Dataset Information

Genetics of Alzheimer disease in the pre- and post-GWAS era.

ABSTRACT: Since the 1990s, the genetics of Alzheimer disease (AD) has been an active area of research. The identification of deterministic mutations in the APP, PSEN1, and PSEN2 genes responsible for early-onset autosomal dominant familial forms of AD led to a better understanding of the pathophysiology of this disease. In the past decade, the plethora of candidate genes and regions emerging from genetic linkage and smaller-scale association studies yielded intriguing 'hits' that have often proven difficult to replicate consistently. In the last two years, 11 published genome-wide association studies (GWASs) in AD confirmed the universally accepted role of APOE as a genetic risk factor for late-onset AD as well as generating additional candidate genes that require confirmation. It is unclear whether GWASs, though a promising novel approach in the genetics of complex diseases, can help explain most of the underlying genetic risk for AD. This review provides a brief summary of the genetic studies in AD preceding the GWAS era, with the main focus on the findings from recent GWASs. Potential approaches that could provide further insight into the genetics of AD in the post-GWAS era are also discussed.

SUBMITTER: Ertekin-Taner N

PROVIDER: S-EPMC2874262 | biostudies-literature | 2010 Mar

REPOSITORIES: biostudies-literature

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Genetics of Alzheimer disease in the pre- and post-GWAS era.

Ertekin-Taner Nilüfer N

Alzheimer's research & therapy 20100305 1

Since the 1990s, the genetics of Alzheimer disease (AD) has been an active area of research. The identification of deterministic mutations in the APP, PSEN1, and PSEN2 genes responsible for early-onset autosomal dominant familial forms of AD led to a better understanding of the pathophysiology of this disease. In the past decade, the plethora of candidate genes and regions emerging from genetic linkage and smaller-scale association studies yielded intriguing 'hits' that have often proven difficu ...[more]

PMID: 20236449

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Project description:Cardiovascular diseases (CVDs), the leading cause of death worldwide, generally refer to a range of pathological conditions with the involvement of the heart and the blood vessels. A sizable fraction of the susceptibility loci is known, but the underlying mechanisms have been established only for a small proportion. Therefore, there is an increasing need to explore the functional relevance of trait-associated variants and, moreover, to search for novel risk genetic variation. We have reported the bioinformatic approach allowing effective identif ication of functional non-coding variants by integrated analysis of genome-wide data. Here, the analysis of 1361 previously identif ied regulatory SNPs (rSNPs) was performed to provide new insights into cardiovascular risk. We found 773,471 coding co-segregating markers for input rSNPs using the 1000 Genomes Project. The intersection of GWAS-derived SNPs with a relevance to cardiovascular traits with these markers was analyzed within a window of 10 Kbp. The effects on the transcription factor (TF) binding sites were explored by DeFine models. Functional pathway enrichment and protein-protein interaction (PPI) network analyses were performed on the targets and the extended genes by STRING and DAVID. Eighteen rSNPs were functionally linked to cardiovascular risk. A signif icant impact on binding sites of thirteen TFs including those involved in blood cells formation, hematopoiesis, macrophage function, inf lammation, and vasoconstriction was found in K562 cells. 21 rSNP gene targets and 5 partners predicted by PPI were enriched for spliceosome and endocytosis KEGG pathways, endosome sorting complex and mRNA splicing REACTOME pathways. Related Gene Ontology terms included mRNA splicing and processing, endosome transport and protein catabolic processes. Together, the f indings provide further insight into the biological basis of CVDs and highlight the importance of the precise regulation of splicing and alternative splicing.

Dataset Information

Genetics of Alzheimer disease in the pre- and post-GWAS era.

Publications

Genetics of Alzheimer disease in the pre- and post-GWAS era.

Similar Datasets

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