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

IF 1.6 3区 医学 Q3 GENETICS & HEREDITY
Nicholas H. Nguyen, T. Mitchell Mazza, Jonathan L. Hess, Avery B. Albert, Sarah Elfstrom, Patricia Forken, Steven D. Blatt, Wanda P. Fremont, Stephen V. Faraone, Stephen J. Glatt
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引用次数: 0

Abstract

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.

在儿童和成人的努力评估和精神病理新的全基因组关联。
研究领域标准(RDoC)倡议是由美国国家精神卫生研究所建立的,作为一个多层次的、障碍不可知性的框架,通过指定的领域和结构来分析人类精神病理学,包括专注于奖励相关行为的“正价系统”领域。本研究调查了1215名6-12岁儿童及其父母(n = 1044)的“努力”奖励评价子结构及其与精神病理学遗传标记、功能神经生物学通路和多基因风险评分的关系。所有参与者都完成了奖励任务的努力支出(efrt),该任务根据两个量化指标:硬任务选择和奖励敏感性来评估“努力”。在MAGMA中进行遗传关联分析,利用EEfRT结果变量作为全基因组关联研究表型来计算SNP和基因水平的关联。全基因组关联分析发现,两个不同的遗传位点与艰苦任务选择的测量显著相关,另一个单独的遗传位点与奖励敏感性相关。基因集富集分析发现,“努力”与奖赏处理相关途径的多个基因集之间存在显著关联,包括多巴胺受体信号、边缘系统和前脑发育,以及对可卡因的生物反应。这些结果有助于在遗传水平上建立“努力”作为理解奖励相关行为的相关结构,并支持评估障碍不可知论精神病理学的RDoC框架。
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来源期刊
CiteScore
5.90
自引率
7.10%
发文量
40
审稿时长
4-8 weeks
期刊介绍: Neuropsychiatric Genetics, Part B of the American Journal of Medical Genetics (AJMG) , provides a forum for experimental and clinical investigations of the genetic mechanisms underlying neurologic and psychiatric disorders. It is a resource for novel genetics studies of the heritable nature of psychiatric and other nervous system disorders, characterized at the molecular, cellular or behavior levels. Neuropsychiatric Genetics publishes eight times per year.
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