Multiple common susceptibility variants near BMP pathway loci GREM1, BMP4, and BMP2 explain part of the missing heritability of colorectal cancer.
Multiple common susceptibility variants near BMP pathway loci GREM1, BMP4, and BMP2 explain part of the missing heritability of colorectal cancer.
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DOI：
10.1371/journal.pgen.1002105
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发表时间：
2011-06
期刊：
影响因子：
4.5
通讯作者：
Dunlop MG
中科院分区：
文献类型：
--
作者：
Tomlinson IP;Carvajal-Carmona LG;Dobbins SE;Tenesa A;Jones AM;Howarth K;Palles C;Broderick P;Jaeger EE;Farrington S;Lewis A;Prendergast JG;Pittman AM;Theodoratou E;Olver B;Walker M;Penegar S;Barclay E;Whiffin N;Martin L;Ballereau S;Lloyd A;Gorman M;Lubbe S;COGENT Consortium;CORGI Collaborators;EPICOLON Consortium;Howie B;Marchini J;Ruiz-Ponte C;Fernandez-Rozadilla C;Castells A;Carracedo A;Castellvi-Bel S;Duggan D;Conti D;Cazier JB;Campbell H;Sieber O;Lipton L;Gibbs P;Martin NG;Montgomery GW;Young J;Baird PN;Gallinger S;Newcomb P;Hopper J;Jenkins MA;Aaltonen LA;Kerr DJ;Cheadle J;Pharoah P;Casey G;Houlston RS;Dunlop MG
全基因组关联研究（GWAS）已经确定了14个与结直肠癌（CRC）风险相关的标签单核苷酸多态性（tagSNPs），其中几个tagSNPs靠近骨形态发生蛋白（BMP）通路位点。GWAS中隐含的多重检测的惩罚增加了疾病基因发现的互补方法的吸引力，包括基于候选基因或路径的分析。最强的候选基因座为额外的易感性单核苷酸多态性可以说是那些已经知道既有功能相关性，并参与疾病风险。为了研究这一命题，我们使用总计24，910例CRC病例和26，275例对照的样本集，寻找与BMP通路基因GREM 1（15q13.3），BMP 4（14q22.2）和BMP 2（20p12.3）接近的新CRC易感性变体。我们发现了新的、独立的CRC易感性SNP，接近BMP 4（rs 1957636，P = 3.93×10−10）和BMP 2（rs 4813802，P = 4.65×10−11）。 在GREM 1附近，我们发现使用精细映射，先前确定的tagSNP rs 4779584和CRC之间的关联实际上是由rs 16969681（P = 5.33×10 - 8）和rs 11632715（P = 2.30×10 - 10）表示的两个独立信号引起的。 由于效应量小和/或风险等位基因频率低，低风险易感性变异变得越来越难以识别，基于知情候选基因选择的方法可能变得越来越有吸引力。我们的数据强调，遗传精细定位研究可以去卷积协会已经出现的独立相关性的tagSNP与一个以上的功能SNP，从而解释了一些常见疾病的明显缺失的遗传性。全基因组关联研究（GWAS）已经在编码骨形态发生蛋白（BMP）通路中蛋白质的基因附近发现了几种结直肠癌（CRC）易感性多态性。然而，大多数遗传易感性CRC仍然无法解释。我们研究了三个最佳候选BMP基因（GREM 1，BMP 4和BMP 2）与CRC相关的其他多态性。通过对多态性的广泛验证，在GWAS的初始阶段只有适度的相关证据，我们确定了新的，独立的CRC易感多态性，接近BMP 4（rs 1957636）和BMP 2（rs 4813802）。在GREM 1附近，我们在GWAS鉴定的多态性rs 4779584周围使用了额外的基因分型，以证明由rs 16969681和rs 11632715代表的两个独立信号。对疾病风险有适度影响的常见基因越来越难以识别，基于知情候选基因选择的方法可能变得越来越有吸引力。此外，围绕GWAS中确定的多态性的遗传精细作图可以解卷积由于两个独立的功能变体而产生的关联。这些类型的研究可以确定一些常见疾病的明显缺失的遗传性。
Genome-wide association studies (GWAS) have identified 14 tagging single nucleotide polymorphisms (tagSNPs) that are associated with the risk of colorectal cancer (CRC), and several of these tagSNPs are near bone morphogenetic protein (BMP) pathway loci. The penalty of multiple testing implicit in GWAS increases the attraction of complementary approaches for disease gene discovery, including candidate gene- or pathway-based analyses. The strongest candidate loci for additional predisposition SNPs are arguably those already known both to have functional relevance and to be involved in disease risk. To investigate this proposition, we searched for novel CRC susceptibility variants close to the BMP pathway genes GREM1 (15q13.3), BMP4 (14q22.2), and BMP2 (20p12.3) using sample sets totalling 24,910 CRC cases and 26,275 controls. We identified new, independent CRC predisposition SNPs close to BMP4 (rs1957636, P = 3.93×10−10) and BMP2 (rs4813802, P = 4.65×10−11). Near GREM1, we found using fine-mapping that the previously-identified association between tagSNP rs4779584 and CRC actually resulted from two independent signals represented by rs16969681 (P = 5.33×10−8) and rs11632715 (P = 2.30×10−10). As low-penetrance predisposition variants become harder to identify—owing to small effect sizes and/or low risk allele frequencies—approaches based on informed candidate gene selection may become increasingly attractive. Our data emphasise that genetic fine-mapping studies can deconvolute associations that have arisen owing to independent correlation of a tagSNP with more than one functional SNP, thus explaining some of the apparently missing heritability of common diseases. Genome-wide association studies (GWAS) have identified several colorectal cancer (CRC) susceptibility polymorphisms near genes that encode proteins in the bone morphogenetic protein (BMP) pathway. However, most of the inherited susceptibility to CRC remains unexplained. We investigated three of the best candidate BMP genes (GREM1, BMP4, and BMP2) for additional polymorphisms associated with CRC. By extensive validation of polymorphisms with only modest evidence of association in the initial phases of the GWAS, we identified new, independent CRC predisposition polymorphisms close to BMP4 (rs1957636) and BMP2 (rs4813802). Near GREM1, we used additional genotyping around the GWAS-identified polymorphism rs4779584 to demonstrate two independent signals represented by rs16969681 and rs11632715. Common genes with modest effects on disease risk are becoming harder to identify, and approaches based on informed candidate gene selection may become increasingly attractive. In addition, genetic fine mapping around polymorphisms identified in GWAS can deconvolute associations which have arisen owing to two independent functional variants. These types of study can identify some of the apparently missing heritability of common disease.
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影响因子：
45.3
作者：
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通讯作者：
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稀有变体会产生整个基因组的关联。
影响因子：
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影响因子：
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作者：
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通讯作者：
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