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PreprintCited by 112Genetic Associations and EpidemiologyAlzheimer's disease research and treatmentsGenetic Mapping and Diversity in Plants and Animals

Proteogenomic analysis of human cerebrospinal fluid identifies neurologically relevant regulation and informs causal proteins for Alzheimer's disease

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Cruchaga, Carlos, Western, Dan, Timsina, Jigyasha, Wang, Lihua, Wang, Ciyang, Yang, Chengran, Ali, Muhammad, Beric, Aleksandra +23 more·2023·Nature Genetics
DOI 10.21203/rs.3.rs-2814616/v1PMC PMC10275048

Preprint — published as 10.1038/s41588-024-01972-8 · Paper page

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Abstract

The integration of quantitative trait loci (QTL) with disease genome-wide association studies (GWAS) has proven successful at prioritizing candidate genes at disease-associated loci. QTL mapping has mainly been focused on multi-tissue expression QTL or plasma protein QTL (pQTL). Here we generated the largest-to-date cerebrospinal fluid (CSF) pQTL atlas by analyzing 7,028 proteins in 3,107 samples. We identified 3,373 independent study-wide associations for 1,961 proteins, including 2,448 novel pQTLs of which 1,585 are unique to CSF, demonstrating unique genetic regulation of the CSF proteome. In addition to the established chr6p22.2-21.32 HLA region, we identified pleiotropic regions on chr3q28 near OSTN and chr19q13.32 near APOE that were enriched for neuron-specificity and neurological development. We also integrated this pQTL atlas with the latest Alzheimer’s disease (AD) GWAS through PWAS, colocalization and Mendelian Randomization and identified 42 putative causal proteins for AD, 15 of which have drugs available. Finally, we developed a proteomics-based risk score for AD that outperforms genetics-based polygenic risk scores. These findings will be instrumental to further understand the biology and identify causal and druggable proteins for brain and neurological traits.

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Cited by

Sorted by citations

Authors
Cruchaga, C., Western, D., Timsina, J., Wang, L., Wang, C., Yang, C., Ali, M., Beric, A., Gorijala, P., Kohlfeld, P., Budde, J., Levey, A., Morris, J., Perrin, R., Ruiz, A., Marquié, M., Boada, M., de Rojas, I., Rutledge, J., Oh, H., Wilson, E., Guen, Y. L., Alvarez, I., Aguilar, M., Greicius, M., Pastor, P., Pulford, D., Ibanez, L., Wyss-Coray, T., Sung, Y. J., & Phillips, B.
Affiliations
  • Washington University in St. Louis (US)
  • Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA
  • Washington University School of Medicine, St Louis, MO, USA
  • Emory University (US)
  • Fundació ACE
  • Instituto de Salud Carlos III (ES)
  • Memory Clinic of Fundaciò ACE, Catalan Institute of Applied Neurosciences
  • Universitat Internacional de Catalunya
  • Stanford University (US)
  • Stanford Medicine (US)
  • Fundació Docència i Recerca MútuaTerrassa, Terrassa, Barcelona, Spain
  • University Hospital Mútua de Terrassa (ES)
  • GlaxoSmithKline (United Kingdom) (GB)
  • University Hospital Germans Trias i Pujol
  • Washington University in St. Louis
  • Stanford University
Corresponding author
Cruchaga, Carlos
ORCID
Venue
Nature Genetics
Publisher
Springer Science and Business Media LLC
Published
2023-06-09
Volume
56
Issue
12
Pages
2672-2684
ISSN
1061-4036 (ISSN-L)
DOI
10.21203/rs.3.rs-2814616/v1
PMC
PMC10275048
OpenAlex
W4404224780
Cited by
112
References
0
Citations by year
2026: 48 · 2025: 41 · 2024: 22 · 2023: 1
FWCI
27.27
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Genetics (publishedVersion)
  • Research Square (acceptedVersion, cc-by)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • Pure Amsterdam UMC (publishedVersion, cc-by)
  • PubMed Central (submittedVersion, cc-by)
  • Research Publications (Maastricht University) (submittedVersion, other-oa)
Funders
  • U.S. Department of Defense (U01 AG024904, W81XWH, W81XWH-12-2-, W81XWH1220012, W81XWH2010849, AG024904)
  • U.S. Department of Health and Human Services (RF1AG058501, RF1 AG053303, U01AG058922, P01AG003991, R01 AG044546)
  • Michael J. Fox Foundation for Parkinson's Research
  • Alzheimer's Association (ZEN-22-848604, SG-20-690363-DIAN, U01 AG024904, W81XWH-12-2-0012)
  • Bristol-Myers Squibb (U01 AG024904, AG024904, W81XWH-12-2-0012)
  • Eli Lilly and Company (U01 AG024904, AG024904, W81XWH-12-2-0012)
  • GlaxoSmithKline (P01AG026276, P30AG066444, P01AG03991)
  • Biogen (W81XWH-12-2-0012, U01 AG024904, AG024904)
  • F. Hoffmann-La Roche (W81XWH-12-2-0012, AG024904, U01 AG024904)
  • Alzheimer's Disease Neuroimaging Initiative (P01AG026276, W81XWH-12-2–0012, U01AG024904, AG024904, W81XWH-12-2-, Department of Defense award number W81XWH-12-2-0012, P01AG03991)
  • BioClinica (U01 AG024904, W81XWH-12-2-0012, AG024904)
  • Fondation Brain Canada
  • Japan Agency for Medical Research and Development
  • Hope Center for Neurological Disorders
  • Chan Zuckerberg Initiative
  • ZonMw
  • Korea Health Industry Development Institute
  • Eisai (W81XWH-12-2-0012, U01 AG024904, AG024904)
  • Deutsches Zentrum für Neurodegenerative Erkrankungen
  • Alzheimer Nederland (WE.03-2018-05)
  • IXICO (AG024904, W81XWH-12-2-0012, U01 AG024904)
  • Fleni
  • Amsterdam Neuroscience
  • National Institutes of Health (3u01ag024904-10s2, W81XWH, W81XWH-12-2-0012, U01-AG024904, Grant U01 AG024904, AG024904, AG066515)
  • Genentech (W81XWH-12-2-0012, AG024904, U01 AG024904)
  • Canadian Institutes of Health Research (U01 AG024904, W81XWH-12-2-0012)
  • Instituto de Salud Carlos III
  • National Institute on Aging (U01-AG-024904, W81XWH-12-2–0012, AG 024904, RF1AG053303, R01AG044546, AG066515, P01AG003991, R01AG064614, RF1AG071706, U19AG032438, R00AG062723, RF1AG074007, U01AG058922, RF1AG058501, R01AG058501, R01AG074007, R01AG078964, P30AG066444, P30AG066515, P01AG026276)
  • National Institute of Biomedical Imaging and Bioengineering (W81XWH-12-2-0012, U01 AG024904, AG024904)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Mapping and Diversity in Plants and Animals
Keywords
cerebrospinal fluid, proteome-wide association study, Alzheimer's disease, causal proteins, pleiotropy, apolipoprotein E, Mendelian randomization, colocalization, disease prediction model, druggable targets

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