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In most applications, SNP-to-gene annotation is based on SNP proximity to gene boundaries. This approach is ill-suited for incorporating non-coding SNPs, which can regulate gene expression over long distances and represent a large proportion of risk variants in complex diseases, such as Alzheimer\u2019s disease (AD). AD therefore provides a useful setting for evaluating whether functionally informed SNP-to-gene annotation improves pathway-PRS construction. Here, we compare AD pathway-PRS performance across annotation strategies that integrate varying levels of functional genomic data, including adult brain chromatin interaction and expression quantitative trait loci (eQTL) data. In the UK Biobank (n=328,526), including AD cases defined by ICD-9\/10 codes (n=3,043) and family history of AD\/dementia (n=38,589), the strategy integrating chromatin interaction and eQTL data consistently improves pathway-PRS performance. We replicate this finding in independent Alzheimer\u2019s Disease Genetics Consortium data (n=3,370). We further observe that pathway-PRS associations with AD vary by annotation strategy and that integrative annotation increases power to detect sex-dependent and age-at-onset associations. Together, these findings support the use of functionally informed SNP-to-gene annotation for pathway-PRS construction and highlight the importance of applying multiple annotation strategies for robust inference.<\/jats:p>","DOI":"10.64898\/2026.05.25.26353905","type":"posted-content","created":{"date-parts":[[2026,5,27]],"date-time":"2026-05-27T00:55:27Z","timestamp":1779843327000},"source":"Crossref","is-referenced-by-count":0,"title":["Functionally informed annotation influences pathway-specific polygenic risk and disease inference in Alzheimer\u2019s disease"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2006-623X","authenticated-orcid":false,"given":"Katrina","family":"Bazemore","sequence":"first","affiliation":[{"name":"Department of Biostatistics, Epidemiology, and Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA"},{"name":"Penn Neurodegeneration Genomics Center, Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Taha","family":"Iqbal","sequence":"additional","affiliation":[{"name":"Penn Neurodegeneration Genomics Center, Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amanda B","family":"Kuzma","sequence":"additional","affiliation":[{"name":"Penn Neurodegeneration Genomics Center, Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2025-5302","authenticated-orcid":false,"given":"Struan F. 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