Rare variants regulate expression of nearby individual genes in multiple tissues.

The rapid decrease in sequencing cost has enabled genetic studies to discover rare variants associated with complex diseases and traits. Once this association is identified, the next step is to understand the genetic mechanism of rare variants on how the variants influence diseases. Similar to the hypothesis of common variants, rare variants may affect diseases by regulating gene expression, and recently, several studies have identified the effects of rare variants on gene expression using heritability and expression outlier analyses. However, identifying individual genes whose expression is regulated by rare variants has been challenging due to the relatively small sample size of expression quantitative trait loci studies and statistical approaches not optimized to detect the effects of rare variants. In this study, we analyze whole-genome sequencing and RNA-seq data of 681 European individuals collected for the Genotype-Tissue Expression (GTEx) project (v8) to identify individual genes in 49 human tissues whose expression is regulated by rare variants. To improve statistical power, we develop an approach based on a likelihood ratio test that combines effects of multiple rare variants in a nonlinear manner and has higher power than previous approaches. Using GTEx data, we identify many genes regulated by rare variants, and some of them are only regulated by rare variants and not by common variants. We also find that genes regulated by rare variants are enriched for expression outliers and disease-causing genes. These results suggest the regulatory effects of rare variants, which would be important in interpreting associations of rare variants with complex traits. Author summary: It has been shown that rare variants may affect many diseases including both rare and common diseases with the advent of next-generation sequencing technology. An important question is how rare variants affect diseases or traits, especially whether or how they regulate gene expression as they may affect diseases through gene regulation. However, it is challenging to identify the regulatory effects of rare variants because it often requires large sample sizes and the existing statistical approaches are not optimized for it. Here, we develop a novel method, LRT-q, based on a likelihood ratio test that aggregates the effects of multiple rare variants nonlinearly to achieve higher statistical power than previous rare variant association methods. We apply LRT-q to the latest GTEx v8 dataset and identify regulatory effect of rare variants on individual genes. We also observe that genes regulated by rare variants are likely to be disease-causing genes. These results demonstrate the functional effects of rare variants, especially on gene expression, which provides important biological insights in understanding the genetic mechanism of rare variants in complex traits and diseases. [ABSTRACT FROM AUTHOR]