Genetics of Alzheimer’s Disease Ridge, Perry G.; Ebbert, Mark T. W.; Kauwe, John S. K.
BioMed research international,
01/2013, Letnik:
2013
Journal Article
Recenzirano
Odprti dostop
Alzheimer’s disease is the most common form of dementia and is the only top 10 cause of death in the United States that lacks disease-altering treatments. It is a complex disorder with environmental ...and genetic components. There are two major types of Alzheimer’s disease, early onset and the more common late onset. The genetics of early-onset Alzheimer’s disease are largely understood with variants in three different genes leading to disease. In contrast, while several common alleles associated with late-onset Alzheimer’s disease, including APOE, have been identified using association studies, the genetics of late-onset Alzheimer’s disease are not fully understood. Here we review the known genetics of early- and late-onset Alzheimer’s disease.
Alzheimer's disease (AD) is an international health concern that has a devastating effect on patients and families. While several genetic risk factors for AD have been identified much of the genetic ...variance in AD remains unexplained. There are limited published assessments of the familiality of Alzheimer's disease. Here we present the largest genealogy-based analysis of AD to date.
We assessed the familiality of AD in The Utah Population Database (UPDB), a population-based resource linking electronic health data repositories for the state with the computerized genealogy of the Utah settlers and their descendants. We searched UPDB for significant familial clustering of AD to evaluate the genetic contribution to disease. We compared the Genealogical Index of Familiality (GIF) between AD individuals and randomly selected controls and estimated the Relative Risk (RR) for a range of family relationships. Finally, we identified pedigrees with a significant excess of AD deaths.
The GIF analysis showed that pairs of individuals dying from AD were significantly more related than expected. This excess of relatedness was observed for both close and distant relationships. RRs for death from AD among relatives of individuals dying from AD were significantly increased for both close and more distant relatives. Multiple pedigrees had a significant excess of AD deaths.
These data strongly support a genetic contribution to the observed clustering of individuals dying from AD. This report is the first large population-based assessment of the familiality of AD mortality and provides the only reported estimates of relative risk of AD mortality in extended relatives to date. The high-risk pedigrees identified show a true excess of AD mortality (not just multiple cases) and are greater in depth and width than published AD pedigrees. The presence of these high-risk pedigrees strongly supports the possibility of rare predisposition variants not yet identified.
Abstract Genome-wide association studies (GWASs) have been effective approaches to dissect common genetic variability underlying complex diseases in a systematic and unbiased way. Recently, GWASs ...have led to the discovery of over 20 susceptibility loci for Alzheimer’s disease (AD). Despite the evidence showing the contribution of these loci to AD pathogenesis, their genetic architecture has not been extensively investigated, leaving the possibility that low frequency and rare coding variants may also occur and contribute to the risk of disease. We have used exome and genome sequencing data to analyse the single independent and joint effect of rare and low frequency protein coding variants in 9 AD GWAS loci with the strongest effect sizes after APOE ( BIN1 , CLU , CR1 , PICALM , MS4A6A , ABCA7 , EPHA1 , CD33 , CD2AP) in a cohort of 332 sporadic AD cases and 676 elderly controls of British and North American ancestry. We identified coding variability in ABCA7 as contributing to AD risk. This locus harbors a low frequency coding variant (p.G215S, rs72973581, MAF=4.3%) conferring a modest but statistically significant protection against AD (p-value= 6x10-4 , OR= 0.57, 95% CI 0.41-0.80). Notably, our results are not driven by an enrichment of loss of function variants in ABCA7 , recently reported as main pathogenic factor underlying AD risk at this locus. In summary, our study confirms the role of ABCA7 in AD and provide new insights that should address functional studies.
, commonly known as giant kingfish or giant trevally, is a large, reef-associated apex predator. It is a prized sportfish, targeted throughout its tropical and subtropical range in the Indian and ...Pacific Oceans. It also gained significant interest in aquaculture due to its unusual freshwater tolerance. Here, we present a draft assembly of the estimated 625.92 Mbp nuclear genome of a
individual from Hawaiian waters, which host a genetically distinct population. Our 97.4% BUSCO-complete assembly has a contig NG50 of 7.3 Mbp and a scaffold NG50 of 46.3 Mbp. Twenty-five of the 203 scaffolds contain 90% of the genome. We also present noisy, long-read DNA, Hi-C, and RNA-seq datasets, the latter containing eight distinct tissues and can help with annotations and studies of freshwater tolerance. Our genome assembly and its supporting data are valuable tools for ecological and comparative genomics studies of kingfishes and other carangoid fishes.
Mitochondrial genetics are an important but largely neglected area of research in Alzheimer's disease. A major impediment is the lack of data sets.
We used an innovative, rigorous approach, combining ...several existing tools with our own, to accurately assemble and call variants in 809 whole mitochondrial genomes.
To help address this impediment, we prepared a data set that consists of 809 complete and annotated mitochondrial genomes with samples from the Alzheimer's Disease Neuroimaging Initiative. These whole mitochondrial genomes include rich phenotyping, such as clinical, fluid biomarker, and imaging data, all of which is available through the Alzheimer's Disease Neuroimaging Initiative website. Genomes are cleaned, annotated, and prepared for analysis.
