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arXiv · 2608.05002

HaploPerturb: Low-rank copula construction of haplotype perturbations improves sequence-to-function analysis of Alzheimer's disease loci

Jichun Xie
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Abstract

Sequence-to-function models predict molecular phenotypes from complete sequence windows. At genome-wide association study loci, however, the prevailing design perturbs only the lead variant on the reference genome, even though the lead is often correlated with nearby variants through linkage disequilibrium. This single-variant perturbation implicitly fixes all linked alleles at their reference-genome states and may therefore create an uncommon or unobserved population haplotype. We study this input-construction problem at 38 Alzheimer's disease loci. We introduce HaploPerturb, which uses phased ROS/MAP genotypes or the European 1000 Genomes panel to fit a fixed-margin latent Gaussian factor model and rank partner configurations conditional on each lead allele. The leading public-panel construction agrees with the donor-panel construction at all loci under a strict linkage-disequilibrium threshold and 36 of 37 loci under a broader threshold after restricting to shared partners. Known-truth simulations show exact recovery of the dominant configuration under strong linkage disequilibrium and expose persistent residual correlation under a misspecified one-factor model. In an AlphaGenome benchmark against cell-type-specific ROS/MAP eQTLs, broader-set public-panel haplotypes yield microglial enrichment of 2.07 (95\% whole-locus bootstrap percentile interval 1.48--3.60), compared with 1.43 (0.69--2.29) for a lead-only edit. Empirical-mode and LD-sign backgrounds yield 2.20 (1.60--3.64), with no detectable advantage or loss relative to the HaploPerturb top configuration. Thus population-informed sequence construction matters in this application, while the choice among reasonable leading haplotype rules is less consequential than the choice between a haplotype and a lead-only reference background.

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Jichun Xie. 2026-08-05. HaploPerturb: Low-rank copula construction of haplotype perturbations improves sequence-to-function analysis of Alzheimer's disease loci. https://arxiv.org/abs/2608.05002

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