Published February 2024 | Version v4
Journal article Open

Dopamine signaling enriched striatal gene set predicts striatal dopamine synthesis and physiological activity in vivo

Creators

  • 1. Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD; Department of Translational Biomedicine and Neuroscience, University of Bari Aldo Moro, Bari, Italy
  • 2. Clinical and Translational Neuroscience Branch, NIMH, Intramural Research Program, Bethesda, MD
  • 3. Department of Translational Biomedicine and Neuroscience, University of Bari Aldo Moro, Bari, Italy
  • 4. Department of Translational Biomedicine and Neuroscience, University of Bari Aldo Moro, Bari, Italy; Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK
  • 5. Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD
  • 6. Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK;NIHR Biomedical Research Centre at South London and Maudsley NHS Foundation Trust, London, UK
  • 7. Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD; Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD
  • 8. Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD
  • 9. MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, Cardiff, UK
  • 10. Neuroradiology Unit - IRCCS Casa Sollievo della Sofferenza Hospital, S. Giovanni Rotondo, IT
  • 11. Department of Translational Biomedicine and Neuroscience, University of Bari Aldo Moro, Bari, Italy; Azienda Ospedaliero-Universitaria Consorziale Policlinico, Bari, Italia
  • 12. Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK
  • 13. Baltimore Research and Education Foundation, Baltimore, MD, USA
  • 14. Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD; Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD; Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD; Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD
  • 15. Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD; Department of Translational Biomedicine and Neuroscience, University of Bari Aldo Moro, Bari, Italy; Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD

Description

The polygenic architecture of schizophrenia implicates several molecular pathways involved in synaptic function. However, it is unclear how polygenic risk funnels through these pathways to translate into syndromic illness. Using tensor decomposition, we analyzed gene co-expression in post-mortem brain from caudate nucleus, hippocampus, and dorsolateral prefrontal cortex in brain samples from 358 individuals.  We identify a set of genes predominantly expressed in the caudate nucleus and associated with both clinical state and genetic risk for schizophrenia that shows dopaminergic selectivity. A higher polygenic risk score for schizophrenia parsed by this set of genes predicts greater dopamine synthesis in the striatum and greater striatal activation during reward anticipation. These results translate dopamine-linked genetic risk variation into in vivo neurochemical and hemodynamic phenotypes in the striatum that have long been implicated in the pathophysiology of schizophrenia.

Table of contents

Supplementary Data 1.

Compressed tar-zipped directory containing output of SDA computed on the LIBD discovery and GTEx replication datasets: individual score, tissue score, gene loading and posterior inclusion probability (PIP) matrices. The gene.loading_PIP_0.5.txt matrix refers to the gene loading matrix in which loadings for genes with PIP < .5 has been set to 0. This was the matrix used to infer component membership for each gene.

Supplementary Data 2.

Excel file with LIBD discovery components summary information, association with both biological covariates and technical confounders (Table S1), and component membership (Table S2).

Table S1: Association between all SDA components and both biological covariates and technical confounders (p-values are reported). The number of genes included in each component is listed, and the 69 components carried forward for further analysis are indicated (column name: removed; value = No).

Table S2: Information about genes assigned to the 69 SDA components. For each gene and for each component a value of 1 indicates that gene is assigned to that specific component.

Supplementary Data 3.

Excel file of discovery C80 (Table S1) and replication C18 (Table S2) genes as wells as relative GO and KEGG enrichment results (Table S3 and S4).

Table S1 and Table S2: List of genes belonging to discovery C80 and replication C18 components. Ensembl IDs are relative to GENCODE release 25. 

Table S3 and Table S4: GO and KEGG results are reported for terms with p[FDR]<.05.

Supplementary Data 4.

Compressed zipped directory containing deidentified PRSs and technical covariates for all discovery and replication cohorts along with aggregated deidentified PET and fMRI data used.

Supplementary Data 5.

Compressed zipped directory containing scripts used for this study

C80_SNPs.

Compressed tar-zipped directory containing compressed text files of:

•           C80.g1000.gz: 1000 Genome SNPs mapped at 100kbp up- and down-stream of each C80 gene (A1 refers to reference allele)

•           C80.g1000.PGC3.gz: PGC3 leave-LIBD-out SNPs matching the 1000 Genome SNPs mapped at C80 genes (A1 refers to effect allele)

•           C80.PRS(1-10)_snpList.txt: LD-independent (after clumping by PRSice) PGC3 leave-LIBD-out SNPs used to compute C80-PRS1 to 10.

Chromosome position refers to human genome Build 37. Additionally, an RData object (C80.g1000_snpList.rds) containing the list of C80 genes with the corresponding 1000 Genome SNPs mapped is included in this compressed directory.

SDA_preprocessed.

Compressed tar-zipped directory containing LIBD and GTEx post-mortem gene expression data preprocessed for input to SDA.

Files

Supplementary Data 4.zip

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Additional details

Dates

Submitted
2024-02