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Identification of novel candidate genes for Alzheimer's disease by autozygosity mapping using genome wide SNP data.

ABSTRACT: Alzheimer's disease (AD) is highly prevalent in Wadi Ara despite the low frequency of apolipoprotein E ?4 in this genetically isolated Arab community in northern Israel. We hypothesized that the reduced genetic variability in combination with increased homozygosity would facilitate identification of genetic variants that contribute to the high rate of AD in this community. AD cases (n = 124) and controls (n = 142) from Wadi Ara were genotyped for a genome-wide set of more than 300,000 single nucleotides polymorphisms (SNPs) which were used to calculate measures of population stratification and inbreeding, and to identify regions of autozygosity. Although a high degree of relatedness was evident in both AD cases and controls, controls were significantly more related and contained more autozygous regions than AD cases (p = 0.004). Eight autozygous regions on seven different chromosomes were more frequent in controls than the AD cases, and 116 SNPs in these regions, primarily on chromosomes 2, 6, and 9, were nominally associated with AD. The association with rs3130283 in AGPAT1 on chromosome 6 was observed in a meta-analysis of seven genome-wide association study (GWAS) datasets. Analysis of the full Wadi Ara GWAS dataset revealed 220 SNP associations with AD at p ? 10??, and seven of these were confirmed in the replication GWAS datasets (p < 0.05). The unique population structure of Wadi Ara enhanced efforts to identify genetic variants that might partially explain the high prevalence of AD in the region. Several of these variants show modest evidence for association in other Caucasian populations.

SUBMITTER: Sherva R

PROVIDER: S-EPMC3819807 | biostudies-literature | 2011

REPOSITORIES: biostudies-literature

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Identification of novel candidate genes for Alzheimer's disease by autozygosity mapping using genome wide SNP data.

Sherva Richard R Baldwin Clinton T CT Inzelberg Rivka R Vardarajan Badri B Cupples L Adrienne LA Lunetta Kathryn K Bowirrat Abdalla A Naj Adam A Pericak-Vance Margaret M Friedland Robert P RP Farrer Lindsay A LA

Journal of Alzheimer's disease : JAD 20110101 2

Alzheimer's disease (AD) is highly prevalent in Wadi Ara despite the low frequency of apolipoprotein E ε4 in this genetically isolated Arab community in northern Israel. We hypothesized that the reduced genetic variability in combination with increased homozygosity would facilitate identification of genetic variants that contribute to the high rate of AD in this community. AD cases (n = 124) and controls (n = 142) from Wadi Ara were genotyped for a genome-wide set of more than 300,000 single nuc ...[more]

PMID: 21098978

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Project description:Genome wide association studies (GWAS) are a population-scale approach to the identification of segments of the genome in which genetic variations may contribute to disease risk. Current methods focus on the discovery of single nucleotide polymorphisms (SNPs) associated with disease traits. As there are many SNPs within identified risk loci, and the majority of these are situated within non-coding regions, a key challenge is to identify and prioritize variants affecting regulatory sequences that are likely to contribute to the phenotype assessed.We focused investigation on SNPs within lung and breast cancer GWAS loci that reached genome-wide significance for potential roles in gene regulation with a specific focus on SNPs likely to disrupt transcription factor binding sites. Within risk loci, the regulatory potential of sub-regions was classified using relevant open chromatin and epigenetic high throughput sequencing data sets from the ENCODE project in available cancer and normal cell lines. Furthermore, transcription factor affinity altering variants were predicted by comparison of position weight matrix scores between disease and reference alleles. Lastly, ChIP-seq data of transcription associated factors and topological domains were included as binding evidence and potential gene target inference.The sets of SNPs, including both the disease-associated markers and those in high linkage disequilibrium with them, were significantly over-represented in regulatory sequences of cancer and/or normal cells; however, over-representation was generally not restricted to disease-relevant tissue specific regions. The calculated regulatory potential, allelic binding affinity scores and ChIP-seq binding evidence were the three criteria used to prioritize candidates. Fitting all three criteria, we highlighted breast cancer susceptibility SNPs and a borderline lung cancer relevant SNP located in cancer-specific enhancers overlapping multiple distinct transcription associated factor ChIP-seq binding sites.Incorporating high throughput sequencing epigenetic and transcription factor data sets from both cancer and normal cells into cancer genetic studies reveals potential functional SNPs and informs subsequent characterization efforts.

