Proteogenomic analysis of human cerebrospinal fluid identifies neurologically relevant regulation and informs causal proteins for Alzheimer’s disease
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.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Jun 09, 2023
- Source ID
- 10.21203/rs.3.rs-2814616/v1
Entities
People
- Agustín Ruíz
- Aleksandra Beric
- Allan Levey
- Carlos Cruchaga
- Chengran Yang
- Ciyang Wang
- Daniel Western
- David Pulford
- Edward N Wilson
- Hamilton Oh
- Ignacio Álvarez
- Itziar De Rojas
- Jarod Rutledge
- Jigyasha Timsina
- John A Morris
- John P Budde
- Laura Ibanez
- Lihua Wang
- Marta Marquié
- Mercè Boada
- Michael Greicius
- Miquel Aguilar
- Muhammad Ali
- Patsy Kohlfeld
- Pau Pastor
- Priyanka Gorijala
- Richard J Perrin
- Tony Wyss-Coray
- Yann Le Guen
- Yun Ju Sung
Organizations
- Emory and Henry University
- Fundació ACE
- GSK
- International University of Catalonia
- Stanford University
- Stanford University School of Medicine
- Washington University in St. Louis