Genome-Wide Meta-Analysis Identifies Three Novel Susceptibility Loci and Reveals Ethnic Heterogeneity of Genetic Susceptibility for IgA Nephropathy
Genome-Wide Meta-Analysis Identifies Three Novel Susceptibility Loci and Reveals Ethnic Heterogeneity of Genetic Susceptibility for IgA Nephropathy
复制标题
全基因组荟萃分析确定了三个新的易感性位点并揭示了 IgA 肾病遗传易感性的种族异质性
DOI：
10.1681/asn.2019080799
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发表时间：
2020-12-01
影响因子：
13.6
通讯作者：
Yu, Xue-Qing
中科院分区：
文献类型：
--
作者：
Li, Ming;Wang, Ling;Yu, Xue-Qing
背景18个已知的IgAN易感基因位点仅占IgAN风险的一小部分。方法对2628例中国血统患者和11,563例对照进行全基因组荟萃分析，并对6879例中国血统患者和9019例对照以及1039例欧洲血统患者和1289例对照进行重复分析。这些数据用于评估IgAN易感基因座与临床表型的关联，并调查两个人群之间IgAN易感性的遗传异质性。基于插补的MHC/HLA区域分析扩展了研究范围。（1q23.1上的rs6427389 [P=8.18x10（29），OR=1.132]，6p25.3上的rs6942325 [P=1.62x10（-11），OR=1.165]，1p36.13上的rs 2240335 [P=5.10x10（29），OR=1.114]），提示FCRL 3、DUSP 22、IRF 4和PADI 4是IgA肾病的易感基因。rs 2240335与PADI 4的表达水平相关，rs6427389与rs 11264799处于高度连锁不平衡，对FCRL 3的表达有较强的定量trail位点效应。在24个确认的风险SNP中，6个显示出遗传效应的显著异质性，DEFA显示出人群之间等位基因异质性的明确证据。对MHC区域的基于插补的分析揭示了三种HLA多态性与（HLA等位基因DPB 1 *02、AA_DRB1_140_32657458_T和AA_DQA1_34_32717152）和两个SNP（rs 9275464和rs 2295119）。结论GWAS数据的荟萃分析揭示了IgAN的三个新的遗传风险位点，MHC区域内的3个HLA多态性和2个SNPs，证实了24个已确认的风险SNPs中7个位点的遗传异质性。这些变异可以解释中国和欧洲人群之间的易感性差异。
Background Eighteen known susceptibility loci for IgAN account for only a small proportion of IgAN risk.Methods Genome-wide meta-analysis was performed in 2628 patients and 11,563 controls of Chinese ancestry, and a replication analysis was conducted in 6879 patients and 9019 controls of Chinese descent and 1039 patients and 1289 controls of European ancestry. The data were used to assess the association of susceptibility loci with clinical phenotypes for IgAN, and to investigate genetic heterogeneity of IgAN susceptibility between the two populations. Imputation- based analysis of theMHC/HLA region extended the scrutiny.Results Identification of three novel loci (rs6427389 on 1q23.1 [P=8.18x10(29), OR=1.132], rs6942325 on 6p25.3 [P=1.62x10(-11), OR=1.165], and rs2240335 on 1p36.13 [P=5.10x10(29), OR=1.114]), implicates FCRL3, DUSP22.IRF4, and PADI4 as susceptibility genes for IgAN. Rs2240335 is associated with the expression level of PADI4, and rs6427389 is in high linkage disequilibriumwith rs11264799, which showed a strong expression quantitative trail loci effect on FCRL3. Of the 24 confirmed risk SNPs, six showed significant heterogeneity of genetic effects and DEFA showed clear evidence of allelic heterogeneity between the populations. Imputation-based analysis of the MHC region revealed significant associations at three HLA polymorphisms (HLA allele DPB1*02, AA_DRB1_140_32657458_T, and AA_DQA1_34_32717152) and two SNPs (rs9275464 and rs2295119).Conclusions A meta-analysis of GWAS data revealed three novel genetic risk loci for IgAN, and three HLA polymorphisms and two SNPs within the MHC region, and demonstrated the genetic heterogeneity of seven loci out of 24 confirmed risk SNPs. These variants may explain susceptibility differences between Chinese and European populations.