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Deciphering the Emerging Complexities of Molecular Mechanisms at GWAS Loci.

ABSTRACT: Genome-wide association studies (GWASs) have identified thousands of loci associated with hundreds of complex diseases and traits, and progress is being made toward elucidating the causal variants and genes underlying these associations. Functional characterization of mechanisms at GWAS loci is a multi-faceted challenge. Challenges include linkage disequilibrium and allelic heterogeneity at each locus, the noncoding nature of most loci, and the time and cost needed for experimentally evaluating the potential mechanistic contributions of genes and variants. As GWAS sample sizes increase, more loci are identified, and the complexities of individual loci emerge. Loci can consist of multiple association signals, each of which can reflect the influence of multiple variants, inseparable by association analyses. Each signal within a locus can influence the same or different target genes. Experimental studies of genes and variants can differ on the basis of cell type, cellular environment, or other context-specific variables. In this review, we describe the complexity of mechanisms at GWAS loci-including multiple signals, multiple variants, and/or multiple genes-and the implications these complexities hold for experimental study design and interpretation of GWAS mechanisms.

SUBMITTER: Cannon ME

PROVIDER: S-EPMC6218604 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature

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Deciphering the Emerging Complexities of Molecular Mechanisms at GWAS Loci.

Cannon Maren E ME Mohlke Karen L KL

American journal of human genetics 20181101 5

Genome-wide association studies (GWASs) have identified thousands of loci associated with hundreds of complex diseases and traits, and progress is being made toward elucidating the causal variants and genes underlying these associations. Functional characterization of mechanisms at GWAS loci is a multi-faceted challenge. Challenges include linkage disequilibrium and allelic heterogeneity at each locus, the noncoding nature of most loci, and the time and cost needed for experimentally evaluating ...[more]

PMID: 30388398

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Project description:BACKGROUND:There are now over 2000 loci in the human genome where genome wide association studies (GWAS) have found one or more SNPs to be associated with altered risk of a complex trait disease. At each of these loci, there must be some molecular level mechanism relevant to the disease. What are these mechanisms and how do they contribute to disease? RESULTS:Here we consider the roles of three primary mechanism classes: changes that directly alter protein function (missense SNPs), changes that alter transcript abundance as a consequence of variants close-by in sequence, and changes that affect splicing. Missense SNPs are divided into those predicted to have a high impact on in vivo protein function, and those with a low impact. Splicing is divided into SNPs with a direct impact on splice sites, and those with a predicted effect on auxiliary splicing signals. The analysis was based on associations found for seven complex trait diseases in the classic Wellcome Trust Case Control Consortium (WTCCC1) GWA study and subsequent studies and meta-analyses, collected from the GWAS catalog. Linkage disequilibrium information was used to identify possible candidate SNPs for involvement in disease mechanism in each of the 356 loci associated with these seven diseases. With the parameters used, we find that 76% of loci have at least of these mechanisms. Overall, except for the low incidence of direct impact on splice sites, the mechanisms are found at similar frequencies, with changes in transcript abundance the most common. But the distribution of mechanisms over diseases varies markedly, as does the fraction of loci with assigned mechanisms. Many of the implicated proteins have previously been suggested as relevant, but the specific mechanism assignments are new. In addition, a number of new disease relevant proteins are proposed. CONCLUSIONS:The high fraction of GWAS loci with proposed mechanisms suggests that these classes of mechanism play a major role. Other mechanism types, such as variants affecting expression of genes remote in the DNA sequence, will contribute in other loci. Each of the identified putative mechanisms provides a hypothesis for further investigation.

Project description:A drug exerts its effects typically through a signal transduction cascade, which is non-linear and involves intertwined networks of multiple signaling pathways. Construction of such a signaling pathway network (SPNetwork) can enable identification of novel drug targets and deep understanding of drug action. However, it is challenging to synopsize critical components of these interwoven pathways into one network. To tackle this issue, we developed a novel computational framework, the Drug-specific Signaling Pathway Network (DSPathNet). The DSPathNet amalgamates the prior drug knowledge and drug-induced gene expression via random walk algorithms. Using the drug metformin, we illustrated this framework and obtained one metformin-specific SPNetwork containing 477 nodes and 1,366 edges. To evaluate this network, we performed the gene set enrichment analysis using the disease genes of type 2 diabetes (T2D) and cancer, one T2D genome-wide association study (GWAS) dataset, three cancer GWAS datasets, and one GWAS dataset of cancer patients with T2D on metformin. The results showed that the metformin network was significantly enriched with disease genes for both T2D and cancer, and that the network also included genes that may be associated with metformin-associated cancer survival. Furthermore, from the metformin SPNetwork and common genes to T2D and cancer, we generated a subnetwork to highlight the molecule crosstalk between T2D and cancer. The follow-up network analyses and literature mining revealed that seven genes (CDKN1A, ESR1, MAX, MYC, PPARGC1A, SP1, and STK11) and one novel MYC-centered pathway with CDKN1A, SP1, and STK11 might play important roles in metformin's antidiabetic and anticancer effects. Some results are supported by previous studies. In summary, our study 1) develops a novel framework to construct drug-specific signal transduction networks; 2) provides insights into the molecular mode of metformin; 3) serves a model for exploring signaling pathways to facilitate understanding of drug action, disease pathogenesis, and identification of drug targets.

Project description:Recent work has shown that much of the missing heritability of complex traits can be resolved by estimates of heritability explained by all genotyped SNPs. However, it is currently unknown how much heritability is missing due to poor tagging or additional causal variants at known GWAS loci. Here, we use variance components to quantify the heritability explained by all SNPs at known GWAS loci in nine diseases from WTCCC1 and WTCCC2. After accounting for expectation, we observed all SNPs at known GWAS loci to explain 1.29 x more heritability than GWAS-associated SNPs on average (P=3.3 x 10??). For some diseases, this increase was individually significant: 2.07 x for Multiple Sclerosis (MS) (P=6.5 x 10??) and 1.48 x for Crohn's Disease (CD) (P = 1.3 x 10?³); all analyses of autoimmune diseases excluded the well-studied MHC region. Additionally, we found that GWAS loci from other related traits also explained significant heritability. The union of all autoimmune disease loci explained 7.15 x more MS heritability than known MS SNPs (P < 1.0 x 10?¹? and 2.20 x more CD heritability than known CD SNPs (P = 6.1 x 10??), with an analogous increase for all autoimmune diseases analyzed. We also observed significant increases in an analysis of > 20,000 Rheumatoid Arthritis (RA) samples typed on ImmunoChip, with 2.37 x more heritability from all SNPs at GWAS loci (P = 2.3 x 10??) and 5.33 x more heritability from all autoimmune disease loci (P < 1 x 10?¹? compared to known RA SNPs (including those identified in this cohort). Our methods adjust for LD between SNPs, which can bias standard estimates of heritability from SNPs even if all causal variants are typed. By comparing adjusted estimates, we hypothesize that the genome-wide distribution of causal variants is enriched for low-frequency alleles, but that causal variants at known GWAS loci are skewed towards common alleles. These findings have important ramifications for fine-mapping study design and our understanding of complex disease architecture.

Dataset Information

Deciphering the Emerging Complexities of Molecular Mechanisms at GWAS Loci.

Publications

Deciphering the Emerging Complexities of Molecular Mechanisms at GWAS Loci.

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