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Connecting the dots: potential of data integration to identify regulatory SNPs in late-onset Alzheimer's disease GWAS findings.

ABSTRACT: Late-onset Alzheimer's disease (LOAD) is a multifactorial disorder with over twenty loci associated with disease risk. Given the number of genome-wide significant variants that fall outside of coding regions, it is possible that some of these variants alter some function of gene expression rather than tagging coding variants that alter protein structure and/or function. RegulomeDB is a database that annotates regulatory functions of genetic variants. In this study, we utilized RegulomeDB to investigate potential regulatory functions of lead single nucleotide polymorphisms (SNPs) identified in five genome-wide association studies (GWAS) of risk and age-at onset (AAO) of LOAD, as well as SNPs in LD (r2?0.80) with the lead GWAS SNPs. Of a total 614 SNPs examined, 394 returned RegulomeDB scores of 1-6. Of those 394 variants, 34 showed strong evidence of regulatory function (RegulomeDB score <3), and only 3 of them were genome-wide significant SNPs (ZCWPW1/rs1476679, CLU/rs1532278 and ABCA7/rs3764650). This study further supports the assumption that some of the non-coding GWAS SNPs are true associations rather than tagged associations and demonstrates the application of RegulomeDB to GWAS data.

SUBMITTER: Rosenthal SL

PROVIDER: S-EPMC3990600 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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Connecting the dots: potential of data integration to identify regulatory SNPs in late-onset Alzheimer's disease GWAS findings.

Rosenthal Samantha L SL Barmada M Michael MM Wang Xingbin X Demirci F Yesim FY Kamboh M Ilyas MI

PloS one 20140417 4

Late-onset Alzheimer's disease (LOAD) is a multifactorial disorder with over twenty loci associated with disease risk. Given the number of genome-wide significant variants that fall outside of coding regions, it is possible that some of these variants alter some function of gene expression rather than tagging coding variants that alter protein structure and/or function. RegulomeDB is a database that annotates regulatory functions of genetic variants. In this study, we utilized RegulomeDB to inve ...[more]

PMID: 24743338

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Project description:BackgroundThe exchangeable aluminum (Al), released from the acid soils, is another addition to the environmental stress factors in the form of Al toxicity stress. Al stress affects the normal crop development and reduces the overall yield of rapeseed (Brassica napus L.). The response mechanism of plants to Al toxicity is complicated and difficult to understand with few QTL related studies in rapeseed under Al toxicity stress.ResultUsing 200,510 SNPs developed by SLAF-seq (specific-locus amplified fragment sequencing) technology, we carried out the genome-wide association analysis (GWAS) in a population of 254 inbred lines of B. napus with large genetic variation and Al-tolerance differences. There were 43 SNPs significantly associated with eight Al-tolerance traits in the seedling stage were detected on 14 chromosomes, and 777 candidate genes were screened at the flanking 100 kb region of these SNPs. Moreover, RNA-seq detected 8291 and 5341 DEGs (the differentially expressed gene) in the Al -tolerant line (ATL) and -sensitive line (ASL), respectively. Based on integration of GWAS and RNA-seq analysis, 64 candidate genes from GWAS analysis differentially expressed at least once in 6 h vs 0 h or 24 h vs 0 h conditions in ATL or ASL. Moreover, four out of sixty-four candidate genes (BnaA03g30320D, BnaA10g11500D, BnaC03g38360D and BnaC06g30030D) were differentially expressed in both 6 h and 24 h compared to 0 h (control) conditions in both lines. The proposed model based on the candidate genes excavated in this study highlighted that Al stress disturb the oxidation-redox balance, causing abnormal synthesis and repair of cell wall and ABA signal transduction, ultimately resulting in inhibition of root elongation.ConclusionsThe integration of GWAS and transcriptome analysis provide an effective strategy to explore the SNPs and candidate genes, which has a potential to develop molecular markers for breeding Al tolerant rapeseed varieties along with theoretical basis of molecular mechanisms for Al toxicity response of Brassica napus plants.

Dataset Information

Connecting the dots: potential of data integration to identify regulatory SNPs in late-onset Alzheimer's disease GWAS findings.

Publications

Connecting the dots: potential of data integration to identify regulatory SNPs in late-onset Alzheimer's disease GWAS findings.

Similar Datasets

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