A biologically-informed polygenic score identifies endophenotypes and clinical conditions associated with the insulin receptor function on specific brain regions

Abstract

Background Activation of brain insulin receptors modulates reward sensitivity, inhibitory control and memory. Variations in the functioning of this mechanism likely associate with individual differences in the risk for related mental disorders (attention deficit hyperactivity disorder or ADHD, addiction, dementia), in agreement with the high co-morbidity between insulin resistance and psychopathology. These neurobiological mechanisms can be explored using genetic studies. We propose a novel, biologically informed genetic score reflecting the mesocorticolimbic and hippocampal insulin receptor-related gene networks, and investigate if it predicts endophenotypes (impulsivity, cognitive ability) in community samples of children, and psychopathology (addiction, dementia) in adults. Methods Lists of genes co-expressed with the insulin receptor in the mesocorticolimbic system or hippocampus were created. SNPs from these genes (post-clumping) were compiled in a polygenic score using the association betas described in a conventional GWAS (ADHD in the mesocorticolimbic score and Alzheimer in the hippocampal score). Across multiple samples ( n = 4502), the biologically informed, mesocorticolimbic or hippocampal specific insulin receptor polygenic scores were calculated, and their ability to predict impulsivity, risk for addiction, cognitive performance and presence of Alzheimer's disease was investigated. Findings The biologically-informed ePRS-IR score showed better prediction of child impulsivity and cognitive performance, as well as risk for addiction and Alzheimer's disease in comparison to conventional polygenic scores for ADHD, addiction and dementia. Interpretation This novel, biologically-informed approach enables the use of genomic datasets to probe relevant biological processes involved in neural function and disorders. Fund Toxic Stress Research network of the JPB Foundation, Jacobs Foundation (Switzerland), Sackler Foundation.

Amygdala 5-HTT Gene Network Moderates the Effects of Postnatal Adversity on Attention Problems: Anatomo-Functional Correlation and Epigenetic Changes

“…We pruned our datasets to common variants (MAF>0.05) that were not in linkage disequilibrium (r 2 < 0.20) with a sliding window (50 kilobases) approach that examined linkage disequilibrium in increments of 5 SNPs using PLINK 1.9 (Price et al, 2006). Principal component analysis was performed using SMARTPCA on this pruned dataset and generated a scree plot (see Hari Dass et al, 2019, for scree plot for the MAVAN cohort). Based on the inspection of the scree plot, the first three principal components were the most informative of population structure in both cohorts and were included in all analyses.…”

“…Final ePRS was obtained by summation over all SNPs accounting for the sign of correlation coefficient between the genes and 5HTT gene expression. For more information on ePRS calculation, see Hari Dass et al (2019). The summation of these values from the total number of SNPs provides the amygdala 5-HTT-ePRS score ( Table 1 shows the final gene list).…”

Mental health dished up—the use of iPSC models in neuropsychiatric research

“…Using GWAS data, each individual disease-associated SNP is assigned a weight based on their effect size, and the total number of SNPs combined with their weights is summed to calculate an individual’s PRS. This approach has already revealed that PRS can significantly predict endophenotypes in disease and control settings, such as cognition (Richards et al 2019 ) and impulsivity (Hari Dass et al 2019 ). Moreover, PRS can also identify specific pathways which are involved both individually and cross-disorder.…”

Polygenic risk scores in psychiatry: Will they be useful for clinicians?

“…Recently, PRS reflecting a selection of SNP sets based on biological processes (for example, signaling pathway membership, protein–protein interactions, or pharmacological treatment response) have been calculated and applied 11, 12 . These pathway-specific PRS may predict phenotypic variation more robustly than risk scores reflecting overall disorder risk and may be more amenable to mapping of specific endophenotypes or phenotypic correlates of disease (such as cognitive and cortical changes which are associated with the disorder or its symptoms) 13– 15 .…”

“…• Inform research on psychiatric endophenotypes or biomarkers 13– 15 . We expect that a true biomarker of genetic risk will more likely be present in persons with a high PRS than persons with a low PRS.…”