# Transcriptome-wide association analysis of brain structures yields insights into pleiotropy with complex neuropsychiatric traits

## TL;DR

This study uses gene expression data to find 278 genes linked to brain structure variations, showing how these genes relate to complex traits and diseases.

## Contribution

The study introduces a cross-tissue TWAS approach that enhances gene discovery and improves polygenic risk prediction for brain structures.

## Key findings

- 278 genes were found to be significantly associated with brain structural traits.
- TWAS-based PRS outperformed traditional GWAS PRS in explaining phenotypic variance.
- The identified genes are linked to a wide range of complex traits and diseases.

## Abstract

Structural variations of the human brain are heritable and highly polygenic traits, with hundreds of associated genes identified in recent genome-wide association studies (GWAS). Transcriptome-wide association studies (TWAS) can both prioritize these GWAS findings and also identify additional gene-trait associations. Here we perform cross-tissue TWAS analysis of 211 structural neuroimaging and discover 278 associated genes exceeding Bonferroni significance threshold of 1.04 × 10−8. The TWAS-significant genes for brain structures have been linked to a wide range of complex traits in different domains. Through TWAS gene-based polygenic risk scores (PRS) prediction, we find that TWAS PRS gains substantial power in association analysis compared to conventional variant-based GWAS PRS, and up to 6.97% of phenotypic variance (p-value = 7.56 × 10−31) can be explained in independent testing data sets. In conclusion, our study illustrates that TWAS can be a powerful supplement to traditional GWAS in imaging genetics studies for gene discovery-validation, genetic co-architecture analysis, and polygenic risk prediction.

Brain structural traits are highly heritable and have been linked to disease. Here the authors have used gene expression data to perform a transcriptome-wide association study on 211 brain structural traits, discovering 273 associated genes.