Elucidating molecular mechanisms of psychological well-being

我们建议研究心理学上个体差异的分子机制。 幸福(PWB)。PWB是一个多维结构，包括积极的情感，生活满意度， 以及生活中的目的感和意义，而不仅仅是没有消极的情绪状态。许多 前瞻性的纵向研究表明，PWB与更好的心理和身体健康有关 在调整了负面情绪和其他相关混杂因素后。事实上，工务局可减低 有自杀念头，抑郁，滥用药物，创伤后应激障碍，阿尔茨海默氏症， 心脏病、糖尿病，并降低各种原因造成的死亡率。 值得注意的是，pwb有很大的遗传贡献，遗传力约为%。 然而，尽管PWB有许多重要的好处，但其遗传机制在很大程度上尚不清楚。至 为了解决这个问题，我们最近进行了一项关于积极情绪的全基因组关联研究，这是一个主要的 压路板的小平面。我们发现单核苷酸多态(SNP)rs322931与 全基因组水平上的积极情绪。自那以后，这种关联在两个独立的 数据集。随后我们发现rs322931是一个顺式表达的数量性状基因座(EQTL) MicroRNAs 181a和181b(miR-181a/b)在人血和脑中表达。有趣的是，miR-181a/b是 丰富的奖赏-动机神经回路，调节突触可塑性和免疫功能 动物研究。综上所述，我们假设miR-181a/b在pwb中发挥作用。 考虑到这些令人兴奋的数据，我们建议利用已经收集的数据来验证和扩展我们的发现 人类死后脑转录、表观基因组、蛋白质组和基因组数据以阐明分子 压路板的作用机理。这个独特的人类大脑数据集，由NIH资助的Rush收集，包含675个人 记忆和衰老计划(MAP)20多年来提供了一个难得的机会来研究 PWB在相关器官，即人脑中，有90%的能量用于我们拟议的分析。 为此，我们提出了以下目标。AIM 1将验证来自我们的GWAS的基因发现 2040名退伍军人和MAP参与者的积极情绪Aim 2将通过调查 使用假设驱动和假设中立的方法研究脑微RNA在PWB中的作用。 值得注意的是，microRNAs是基因表达的重要转录后调节因子 调控一半以上的蛋白质编码基因。AIM 3将采用创新的系统生物学 识别pWB的基因网络和关键表达调控驱动因素的方法，以及确定 它们的蛋白质水平在pWB中是否发生了相应的变化。 总而言之，这一新颖和创新的建议利用了之前收集的老兵基因样本 以及来自美国国立卫生研究院资助的独特MAP队列的人类死后大脑的组学数据 20年了。我们计划将这些数据与我们将生成的数据结合起来，并使用创新技术对其进行分析 用系统生物学方法阐明PWB的分子机制。我们渴望阐明基因 PWB的架构将有助于未来开发基于生物标记物的风险筛查 分层和干预，以提高PWB及其有益效果。

We propose to investigate molecular mechanisms that underlie individual differences in psychological well-being (PWB). PWB is a multidimensional construct that encompasses positive emotion, life satisfaction, and sense of purpose and meaning in life, and is more than the absence of negative emotional states. Many prospective longitudinal studies have shown that PWB is associated with better mental and physical health after adjusting for negative emotion and other relevant confounding factors. Indeed, PWB mitigates risks of having suicide ideation, depression, substance abuse, post-traumatic stress disorder, Alzheimer's dementia, heart disease, diabetes, and reduces all-cause mortality. Notably, PWB has a substantial genetic contribution with a heritability of approximately 64%. However, the genetic mechanisms of PWB are largely unknown despite its many important benefits. To address this, we recently performed a genome-wide association study (GWAS) of positive emotion, a major facet of PWB. We found a single nucleotide polymorphism (SNP), rs322931, significantly associated with positive emotion at genome-wide level. This association has since been replicated in two independent datasets. We subsequently found that rs322931 is a cis-expression quantitative trait locus (eQTL) for microRNAs 181a and 181b (miR-181a/b) expressed in human blood and brain. Intriguingly, miR-181a/b are enriched in the reward-motivation neural circuit and regulate synaptic plasticity and immune functioning in animal studies. Taken together, we hypothesize that miR-181a/b play a role in PWB. Given these exciting data, we propose to validate and extend our findings, leveraging already collected human post-mortem brain transcriptomic, epigenomic, proteomic, and genomic data to elucidate molecular mechanisms of PWB. This unique human brain dataset of 675 individuals, gathered by the NIH-funded Rush Memory and Aging Project (MAP) over 20 years, provides a rare opportunity to investigate mechanisms of PWB in the relevant organ, i.e. human brain, with 90% power for our proposed analyses. To that end, we propose the following aims. Aim 1 will validate the genetic findings from our GWAS of positive emotion in 2040 Veterans and MAP participants. Aim 2 will extend our findings by investigating the contribution of brain microRNAs in PWB using both a hypothesis-driven and hypothesis-neutral approach. Notably, microRNAs are important post-transcriptional regulators of gene expression and collectively regulate more than half of the protein-coding genes. Aim 3 will employ innovative systems biology approaches to identify gene networks and key expression regulatory drivers of PWB, as well as determine whether their protein levels are correspondingly altered in PWB. In sum, this novel and innovative proposal capitalizes on previously collected Veteran genetic samples and human post-mortem brain “omic” data from the unique NIH-funded MAP cohort recruited over the last 20 years. We plan to combine these data with the ones we will generate and analyze them with innovative systems biology approaches to elucidate molecular mechanisms of PWB. We aspire to elucidate the genetic architecture of PWB to contribute to future efforts in developing biomarker based screening for risk stratification and intervention to enhance PWB and its beneficial effects.