Genomic atlas of the proteome from brain, CSF and plasma prioritizes proteins implicated in neurological disorders

被引：153

作者：

Yang, Chengran ^{[1
,2
,3
]}

Farias, Fabiana H. G. ^{[1
,2
,3
]}

Ibanez, Laura ^{[1
,2
,3
]}

Suhy, Adam ^{[1
,2
,3
]}

Sadler, Brooke ^{[4
]}

Fernandez, Maria Victoria ^{[1
,2
,3
]}

Wang, Fengxian ^{[1
,2
,3
]}

Bradley, Joseph L. ^{[1
,2
,3
]}

Eiffert, Brett ^{[1
,2
,3
]}

Bahena, Jorge A. ^{[1
,2
,3
]}

Budde, John P. ^{[1
,2
,3
]}

Li, Zeran ^{[1
,2
,3
]}

Dube, Umber ^{[1
,2
,3
]}

Sung, Yun Ju ^{[1
,2
,3
]}

Mihindukulasuriya, Kathie A. ^{[1
,2
,3
]}

Morris, John C. ^{[3
,5
,6
]}

Fagan, Anne M. ^{[3
,5
,6
]}

Perrin, Richard J. ^{[3
,5
,6
,7
]}

Benitez, Bruno A. ^{[1
,2
,3
]}

Rhinn, Herve ^{[8
]}

Harari, Oscar ^{[1
,2
,3
,6
]}

Cruchaga, Carlos ^{[1
,2
,3
,6
]}

机构：

[1] Washington Univ, Sch Med, Dept Psychiat, St Louis, MO 63110 USA

[2] Washington Univ, Sch Med, NeuroGenom & Informat Ctr, St Louis, MO 63110 USA

[3] Washington Univ, Sch Med, Hope Ctr Neurol Disorders, St Louis, MO 63110 USA

[4] Washington Univ, Sch Med, Pediat Hematol Oncol, St Louis, MO USA

[5] Washington Univ, Sch Med, Dept Neurol, St Louis, MO 63110 USA

[6] Washington Univ, Sch Med, Charles F & Joanne Knight Alzheimers Dis Res Ctr, St Louis, MO 63110 USA

[7] Washington Univ, Sch Med, Dept Pathol & Immunol, St Louis, MO USA

[8] Alector Inc, Dept Bioinformat, San Francisco, CA USA

来源：

NATURE NEUROSCIENCE | 2021年 / 24卷 / 09期

基金：

美国国家卫生研究院;

关键词：

ALZHEIMERS-DISEASE; GENETIC ARCHITECTURE; RISK LOCI; ASSOCIATION; METAANALYSIS; EXPRESSION; DISCOVERY; IDENTIFICATION; VISUALIZATION; TRANSCRIPTOME;

D O I：

10.1038/s41593-021-00886-6

中图分类号：

Q189 [神经科学];

学科分类号：

071006 ;

摘要：

Yang et al. generated a genomic atlas of protein levels in brain, cerebrospinal fluid and plasma and used human genetics approaches to identify proteins implicated in neurological diseases as well as druggable targets. 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.

引用

页码：1302 / 1312

页数：11

共 73 条

[1] The GTEx Consortium atlas of genetic regulatory effects across human tissues [J].

Aguet, Francois ;

Barbeira, Alvaro N. ;

Bonazzola, Rodrigo ;

Brown, Andrew ;

Castel, Stephane E. ;

Jo, Brian ;

Kasela, Silva ;

Kim-Hellmuth, Sarah ;

Liang, Yanyu ;

Parsana, Princy ;

Flynn, Elise ;

Fresard, Laure ;

Gamazon, Eric R. ;

Hamel, Andrew R. ;

He, Yuan ;

Hormozdiari, Farhad ;

Mohammadi, Pejman ;

Munoz-Aguirre, Manuel ;

Ardlie, Kristin G. ;

Battle, Alexis ;

Bonazzola, Rodrigo ;

Brown, Christopher D. ;

Cox, Nancy ;

Dermitzakis, Emmanouil T. ;

Engelhardt, Barbara E. ;

Garrido-Martin, Diego ;

Gay, Nicole R. ;

Getz, Gad ;

Guigo, Roderic ;

Hamel, Andrew R. ;

Handsaker, Robert E. ;

He, Yuan ;

Hoffman, Paul J. ;

Hormozdiari, Farhad ;

Im, Hae Kyung ;

Jo, Brian ;

Kasela, Silva ;

Kashin, Seva ;

Kim-Hellmuth, Sarah ;

Kwong, Alan ;

Lappalainen, Tuuli ;

Li, Xiao ;

Liang, Yanyu ;

MacArthur, Daniel G. ;

Mohammadi, Pejman ;

Montgomery, Stephen B. ;

Munoz-Aguirre, Manuel ;

Rouhana, John M. ;

Hormozdiari, Farhad ;

Im, Hae Kyung .

SCIENCE, 2020, 369 (6509) :1318-1330

[2] Genetic effects on gene expression across human tissues [J].

