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Integrating human brain proteomic data with genome-wide association study findings identifies novel brain proteins in substance use traits

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Abstract

Despite the identification of a growing number of genetic risk loci for substance use traits (SUTs), the impact of these loci on protein abundance and the potential utility of relevant proteins as therapeutic targets are unknown. We conducted a proteome-wide association study (PWAS) in which we integrated human brain proteomes from discovery (Banner; N = 152) and validation (ROSMAP; N = 376) datasets with genome-wide association study (GWAS) summary statistics for 4 SUTs. The 4 samples comprised GWAS of European-ancestry individuals for smoking initiation [Smk] (N = 1,232,091), alcohol use disorder [AUD] (N = 313,959), cannabis use disorder [CUD] (N = 384,032), and opioid use disorder [OUD] (N = 302,585). We conducted transcriptome-wide association studies (TWAS) with human brain transcriptomic data to examine the overlap of genetic effects at the proteomic and transcriptomic levels and characterize significant genes through conditional, colocalization, and fine-mapping analyses. We identified 27 genes (Smk = 21, AUD = 3, CUD = 2, OUD = 1) that were significantly associated with cis-regulated brain protein abundance. Of these, 7 showed evidence for causality (Smk: NT5C2, GMPPB, NQO1, RHOT2, SRR and ACTR1B; and AUD: CTNND1). Cis-regulated transcript levels for 8 genes (Smk = 6, CUD = 1, OUD = 1) were associated with SUTs, indicating that genetic loci could confer risk for these SUTs by modulating both gene expression and proteomic abundance. Functional studies of the high-confidence risk proteins identified here are needed to determine whether they are modifiable targets and useful in developing medications and biomarkers for these SUTs.

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Fig. 1: Overview of the study.
Fig. 2: PWAS identified 27 genes and replicated 6 genes for substance use traits.
Fig. 3: Drug-gene interaction prioritized 5 genes.

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Funding

This study was supported by the Veterans Integrated Service Network 4 Mental Illness Research, Education and Clinical Center and NIH grants DA046345, AA028292, and AA02636.

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Substantial contributions to the conception or design of the work: ST, HX, RLK, HRK. Acquisition, analysis, or interpretation of data for the work: ST, HX, JG, RLK, HRK. Drafting the work or revising it critically for important intellectual content: ST, HX, RLK, HRK. Final approval of the version to be published: ST, HX, JG, RLK, HRK. Agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved: ST, RLK, HRK.

Corresponding authors

Correspondence to Rachel L. Kember or Henry R. Kranzler.

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Competing interests

HRK is a member of advisory boards for Dicerna Pharmaceuticals, Sophrosyne Pharmaceuticals, and Enthion Pharmaceuticals; a consultant to Sobrera Pharmaceuticals; the recipient of research funding and medication supplies for an investigator-initiated study from Alkermes; and a member of the American Society of Clinical Psychopharmacology’s Alcohol Clinical Trials Initiative, which was supported in the last 3 years by Alkermes, Dicerna, Ethypharm, Lundbeck, Mitsubishi, and Otsuka. JG and HRK are holders of U.S. patent 10,900,082 titled: “Genotype-guided dosing of opioid agonists,” issued 26 January 2021. The other authors have no disclosures to make.

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Toikumo, S., Xu, H., Gelernter, J. et al. Integrating human brain proteomic data with genome-wide association study findings identifies novel brain proteins in substance use traits. Neuropsychopharmacol. 47, 2292–2299 (2022). https://doi.org/10.1038/s41386-022-01406-1

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