PT  - JOURNAL ARTICLE
AU  - Chloe Robins
AU  - Aliza P. Wingo
AU  - Wen Fan
AU  - Duc M. Duong
AU  - Jacob Meigs
AU  - Ekaterina S. Gerasimov
AU  - Eric B. Dammer
AU  - David J. Cutler
AU  - Philip L. De Jager
AU  - David A. Bennett
AU  - James J. Lah
AU  - Allan I. Levey
AU  - Nicholas T. Seyfried
AU  - Thomas S. Wingo
TI  - Genetic control of the human brain proteome
AID  - 10.1101/816652
DP  - 2019 Jan 01
TA  - bioRxiv
PG  - 816652
4099  - http://biorxiv.org/content/early/2019/11/15/816652.short
4100  - http://biorxiv.org/content/early/2019/11/15/816652.full
AB  - 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.