Identification of the functional variant driving ORMDL3 and GSDMB expression in human chromosome 17q12-21 in primary biliary cholangitis.
Identification of the functional variant driving ORMDL3 and GSDMB expression in human chromosome 17q12-21 in primary biliary cholangitis.
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DOI：
10.1038/s41598-017-03067-3
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发表时间：
2017-06-06
影响因子：
4.6
通讯作者：
Tokunaga K
中科院分区：
文献类型：
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作者：
Hitomi Y;Kojima K;Kawashima M;Kawai Y;Nishida N;Aiba Y;Yasunami M;Nagasaki M;Nakamura M;Tokunaga K
许多全基因组关联研究（GWAS）已被执行，以确定各种人类复杂疾病的易感基因。然而，在许多情况下，既没有一个功能性变异，也没有一个疾病易感基因已澄清。在这里，我们展示了一种有效的方法来识别原发性胆管炎（PBC）易感区域，染色体17 q12 -21（ORMDL 3-GSDMB-ZPBP 2-IKZF 3）的功能变异。使用来自1，070名日本个体（1 KJPN）的参考组的全基因组序列数据，以及我们之前GWAS的基因型数据（PBC患者：n = 1，389;健康对照：n = 1，508），基于SNP插补分析进行高密度关联作图。在P < 1.0 × 10 - 8的23个单核苷酸多态性（SNP）中，rs 12946510被确定为通过改变叉头盒蛋白O 1（FOXO 1）体外结合亲和力影响基因表达的功能变体。此外，表达-数量性状位点（e-QTL）分析表明，PBC易感等位基因rs 12946510与全血和脾脏中ORMDL 3和GSDMB的内源性表达降低显著相关。这项研究不仅确定了chr.17q12-21中的功能变体及其赋予PBC易感性的分子机制，而且还说明了适用于其他复杂疾病的GWAS后分析的有效系统方法。
Numerous genome-wide association studies (GWAS) have been performed to identify susceptibility genes to various human complex diseases. However, in many cases, neither a functional variant nor a disease susceptibility gene have been clarified. Here, we show an efficient approach for identification of a functional variant in a primary biliary cholangitis (PBC)-susceptible region, chromosome 17q12-21 (ORMDL3-GSDMB-ZPBP2-IKZF3). High-density association mapping was carried out based on SNP imputation analysis by using the whole-genome sequence data from a reference panel of 1,070 Japanese individuals (1KJPN), together with genotype data from our previous GWAS (PBC patients: n = 1,389; healthy controls: n = 1,508). Among 23 single nucleotide polymorphisms (SNPs) with P < 1.0 × 10−8, rs12946510 was identified as the functional variant that influences gene expression via alteration of Forkhead box protein O1 (FOXO1) binding affinity in vitro. Moreover, expression-quantitative trait locus (e-QTL) analyses showed that the PBC susceptibility allele of rs12946510 was significantly associated with lower endogenous expression of ORMDL3 and GSDMB in whole blood and spleen. This study not only identified the functional variant in chr.17q12-21 and its molecular mechanism through which it conferred susceptibility to PBC, but it also illustrated an efficient systematic approach for post-GWAS analysis that is applicable to other complex diseases.