A biologically-informed polygenic score identifies endophenotypes and clinical conditions associated with the insulin receptor function on specific brain regions
Bibliographic record
Abstract
Abstract Importance Activation of brain insulin receptors occurs on mesocorticolimbic regions, modulating reward sensitivity and inhibitory control. Variations in the functioning of this mechanism likely associate with individual differences in the risk for related psychopathologies (attention-deficit hyperactivity disorder, addiction), an idea that agrees with the high comorbidity between insulin resistant states and psychiatric conditions. While genetic studies comprise an interesting tool to explore neurobiological mechanisms in community samples, the conventional genome-wide association studies and polygenic risk score methodologies completely ignore the fact that genes operate in networks, and code for precise biological functions in specific tissues. Objective We propose a novel, biologically informed genetic score reflecting the mesocorticolimbic insulin receptor-related gene network, and investigate if it predicts dopamine-related psychopathology (impulsivity and addiction) in community samples. Design Birth cohort (Maternal Adversity, Vulnerability and Neurodevelopment, MAVAN) and adult cohort (Study of Addiction, Genes and Environment, SAGE). Setting General community. Participants 212 4-year-old children (MAVAN), and 1626 adults (SAGE). Exposure The biologically informed, mesocorticolimbic specific, insulin receptor polygenic score was created based on levels of co-expression with the insulin receptor in striatum and prefrontal cortex, and calculated in the two samples using the genotype data (Psychip/Psycharray). Main outcome childhood impulsivity in the Information Sampling task, and risk for early addiction onset. Results The insulin receptor polygenic score showed improved prediction of childhood impulsivity in boys and risk for early addiction onset in males in comparison to conventional polygenic risk scores for attention-deficit hyperactivity disorder or addiction. Conclusions and relevance This novel genomic approach reveals insulin action as a relevant biological process involved in the risk for dopamine-related psychopathology. Key points Question Considering the modulation of mesocorticolimbic dopaminergic pathways by insulin through the action on its receptors (IR), we investigated if a novel, region specific polygenic score on the IR-related gene network (ePRS-IR) is associated with dopamine-related behaviors (impulsivity and addiction). Findings The ePRS-IR showed improved prediction of childhood impulsivity and risk for early addiction onset in comparison to conventional polygenic risk scores for ADHD or addiction. Meaning This novel genomic approach reveals insulin action as a biological process involved in the risk for dopamine-related psychopathology.
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.003 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.001 |
| Bibliometrics | 0.002 | 0.002 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.000 | 0.001 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.004 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".