Novel genome-wide associations for effort valuation and psychopathology in children and adults.

The Research Domain Criteria (RDoC) initiative was established by the US National Institute of Mental Health as a multilevel, disorder-agnostic framework for analysis of human psychopathology through designated domains and constructs, including the "Positive Valence Systems" domain focused on reward-related behavior. This study investigates the reward valuation subconstruct of "effort" and its association with genetic markers, functional neurobiological pathways, and polygenic risk scores for psychopathology in 1215 children aged 6-12 and their parents (n = 1044). All participants completed the effort expenditure for rewards task (EEfRT), which assesses "effort" according to two quantitative measures: hard-task choice and reward sensitivity. Genetic association analyses were undertaken in MAGMA, utilizing EEfRT outcome variables as genome-wide association studies phenotypes to compute SNP and gene-level associations. Genome-wide association analyses found two distinct genetic loci that were significantly associated with measures of reward sensitivity and a separate genetic locus associated with hard task choice. Gene-set enrichment analysis yielded significant associations between "effort" and multiple gene sets involved in reward processing-related pathways, including dopamine receptor signaling, limbic system and forebrain development, and biological response to cocaine. These results serve to establish "effort" as a relevant construct for understanding reward-related behavior at the genetic level and support the RDoC framework for assessing disorder-agnostic psychopathology.

Gene co-expression networks in peripheral blood capture dimensional measures of emotional and behavioral problems from the Child Behavior Checklist (CBCL).

The U.S. National Institute of Mental Health (NIMH) introduced the research domain criteria (RDoC) initiative to promote the integration of information across multiple units of analysis (i.e., brain circuits, physiology, behavior, self-reports) to better understand the basic dimensions of behavior and cognitive functioning underlying normal and abnormal mental conditions. Along those lines, this study examined the association between peripheral blood gene expression levels and emotional and behavioral problems in school-age children. Children were chosen from two age- and sex-matched groups: those with or without parental reports of any prior or current psychiatric diagnosis. RNA-sequencing was performed on whole blood from 96 probands aged 6-12 years who were medication-free at the time of assessment. Module eigengenes were derived using weighted gene co-expression network analysis (WGCNA). Associations were tested between module eigengene expression levels and eight syndrome scales from parent ratings on the Child Behavior Checklist (CBCL). Nine out of the 36 modules were significantly associated with at least one syndrome scale measured by the CBCL (i.e., aggression, social problems, attention problems, and/or thought problems) after accounting for covariates and correcting for multiple testing. Our study demonstrates that variation in peripheral blood gene expression relates to emotional and behavioral profiles in children. If replicated and validated, our results may help in identifying problem or at-risk behavior in pediatric populations, and in elucidating the biological pathways that modulate complex human behavior.

Effort valuation and psychopathology in children and adults.

BACKGROUND: The Research Domain Criteria initiative was launched by the US National Institute of Mental Health to establish a multi-level framework for understanding psychological constructs relevant to human psychiatric disorders, and identified 'effort valuation/willingness to work' as a clinically useful construct worthy of further study. This construct encompasses the processes by which the cost(s) of obtaining an outcome are calculated, and the tendency to overcome response costs to obtain a reinforcer. The current study aims to examine effort valuation as a correlate of psychopathology in children and adults, and the moderating effects of sex on this relationship. METHODS: Participants were 1215 children aged 6-12 and their parents (n = 1044). All participants completed the Effort Expenditure for Rewards Task as a measure of effort expenditure. Child psychopathology was measured via the Child Behavior Checklist, while adult psychopathology was measured via the Adult Self Report. Additionally, the Social Adjustment Inventory for Children and Adolescents and Injury Behavior Checklist were used to examine child social impairments/problem behaviors. RESULTS: In children, significant interactions between reward sensitivity and sex were observed in association with anxiety and thought problems, specifically at low reward sensitivity levels. In adults, main effects of effort expenditure were seen in drug and alcohol abuse, where higher effort was associated with higher degrees of abuse. CONCLUSIONS: These results establish effort valuation as a relevant psychological construct for understanding psychopathology, but with different profiles of associated psychopathology across sex in children and adults.