The missing link between genetic association and regulatory function

作者：Noah J Connally, Sumaiya Nazeen, Daniel Lee, Huwenbo Shi, J Stamatoyannopoulos, Sung Chun, Chris Cotsapas, Christopher A. Cassa, Shamil Sunyaev · 发表于：eLife · 年份：2022 · DOI：10.7554/elife.74970 · 被引用次数：162 · 研究领域：Genetic Mapping and Diversity in Plants and Animals、Genomics and Chromatin Dynamics、Genetic Associations and Epidemiology

-linked genes. However, despite the availability of gene expression and epigenomic datasets, few variant-to-gene links have emerged. It is unclear whether these sparse results are due to limitations in available data and methods, or to deficiencies in the underlying assumed model. 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. 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). These results contradict the hypothesis that most complex trait-associated variants coincide with homeostatic expression QTLs, suggesting that better models are needed. The field must confront this deficit and pursue this 'missing regulation.'