Carrier-set topology reveals composite MHC tagging at the MICA rs2596542 locus: insights from a flip-flop association example

Abstract Cross-population reversal of signed linkage disequilibrium (LD), or the “flip-flop” phenomenon, can arise when a tag SNP captures different extended haplotype backgrounds across populations. The MICA hepatocellular carcinoma susceptibility variant rs2596542 exemplifies this problem in the MHC, where signed LD reverses between Japanese and European populations but the relevant regulatory backgrounds are obscured by haplotypic complexity. We analyzed 7,303 biallelic SNVs surrounding rs2596542 across 26 populations using carrier-set topology classification followed by non-negative matrix factorization of carrier haplotypes. This identified two regulatory axes. Axis I, represented by components c4/c6, was population-stable and MICA-regulatory, with coherent MICA cis-eQTL enrichment and depletion for signed-LD reversal. Axis II, represented by component c5, was enriched for signed-LD reversal and showed an HLA-B↑/HLA-C↓ expression signature with no MICA overlap across six GTEx tissues. The previously proposed cross-population tag rs2244546 mapped to a population-stable component rather than Axis II. Together, these findings indicate that rs2596542-T is not a single MICA-regulatory proxy but a composite MHC tag that captures separable MICA- and HLA-B/HLA-C-regulatory haplotypic backgrounds. Carrier-set topology combined with NMF provides a practical approach for resolving such composite tag signals and for interpreting cross-population signed-LD reversal in complex MHC loci.