Batra Aashita, Chen Lawrence M, Wang Zihan, Parent Carine, Pokhvisneva Irina, Patel Sachin, Levitan Robert D, Meaney Michael J, Silveira Patricia Pelufo
Integrated Program in Neuroscience, McGill University, Montreal, QC, Canada.
Douglas Mental Health University Institute, McGill University, Montreal, QC, Canada.
Front Neurosci. 2021 Sep 1;15:704785. doi: 10.3389/fnins.2021.704785. eCollection 2021.
While the co-morbidity between metabolic and psychiatric behaviors is well-established, the mechanisms are poorly understood, and exposure to early life adversity (ELA) is a common developmental risk factor. ELA is associated with altered insulin sensitivity and poor behavioral inhibition throughout life, which seems to contribute to the development of metabolic and psychiatric disturbances in the long term. We hypothesize that a genetic background associated with higher fasting insulin interacts with ELA to influence the development of executive functions (e.g., impulsivity in young children). We calculated the polygenic risk scores (PRSs) from the genome-wide association study (GWAS) of fasting insulin at different thresholds and identified the subset of single nucleotide polymorphisms (SNPs) that best predicted peripheral insulin levels in children from the Avon Longitudinal Study of Parents and Children (ALSPAC) cohort [ = 467; = 0.24 (10,296 SNPs), = 0.05 (57 SNPs)]. We then calculated the refined PRS (rPRS) for fasting insulin at this specific threshold in the children from the Maternal Adversity, Vulnerability and Neurodevelopment (MAVAN) cohort and investigated its interaction effect with adversity on an impulsivity task applied at 36 months. We found a significant effect of interaction between fasting insulin rPRS and adversity exposure predicting impulsivity measured by the Snack Delay Task at 36 months [β = -0.329, = 0.024], such that higher PRS [β = -0.551, = 0.009] was linked to more impulsivity in individuals exposed to more adversity. Enrichment analysis (MetaCore) of the SNPs that compose the fasting insulin rPRS at this threshold was significant for certain nervous system development processes including dopamine D2 receptor signaling. Additional enrichment analysis (FUMA) of the genes mapped from the SNPs in the fasting insulin rPRS showed enrichment with the accelerated cognitive decline GWAS. Therefore, the genetic background associated with risk for adult higher fasting insulin moderates the impact of early adversity on childhood impulsivity.
虽然代谢行为与精神行为之间的共病关系已得到充分证实，但其机制仍知之甚少，而早年逆境暴露（ELA）是一个常见的发育风险因素。ELA与一生当中胰岛素敏感性改变及行为抑制能力差有关，从长期来看，这似乎会促使代谢和精神障碍的发展。我们推测，与较高空腹胰岛素相关的遗传背景与ELA相互作用，影响执行功能（如幼儿冲动性）的发展。我们根据空腹胰岛素的全基因组关联研究（GWAS）在不同阈值下计算了多基因风险评分（PRSs），并在阿冯父母与儿童纵向研究（ALSPAC）队列中确定了最能预测儿童外周胰岛素水平的单核苷酸多态性（SNPs）子集[ = 467； = 0.24（10,296个SNPs）， = 0.05（57个SNPs）]。然后，我们在母婴逆境、易感性和神经发育（MAVAN）队列的儿童中，针对该特定阈值计算空腹胰岛素的精细PRS（rPRS），并研究其与逆境在36个月时应用的冲动性任务上的交互作用。我们发现空腹胰岛素rPRS与逆境暴露之间的交互作用对36个月时通过零食延迟任务测量的冲动性有显著影响[β = -0.329， = 0.024]，即较高的PRS[β = -0.551， = 0.009]与更多暴露于更多逆境个体的冲动性相关。对构成该阈值下空腹胰岛素rPRS的SNPs进行的富集分析（MetaCore）对于某些神经系统发育过程（包括多巴胺D2受体信号传导）具有显著性。对空腹胰岛素rPRS中的SNPs映射的基因进行的额外富集分析（FUMA）显示与加速认知衰退GWAS存在富集。因此，与成人较高空腹胰岛素风险相关的遗传背景会缓和早年逆境对儿童期冲动性的影响。
