The MIR137 region in schizophrenia: genomics, variant discovery & association

描述（由申请人提供）：精神分裂症（SCZ）是一种通常具有破坏性的神经精神疾病，终生患病率为0.4%。目前对这种疾病的多基因性质的理解强调了理解SCZ病因学的复杂性。来自精神病学GWAS联盟（PGC）的令人兴奋的新发现已经确定了1号染色体上靠近MIR137的一个区域的显著和可复制的关联。对一份瑞典样本（N=21,856）发表的PGC GWAS数据进行meta分析，发现最显著的SNP为p=1.7X10-9，位于编码MIR137茎环序列的区域向上约40kb处。通过鉴定miR-137的四个靶点（CACNA1C、TCF4、CSMD1和C10orf26）的全基因组显著相关性，MIR137也在功能上有牵连。对PGC- GWAS数据的分析还显示，与大小和标记密度匹配的基因相比，预测的miR-137靶标具有丰富的关联（p<0.01）。这些发现表明，该区域存在一种变异，可能影响miR-137的功能，从而改变SCZ的风险。然而，到目前为止，还没有功能性变异与SCZ风险相关的报道。因此，我们提出了一组实验，旨在确定新的和已知的变异，这些变异是在功能上影响MIR137或其他基因的最佳候选者，从而直接导致SCZ风险。这项工作包括：1)通过新颖和创新的技术验证转录和基因组结构，包括新生RNA测序（GRO-seq）和选择个体的长读测序；2)对SCZ病例和对照进行测序以鉴定新的变异；3)使用现有数据库和我们在该地区的工作数据进行功能注释；4)对大型病例对照数据集进行基因分型以确定哪些变异与SCZ相关。这将产生非常详细和优先排序的变异列表，这些变异可能会导致人群中SCZ的风险。这将为未来的拨款申请提供基础，从分子上确认变异对附近基因和SCZ群体的功能影响。这个区域提供了最好的机会来识别SCZ病因学的复杂谜团。

DESCRIPTION (provided by applicant): Schizophrenia (SCZ) is an often devastating neuropsychiatric illness with a lifetime prevalence of 0.4%. The current understanding of the polygenic nature of this disease underscores the complexity of understanding SCZ etiology. New and exciting novel findings from the Psychiatric GWAS Consortium (PGC) have identified significant and replicated association for a region on chromosome 1 near MIR137. Meta-analysis of the published PGC GWAS data with a Swedish sample (N=21,856) yielded a top significant SNP of p=1.7X10-9, located approximately 40kb upsteam of the region encoding the MIR137 stem-loop sequence. MIR137 has also been functionally implicated through identification of significant genome wide association for four genes which have confirmed miR-137 target sites (CACNA1C, TCF4, CSMD1, and C10orf26). Analysis of the PGC- GWAS data also shows that predicted miR-137 targets were enriched for association compared with genes matched for size and marker density (p<0.01). These findings suggest that there exists a variant in this region, likely affecting miR-137 function that alters risk for SCZ. However, to date, no functional variants have been reported and linked to SCZ risk. We therefore propose a set of experiments designed to identify both novel and known variants that are the best candidates for functionally affecting either MIR137 or other genes, thereby directly contributing to SCZ risk. This work involves: 1) verification of transcriptional and genomic architecture through novel and innovative techniques, including sequencing of nascent RNA (GRO-seq) and long-read sequencing of select individuals; 2) sequencing SCZ cases and controls for identification of novel variants 3) functional annotation using existing databases and data from our work on the region and 4) genotyping of a large case control dataset to determine which variants are associated with SCZ. This will yield highly detailed and prioritized list of variants that are likey to contribute to risk of SCZ in the population. This will provide for the basis of future grant applications molecularly confirming the functional effect of variants on nearby genes and in the SCZ population. This region provides the best opportunity yet to identify pieces to the complex puzzle of SCZ etiology.