Rare coding and noncoding variants map 1,342 diseases and biomarkers in 490,549 whole genomes

Area of Science:

• Genomics
• Human Genetics
• Statistical Genetics

Background:

• Rare genetic variants, particularly noncoding ones, significantly contribute to human trait heritability but are understudied in large biobanks.
• These variants are often biologically specific and less polygenic than common variants, necessitating specialized analytical approaches.

Purpose of the Study:

• To comprehensively assess the impact of rare coding and noncoding variants across a wide range of human phenotypes using whole genome sequencing data.
• To develop and apply a scalable framework for phenome-wide association studies of rare variants.

Main Methods:

• Analysis of whole genome sequencing (WGS) data from up to 490,549 UK Biobank participants.
• Development and application of STAARpipelinePheWAS, a scalable framework for WGS phenome-wide rare variant association analysis.
• Assessment of 1,342 phenotypes, including diseases, clinical biomarkers, and metabolomics traits.

Main Results:

• Identification of 49,121 genome-wide significant gene-trait pairs, highlighting the role of rare variants in human traits.
• Discovery of numerous associations involving noncoding rare variants, many previously undetected by exome or array-based studies.
• Enrichment of identified associations in drug targets and biologically relevant pathways, suggesting translational potential.

Conclusions:

• This study provides a comprehensive map of rare noncoding variant associations across disease and biomarker domains.
• The findings offer a foundational resource for rare variant discovery, functional interpretation, and advancing translational genomics.
• Public accessibility of results via an interactive portal facilitates further research and application.