PDF(Pubmed)
Abstract：
Delay discounting refers to the behavioral tendency to devalue rewards as a function of their delay in receipt. Heightened delay discounting has been associated with substance use disorders and multiple co-occurring psychopathologies. Human and animal genetic studies have established that delay discounting is heritable, but only a few associated genes have been identified. We aimed to identify novel genetic loci associated with delay discounting through a genome-wide association study (GWAS) using Heterogeneous Stock (HS) rats, a genetically diverse outbred population derived from eight inbred founder strains. We assessed delay discounting in 650 male and female HS rats using an adjusting amount procedure in which rats chose between smaller immediate sucrose rewards or a larger reward at various delays. Preference switch points were calculated and both exponential and hyperbolic functions were fitted to these indifference points. Area under the curve (AUC) and the discounting parameter k of both functions were used as delay discounting measures. GWAS for AUC, exponential k, and one indifference point identified significant loci on chromosomes 20 and 14. The gene Slc35f1, which encodes a member of the solute carrier family, was the sole gene within the chromosome 20 locus. That locus also contained an eQTL for Slc35f1, suggesting that heritable differences in the expression might be responsible for the association with behavior. Adgrl3, which encodes a latrophilin subfamily G-protein coupled receptor, was the sole gene within the chromosome 14 locus. These findings implicate novel genes in delay discounting and highlight the need for further exploration.
摘要：
延迟折扣是指由于其收到延迟而使奖励贬值的行为倾向。延迟折扣的增加与物质使用障碍和多种并存的精神病理学有关。人类和动物遗传研究已经确定延迟折扣是可遗传的，但是只有少数相关基因被鉴定出来。我们旨在通过使用异质性股票（HS）大鼠的全基因组关联研究（GWAS）来鉴定与延迟折扣相关的新遗传基因座，来自八种近交创始人品系的遗传多样性近交群体。我们使用调整量程序评估了650只雄性和雌性HS大鼠的延迟折扣，其中大鼠在各种延迟下在较小的即时蔗糖奖励或较大的奖励之间进行选择。计算偏好切换点，并将指数函数和双曲函数拟合到这些无差别点。曲线下面积(AUC)和两个函数的贴现参数k用作延迟贴现量度。AUC的GWAS，指数k，一个无差别点确定了20号和14号染色体上的重要基因座。基因Slc35f1，它编码溶质载体家族的成员，是20号染色体基因座中唯一的基因.该基因座还包含Slc35f1的eQTL，表明表达的可遗传差异可能与行为有关。Adgrl3，它编码latrophilin亚家族G蛋白偶联受体，是14号染色体基因座内的唯一基因。这些发现暗示了延迟折扣的新基因，并强调了进一步探索的必要性。
