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.