The Missing Link Between Genetic Association and Regulatory Function

Overview

Journal Elife

Specialty Biology

Date 2022 Dec 14

PMID 36515579

Authors

Noah J Connally

Sumaiya Nazeen

Daniel Lee

Huwenbo Shi

John Stamatoyannopoulos

Sung Chun

Chris Cotsapas

Christopher A Cassa

Shamil R Sunyaev

Affiliations

Soon will be listed here.

Abstract

The genetic basis of most traits is highly polygenic and dominated by non-coding alleles. It is widely assumed that such alleles exert small regulatory effects on the expression of -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.'

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