Dataset Information

From SNPs to pathways: Biological interpretation of type 2 diabetes (T2DM) genome wide association study (GWAS) results.

ABSTRACT: Genome-wide association studies (GWAS) have become a common method for discovery of gene-disease relationships, in particular for complex diseases like Type 2 Diabetes Mellitus (T2DM). The experience with GWAS analysis has revealed that the genetic risk for complex diseases involves cumulative, small effects of many genes and only some genes with a moderate effect. In order to explore the complexity of the relationships between T2DM genes and their potential function at the process level as effected by polymorphism effects, a secondary analysis of a GWAS meta-analysis is presented. Network analysis, pathway information and integration of different types of biological information such as eQTLs and gene-environment interactions are used to elucidate the biological context of the genetic variants and to perform an analysis based on data visualization. We selected a T2DM dataset from a GWAS meta-analysis, and extracted 1,971 SNPs associated with T2DM. We mapped 580 SNPs to 360 genes, and then selected 460 pathways containing these genes from the curated collection of WikiPathways. We then created and analyzed SNP-gene and SNP-gene-pathway network modules in Cytoscape. A focus on genes with robust connections to pathways permitted identification of many T2DM pertinent pathways. However, numerous genes lack literature evidence of association with T2DM. We also speculate on the genes in specific network structures obtained in the SNP-gene network, such as gene-SNP-gene modules. Finally, we selected genes relevant to T2DM from our SNP-gene-pathway network, using different sources that reveal gene-environment interactions and eQTLs. We confirmed functions relevant to T2DM for many genes and have identified some-LPL and APOB-that require further validation to clarify their involvement in T2DM.

SUBMITTER: Cirillo E

PROVIDER: S-EPMC5884486 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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From SNPs to pathways: Biological interpretation of type 2 diabetes (T2DM) genome wide association study (GWAS) results.

Cirillo Elisa E Kutmon Martina M Gonzalez Hernandez Manuel M Hooimeijer Tom T Adriaens Michiel E ME Eijssen Lars M T LMT Parnell Laurence D LD Coort Susan L SL Evelo Chris T CT

PloS one 20180404 4

Genome-wide association studies (GWAS) have become a common method for discovery of gene-disease relationships, in particular for complex diseases like Type 2 Diabetes Mellitus (T2DM). The experience with GWAS analysis has revealed that the genetic risk for complex diseases involves cumulative, small effects of many genes and only some genes with a moderate effect. In order to explore the complexity of the relationships between T2DM genes and their potential function at the process level as effe ...[more]

PMID: 29617380

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Project description:Genetic risk factors for osteoporosis, a prevalent disease associated with aging, have been examined in many genome-wide association studies (GWASs). A major challenge is to prioritize transcription-regulatory GWAS-derived variants that are likely to be functional. Given the critical role of epigenetics in gene regulation, we have used an unusual epigenetics-based and transcription-based approach to identify some of the credible regulatory single-nucleotide polymorphisms (SNPs) relevant to osteoporosis from 38 reported bone mineral density (BMD) GWASs. Using Roadmap databases, we prioritized SNPs based upon their overlap with strong enhancer or promoter chromatin preferentially in osteoblasts relative to 12 heterologous cell culture types. We also required that these SNPs overlap open chromatin (Deoxyribonuclease I [DNaseI]-hypersensitive sites) and DNA sequences predicted to bind to osteoblast-relevant transcription factors in an allele-specific manner. From >50,000 GWAS-derived SNPs, we identified 14 novel and credible regulatory SNPs (Tier-1 SNPs) for osteoporosis risk. Their associated genes, BICC1, LGR4, DAAM2, NPR3, or HMGA2, are involved in osteoblastogenesis or bone homeostasis and regulate cell signaling or enhancer function. Four of these genes are preferentially expressed in osteoblasts. BICC1, LGR4, and DAAM2 play important roles in canonical Wnt signaling, a pathway critical for bone formation and repair. The transcription factors predicted to bind to the Tier-1 SNP-containing DNA sequences also have bone-related functions. We present evidence that some of the Tier-1 SNPs exert their effects on BMD risk indirectly through little-studied long noncoding RNA (lncRNA) genes, which may, in turn, control the nearby bone-related protein-encoding gene. Our study illustrates a method to identify novel BMD-related causal regulatory SNPs for future study and to prioritize candidate regulatory GWAS-derived SNPs, in general. © 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Dataset Information

From SNPs to pathways: Biological interpretation of type 2 diabetes (T2DM) genome wide association study (GWAS) results.

Publications

From SNPs to pathways: Biological interpretation of type 2 diabetes (T2DM) genome wide association study (GWAS) results.

Similar Datasets

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