Abundant local interactions in the 4p16.1 region suggest functional mechanisms underlying SLC2A9 associations with human serum uric acid.
Abundant local interactions in the 4p16.1 region suggest functional mechanisms underlying SLC2A9 associations with human serum uric acid.
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DOI：
10.1093/hmg/ddu227
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发表时间：
2014-10-01
影响因子：
3.5
通讯作者：
Haley CS
中科院分区：
文献类型：
--
作者：
Wei WH;Guo Y;Kindt AS;Merriman TR;Semple CA;Wang K;Haley CS
人血清尿酸浓度（SUA）是一个复杂的特征。最近一项对多个全基因组关联研究（GWAS）的荟萃分析发现，与SUA相关的28个基因座共同解释了7.7%的SUA变异，其中3.4%由两个主要基因座（SLC2A9和ABCG2）解释。在这里，我们使用meta分析中的两个大型GWAS队列[社区动脉粥样硬化风险研究队列（ARIC）和弗雷明汉心脏研究队列（FHS）]来检查基因-基因相互作用是否在调节SUA中起作用。我们发现，在4p16.1区域的ARIC中，大量的显著的局部相互作用主要位于SLC2A9附近的基因间区域，这些相互作用不是由连锁不平衡驱动的，并且在FHS中被复制。采用正向选择方法，构建了5个具有边际效应的SNP和3对aric的上位性SNP - 3个边际SNP位于SLC2A9内，其余SNP均位于邻近的基因间区。与单独的先导SNP相比，完整模型解释的SUA方差增加了1.5%，但基因间区域SNP的边际效应和上位效应仅贡献了0.3%。功能分析显示，在ENCODE肝细胞（HepG2, P = 4.7E−05）和前体红细胞（K562, P = 5.0E−06）中，基因间区域的上位性相互作用snp异常富集，推测可调节WDR1和SLC2A9的转录。这些结果表明，探索上位相互作用对于揭示4p16.1区域的复杂功能机制是有价值的。
Human serum uric acid concentration (SUA) is a complex trait. A recent meta-analysis of multiple genome-wide association studies (GWAS) identified 28 loci associated with SUA jointly explaining only 7.7% of the SUA variance, with 3.4% explained by two major loci (SLC2A9 and ABCG2). Here we examined whether gene–gene interactions had any roles in regulating SUA using two large GWAS cohorts included in the meta-analysis [the Atherosclerosis Risk in Communities study cohort (ARIC) and the Framingham Heart Study cohort (FHS)]. We found abundant genome-wide significant local interactions in ARIC in the 4p16.1 region located mostly in an intergenic area near SLC2A9 that were not driven by linkage disequilibrium and were replicated in FHS. Taking the forward selection approach, we constructed a model of five SNPs with marginal effects and three epistatic SNP pairs in ARIC—three marginal SNPs were located within SLC2A9 and the remaining SNPs were all located in the nearby intergenic area. The full model explained 1.5% more SUA variance than that explained by the lead SNP alone, but only 0.3% was contributed by the marginal and epistatic effects of the SNPs in the intergenic area. Functional analysis revealed strong evidence that the epistatically interacting SNPs in the intergenic area were unusually enriched at enhancers active in ENCODE hepatic (HepG2, P = 4.7E−05) and precursor red blood (K562, P = 5.0E−06) cells, putatively regulating transcription of WDR1 and SLC2A9. These results suggest that exploring epistatic interactions is valuable in uncovering the complex functional mechanisms underlying the 4p16.1 region.
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影响因子：
64.8
作者：
Ernst, Jason;Kheradpour, Pouya;Mikkelsen, Tarjei S.;Shoresh, Noam;Ward, Lucas D.;Epstein, Charles B.;Zhang, Xiaolan;Wang, Li;Issner, Robbyn;Coyne, Michael;Ku, Manching;Durham, Timothy;Kellis, Manolis;Bernstein, Bradley E.
通讯作者：
Bernstein, Bradley E.
DOI：
10.1038/nrg2579
发表时间：
2009-06
期刊：
Nature reviews. Genetics
影响因子：
--
作者：
Cordell HJ
通讯作者：
Cordell HJ
影响因子：
14.9
作者：
Gyenesei A;Moody J;Laiho A;Semple CA;Haley CS;Wei WH
通讯作者：
Wei WH
影响因子：
4.5
作者：
Evans, David M.;Marchini, Jonathan;Morris, Andrew P.;Cardon, Lon R.
通讯作者：
Cardon, Lon R.
影响因子：
4.5
作者：
Ma L;Brautbar A;Boerwinkle E;Sing CF;Clark AG;Keinan A
通讯作者：
Keinan A