Improved molecular understanding of the pathogenesis of type 2 diabetes is essential if current therapeutic and preventative options are to be extended. To identify diabetes-susceptibility genes, we have completed a primary (418-marker, 9-cM) autosomal-genome scan of 743 sib pairs (573 pedigrees) with type 2 diabetes who are from the Diabetes UK Warren 2 repository. Nonparametric linkage analysis of the entire data set identified seven regions showing evidence for linkage, with allele-sharing LOD scores > or =1.18 (P< or =.01). The strongest evidence was seen on chromosomes 8p21-22 (near D8S258 [LOD score 2.55]) and 10q23.3 (near D10S1765 [LOD score 1.99]), both coinciding with regions identified in previous scans in European subjects. This was also true of two lesser regions identified, on chromosomes 5q13 (D5S647 [LOD score 1.22] and 5q32 (D5S436 [LOD score 1.22]). Loci on 7p15.3 (LOD score 1.31) and 8q24.2 (LOD score 1.41) are novel. The final region showing evidence for linkage, on chromosome 1q24-25 (near D1S218 [LOD score 1.50]), colocalizes with evidence for linkage to diabetes found in Utah, French, and Pima families and in the GK rat. After dense-map genotyping (mean marker spacing 4.4 cM), evidence for linkage to this region increased to a LOD score of 1.98. Conditional analyses revealed nominally significant interactions between this locus and the regions on chromosomes 10q23.3 (P=.01) and 5q32 (P=.02). These data, derived from one of the largest genome scans undertaken in this condition, confirm that individual susceptibility-gene effects for type 2 diabetes are likely to be modest in size. Taken with genome scans in other populations, they provide both replication of previous evidence indicating the presence of a diabetes-susceptibility locus on chromosome 1q24-25 and support for the existence of additional loci on chromosomes 5, 8, and 10. These data should accelerate positional cloning efforts in these regions of interest.

中文翻译：

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对英国人群中易患 2 型糖尿病的位点进行全基因组扫描（英国糖尿病协会 Warren 2 存储库）：对 573 个家系的分析提供了 1q 染色体上易感位点的独立复制。


如果要扩展当前的治疗和预防选择，提高对 2 型糖尿病发病机制的分子了解至关重要。为了识别糖尿病易感基因，我们完成了对来自英国糖尿病协会 Warren 2 存储库的 743 对 2 型糖尿病同胞（573 个家系）的主要（418 个标记，9-cM）常染色体基因组扫描。整个数据集的非参数连锁分析确定了七个显示连锁证据的区域，等位基因共享 LOD 评分为 > 或 =1.18（P< 或 =.01）。最有力的证据出现在染色体 8p21-22（靠近 D8S258 [LOD 得分 2.55]）和 10q23.3（靠近 D10S1765 [LOD 得分 1.99]），两者都与先前在欧洲受试者中扫描中识别的区域一致。染色体 5q13（D5S647 [LOD 得分 1.22] 和 5q32（D5S436 [LOD 得分 1.22]）上确定的两个较小区域也是如此。7p15.3（LOD 得分 1.31）和 8q24.2（LOD 得分 1.41）上的基因座显示连锁证据的最后一个区域位于染色体 1q24-25（靠近 D1S218 [LOD 评分 1.50]），与在犹他州、法国和皮马家族以及 GK 大鼠中发现的糖尿病连锁证据共定位。 -图谱基因分型（平均标记间距 4.4 cM），与该区域连锁的证据增加至 1.98 的 LOD 分数。条件分析显示该基因座与染色体 10q23.3 (P=.01) 和 5q32 上的区域之间名义上存在显着的相互作用。 (P=.02)。这些数据来自在这种情况下进行的最大的基因组扫描之一，证实了 2 型糖尿病的个体易感性基因影响可能不大。 通过对其他人群的基因组扫描，它们既复制了先前的证据，表明染色体 1q24-25 上存在糖尿病易感基因座，又支持染色体 5、8 和 10 上存在其他基因座。这些数据应该会加速在这些感兴趣的区域进行定位克隆工作。