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.

在几项使用横断面设计的全基因组关联研究 （GWAS） 中已经确定了冲动性的基因组相关性，但没有研究使用纵向构建的性状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 名无关欧洲参与者中，我们通过在 24 、 26 和 28 岁时的评估构建了延迟折扣和冲动人格特征（通过 UPPS-P 冲动行为量表测量）的纵向表型。我们使用横断面和纵向表型进行了冲动的 GWAS，估计了遗传力及其表型和遗传相关性，并评估了它们与冲动指标本身和相关精神状况的最近开发的多基因风险评分 （PRS） 的关联。潜在生长曲线模型显示所有冲动表型随时间推移的稳定截距。随着时间的推移，横断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。与横断面表型相比，稳定纵向表型的遗传力估计大幅提高，揭示了延迟贴现的显着 SNP 遗传性 （0.22;p = 0.03） 和寻求感觉 （0.35;p = 0.0007）。与以前的报告一致，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。 冲动指标和自我调节相关障碍的 PRS 也与纵向冲动性特征显著相关。最后，我们在一项独立的 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好处。在冲动性特征的首次纵向遗传研究中，结果揭示了随着时间的推移，延迟折扣和感觉寻求的稳定基因组相关性，并进一步验证了最近开发的 PRS 的效用，无论是与观察到的特征有关，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，以增强遗传力信号和导致精神疾病易感机制的基因组相关性。