![]() Another is that expression levels mediate a minority of complex trait heritability ( Yao et al., 2020). ![]() One challenge is the difference between spatial distributions of eQTLs, which are dramatically enriched in close proximity to genes, and GWAS peaks, which are usually farther away ( Stranger et al., 2007 Farh et al., 2015 Mostafavi et al., 2022). Our argument begins with several observations that challenge the unembellished model. We highlight the challenges of current strategies linking GWAS variants to genes and call for a reevaluation of the basic model in favor of more complex models possibly involving context-specificity with respect to cell types, developmental stages, cell states, or the constancy of expression effects. Here we argue that this unembellished model-in which genome-wide association study (GWAS) peaks are mediated by the effects on the homeostatic expression assayed in tissue samples-is the exception rather than the rule. Thus, a model has emerged in which most trait-associated variants influence proximal gene regulation. The genetic variant causing expression changes may lie outside the locus and involve a knock-on effect on gene regulation, with the variant altering transcript abundances for genes elsewhere in the genome (a trans-eQTL), but the consensus view is that trans-eQTLs are typically mediated by the variant influencing a gene in the region (a cis-eQTL) ( GTEx Consortium, 2020). Equivalent sQTL (splice QTL) analyses of exon usage data have revealed a more modest overlap with trait-associated alleles, suggesting that a fraction of trait-associated variants influence splicing, and hence the relative abundance of different transcript isoforms, rather than overall expression levels. Combined, these observations have led to the inference that most trait-associated variants are eQTLs, and their effects arise from altering transcript abundance, rather than protein sequence. Furthermore, genes in trait-associated loci are more likely to have genetic variants that affect their expression levels (expression quantitative trait loci, or eQTLs), and the variants with the strongest trait associations are more likely also to be associated with transcript abundance of at least one proximal gene ( Nicolae et al., 2010). Enrichment analyses have demonstrated that a large fraction of heritability resides in regions with gene regulatory potential, predominantly tissue-specific accessible chromatin and enhancer elements, suggesting that trait-associated variants influence gene regulation ( Maurano et al., 2012 Trynka et al., 2013 Gusev et al., 2014). Further work has revealed unexpectedly high polygenicity for most human traits and very small effect sizes for individual variants. Modern complex trait genetics has uncovered surprises at every turn, including the paucity of associations between traits and coding variants of large effect, and the ‘mystery of missing heritability,’ in which no combination of common and rare variants can explain a large fraction of trait heritability ( Manolio et al., 2009). The field must confront this deficit and pursue this ‘missing regulation.’ Editor's evaluation These results contradict the hypothesis that most complex trait-associated variants coincide with homeostatic expression QTLs, suggesting that better models are needed. Despite the presence of expression quantitative trait loci near most GWAS associations, by applying a gene-based approach we found limited evidence that the baseline expression of trait-related genes explains GWAS associations, whether using colocalization methods (8% of genes implicated), transcription-wide association (2% of genes implicated), or a combination of regulatory annotations and distance (4% of genes implicated). To better distinguish between these possibilities, we identified 220 gene–trait pairs in which protein-coding variants influence a complex trait or its Mendelian cognate. It is unclear whether these sparse results are due to limitations in available data and methods, or to deficiencies in the underlying assumed model. However, despite the availability of gene expression and epigenomic datasets, few variant-to-gene links have emerged. It is widely assumed that such alleles exert small regulatory effects on the expression of cis-linked genes. The genetic basis of most traits is highly polygenic and dominated by non-coding alleles.
0 Comments
Leave a Reply. |
Details
AuthorWrite something about yourself. No need to be fancy, just an overview. ArchivesCategories |