Elucidating molecular mechanisms of psychological well-being

我们建议研究心理学个体差异的分子机制， 幸福（PWB）PWB是一个多维度的结构，包括积极情绪，生活满意度， 以及生活的目的和意义感，而不仅仅是没有消极的情绪状态。许多 前瞻性纵向研究表明，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，PWB降低了 有自杀意念，抑郁，滥用药物，创伤后应激障碍，阿尔茨海默氏痴呆， 心脏病、糖尿病，并降低全因死亡率。 值得注意的是，PWB具有相当大的遗传贡献，遗传率约为64%。 然而，PWB的遗传机制在很大程度上是未知的，尽管它有许多重要的好处。到 为了解决这个问题，我们最近进行了一项积极情绪的全基因组关联研究（GWAS），这是一项主要的 PWB的一面。我们发现一个单核苷酸多态性（SNP）rs322931，与 在基因组水平上的积极情绪。此后，这种联系在两个独立的 数据集。我们随后发现rs322931是一个顺式表达的数量性状基因座（eQTL）， microRNA 181 a和181 B（miR-181 a/B）在人血液和脑中表达。有趣的是，miR-181 a/B是 丰富的奖励动机神经回路，并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-181 a/B在PWB中发挥作用。 鉴于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。 人类死后脑转录组学、表观基因组学、蛋白质组学和基因组学数据，以阐明分子 PWB的机制。这个由675人组成的独特人脑数据集，由NIH资助的Rush收集 记忆和衰老项目（MAP）超过20年，提供了一个难得的机会，调查机制， PWB在相关器官，即人脑，与90%的权力，我们提出的分析。 为此，我们提出以下目标。目标1将验证我们的GWAS的遗传发现， 2040年退伍军人和MAP参与者的积极情绪。目标2将通过调查 使用假设驱动和假设中立的方法来研究PWB中脑microRNA的贡献。 值得注意的是，microRNA是基因表达的重要转录后调节因子， 控制着超过一半的蛋白质编码基因。目标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 它们的蛋白质水平是否在PWB中相应地改变。 总之，这个新颖和创新的建议利用了以前收集的退伍军人遗传样本 和人类死后的大脑“组学”数据，这些数据来自于过去一年中招募的独特的NIH资助的MAP队列。 20年我们计划联合收割机将这些数据与我们将生成的数据相结合，并以创新的方式进行分析。 系统生物学方法来阐明PWB的分子机制。我们渴望阐明 PWB的架构有助于未来开发基于生物标志物的风险筛查 分层和干预，以加强工作场所预算及其有益的影响。

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.