Recent genome-wide association studies (GWAS) identified numerous schizophrenia (SZ) and Alzheimer's disease (AD) associated loci, most outside protein-coding regions and hypothesized to affect gene transcription. We used a massively parallel reporter assay to screen, 1,049 SZ and 30 AD variants in 64 and nine loci, respectively for allele differences in driving reporter gene expression. A library of synthetic oligonucleotides assaying each allele five times was transfected into K562 chronic myelogenous leukemia lymphoblasts and SK-SY5Y human neuroblastoma cells. One hundred forty eight variants showed allelic differences in K562 and 53 in SK-SY5Y cells, on average 2.6 variants per locus. Nine showed significant differences in both lines, a modest overlap reflecting different regulatory landscapes of these lines that also differ significantly in chromatin marks. Eight of nine were in the same direction. We observe no preference for risk alleles to increase or decrease expression. We find a positive correlation between the number of SNPs in linkage disequilibrium and the proportion of functional SNPs supporting combinatorial effects that may lead to haplotype selection. Our results prioritize future functional follow up of disease associated SNPs to determine the driver GWAS variant(s), at each locus and enhance our understanding of gene regulation dynamics.

中文翻译：

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对 1,049 种精神分裂症和 30 种阿尔茨海默病相关变异的监管潜力进行了筛选。


最近的全基因组关联研究 (GWAS) 发现了许多精神分裂症 (SZ) 和阿尔茨海默氏病 (AD) 相关基因座，大部分位于蛋白质编码区之外，并假设影响基因转录。我们使用大规模并行报告基因测定法分别筛选了 64 个和 9 个基因座中的 1,049 个 SZ 和 30 个 AD 变体，以确定驱动报告基因表达的等位基因差异。将每个等位基因分析五次的合成寡核苷酸文库转染至 K562 慢性粒细胞白血病淋巴母细胞和 SK-SY5Y 人神经母细胞瘤细胞中。 SK-SY5Y 细胞中的 K562 和 53 中有 148 个变体显示出等位基因差异，平均每个位点有 2.6 个变体。九个在两条品系中都显示出显着差异，适度的重叠反映了这些品系的不同监管景观，这些品系在染色质标记上也存在显着差异。九个中有八个朝同一方向。我们观察到风险等位基因不偏好增加或减少表达。我们发现连锁不平衡中的 SNP 数量与支持可能导致单倍型选择的组合效应的功能性 SNP 比例之间存在正相关。我们的结果优先考虑疾病相关 SNP 的未来功能随访，以确定每个位点的驱动 GWAS 变异，并增强我们对基因调控动态的理解。