Integrating human brain proteomes with genome-wide association data implicates novel proteins in post-traumatic stress disorder

Abstract

Genome-wide association studies (GWAS) have identified several risk loci for post-traumatic stress disorder (PTSD); however, how they confer PTSD risk remains unclear. We aimed to identify genes that confer PTSD risk through their effects on brain protein abundance to provide new insights into PTSD pathogenesis. To that end, we integrated human brain proteomes with PTSD GWAS results to perform a proteome-wide association study (PWAS) of PTSD, followed by Mendelian randomization, using a discovery and confirmatory study design. Brain proteomes (N=525) were profiled from the dorsolateral prefrontal cortex using mass spectrometry. The Million Veteran Program (MVP) PTSD GWAS (n=186,689) was used for the discovery PWAS, and the Psychiatric Genomics Consortium PTSD GWAS (n=174,659) was used for the confirmatory PWAS. To understand whether genes identified at the protein-level were also evident at the transcript-level, we performed a transcriptome-wide association study (TWAS) using human brain transcriptomes (N=888) and the MVP PTSD GWAS results. We identified 11 genes that contribute to PTSD pathogenesis via their respective cis -regulated brain protein abundance. Seven of 11 genes (64%) replicated in the confirmatory PWAS and 4 of 11 also had their cis -regulated brain mRNA levels associated with PTSD. High confidence level was assigned to 9 of 11 genes after considering evidence from the confirmatory PWAS and TWAS. Most of the identified genes are expressed in other PTSD-relevant brain regions and several are preferentially expressed in excitatory neurons, astrocytes, and oligodendrocyte precursor cells. These genes are novel, promising targets for mechanistic and therapeutic studies to find new treatments for PTSD.

Batch correction and harmonization of –Omics datasets with a tunable median polish of ratio

“…Systems biology analyses of AD focusing on co-expression modules and their biology are well powered with hundreds to thousands of samples. Recent studies have already achieved this power (McKenzie et al, 2017;Allen et al, 2018;De Jager et al, 2018;Yu et al, 2018;Johnson et al, 2020;Neff et al, 2021;Wingo A. P. et al, 2021;Wingo T. S. et al, 2021;Gandal et al, 2022;Johnson et al, 2022;Wingo et al, 2022). Once samples can be harmonized in the ten to hundreds of thousands, with thousands of quantified gene products in each sample, additional analyses leveraging machine learning become feasible.…”

Supplementary Pharmacotherapy for the Behavioral Abnormalities Caused by Stressors in Humans, Focused on Post-Traumatic Stress Disorder (PTSD)

“…While under optimal conditions, oligodendrocytes use glycolysis, under metabolic stress, as in PTSD, they have reduced glycolysis and impaired function [ 22 ]. Among seven genes identified by Wingo et al, that contribute to the pathogenesis of PTSD, three were expressed by oligodendrocyte precursor cells (OPC) [ 23 ]. The fibroblast growth factor 17 (Fgf17) is involved in this: Fgf17 infusion induced OPC proliferation [ 24 ]; its receptor is FGFR3, and FGFR3-deficient mice had reduced numbers of differentiated oligodendrocytes in the forebrain, cerebellum, hindbrain, and spinal cord and, in parallel, myelination was delayed [ 25 ].…”

Genetic and Multi-omic Risk Assessment of Alzheimer’s Disease Implicates Core Associated Biological Domains

“…The genomic branch of our investigation involved the interrogation of the primary large postmortem transcriptomic or proteomic studies performed in the last five years. There are a multitude of brain proteomic studies associated with TREAT-AD or AMP-AD investigations that have identified functional modules of co-expressed genes that associate with various parameters of neurodegenerative pathology 21,30,32,33,35,58,65,[100][101][102][103][104][105][106] . These modules generally center upon specific biological functions, and hence are amenable to biological domain subordination.…”

“…However, each of these datasets can suggest hundreds of genes as potential new therapeutic targets without clear priority. Genome-wide association studies (GWAS) alone have identified over 75 risk loci [15][16][17][18][19] and analyses of transcriptomic [20][21][22][23][24][25][26][27][28][29] and proteomic [30][31][32][33][34][35] data have identified dozens of co-expression modules that consist of hundreds to thousands of genes or proteins each. There are currently over 600 targets that have been nominated by AMP-AD researchers for further therapeutic development (agora.adknowledgeportal.org).…”