TY - JOUR
T1 - Proteogenomic analysis of human cerebrospinal fluid identifies neurologically relevant regulation and implicates causal proteins for Alzheimer’s disease
AU - Dominantly Inherited Alzheimer Network (DIAN)
AU - The Alzheimer’s Disease Neuroimaging Initiative (ADNI)
AU - Western, Daniel
AU - Timsina, Jigyasha
AU - Wang, Lihua
AU - Wang, Ciyang
AU - Yang, Chengran
AU - Phillips, Bridget
AU - Wang, Yueyao
AU - Liu, Menghan
AU - Ali, Muhammad
AU - Beric, Aleksandra
AU - Gorijala, Priyanka
AU - Kohlfeld, Pat
AU - Budde, John
AU - Levey, Allan I.
AU - Morris, John C.
AU - Perrin, Richard J.
AU - Ruiz, Agustin
AU - Marquié, Marta
AU - Boada, Mercè
AU - de Rojas, Itziar
AU - Rutledge, Jarod
AU - Oh, Hamilton
AU - Wilson, Edward N.
AU - Le Guen, Yann
AU - Reus, Lianne M.
AU - Tijms, Betty
AU - Visser, Pieter Jelle
AU - van der Lee, Sven J.
AU - Pijnenburg, Yolande A.L.
AU - Teunissen, Charlotte E.
AU - del Campo Milan, Marta
AU - Alvarez, Ignacio
AU - Aguilar, Miquel
AU - Greicius, Michael D.
AU - Pastor, Pau
AU - Pulford, David J.
AU - Ibanez, Laura
AU - Wyss-Coray, Tony
AU - Sung, Yun Ju
AU - Cruchaga, Carlos
N1 - Publisher Copyright:
© The Author(s), under exclusive licence to Springer Nature America, Inc. 2024.
PY - 2024/12
Y1 - 2024/12
N2 - The integration of quantitative trait loci (QTLs) with disease genome-wide association studies (GWASs) has proven successful in prioritizing candidate genes at disease-associated loci. QTL mapping has been focused on multi-tissue expression QTLs or plasma protein QTLs (pQTLs). We generated a cerebrospinal fluid (CSF) pQTL atlas by measuring 6,361 proteins in 3,506 samples. We identified 3,885 associations for 1,883 proteins, including 2,885 new pQTLs, demonstrating unique genetic regulation in CSF. We identified CSF-enriched pleiotropic regions on chromosome (chr)3q28 near OSTN and chr19q13.32 near APOE that were enriched for neuron specificity and neurological development. We integrated our associations with Alzheimer’s disease (AD) through proteome-wide association study (PWAS), colocalization and Mendelian randomization and identified 38 putative causal proteins, 15 of which have drugs available. Finally, we developed a proteomics-based AD prediction model that outperforms genetics-based models. These findings will be instrumental to further understand the biology and identify causal and druggable proteins for brain and neurological traits.
AB - The integration of quantitative trait loci (QTLs) with disease genome-wide association studies (GWASs) has proven successful in prioritizing candidate genes at disease-associated loci. QTL mapping has been focused on multi-tissue expression QTLs or plasma protein QTLs (pQTLs). We generated a cerebrospinal fluid (CSF) pQTL atlas by measuring 6,361 proteins in 3,506 samples. We identified 3,885 associations for 1,883 proteins, including 2,885 new pQTLs, demonstrating unique genetic regulation in CSF. We identified CSF-enriched pleiotropic regions on chromosome (chr)3q28 near OSTN and chr19q13.32 near APOE that were enriched for neuron specificity and neurological development. We integrated our associations with Alzheimer’s disease (AD) through proteome-wide association study (PWAS), colocalization and Mendelian randomization and identified 38 putative causal proteins, 15 of which have drugs available. Finally, we developed a proteomics-based AD prediction model that outperforms genetics-based models. These findings will be instrumental to further understand the biology and identify causal and druggable proteins for brain and neurological traits.
UR - http://www.scopus.com/inward/record.url?scp=85208795962&partnerID=8YFLogxK
U2 - 10.1038/s41588-024-01972-8
DO - 10.1038/s41588-024-01972-8
M3 - Article
C2 - 39528825
AN - SCOPUS:85208795962
SN - 1061-4036
VL - 56
SP - 2672
EP - 2684
JO - Nature Genetics
JF - Nature Genetics
IS - 12
M1 - eaau2291
ER -