This study, co-authored by researchers from Bio2Q, Keio University, and RIKEN, introduces UNIChro-seq, a new method for accurately and efficiently measuring how disease-associated genetic variants affect chromatin accessibility at specific genomic regions.

Although genome-wide association studies have identified many variants associated with complex diseases, determining their molecular functions remains challenging as conventional approaches often require large numbers of donors and may lack the sensitivity to detect subtle or cell state specific effects.

Here, these researchers developed a method called UNIChro-seq, which uses unique molecular identifiers, and targeted amplification, to digitally count accessible chromatin molecules and precisely quantify allele-specific effects. Applying the method to autoimmune disease risk variants across multiple immune cell types and conditions, they demonstrated its ability to detect both baseline and dynamic effects on chromatin accessibility using relatively few donors. By combining UNIChro-seq with genome editing, this research team also identified a previously underappreciated bias caused by the editing process itself and showed that bi-directional genome editing can distinguish this bias from genuine causal effects. Finally, functional analysis of a rheumatoid arthritis-associated variant at the LEF1 locus linked altered chromatin accessibility to LEF1 dysregulation in CD4+ T cells.

Together, this work establishes UNIChro-seq as a sensitive and scalable platform for investigating how disease-associated genetic variants influence gene regulation and contribute to complex disease.