Genome-wide association study and mouse model identify interaction between RET and EDNRB pathways in Hirschsprung disease
Genome-wide association study and mouse model identify interaction between RET and EDNRB pathways in Hirschsprung disease
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DOI：
10.1038/ng998
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发表时间：
2002-10-01
期刊：
影响因子：
30.8
通讯作者：
Chakravarti, A
中科院分区：
文献类型：
--
作者：
Carrasquillo, MM;McCallion, AS;Chakravarti, A
先天性巨结肠是一种常见的先天性畸形，其遗传学研究已经确定了8个可能与这种疾病相关的基因突变。然而，单个基因座的突变既不是引起临床疾病的必要条件，也不足以引起临床疾病。我们使用2，083个微卫星和单核苷酸多态性以及一种新的多点连锁不平衡方法对43个门诺派家族三人组进行了全基因组关联研究，该方法搜索来自共同祖先的关联。我们确定了10 q11、13 q22和16 q23的易感基因座; 13 q22的基因是EDNRB，编码G蛋白偶联受体（GPCR），10 q11的基因是RET，编码受体酪氨酸激酶（RTK）。RET和EDNRB等位基因在受影响的个人和非互补的无神经节细胞瘤在小鼠之间的Ret空和Ednrb亚型花斑等位基因的杂交统计学显着的联合传输提示EDNRB和RET之间的上位性。因此，RET和EDNRB突变之间的遗传相互作用是这种复杂疾病的潜在机制。
Genetic studies of Hirschsprung disease, a common congenital malformation, have identified eight genes with mutations that can be associated with this condition. Mutations at individual loci are, however, neither necessary nor sufficient to cause clinical disease. We conducted a genome-wide association study in 43 Mennonite family trios using 2,083 microsatellites and single-nucleotide polymorphisms and a new multipoint linkage disequilibrium method that searches for association arising from common ancestry. We identified susceptibility loci at 10q11, 13q22 and 16q23; the gene at 13q22 is EDNRB, encoding a G protein-coupled receptor (GPCR) and the gene at 10q11 is RET, encoding a receptor tyrosine kinase (RTK). Statistically significant joint transmission of RET and EDNRB alleles in affected individuals and non-complementation of aganglionosis in mouse intercrosses between Ret null and the Ednrb hypomorphic piebald allele are suggestive of epistasis between EDNRB and RET. Thus, genetic interaction between mutations in RET and EDNRB is an underlying mechanism for this complex disorder.