Integrative multi-omics QTL colocalization maps regulatory architecture in aging human brain Article Swipe
Xuewei Cao
,
Haochen Sun
,
Ru Feng
,
Rahul Mazumder
,
Carlos F. Buen Abad Najar
,
Yang Li
,
Philip L. De Jager
,
David A. Bennett
,
Kushal K. Dey
,
Gao Wang
·
YOU?
·
· 2025
· Open Access
·
· DOI: https://doi.org/10.1101/2025.04.17.25326042
YOU?
·
· 2025
· Open Access
·
· DOI: https://doi.org/10.1101/2025.04.17.25326042
Multi-trait QTL (xQTL) colocalization has shown great promises in identifying causal variants with shared genetic etiology across multiple molecular modalities, contexts, and complex diseases. However, the lack of scalable and efficient methods to integrate large-scale multi-omics data limits deeper insights into xQTL regulation. Here, we propose ColocBoost , a multi-task learning colocalization method that can scale to hundreds of traits, while accounting for multiple causal variants within a genomic region of interest. ColocBoost employs a specialized gradient boosting framework that can adaptively couple colocalized traits while performing causal variant selection, thereby enhancing the detection of weaker shared signals compared to existing pairwise and multi-trait colocalization methods. We applied ColocBoost genome-wide to 17 gene-level single-nucleus and bulk xQTL data from the aging brain cortex of ROSMAP individuals (average N = 595), encompassing 6 cell types, 3 brain regions and 3 molecular modalities (expression, splicing, and protein abundance). Across molecular xQTLs, ColocBoost identified 16,503 distinct colocalization events, exhibiting 10.7(± 0.74)-fold enrichment for heritability across 57 complex diseases/traits and showing strong concordance with element-gene pairs validated by CRISPR screening assays. When colocalized against Alzheimer’s disease (AD) GWAS, ColocBoost identified up to 2.5-fold more distinct colocalized loci, explaining twice the AD disease heritability compared to fine-mapping without xQTL integration. This improvement is largely attributable to ColocBoost ’s enhanced sensitivity in detecting gene-distal colocalizations, as supported by strong concordance with known enhancer-gene links, highlighting its ability to identify biologically plausible AD susceptibility loci with underlying regulatory mechanisms. Notably, several genes including BLNK and CTSH showed sub-threshold associations in GWAS, but were identified through multi-omics colocalizations which provide new functional support for their involvement in AD pathogenesis.
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- Type
- preprint
- Language
- en
- Landing Page
- https://doi.org/10.1101/2025.04.17.25326042
- https://www.medrxiv.org/content/medrxiv/early/2025/04/20/2025.04.17.25326042.full.pdf
- OA Status
- green
- Cited By
- 5
- References
- 96
- Related Works
- 10
- OpenAlex ID
- https://openalex.org/W4409676964
All OpenAlex metadata
Raw OpenAlex JSON
- OpenAlex ID
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https://openalex.org/W4409676964Canonical identifier for this work in OpenAlex
- DOI
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https://doi.org/10.1101/2025.04.17.25326042Digital Object Identifier
- Title
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Integrative multi-omics QTL colocalization maps regulatory architecture in aging human brainWork title
- Type
-
preprintOpenAlex work type
- Language
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enPrimary language
- Publication year
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2025Year of publication
- Publication date
-
2025-04-20Full publication date if available
- Authors
-
Xuewei Cao, Haochen Sun, Ru Feng, Rahul Mazumder, Carlos F. Buen Abad Najar, Yang Li, Philip L. De Jager, David A. Bennett, Kushal K. Dey, Gao WangList of authors in order
- Landing page
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https://doi.org/10.1101/2025.04.17.25326042Publisher landing page
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https://www.medrxiv.org/content/medrxiv/early/2025/04/20/2025.04.17.25326042.full.pdfDirect link to full text PDF
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YesWhether a free full text is available
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greenOpen access status per OpenAlex
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https://www.medrxiv.org/content/medrxiv/early/2025/04/20/2025.04.17.25326042.full.pdfDirect OA link when available
- Concepts
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Colocalization, Quantitative trait locus, Computational biology, Genetic architecture, Human brain, Neuroscience, Biology, Architecture, Computer science, Genetics, Geography, Gene, ArchaeologyTop concepts (fields/topics) attached by OpenAlex
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5Total citation count in OpenAlex
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2025: 5Per-year citation counts (last 5 years)
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96Number of works referenced by this work
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10Other works algorithmically related by OpenAlex
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