Genomic correlates of impulsivity have been identified in several genome-wide association studies (GWAS) using cross-sectional designs, but no studies have investigated the molecular genetic correlates of impulsivity phenotypes using longitudinally constructed traits. In 3860 unrelated European participants in the Avon Longitudinal Study of Parents and Children (ALSPAC), we constructed longitudinal phenotypes for delay discounting and impulsive personality traits (as measured by the UPPS-P impulsive behavior scales) via assessment at ages 24, 26, and 28. We conducted GWASs of impulsivity using both cross-sectional and longitudinal phenotypes, estimated heritability and their phenotypic and genetic correlations, and evaluated their association with recently-developed polygenic risk scores (PRSs) for the impulsivity indicators themselves and also related psychiatric conditions. Latent growth curve modeling revealed a stable intercept over time for all impulsivity phenotypes. High genetic correlation of cross-sectional measures over time suggested a stable genetic component for delay discounting (r_g = 0.53–0.99) and sensation seeking (r_g = 0.99). Heritability estimates of the stable longitudinal phenotypes substantively improved as compared to their cross-sectional counterparts, revealing a significant SNP-heritability for delay discounting (0.22; p = 0.03) and sensation seeking (0.35; p = 0.0007). Consistent with previous reports, GWAS and gene-based analyses revealed associations between specific longitudinal impulsivity indicators and CADM2 and NCAM1 genes. The PRSs for the impulsivity indicators and disorders related to self-regulation were also significantly associated with longitudinal impulsivity traits. Finally, we validated the associations between longitudinal impulsivity phenotypes and their PRSs in an independent 13-wave longitudinal study (n = 1019) and the benefit of longitudinal phenotypes in simulation studies. In this first longitudinal genetic study of impulsivity traits, the results revealed stable genomic correlates of delay discounting and sensation seeking over time and further validated the utility of recently-developed PRSs, both in relation to the observed traits and in connecting them to psychiatric disorders. More generally, these findings support using latent intercepts as novel longitudinal phenotypes to boost signal for heritability and genomic correlates of mechanisms contributing to psychiatric disease liability.

一些使用横断面设计的全基因组关联研究（GWAS）已经确定了冲动的基因组相关性，但没有研究使用纵向构建的特征来调查冲动表型的分子遗传相关性。在雅芳父母和儿童纵向研究 (ALSPAC) 的 3860 名不相关的欧洲参与者中，我们通过对 24 岁、26 岁和28. 我们使用横截面和纵向表型进行了冲动性全基因组关联分析，估计了遗传力及其表型和遗传相关性，并评估了它们与最近开发的冲动性指标本身以及相关精神疾病的多基因风险评分（PRS）的关联。潜在生长曲线模型揭示了所有冲动表型随时间的稳定截距。随着时间的推移，横截面测量的高度遗传相关性表明延迟贴现（ r _g = 0.53-0.99）和感觉寻求（ r _g = 0.99）具有稳定的遗传成分。与横截面对应物相比，稳定纵向表型的遗传力估计得到了实质性改善，揭示了延迟贴现（0.22； p = 0.03）和感觉寻求（0.35； p = 0.0007）的显着 SNP 遗传力。与之前的报告一致，GWAS 和基于基因的分析揭示了特定纵向冲动指标与CADM2和NCAM1基因之间的关联。 冲动指标和与自我调节相关的障碍的 PRS 也与纵向冲动特征显着相关。最后，我们在独立的 13 波纵向研究 ( n = 1019) 中验证了纵向冲动表型与其 PRS 之间的关联，以及纵向表型在模拟研究中的益处。在第一个关于冲动性状的纵向遗传学研究中，结果揭示了随着时间的推移，延迟贴现和感觉寻求之间存在稳定的基因组相关性，并进一步验证了最近开发的 PRS 的实用性，无论是与观察到的性状相关，还是将它们与精神疾病联系起来。更一般地说，这些发现支持使用潜在截距作为新的纵向表型，以增强遗传性和导致精神疾病倾向的机制的基因组相关性的信号。