AAO using higher‐quality genome‐wide imputation data and pooled‐data analysis instead of meta‐analysis to identify novel genetic contributors to AAO of AD.
Methods
We combined data from 20 non‐Hispanic white prospective and case‐control ADGC datasets, excluding family‐based datasets. Genotype data were imputed to the Haplotype Reference Consortium (HRC) r1.1 reference panel using the Michigan Imputation Server and consistent quality control applied to each dataset, after which genotype data were merged across datasets using QCTOOL and GTOOL. We performed case‐only association analyses for log10(AAO) using multivariable linear regression with covariate adjustment for sex, cohort, and principal components capturing population substructure, and then conducted analyses conditioning on dosage of APOE ε4 alleles. Variants with P < 10−5 from conditional analyses were re‐analyzed using linear mixed modeling treating cohort as a random effect.
Results
We used 9,228 AD cases, including 5,307 females (57.4%) with mean (SD) AAO of 74.2(7.7) years. In addition to the APOE region, which reached genome‐wide significance (P < 5 × 10−8), we observed strong novel associations with variants in NTM (encoding neurotrimin) on chr11q25 (rs117589002, P = 1.24 × 10−7) and in an intergenic region on chr3p22.3 (Pmin
= 1.89 × 10−7). Other AAO loci previously identified in the smaller ADGC dataset (Naj et al 2014) remained nominally significant. After adjusting for APOE ε4, thirty‐two regions showed suggestive association (P < 10−5), with chr3p22.3 and NTM remaining the top loci. Chromosome 11q25 includes a known AD linkage region (Blacker et al. 2003). In addition, NTM variation has been found to be correlated with cognitive function tests (Liu et al. 2007) and intelligence (Pan et al. 2010).
Conclusions
In an expanded ADGC dataset, we confirmed AAO associations in the APOE region and observed evidence for potential novel AD AAO loci including NTM
New insights into the genetic etiology of Alzheimer’s disease and related dementias
No full textAbstract Characterization of the genetic landscape of Alzheimer’s disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/‘proxy’ AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele.Abstract Characterization of the genetic landscape of Alzheimer’s disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/‘proxy’ AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele
P3‐081: POST‐VARIANT CALLING QUALITY CONTROL (QC) PIPELINE AND MULTI‐PIPELINE GENOTYPE CONSENSUS CALLER FOR LARGE‐SCALE WHOLE GENOME AND WHOLE EXOME SEQUENCING STUDIES
No full text[P3–065]: POST‐VARIANT CALLING QUALITY CONTROL (QC) PIPELINE AND MULTI‐PIPELINE GENOTYPE CONSENSUS CALLER FOR LARGE‐SCALE WHOLE GENOME AND WHOLE EXOME SEQUENCING STUDIES
No full textAuthor Correction: Genetic meta-analysis of diagnosed Alzheimer’s disease identifies new risk loci and implicates Aβ, tau, immunity and lipid processing
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