These data provide an important resource for investigating the impact of mitochondrial genetic variation on risk for Alzheimer's disease and other phenotypes that have been measured in the Alzheimer's Disease Neuroimaging Initiative samples.
A recent genome-wide association study (GWAS) of 59 cerebrospinal fluid (CSF) proteins with a connection to Alzheimer's disease (AD) demonstrated an association between increased levels of chemokine ...ligand 2 (CCL2) with an atypical chemokine receptor chemokine-binding protein 2 variant V41A (ACKR2-V41A; rs2228467). High levels of CCL2 are associated with increased risk of AD development as well as other inflammatory diseases. In this study we characterized the biological function of the ACKR2-V41A receptor compared to the wild type allele by measuring its ligand binding affinity, CCL2 scavenging efficiency, and cell activation sensitivity. We transfected Chinese hamster ovary cells with plasmids carrying wild type ACKR2 (ACKR2-WT) or the mutant ACKR2-V41A receptor. Binding affinity assays showed that ACKR2-V41A has a lower binding affinity for CCL2 and CCL4 than ACKR2-WT. CCL2 scavenging results aligned with binding affinity assays, with ACKR2-V41A cells scavenging CCL2 with a lower efficiency than ACKR2-WT. Cell activation assays also showed that ACKR2-V41A cells had significantly lower receptor upregulation (β-Arrestin-dependent signaling pathway) upon stimulation compared to ACKR2-WT cells. These findings provide molecular and biological mechanistic insights into the GWAS association of ACKR2-V41A with increased levels of CCL2 in CSF and possibly other chemokine ligands. Increased CCL2 levels are associated with accelerated cognitive decline and increased risk of AD. Understanding how this atypical chemokine receptor allele increases serum markers of inflammation could lead to novel therapeutic solutions for AD.
Although many studies have documented codon usage bias in different species, the importance of codon usage in a phylogenetic framework remains largely unknown. We demonstrate that a phylogenetic ...signal is present in the codon usage and non‐usage biases of 17 717 orthologues evaluated across 72 tetrapod species using a simple parsimony analysis of a binary matrix of codon characters. Phylogenies estimated using stop codons were more congruent with previous hypotheses than phylogenies based on any other single codon or a combination of codons. Although each codon is present in every species, specific genes have different codon preferences and may or may not use every possible codon. This observation allowed us to map the pattern of codon usage and non‐usage across the topology. These results suggest that codon usage is phylogenetically conserved across shallow and deep levels within tetrapods.
Members of the Mycobacterium chelonae-abscessus complex represent Mycobacterium species that cause invasive infections in immunocompetent and immunocompromised hosts. We report the detection of a new ...pathogen that had been misidentified as M. chelonae with an atypical antimicrobial drug susceptibility profile. The discovery prompted a multicenter investigation of 26 patients. Almost all patients were from the northeastern United States, and most had underlying sinus or pulmonary disease. Infected patients had clinical features similar to those with M. abscessus infections. Taxonomically, the new pathogen shared molecular identity with members of the M. chelonae-abscessus complex. Multilocus DNA target sequencing, DNA-DNA hybridization, and deep multilocus sequencing (43 full-length genes) support a new taxon for these microorganisms. Because most isolates originated in Pennsylvania, we propose the name M. franklinii sp. nov. This investigation underscores the need for accurate identification of Mycobacterium spp. to detect new pathogens implicated in human disease.
The roundjaw bonefish,
, is the most widespread albulid in the Indo-Pacific and is vulnerable to extinction. We assembled the genome of a roundjaw bonefish from Hawai'i, USA, which will be ...instrumental for effective transboundary management and conservation when paired with population genomics datasets. The 1.05 gigabase pair (Gbp) contig-level assembly had a 4.75 megabase pair (Mbp) NG50 and a maximum contig length of 28.2 Mbp. Scaffolding yielded an LG50 of 20 and an NG50 of 14.49 Mbp, with the longest scaffold reaching 42.29 Mbp. The genome comprised 6.5% repetitive elements and was annotated with 28.3 K protein-coding genes. We then evaluated population genetic connectivity between six atolls in the Western Indian Ocean with 38,355 SNP loci across 66
individuals. We discerned shallow population structure and observed genetic homogeneity between atolls in Seychelles and reduced gene flow between Seychelles and Mauritius. The South Equatorial Current might be the limiting mechanism of this reduced gene flow. The genome assembly will be useful for addressing taxonomic uncertainties of bonefishes globally.
Genome-wide association studies (GWAS) have effectively identified genetic factors for many diseases. Many diseases, including Alzheimer's disease (AD), have epistatic causes, requiring more ...sophisticated analyses to identify groups of variants which together affect phenotype.
Based on the GWAS statistical model, we developed a multi-SNP GWAS analysis to identify pairs of variants whose common occurrence signaled the Alzheimer's disease phenotype.
Despite not having sufficient data to demonstrate significance, our preliminary experimentation identified a high correlation between GRIA3 and HLA-DRB5 (an AD gene). GRIA3 has not been previously reported in association with AD, but is known to play a role in learning and memory.
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