Fine-Mapping Genome-Wide Associated Loci using Multi-omics Data to Identify Mechanisms Affecting Serious Mental Illness

全基因组关联研究一直是识别相关遗传变异的关键 患有精神障碍。然而，每当这些GWA是基于大样本大小时， 它们在风险中涉及过多的单核苷酸多态(SNPs)。这种多源性 提出了将风险变化映射到易患的生物机制上的挑战 个人对疾病的反应。许多研究已经将基因组和转录变异与 共同定位GWASSNP关联和顺式转录模式的目标由 表达数量性状基因座(EQTL)，以及其他QTL。在某些情况下，这些研究 突出一个或多个基因，其转录变异主要由特定基因的变异驱动 存在SNPs风险。然而，对于很大一部分风险基因座来说，共定位在以下方面不一致 研究或没有观察到对转录的影响。这些缺失的基因风险变异之间的联系 生物变异可能是由许多因素引起的，包括细胞类型特异性、发育 模式，或缺失组学特征。值得注意的是，块状组织甚至单细胞的mrna 蛋白质水平并不能很好地预测它们编码的蛋白质的细胞水平。我们假设 这些缺失的环节中有很大一部分是由于我们对蛋白质组学的有限了解 变异与人类大脑中的遗传变异有关。SNPs通过对蛋白质组的调控 “跳过”转录水平和蛋白质水平的机制受到翻译后基因的严格调控 不容易从转录组中预测的修饰(PTM)。 我们建议表征人类死后的转录和蛋白质组学变异。 大脑，特别是蛋白质表达(目标1)；PTMS(目标2)；将遗传变异映射到 转录(EQTL)、蛋白质组和PTM变异(pQTL和PTMQTL) 相互关系(目标3)；然后执行共定位分析，以告知生物 基因变异导致精神疾病风险的途径(目标4)。在我们的预赛中 蛋白质组学实验，我们将蛋白质组学和SNP基因分型相结合来鉴定pQTL。 我们发现相当一部分pQTL绕过了转录组(~50%)，这与 最近的另一项人类大脑pQTL研究和我们的假设。 我们的目标与RFA-MH-21-100的目标是一致的：(1)开发新的蛋白质组学 和其他组学资源；(2)使用它们来绘制遗传风险变异如何影响 神经组织和细胞类型的组学特征；以及(3)提供了一组高度可信的 可能导致疾病风险的因果变异、基因和异构体，增强我们的 对近似性疾病机制的洞察。

Genome-wide association studies have been key for identifying genetic variation associated with psychiatric disorders. Whenever these GWAS are based on large sample sizes, however, they implicate a plethora of single nucleotide polymorphisms (SNPs) in risk. This polygenicity presents challenges for mapping risk variation onto the biological mechanisms that predispose individuals to illness. Many studies have integrated genomic and transcriptomic variation with the goal of colocalizing the GWAS SNP associations and cis transcriptional patterns determined by expression quantitative trait loci (eQTLs), as well as other QTLs. In some instances, these studies highlight one or more genes whose transcriptomic variation is driven largely by variation in specific risk SNPs. For a substantial fraction of the risk loci, however, colocalization is inconsistent across studies or no effect on transcription is observed. These missing links between genetic risk variation and biological variation could be due to many factors, including cell-type specificity, developmental patterns, or missing -omics characterizations. Notably, bulk tissue and even single cell mRNA levels are imperfect predictors of the cellular levels of the proteins they code for. We hypothesize that a substantial portion of these missing links is due to our limited knowledge of how proteomic variation relates to genetic variation in the human brain. SNPs can regulate the proteome via mechanisms that “skip” transcript levels and protein levels are tightly regulated by posttranslational modifications (PTMs) that are not readily predictable from the transcriptome. We propose to characterize transcriptomic and proteomic variation in human post-mortem brain, specifically protein expression (Aim 1); PTMs (Aim 2); map genetic variation onto transcriptomic (eQTLs) and proteome and PTM variation (pQTLs and PTMQTLs) and evaluate their interrelationships (Aim 3); and then perform colocalization analysis to inform the biological pathways by which genetic variation confers risk to psychiatric disorders (Aim 4). In our preliminary proteogenomic experiments, we combined proteomics with SNP genotyping to identify pQTLs. We discovered that a substantial fraction of pQTLs bypass the transcriptome (~50%), in line with another recent human brain pQTL study and our hypothesis. Our aims are consistent with goals from RFA-MH-21-100: (1) develop novel proteomic and other omics resources; (2) use them to map how genetic risk variation influences omics features in neural tissue and cell types; and (3) provide a high confidence set of causal variants, genes, and isoforms that likely contribute to disease risk, enhancing our insights into proximate disease mechanisms.