Dataset Information

Refinement of schizophrenia GWAS loci using methylome-wide association data.

ABSTRACT: Recent genome-wide association studies (GWAS) have made substantial progress in identifying disease loci. The next logical step is to design functional experiments to identify disease mechanisms. This step, however, is often hampered by the large size of loci identified in GWAS that is caused by linkage disequilibrium between SNPs. In this study, we demonstrate how integrating methylome-wide association study (MWAS) results with GWAS findings can narrow down the location for a subset of the putative casual sites. We use the disease schizophrenia as an example. To handle "data analytic" variation, we first combined our MWAS results with two GWAS meta-analyses (N = 32,143 and 21,953), that had largely overlapping samples but different data analysis pipelines, separately. Permutation tests showed significant overlapping association signals between GWAS and MWAS findings. This significant overlap justified prioritizing loci based on the concordance principle. To further ensure that the methylation signal was not driven by chance, we successfully replicated the top three methylation findings near genes SDCCAG8, CREB1 and ATXN7 in an independent sample using targeted pyrosequencing. In contrast to the SNPs in the selected region, the methylation sites were largely uncorrelated explaining why the methylation signals implicated much smaller regions (median size 78 bp). The refined loci showed considerable enrichment of genomic elements of possible functional importance and suggested specific hypotheses about schizophrenia etiology. Several hypotheses involved possible variation in transcription factor-binding efficiencies.

SUBMITTER: Kumar G

PROVIDER: S-EPMC4282961 | biostudies-literature | 2015 Jan

REPOSITORIES: biostudies-literature

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Refinement of schizophrenia GWAS loci using methylome-wide association data.

Kumar Gaurav G Clark Shaunna L SL McClay Joseph L JL Shabalin Andrey A AA Adkins Daniel E DE Xie Linying L Chan Robin R Nerella Srilaxmi S Kim Yunjung Y Sullivan Patrick F PF Hultman Christina M CM Magnusson Patrik K E PK Aberg Karolina A KA van den Oord Edwin J C G EJ

Human genetics 20141007 1

Recent genome-wide association studies (GWAS) have made substantial progress in identifying disease loci. The next logical step is to design functional experiments to identify disease mechanisms. This step, however, is often hampered by the large size of loci identified in GWAS that is caused by linkage disequilibrium between SNPs. In this study, we demonstrate how integrating methylome-wide association study (MWAS) results with GWAS findings can narrow down the location for a subset of the puta ...[more]

PMID: 25284466

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Project description:ImportanceEpigenetic studies present unique opportunities to advance schizophrenia research because they can potentially account for many of its clinical features and suggest novel strategies to improve disease management.ObjectiveTo identify schizophrenia DNA methylation biomarkers in blood.Design, setting, and participantsThe sample consisted of 759 schizophrenia cases and 738 controls (N = 1497) collected in Sweden. We used methyl-CpG-binding domain protein-enriched genome sequencing of the methylated genomic fraction, followed by next-generation DNA sequencing. We obtained a mean (SD) number of 68 (26.8) million reads per sample. This massive data set was processed using a specifically designed data analysis pipeline. Critical top findings from our methylome-wide association study (MWAS) were replicated in independent case-control participants using targeted pyrosequencing of bisulfite-converted DNA.Main outcomes and measuresStatus of schizophrenia cases and controls.ResultsOur MWAS suggested a considerable number of effects, with 25 sites passing the highly conservative Bonferroni correction and 139 sites significant at a false discovery rate of 0.01. Our top MWAS finding, which was located in FAM63B, replicated with P = 2.3 × 10-10. It was part of the networks regulated by microRNA that can be linked to neuronal differentiation and dopaminergic gene expression. Many other top MWAS results could be linked to hypoxia and, to a lesser extent, infection, suggesting that a record of pathogenic events may be preserved in the methylome. Our findings also implicated a site in RELN, one of the most frequently studied candidates in methylation studies of schizophrenia.Conclusions and relevanceTo our knowledge, the present study is one of the first MWASs of disease with a large sample size using a technology that provides good coverage of methylation sites across the genome. Our results demonstrated one of the unique features of methylation studies that can capture signatures of environmental insults in peripheral tissues. Our MWAS suggested testable hypotheses about disease mechanisms and yielded biomarkers that can potentially be used to improve disease management.

Dataset Information

Refinement of schizophrenia GWAS loci using methylome-wide association data.

Publications

Refinement of schizophrenia GWAS loci using methylome-wide association data.

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