Mapping rare protein-coding variants on multi-organ imaging traits

Area of Science:

• Genetics
• Medical Imaging
• Human Physiology

Background:

• Human organ structure and function are key indicators of clinical outcomes.
• Genome-wide association studies (GWAS) have linked common genetic variants to brain and body phenotypes from magnetic resonance imaging (MRI).
• The impact of rare protein-coding variations on organ size and function remains largely unexplored.

Purpose of the Study:

• To conduct an exome-wide association study (EWAS) investigating rare genetic variants across multiple organ systems.
• To evaluate 596 multi-organ MRI traits in a large cohort to uncover novel genetic associations.
• To understand the role of rare coding variations in human organ morphology and function.

Main Methods:

• Performed an exome-wide association study on 596 multi-organ MRI traits.
• Analyzed data from over 50,000 individuals in the UK Biobank.
• Utilized singleton burden models and AlphaMissense annotations to identify gene-trait pairs.

Main Results:

• Identified 107 variant-level and 224 gene-based associations across various MRI modalities.
• Discovered specific associations, including PTEN with total brain volume, TTN with heart function, and TNFRSF13B with spleen volume.
• Found 8 unique gene-trait pairs using singleton burden models and AlphaMissense, including a link between KCNA5 and brain activity.

Conclusions:

• Rare coding variants significantly contribute to understanding genetic effects on human organ morphology and function.
• The findings highlight shared genetic influences across different organs and prioritize loci identified by previous GWAS.
• The study identified numerous drug targets and provides insights into the genetic underpinnings of complex diseases.