Unknown,Transcriptomics,Genomics,Proteomics

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Affymetrix 6.0 SNP arrays interrogated to detect allele-specific DNA modification in the brain

ABSTRACT: It has long been hypothesized that knowledge of allele-specific modification (ASM; "modification" is used to denote various types of epigenetic cytosine marks, not only methylation) can supplement and inform GWAS of complex diseases and traits. To explore the relationship between GWAS subthreshold SNPs and ASM, we identified brain ASM-SNPs from Caucasian control individuals (n=76) and Caucasian patients affected by schizophrenia (n=65) or bipolar (n=67) using the Affymetrix SNP 6.0 microarray, one of the most common GWAS platforms which has also been thoroughlyt validated for ASM mapping. The brain samples (N=230, all ethnicities) were interrogated twice on Affymetrix SNP 6.0 microarrays. First, regular SNP genotyping was performed following the manufacturer's protocol. Second, we investigated allelic differences in DNA methylation by enriching the unmodified DNA fraction using DNA methylation-sensitive restriction enzymes.

ORGANISM(S): Homo sapiens

SUBMITTER: Arturas Petronis

PROVIDER: E-GEOD-71443 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:The Systemic Capillary Leak Syndrome (SCLS) is an extremely rare, orphan disease that resembles systemic anaphylaxis. The disorder is characterized by repeated, transient, and seemingly unprovoked episodes of hypotensive shock and peripheral edema due to transient endothelial hyperpermeability. SCLS is often accompanied by a monoclonal gammopathy of unknown significance (MGUS). Using Affymetrix Single Nucleotide Polymorphism (SNP) microarrays, we performed the first genome-wide SNP analysis of SCLS in a cohort of 12 disease subjects and 18 controls. Exome capture sequencing was performed on genomic DNA from nine of these patients as validation for the SNP-chip discoveries and de novo data generation. We identified candidate susceptibility loci for SCLS, which included a region flanking CAV3 (3p25.3) as well as SNP clusters in PON1 (7q21.3), PSORS1C1 (6p21.3), and CHCHD3 (7q33). Among the most highly ranked discoveries were gene-associated SNPs in the uncharacterized LOC100130480 gene (rs6417039, rs2004296). Top case-associated SNPs were observed in BTRC (rs1235580, 3rs4436485), ARHGEF18 (rs11668246), CDH13 (rs4782779), and EDG2 (rs12552348), which encode proteins with known or suspected roles in B cell function and/or vascular integrity. SNPs that were significantly associated with SCLS by microarray analysis were also detected and validated by exome deep sequencing. Functional annotation of highly ranked SNPs revealed enrichment of cell projections, cell junctions and adhesion, and molecules containing pleckstrin homology, Ras/Rho regulatory, and immunoglobulin Ig-like C2/fibronectin type III domains, all of which involve mechanistic functions that correlate with the SCLS phenotype. These results highlight SNPs with potential relevance to SCLS. Our study cohort included 12 patients with SCLS. The control group included 17 age, sex and ethnicity-matched healthy donors (including two relatives of SCLS patients), and a reference sample supplied by the SNP-chip manufacturer (Affymetrix), for which age information was not available. Affymetrix SNP arrays were performed according to the manufacturer's directions on DNA extracted from purified B lymphocytes.

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Affymetrix 6.0 SNP arrays interrogated to detect allele-specific DNA modification in the brain

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