Aguet, Francois ;

Brown, Andrew A. ;

Castel, Stephane E. ;

Davis, Joe R. ;

He, Yuan ;

Jo, Brian ;

Mohammadi, Pejman ;

Park, Yoson ;

Parsana, Princy ;

Segre, Ayellet V. ;

Strober, Benjamin J. ;

Zappala, Zachary ;

Cummings, Beryl B. ;

Gelfand, Ellen T. ;

Hadley, Kane ;

Huang, Katherine H. ;

Lek, Monkol ;

Li, Xiao ;

Nedzel, Jared L. ;

Nguyen, Duyen Y. ;

Noble, Michael S. ;

Sullivan, Timothy J. ;

Tukiainen, Taru ;

MacArthur, Daniel G. ;

Getz, Gad ;

Management, Nih Program ;

Addington, Anjene ;

Guan, Ping ;

Koester, Susan ;

Little, A. Roger ;

Lockhart, Nicole C. ;

Moore, Helen M. ;

Rao, Abhi ;

Struewing, Jeffery P. ;

Volpi, Simona ;

Collection, Biospecimen ;

Brigham, Lori E. ;

Hasz, Richard ;

Hunter, Marcus ;

Johns, Christopher ;

Johnson, Mark ;

Kopen, Gene ;

Leinweber, William F. ;

Lonsdale, John T. ;

McDonald, Alisa ;

Mestichelli, Bernadette ;

Myer, Kevin ;

Roe, Bryan ;

Salvatore, Michael ;

Shad, Saboor .

NATURE, 2017, 550 (7675) :204-+

[3]

Alector Inc, 2019, 1 HUM STUDY SAF TOL

[4] Genetic Mapping in Human Disease [J].

Altshuler, David ;

Daly, Mark J. ;

Lander, Eric S. .

SCIENCE, 2008, 322 (5903) :881-888

[5] UniProt: a worldwide hub of protein knowledge [J].

Bateman, Alex ;

Martin, Maria-Jesus ;

Orchard, Sandra ;

Magrane, Michele ;

Alpi, Emanuele ;

Bely, Benoit ;

Bingley, Mark ;

Britto, Ramona ;

Bursteinas, Borisas ;

Busiello, Gianluca ;

Bye-A-Jee, Hema ;

Da Silva, Alan ;

De Giorgi, Maurizio ;

Dogan, Tunca ;

Castro, Leyla Garcia ;

Garmiri, Penelope ;

Georghiou, George ;

Gonzales, Daniel ;

Gonzales, Leonardo ;

Hatton-Ellis, Emma ;

Ignatchenko, Alexandr ;

Ishtiaq, Rizwan ;

Jokinen, Petteri ;

Joshi, Vishal ;

Jyothi, Dushyanth ;

Lopez, Rodrigo ;

Luo, Jie ;

Lussi, Yvonne ;

MacDougall, Alistair ;

Madeira, Fabio ;

Mahmoudy, Mahdi ;

Menchi, Manuela ;

Nightingale, Andrew ;

Onwubiko, Joseph ;

Palka, Barbara ;

Pichler, Klemens ;

Pundir, Sangya ;

Qi, Guoying ;

Raj, Shriya ;

Renaux, Alexandre ;

Lopez, Milagros Rodriguez ;

Saidi, Rabie ;

Sawford, Tony ;

Shypitsyna, Aleksandra ;

Speretta, Elena ;

Turner, Edward ;

Tyagi, Nidhi ;

Vasudev, Preethi ;

Volynkin, Vladimir ;

Wardell, Tony .

NUCLEIC ACIDS RESEARCH, 2019, 47 (D1) :D506-D515

[6]

Bethea J.W., 2010, Anesthesiology, V112, P767, DOI [DOI 10.1097/ALN.0B013E3181CE9EA5, 10.1097/ALN.0b013e3181ce9ea5]

[7] Elucidating the Contribution of Skeletal Muscle Ion Channels to Amyotrophic Lateral Sclerosis in search of new therapeutic options [J].

Camerino, Giulia Maria ;

Fonzino, Adriano ;

Conte, Elena ;

De Bellis, Michela ;

Mele, Antonietta ;

Liantonio, Antonella ;

Tricarico, Domenico ;

Tarantino, Nancy ;

Dobrowolny, Gabriella ;

Musaro, Antonio ;

Desaphy, Jean-Francois ;

De Luca, Annamaria ;

Pierno, Sabata .

SCIENTIFIC REPORTS, 2019, 9 (1)

[8] Second-generation PLINK: rising to the challenge of larger and richer datasets [J].

Chang, Christopher C. ;

Chow, Carson C. ;

Tellier, Laurent C. A. M. ;

Vattikuti, Shashaank ;

Purcell, Shaun M. ;

Lee, James J. .

GIGASCIENCE, 2015, 4

[9]

Chen H, 2018, VENNDIAGRAM GENERATE

[10] A brief history of human disease genetics [J].

Claussnitzer, Melina ;

Cho, Judy H. ;

Collins, Rory ;

Cox, Nancy J. ;

Dermitzakis, Emmanouil T. ;

Hurles, Matthew E. ;

Kathiresan, Sekar ;

Kenny, Eimear E. ;

Lindgren, Cecilia M. ;

MacArthur, Daniel G. ;

North, Kathryn N. ;

Plon, Sharon E. ;

Rehm, Heidi L. ;

Risch, Neil ;

Rotimi, Charles N. ;

Shendure, Jay ;

Soranzo, Nicole ;

McCarthy, Mark I. .

NATURE, 2020, 577 (7789) :179-189

← 1 2 3 4 5 6 7 8 →