Population genomics in a disease targeted primary cell model
Population genomics in a disease targeted primary cell model
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DOI：
10.1101/gr.095224.109
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发表时间：
2009-11-01
期刊：
影响因子：
7
通讯作者：
Pastinen, Tomi
中科院分区：
文献类型：
--
作者：
Grundberg, Elin;Kwan, Tony;Pastinen, Tomi
与复杂性状相关的常见遗传变异通常存在于非编码DNA中，并可能以特定细胞类型的方式改变基因调控。因此，组织或细胞模型的选择在疾病关联的解剖中是重要的。我们对来自95个瑞典血统无关供者的原代人类成骨细胞(HOB)进行了表达数量性状基因座(EQTL)研究，每个原代细胞由两个独立衍生的原代系代表，以提供生物复制。我们将我们的数据与一项关于骨矿密度的全基因组关联研究的公开信息结合在一起。使用公开可用的数据对前2000个与BMD相关的SNPs(P<；类似于10(-3))在HOBS和淋巴母细胞系(LCL)中的基因表达顺式关联性进行了测试，结果表明HOBS具有比LCLS显著丰富(三倍)的聚合顺式-eQTL。在两个高加索男性队列中，选择了前10个SNP对基因表达有强烈顺式影响的BMD基因座(P=6 x 10(-10)-7 x 10(-16))进行进一步验证。所有10个变异都在瑞典MROS队列中进行了测试(n=3014)，为两个新的BMD基因座(SRR和MSH3)提供了证据。这些变异随后在鹿特丹研究中进行了测试(n=2090)，得出了17p13.3 SRR基因座与BMD关联的聚合证据(P-组合=5.6x10(-5))。进一步将顺式调控作用定位于SRR基因的近端启动子(rs3744270，r(2)=0.5，P=2.6×10(15))。我们的结果表明，与疾病表型相关的原代细胞补充了传统的方法，用于优先排序和验证后续研究的GWAHITS。
The common genetic variants associated with complex traits typically lie in noncoding DNA and may alter gene regulation in a cell type-specific manner. Consequently, the choice of tissue or cell model in the dissection of disease associations is important. We carried out an expression quantitative trait loci (eQTL) study of primary human osteoblasts (HOb) derived from 95 unrelated donors of Swedish origin, each represented by two independently derived primary lines to provide biological replication. We combined our data with publicly available information from a genome-wide association study (GWAS) of bone mineral density (BMD). The top 2000 BMD-associated SNPs (P < similar to 10(-3)) were tested for cis-association of gene expression in HObs and in lymphoblastoid cell lines (LCLs) using publicly available data and showed that HObs have a significantly greater enrichment ( threefold) of converging cis-eQTLs as compared to LCLs. The top 10 BMD loci with SNPs showing strong cis-effects on gene expression in HObs (P = 6 x 10(-10) - 7 x 10(-16)) were selected for further validation using a staged design in two cohorts of Caucasian male subjects. All 10 variants were tested in the Swedish MrOS Cohort (n = 3014), providing evidence for two novel BMD loci (SRR and MSH3). These variants were then tested in the Rotterdam Study ( n = 2090), yielding converging evidence for BMD association at the 17p13.3 SRR locus (P-combined = 5.6 x 10(-5)). The cis-regulatory effect was further fine-mapped to the proximal promoter of the SRR gene (rs3744270, r(2) = 0.5, P = 2.6 x 10 (15)). Our results suggest that primary cells relevant to disease phenotypes complement traditional approaches for prioritization and validation of GWAS hits for follow-up studies.