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Genetic control of the human brain proteome

Chloe Robins, Aliza P. Wingo, Wen Fan, Duc M. Duong, Jacob Meigs, Ekaterina S. Gerasimov, Eric B. Dammer, David J. Cutler, Philip L. De Jager, David A. Bennett, James J. Lah, Allan I. Levey, Nicholas T. Seyfried, View ORCID ProfileThomas S. Wingo
doi: https://doi.org/10.1101/816652
Chloe Robins
1Department of Neurology, Emory University School of Medicine, Atlanta, GA, USA
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Aliza P. Wingo
2Division of Mental Health, Atlanta VA Medical Center, Decatur, GA, USA
3Department of Psychiatry, Emory University School of Medicine, Atlanta, GA, USA
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Wen Fan
1Department of Neurology, Emory University School of Medicine, Atlanta, GA, USA
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Duc M. Duong
4Department of Biochemistry, Emory University School of Medicine, Atlanta, GA, USA
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Jacob Meigs
1Department of Neurology, Emory University School of Medicine, Atlanta, GA, USA
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Ekaterina S. Gerasimov
1Department of Neurology, Emory University School of Medicine, Atlanta, GA, USA
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Eric B. Dammer
4Department of Biochemistry, Emory University School of Medicine, Atlanta, GA, USA
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David J. Cutler
5Department of Human Genetics, Emory University School of Medicine, Atlanta, Georgia, USA
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Philip L. De Jager
6Cell Circuits Program, Broad Institute, Cambridge, MA, USA
7Center for Translational and Computational Neuroimmunology, Department of Neurology, Columbia University Medical Center, New York, NY, USA
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David A. Bennett
8Rush Alzheimer’s Disease Center, Rush University Medical Center, Chicago, Illinois, USA
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James J. Lah
1Department of Neurology, Emory University School of Medicine, Atlanta, GA, USA
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Allan I. Levey
1Department of Neurology, Emory University School of Medicine, Atlanta, GA, USA
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  • For correspondence: thomas.wingo@emory.edu nseyfri@emory.edu alevey@emory.edu
Nicholas T. Seyfried
2Division of Mental Health, Atlanta VA Medical Center, Decatur, GA, USA
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  • For correspondence: thomas.wingo@emory.edu nseyfri@emory.edu alevey@emory.edu
Thomas S. Wingo
1Department of Neurology, Emory University School of Medicine, Atlanta, GA, USA
3Department of Psychiatry, Emory University School of Medicine, Atlanta, GA, USA
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  • ORCID record for Thomas S. Wingo
  • For correspondence: thomas.wingo@emory.edu nseyfri@emory.edu alevey@emory.edu
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Abstract

Alteration of protein abundance and conformation are widely believed to be the hallmark of neurodegenerative diseases. Yet relatively little is known about the genetic variation that controls protein abundance in the healthy human brain. The genetic control of protein abundance is generally thought to parallel that of RNA expression, but there is little direct evidence to support this view. Here, we performed a large-scale protein quantitative trait locus (pQTL) analysis using single nucleotide variants (SNVs) from whole-genome sequencing and tandem mass spectrometry-based proteomic quantification of 12,691 unique proteins (7,901 after quality control) from the dorsolateral prefrontal cortex (dPFC) in 144 cognitively normal individuals. We identified 28,211 pQTLs that were significantly associated with the abundance of 864 proteins. These pQTLs were compared to dPFC expression quantitative trait loci (eQTL) in cognitive normal individuals (n=169; 81 had protein data) and a meta-analysis of dPFC eQTLs (n=1,433). We found that strong pQTLs are generally only weak eQTLs, and that the majority of strong eQTLs are not detectable pQTLs. These results suggest that the genetic control of mRNA and protein abundance may be substantially distinct and suggests inference concerning protein abundance made from mRNA in human brain should be treated with caution.

Footnotes

  • Added supplementary materials.

  • https://brainqtl.org

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Genetic control of the human brain proteome
Chloe Robins, Aliza P. Wingo, Wen Fan, Duc M. Duong, Jacob Meigs, Ekaterina S. Gerasimov, Eric B. Dammer, David J. Cutler, Philip L. De Jager, David A. Bennett, James J. Lah, Allan I. Levey, Nicholas T. Seyfried, Thomas S. Wingo
bioRxiv 816652; doi: https://doi.org/10.1101/816652
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Genetic control of the human brain proteome
Chloe Robins, Aliza P. Wingo, Wen Fan, Duc M. Duong, Jacob Meigs, Ekaterina S. Gerasimov, Eric B. Dammer, David J. Cutler, Philip L. De Jager, David A. Bennett, James J. Lah, Allan I. Levey, Nicholas T. Seyfried, Thomas S. Wingo
bioRxiv 816652; doi: https://doi.org/10.1101/816652

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