HapTWAS: A Haplotype-Resolved Transcriptome-Wide Association Framework

HapTWAS provides a unified haplotype-resolved transcriptome-wide association framework, employing haplotypes to capture the concerted cis-regulatory effects of local genetic architectures for genetically regulated expression modeling, effectively integrating the LD structure and phase information that are often fragmented in single-variant analyses. Specifically, it is engineered to be computationally universal, supporting both individual-level genotypes and summary-level statistics through a novel SNP-to-haplotype transformation strategy. It can also extend to other SNP-incorporated strategies for conditional analyses, such as integrating biological priors to divide specific functional regions. Our results establish HapTWAS as a powerful and scalable strategy, not only enhancing the predictive accuracy of gene expression but also achieving a refined resolution for fine-mapping causal genes. The framework is publicly available via an interactive website (https://twas.farmgtex.org/), providing a statistically rigorous and versatile toolset to resolve an even greater fraction of the missing heritability and fully bridge the gap from genetic variation to biological function. This platform democratizes the use of our advanced models, empowering the research community without specialized computational expertise to conveniently apply HapTWAS on their own data, thereby accelerating discovery and interpretation across complex traits and species.