Association of Protein Distribution and Gene Expression Revealed by PET and Post-Mortem Quantification in the Serotonergic System of the Human Brain

Abstract

Regional differences in posttranscriptional mechanisms may influence in vivo protein densities. The association of positron emission tomography (PET) imaging data from 112 healthy controls and gene expression values from the Allen Human Brain Atlas, based on post-mortem brains, was investigated for key serotonergic proteins. PET binding values and gene expression intensities were correlated for the main inhibitory (5-HT1A) and excitatory (5-HT2A) serotonin receptor, the serotonin transporter (SERT) as well as monoamine oxidase-A (MAO-A), using Spearman's correlation coefficients (rs) in a voxel-wise and region-wise analysis. Correlations indicated a strong linear relationship between gene and protein expression for both the 5-HT1A (voxel-wise rs = 0.71; region-wise rs = 0.93) and the 5-HT2A receptor (rs = 0.66; 0.75), but only a weak association for MAO-A (rs = 0.26; 0.66) and no clear correlation for SERT (rs = 0.17; 0.29). Additionally, region-wise correlations were performed using mRNA expression from the HBT, yielding comparable results (5-HT1Ars = 0.82; 5-HT2Ars = 0.88; MAO-A rs = 0.50; SERT rs = −0.01). The SERT and MAO-A appear to be regulated in a region-specific manner across the whole brain. In contrast, the serotonin-1A and -2A receptors are presumably targeted by common posttranscriptional processes similar in all brain areas suggesting the applicability of mRNA expression as surrogate parameter for density of these proteins.

A practical guide to linking brain-wide gene expression and neuroimaging data

“…Many analyses interested in transcriptomic signatures of IDPs will be primarily interested in these brain-specific genes. Various methods for pre-selecting genes of interest have been adopted, including selecting: (i) disease-specific genes , Romme et al, 2017, Yokoyama et al, 2017, (ii) genes related to a priori hypotheses (Goyal et al, 2014, Komorowski et al, 2016, Krienen et al, 2016, Acevedo-Triana et al, 2017 genes that are expressed consistently across all six AHBA brains, as quantified using the DS measure (Hawrylycz et al, 2015). Genes with high DS values demonstrate consistent patterns of regional variation in expression across the six AHBA subjects, and have been shown to be enriched for brain-related biological function (Hawrylycz et al, 2015).…”

“…Filtering based on DS thus offers a more targeted approach for investigating relationships between IDPs and gene expression compared to the whole-genome analysis. The selection of disease-specific genes is traditionally based on previous GWAS studies (Satake et al, 2009, Simón-Sánchez et al, 2009, Höglinger et al, 2011, Ferrari et al, 2014, Ripke et al, 2014, Kouri et al, 2015, while gene selection based on an a priori hypothesis can depend on other factors such as a specific involvement in clinical disorders (Komorowski et al, 2016, Acevedo-Triana et al, 2017. One particular set of 19 genes demonstrating a selective enrichment in the upper layers of the human cortex compared to mouse [Human Supragranular Enriched (HSE) genes] has been extensively investigated and was found to be implicated in both the functional (Krienen et al, 2016) and topological organisation of the brain , Romero-Garcia et al, 2018b.…”

Regional gene expression patterns are associated with task-specific brain activation during reward and emotion processing measured with functional MRI

“…While single neuroscientific methods contributed to the comprehension of physiological processes as well as pathological alterations in psychiatric disorders, a multimodal integration of large-scale data has proven to be even more conducive for in-depth understanding, especially on the molecular scale 1,2 . In particular, post-mortem gene expression data from the Allen Human Brain Atlas (AHBA) was repeatedly applied to investigate the relationship between the transcriptome and protein distribution 3 , brain connectivity 4 , or morphology 5 . These studies add up to numerous wideranging research findings combining topological mRNA expression with neuroimaging properties, partially offering toolboxes for an integrative data analysis 6,7 .…”

MAOA‐VNTR genotype affects structural and functional connectivity in distributed brain networks

“…First, positron emission tomography (PET) and postmortem studies revealed a broad topological distribution of MAOA binding potentials and mRNA expression levels across the human brain (Komorowski et al, 2017;Tong et al, 2013). First, positron emission tomography (PET) and postmortem studies revealed a broad topological distribution of MAOA binding potentials and mRNA expression levels across the human brain (Komorowski et al, 2017;Tong et al, 2013).…”

“…Several lines of evidence suggest more widespread effects of MAOA on neural structural and functional network architecture. First, positron emission tomography (PET) and postmortem studies revealed a broad topological distribution of MAOA binding potentials and mRNA expression levels across the human brain (Komorowski et al, 2017;Tong et al, 2013). Second, the encoded enzyme is a central modulator of stem cell neural differentiation and neural circuit segregation during early brain development (Ou, Chen, & Shih, 2006;Wang, Chen, Ying, Li, & Shih, 2011).…”