find-tfbs

find-tfbs identifies transcription factor binding sites altered by non-coding variants by scanning open chromatin maps and phased whole-genome sequences (WGS) to prioritize variants that disrupt or create transcription factor binding sites (TFBS) and associate them with complex human traits.

Key Features:

• Efficient scanning of phased WGS: Scans phased whole-genome sequences in large cohorts to identify and count TFBS within regulatory sequences.
• Association testing for functional variants: Uses TFBS counts and variant information in association testing frameworks to prioritize putatively functional non-coding variants linked to traits or diseases.
• Application to large cohorts: Demonstrated on the NHLBI Trans-Omics for Precision Medicine (TOPMed) WGS dataset and scalable to cohorts up to 44,709 individuals.
• Discovery of significant associations: Identified over 2,000 associations with p-values < 1×10⁻⁹ related to hematological traits, highlighting specific blood cell types, transcription factors, and causal genes with overlap to GWAS signals.
• Computational efficiency and robustness: Implements a computational approach capable of rapid identification of non-coding variants affecting TFBS across multiple human phenotypes in very large datasets.

Scientific Applications:

• Genomic research: Enables exploration of the genetic architecture of complex traits by focusing on regulatory sequence variation and TFBS alterations.
• Disease association studies: Identifies putatively functional non-coding variants contributing to disease mechanisms, exemplified by hematological trait associations.
• Transcriptional regulation analysis: Facilitates identification of TFBS changes that can inform gene regulation networks and causal gene prioritization.

Methodology:

Scan phased WGS for regulatory sequences containing TFBS, count TFBS occurrences per sequence, and use these counts in association testing frameworks to link non-coding variants with phenotypic traits or diseases.