TY - JOUR
T1 - Genomic atlas of the proteome from brain, CSF and plasma prioritizes proteins implicated in neurological disorders
AU - Yang, Chengran
AU - Farias, Fabiana H.G.
AU - Ibanez, Laura
AU - Suhy, Adam
AU - Sadler, Brooke
AU - Fernandez, Maria Victoria
AU - Wang, Fengxian
AU - Bradley, Joseph L.
AU - Eiffert, Brett
AU - Bahena, Jorge A.
AU - Budde, John P.
AU - Li, Zeran
AU - Dube, Umber
AU - Sung, Yun Ju
AU - Mihindukulasuriya, Kathie A.
AU - Morris, John C.
AU - Fagan, Anne M.
AU - Perrin, Richard J.
AU - Benitez, Bruno A.
AU - Rhinn, Herve
AU - Harari, Oscar
AU - Cruchaga, Carlos
N1 - Publisher Copyright:
© 2021, The Author(s), under exclusive licence to Springer Nature America, Inc.
PY - 2021/9
Y1 - 2021/9
N2 - Understanding the tissue-specific genetic controls of protein levels is essential to uncover mechanisms of post-transcriptional gene regulation. In this study, we generated a genomic atlas of protein levels in three tissues relevant to neurological disorders (brain, cerebrospinal fluid and plasma) by profiling thousands of proteins from participants with and without Alzheimer’s disease. We identified 274, 127 and 32 protein quantitative trait loci (pQTLs) for cerebrospinal fluid, plasma and brain, respectively. cis-pQTLs were more likely to be tissue shared, but trans-pQTLs tended to be tissue specific. Between 48.0% and 76.6% of pQTLs did not co-localize with expression, splicing, DNA methylation or histone acetylation QTLs. Using Mendelian randomization, we nominated proteins implicated in neurological diseases, including Alzheimer’s disease, Parkinson’s disease and stroke. This first multi-tissue study will be instrumental to map signals from genome-wide association studies onto functional genes, to discover pathways and to identify drug targets for neurological diseases.
AB - Understanding the tissue-specific genetic controls of protein levels is essential to uncover mechanisms of post-transcriptional gene regulation. In this study, we generated a genomic atlas of protein levels in three tissues relevant to neurological disorders (brain, cerebrospinal fluid and plasma) by profiling thousands of proteins from participants with and without Alzheimer’s disease. We identified 274, 127 and 32 protein quantitative trait loci (pQTLs) for cerebrospinal fluid, plasma and brain, respectively. cis-pQTLs were more likely to be tissue shared, but trans-pQTLs tended to be tissue specific. Between 48.0% and 76.6% of pQTLs did not co-localize with expression, splicing, DNA methylation or histone acetylation QTLs. Using Mendelian randomization, we nominated proteins implicated in neurological diseases, including Alzheimer’s disease, Parkinson’s disease and stroke. This first multi-tissue study will be instrumental to map signals from genome-wide association studies onto functional genes, to discover pathways and to identify drug targets for neurological diseases.
UR - http://www.scopus.com/inward/record.url?scp=85109954431&partnerID=8YFLogxK
U2 - 10.1038/s41593-021-00886-6
DO - 10.1038/s41593-021-00886-6
M3 - Article
C2 - 34239129
AN - SCOPUS:85109954431
SN - 1097-6256
VL - 24
SP - 1302
EP - 1312
JO - Nature neuroscience
JF - Nature neuroscience
IS - 9
ER -