Dataset Information

Extensive Association of Common Disease Variants with Regulatory Sequence.

ABSTRACT: Overlap between non-coding DNA regulatory sequences and common variant associations can help to identify specific cell and tissue types that are relevant for particular diseases. In a systematic manner, we analyzed variants from 94 genome-wide association studies (reporting at least 12 loci at p<5x10-8) by projecting them onto 466 epigenetic datasets (characterizing DNase I hypersensitive sites; DHSs) derived from various adult and fetal tissue samples and cell lines including many biological replicates. We were able to confirm many expected associations, such as the involvement of specific immune cell types in immune-related diseases and tissue types in diseases that affect specific organs, for example, inflammatory bowel disease and coronary artery disease. Other notable associations include adrenal glands in coronary artery disease, the immune system in Alzheimer's disease, and the kidney for bone marrow density. The association signals for some GWAS (for example, myopia or age at menarche) did not show a clear pattern with any of the cell or tissue types studied. In general, the identified variants from GWAS tend to be located outside coding regions. Altogether, we have performed an extensive characterization of GWAS signals in relation to cell and tissue-specific DHSs, demonstrating a key role for regulatory mechanisms in common diseases and complex traits.

SUBMITTER: Mokry M

PROVIDER: S-EPMC5119736 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature

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Extensive Association of Common Disease Variants with Regulatory Sequence.

Mokry Michal M Harakalova Magdalena M Asselbergs Folkert W FW de Bakker Paul I W PI Nieuwenhuis Edward E S EE

PloS one 20161122 11

Overlap between non-coding DNA regulatory sequences and common variant associations can help to identify specific cell and tissue types that are relevant for particular diseases. In a systematic manner, we analyzed variants from 94 genome-wide association studies (reporting at least 12 loci at p<5x10-8) by projecting them onto 466 epigenetic datasets (characterizing DNase I hypersensitive sites; DHSs) derived from various adult and fetal tissue samples and cell lines including many biological re ...[more]

PMID: 27875544

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Project description:Historically, association of disease with the major histocompatibility complex (HLA) genes has been tested with HLA alleles that encode antigen-binding affinity. The association with Parkinson disease (PD), however, was discovered with noncoding SNPs in a genome-wide association study (GWAS). We show here that several HLA-region SNPs that have since been associated with PD form two blocks tagged by rs3129882 (p = 9 × 10(-11)) and by rs9268515 and/or rs2395163 (p = 3 × 10(-11)). We investigated whether these SNP-associations were driven by HLA-alleles at adjacent loci. We imputed class I and class II HLA-alleles for 2000 PD cases and 1986 controls from the NeuroGenetics Research Consortium GWAS and sequenced a subset of 194 cases and 204 controls. We were therefore able to assess accuracy of two imputation algorithms against next-generation-sequencing while taking advantage of the larger imputed data sets for disease study. Additionally, we imputed HLA alleles for 843 cases and 856 controls from another GWAS for replication. PD risk was positively associated with the B(?)07:02_C(?)07:02_DRB5(?)01_DRB1(?)15:01_DQA1(?)01:02_DQB1(?)06:02 haplotype and negatively associated with the C(?)03:04, DRB1(?)04:04 and DQA1(?)03:01 alleles. The risk haplotype and DQA1(?)03:01 lost significance when conditioned on the SNPs, but C(?)03:04 (OR = 0.72, p = 8 × 10(-6)) and DRB1(?)04:04 (OR = 0.65, p = 4 × 10(-5)) remained significant. Similarly, rs3129882 and the closely linked rs9268515 and rs2395163 remained significant irrespective of HLA alleles. rs3129882 and rs2395163 are expression quantitative trait loci (eQTLs) for HLA-DR and HLA-DQ (9 × 10(-5) ? PeQTL ? 2 × 10(-79)), suggesting that HLA gene expression might influence PD. Our data suggest that PD is associated with both structural and regulatory elements in HLA. Furthermore, our study demonstrates that noncoding SNPs in the HLA region can be associated with disease irrespective of HLA alleles, and that observed associations with HLA alleles can sometimes be secondary to a noncoding variant.

Dataset Information

Extensive Association of Common Disease Variants with Regulatory Sequence.

Publications

Extensive Association of Common Disease Variants with Regulatory Sequence.

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