King Christopher P, Chitre Apurva S, Leal-Gutiérrez Joel D, Tripi Jordan A, Netzley Alesa H, Horvath Aidan P, Lamparelli Alexander C, George Anthony, Martin Connor, St Pierre Celine L, Missfeldt Sanches Thiago, Bimschleger Hannah V, Gao Jianjun, Cheng Riyan, Nguyen Khai-Minh, Holl Katie L, Polesskaya Oksana, Ishiwari Keita, Chen Hao, Robinson Terry E, Flagel Shelly B, Solberg Woods Leah C, Palmer Abraham A, Meyer Paul J
Department of Psychology, University at Buffalo, Buffalo, New York, USA.
Clinical and Research Institute on Addictions, Buffalo, New York, USA.
Genes Brain Behav. 2025 Apr;24(2):e70018. doi: 10.1111/gbb.70018.
Addiction vulnerability is associated with the tendency to attribute incentive salience to reward predictive cues. Both addiction and the attribution of incentive salience are influenced by environmental and genetic factors. To characterize the genetic contributions to incentive salience attribution, we performed a genome-wide association study (GWAS) in a cohort of 1596 heterogeneous stock (HS) rats. Rats underwent a Pavlovian conditioned approach task that characterized the responses to food-associated stimuli ("cues"). Responses ranged from cue-directed "sign-tracking" behavior to food-cup directed "goal-tracking" behavior (12 measures, SNP heritability: 0.051-0.215). Next, rats performed novel operant responses for unrewarded presentations of the cue using the conditioned reinforcement procedure. GWAS identified 14 quantitative trait loci (QTLs) for 11 of the 12 traits across both tasks. Interval sizes of these QTLs varied widely. Seven traits shared a QTL on chromosome 1 that contained a few genes (e.g., Tenm4, Mir708) that have been associated with substance use disorders and other psychiatric disorders in humans. Other candidate genes (e.g., Wnt11, Pak1) in this region had coding variants and expression-QTLs in mesocorticolimbic regions of the brain. We also conducted a Phenome-Wide Association Study (PheWAS) on addiction-related behaviors in HS rats and found that the QTL on chromosome 1 was also associated with nicotine self-administration in a separate cohort of HS rats. These results provide a starting point for the molecular genetic dissection of incentive motivational processes and provide further support for a relationship between the attribution of incentive salience and drug abuse-related traits.
成瘾易感性与将动机显著性归因于奖励预测线索的倾向有关。成瘾和动机显著性的归因均受环境和遗传因素影响。为了描述遗传因素对动机显著性归因的作用，我们在一个由1596只异质品系（HS）大鼠组成的队列中进行了全基因组关联研究（GWAS）。大鼠接受了巴甫洛夫条件性接近任务，该任务用于表征对与食物相关刺激（“线索”）的反应。反应范围从线索导向的“符号追踪”行为到食杯导向的“目标追踪”行为（12项测量指标，单核苷酸多态性遗传力：0.051 - 0.215）。接下来，大鼠使用条件性强化程序对未给予奖励的线索呈现进行新的操作性反应。GWAS在两项任务中的12个性状中的11个中鉴定出14个数量性状位点（QTL）。这些QTL的区间大小差异很大。七个性状在1号染色体上共享一个QTL，该QTL包含一些与人类物质使用障碍和其他精神疾病相关的基因（例如，Tenm4、Mir708）。该区域的其他候选基因（例如，Wnt11、Pak1）在大脑的中脑边缘区域具有编码变体和表达QTL。我们还对HS大鼠的成瘾相关行为进行了全表型关联研究（PheWAS），发现1号染色体上的QTL也与另一组HS大鼠的尼古丁自我给药有关。这些结果为动机激励过程的分子遗传学剖析提供了一个起点，并为动机显著性归因与药物滥用相关性状之间的关系提供了进一步支持。