Project description:ImportanceSubstantial genome-wide association study (GWAS) work in Parkinson disease (PD) has led to the discovery of an increasing number of loci shown reliably to be associated with increased risk of disease. Improved understanding of the underlying genes and mechanisms at these loci will be key to understanding the pathogenesis of PD.ObjectiveTo investigate what genes and genomic processes underlie the risk of sporadic PD.Design and settingThis genetic association study used the bioinformatic tools Coloc and transcriptome-wide association study (TWAS) to integrate PD case-control GWAS data published in 2017 with expression data (from Braineac, the Genotype-Tissue Expression [GTEx], and CommonMind) and methylation data (derived from UK Parkinson brain samples) to uncover putative gene expression and splicing mechanisms associated with PD GWAS signals. Candidate genes were further characterized using cell-type specificity, weighted gene coexpression networks, and weighted protein-protein interaction networks.Main outcomes and measuresIt was hypothesized a priori that some genes underlying PD loci would alter PD risk through changes to expression, splicing, or methylation. Candidate genes are presented whose change in expression, splicing, or methylation are associated with risk of PD as well as the functional pathways and cell types in which these genes have an important role.ResultsGene-level analysis of expression revealed 5 genes (WDR6 [OMIM 606031], CD38 [OMIM 107270], GPNMB [OMIM 604368], RAB29 [OMIM 603949], and TMEM163 [OMIM 618978]) that replicated using both Coloc and TWAS analyses in both the GTEx and Braineac expression data sets. A further 6 genes (ZRANB3 [OMIM 615655], PCGF3 [OMIM 617543], NEK1 [OMIM 604588], NUPL2 [NCBI 11097], GALC [OMIM 606890], and CTSB [OMIM 116810]) showed evidence of disease-associated splicing effects. Cell-type specificity analysis revealed that gene expression was overall more prevalent in glial cell types compared with neurons. The weighted gene coexpression performed on the GTEx data set showed that NUPL2 is a key gene in 3 modules implicated in catabolic processes associated with protein ubiquitination and in the ubiquitin-dependent protein catabolic process in the nucleus accumbens, caudate, and putamen. TMEM163 and ZRANB3 were both important in modules in the frontal cortex and caudate, respectively, indicating regulation of signaling and cell communication. Protein interactor analysis and simulations using random networks demonstrated that the candidate genes interact significantly more with known mendelian PD and parkinsonism proteins than would be expected by chance.Conclusions and relevanceTogether, these results suggest that several candidate genes and pathways are associated with the findings observed in PD GWAS studies.

Project description:BackgroundFrost is a limiting abiotic stress for the winter pea crop (Pisum sativum L.) and identifying the genetic determinants of frost tolerance is a major issue to breed varieties for cold northern areas. Quantitative trait loci (QTLs) have previously been detected from bi-parental mapping populations, giving an overview of the genome regions governing this trait. The recent development of high-throughput genotyping tools for pea brings the opportunity to undertake genetic association studies in order to capture a higher allelic diversity within large collections of genetic resources as well as to refine the localization of the causal polymorphisms thanks to the high marker density. In this study, a genome-wide association study (GWAS) was performed using a set of 365 pea accessions. Phenotyping was carried out by scoring frost damages in the field and in controlled conditions. The association mapping collection was also genotyped using an Illumina Infinium® BeadChip, which allowed to collect data for 11,366 single nucleotide polymorphism (SNP) markers.ResultsGWAS identified 62 SNPs significantly associated with frost tolerance and distributed over six of the seven pea linkage groups (LGs). These results confirmed 3 QTLs that were already mapped in multiple environments on LG III, V and VI with bi-parental populations. They also allowed to identify one locus, on LG II, which has not been detected yet and two loci, on LGs I and VII, which have formerly been detected in only one environment. Fifty candidate genes corresponding to annotated significant SNPs, or SNPs in strong linkage disequilibrium with the formers, were found to underlie the frost damage (FD)-related loci detected by GWAS. Additionally, the analyses allowed to define favorable haplotypes of markers for the FD-related loci and their corresponding accessions within the association mapping collection.ConclusionsThis study led to identify FD-related loci as well as corresponding favorable haplotypes of markers and representative pea accessions that might to be used in winter pea breeding programs. Among the candidate genes highlighted at the identified FD-related loci, the results also encourage further attention to the presence of C-repeat Binding Factors (CBF) as potential genetic determinants of the frost tolerance locus on LG VI.

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Identification of novel candidate genes for Alzheimer's disease by autozygosity mapping using genome wide SNP data.

Publications

Identification of novel candidate genes for Alzheimer's disease by autozygosity mapping using genome wide SNP data.

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