Identifying enhancer properties associated with genetic risk for complex traits using regulome-wide association...

Area of Science:

• Genomics
• Computational Biology
• Human Genetics

Background:

• Genetic risk for complex traits is concentrated in non-coding regulatory regions, particularly enhancers.
• Existing tools are insufficient for connecting enhancer disruptions to genetic disease risk.

Purpose of the Study:

• To introduce Regulome Wide Association Study (RWAS), a novel method for identifying enhancer characteristics associated with genetic disease risk.
• To apply RWAS to understand genetic risk factors for schizophrenia.

Main Methods:

• RWAS assigns single nucleotide polymorphisms (SNPs) to cell type-specific regulatory features like enhancers.
• It tests associations between regulatory features and traits using genome-wide association study (GWAS) summary statistics.
• Enhancer-set enrichment analyses identify specific regulatory element features linked to traits.

Main Results:

• RWAS identified AT-rich enhancers active in the developing brain as being associated with schizophrenia risk.
• These risk-associated enhancers contain transcription factor binding sites crucial for neurodevelopment.
• The study provides extensive annotations for tissue-specific enhancers, including evolutionary conservation and transcription factor binding.

Conclusions:

• RWAS is a powerful, open-source tool for characterizing regulatory elements contributing to genetic risk.
• This method enables the investigation of regulatory feature properties across various complex traits with available GWAS data.