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遗传变异相关的关键 患有精神疾病然而，每当这些GWAS基于大样本量时， 它们暗示了过多的单核苷酸多态性（SNPs）的风险。这种多源性 提出了将风险变化映射到易患疾病的生物机制的挑战， 个人生病。许多研究已经将基因组和转录组变异与 目标是共定位GWAS SNP关联和顺式转录模式， 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，其转录组变异主要由特异性 风险SNP。然而，对于相当一部分的风险位点，共定位在不同的区域是不一致的。 研究或没有观察到对转录的影响。这些遗传风险变异 生物学变异可能是由于许多因素，包括细胞类型特异性，发育 模式或缺失的组学特征。值得注意的是，大块组织甚至单细胞mRNA 水平是它们编码的蛋白质的细胞水平的不完美预测器。我们假设 这些缺失环节的很大一部分是由于我们对蛋白质组学如何 变异与人类大脑中的遗传变异有关。SNP可以通过以下途径调节蛋白质组： “跳过”转录水平和蛋白质水平的机制是由翻译后 这些修饰（PTM）不容易从转录组中预测。 我们建议描述人类死后组织中转录组和蛋白质组的变化， 大脑，特别是蛋白质表达（目标1）; PTM（目标2）;将遗传变异映射到 转录组（eQTL）和蛋白质组和PTM变异（pQTL和PTMQTL），并评估其 相互关系（目标3）;然后进行共定位分析，以告知生物学 遗传变异赋予精神疾病风险的途径（目标4）。在我们的初步调查中 在蛋白质组学实验中，我们将蛋白质组学与SNP基因分型相结合来鉴定pQTL。 我们发现，相当一部分pQTL绕过转录组（约50%），这与 另一个最近的人脑pQTL研究和我们的假设。 我们的目标与RFA-MH-21-100的目标一致：（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）提供神经组织和细胞类型的高置信度组学特征。 因果变异，基因和亚型，可能有助于疾病的风险，提高我们的 深入了解疾病的发病机制。

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.