SigNet overview.
<p>Population cohorts (top) are genotyped and phenotyped in a genome-wide association study (GWAS). The study identifies genetic variants, usually single-nucleotide polymorphisms (SNPs, indicated by vertical bars overlayed on double-stranded DNA), that are associated with the phenotype at geno...
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2025
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| Summary: | <p>Population cohorts (top) are genotyped and phenotyped in a genome-wide association study (GWAS). The study identifies genetic variants, usually single-nucleotide polymorphisms (SNPs, indicated by vertical bars overlayed on double-stranded DNA), that are associated with the phenotype at genome-wide significance. These SNPs occur throughout the genome, and each SNP defines a genomic region, or locus, that likely contains a gene with a causal relationship with the phenotype. Each locus may contain several genes (arrows above and below the double helix indicate genes on the positive and negative strand), and three loci are depicted. The SigNet method integrates within-locus and between-locus information from DNA-based, RNA-based, and protein-based evidence to select the most likely causal gene at each locus. <b>Locus 1 (red):</b> a SNP in a protein-coding region may change the amino acid sequence of the encoded protein, indicated by the star overlaying the gene symbol and protein. Similarly, a gene in the region may be known to cause a Mendelian disease related to the GWAS phenotype, indicated as a familial case. At this locus, the red gene is selected as most likely. <b>Locus 2 (orange):</b> a SNP may affect the transcriptional regulation of a nearby gene, indicated by the orange arrow from the SNP to the gene transcription start site. The corresponding mRNA transcript may have altered abundance, indicated by the multiple transcripts. These SNPs are expression quantitative trait loci (eQTL), and colocalization of a GWAS association with an eQTL association provides evidence for the most likely causal gene. Methods such as transcriptome-wide association studies (TWAS) provide a similar type of evidence. <b>Locus 3 (green):</b> Many loci are information-poor, with no within-locus evidence and a default approach of selecting the gene closest to the SNP. The SigNet method adds between-locus information using a probability model for the network formed by protein-protein interactions and gene-regulatory interaction of the genes selected at each locus. The green gene product interacts with proteins encoded by genes selected at the other loci, and its causal likelihood is calculated to be higher than the other genes in the locus, including the gene closest to the GWAS SNP.</p> |
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