Linkage disequilibrium mapping of the replicated type 2 diabetes linkage signal on chromosome 1q.
Linkage disequilibrium mapping of the replicated type 2 diabetes linkage signal on chromosome 1q.
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DOI：
10.2337/db09-0081
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发表时间：
2009-07
期刊：
影响因子：
7.7
通讯作者：
International Type 2 Diabetes 1q Consortium
中科院分区：
文献类型：
--
作者：
Prokopenko I;Zeggini E;Hanson RL;Mitchell BD;Rayner NW;Akan P;Baier L;Das SK;Elliott KS;Fu M;Frayling TM;Groves CJ;Gwilliam R;Scott LJ;Voight BF;Hattersley AT;Hu C;Morris AD;Ng M;Palmer CN;Tello-Ruiz M;Vaxillaire M;Wang CR;Stein L;Chan J;Jia W;Froguel P;Elbein SC;Deloukas P;Bogardus C;Shuldiner AR;McCarthy MI;International Type 2 Diabetes 1q Consortium
染色体1q21-25区域与2型糖尿病的关联已在多个民族中得到证实。我们在一个多种族样本中进行了23 mb间隔的常见变异精细映射，以搜索导致该连锁信号的变异。总共，来自8个人群的3179例2型糖尿病患者和对照组的5290个单核苷酸多态性（snp）成功地进行了基因分型，证明了1q连锁。使用旨在增强检测导致1q连锁的变异的能力的策略来确定样本。在估算后，我们估计整个区域的共同变异覆盖率为~ 80% （r 2 ~ 0 0.8，欧洲）。通过在约8,500例受试者和12,400例对照受试者中进行计算机复制和从头基因分型，评估感兴趣的关联信号。23mb区域的关联映射确定了两个强烈的信号，这两个信号都局限于欧洲后裔样本的子集。第一个定位于NOS1AP （CAPON）基因区域（先导SNP: rs7538490，优势比1.38 [95% CI 1.21-1.57], P = 1.4 × 10−6,999例病例和1190例对照）；第二种定位于包括ASH1L和pkr基因在内的广泛连锁不平衡区域（先导SNP: rs11264371，优势比为1.48[1.18-1.76]，优势模型下P = 1.0 × 10−5）。然而，没有证据表明在复制的两个信号之间存在关联，并且，在所有数据中（bbb24000名受试者），没有迹象表明这些变异与2型糖尿病状态有因果关系。对复制连锁的23mb区域的详细精细映射未能识别对观察到的信号有贡献的共同变异信号。未来的研究应侧重于鉴定频率较低、外显率较高的因果等位基因。
Linkage of the chromosome 1q21–25 region to type 2 diabetes has been demonstrated in multiple ethnic groups. We performed common variant fine-mapping across a 23-Mb interval in a multiethnic sample to search for variants responsible for this linkage signal. In all, 5,290 single nucleotide polymorphisms (SNPs) were successfully genotyped in 3,179 type 2 diabetes case and control subjects from eight populations with evidence of 1q linkage. Samples were ascertained using strategies designed to enhance power to detect variants causal for 1q linkage. After imputation, we estimate ∼80% coverage of common variation across the region (r 2 > 0.8, Europeans). Association signals of interest were evaluated through in silico replication and de novo genotyping in ∼8,500 case subjects and 12,400 control subjects. Association mapping of the 23-Mb region identified two strong signals, both of which were restricted to the subset of European-descent samples. The first mapped to the NOS1AP (CAPON) gene region (lead SNP: rs7538490, odds ratio 1.38 [95% CI 1.21–1.57], P = 1.4 × 10−6, in 999 case subjects and 1,190 control subjects); the second mapped within an extensive region of linkage disequilibrium that includes the ASH1L and PKLR genes (lead SNP: rs11264371, odds ratio 1.48 [1.18–1.76], P = 1.0 × 10−5, under a dominant model). However, there was no evidence for association at either signal on replication, and, across all data (>24,000 subjects), there was no indication that these variants were causally related to type 2 diabetes status. Detailed fine-mapping of the 23-Mb region of replicated linkage has failed to identify common variant signals contributing to the observed signal. Future studies should focus on identification of causal alleles of lower frequency and higher penetrance.
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DOI：
10.1016/j.tig.2008.09.004
发表时间：
2008-12
期刊：
Trends in genetics : TIG
影响因子：
--
作者：
Prokopenko I;McCarthy MI;Lindgren CM
通讯作者：
Lindgren CM
影响因子：
30.8
作者：
Zeggini, Eleftheria;Scott, Laura J.;Saxena, Richa;Voight, Benjamin F.;Marchini, Jonathan L.;Hu, Tianle;de Bakker, Paul I. W.;Abecasis, Goncalo R.;Almgren, Peter;Andersen, Gitte;Ardlie, Kristin;Bostroem, Kristina Bengtsson;Bergman, Richard N.;Bonnycastle, Lori L.;Borch-Johnsen, Knut;Burtt, Noel P.;Chen, Hong;Chines, Peter S.;Daly, Mark J.;Deodhar, Parimal;Ding, Chia-Jen;Doney, Alex S. F.;Duren, William L.;Elliott, Katherine S.;Erdos, Michael R.;Frayling, Timothy M.;Freathy, Rachel M.;Gianniny, Lauren;Grallert, Harald;Grarup, Niels;Groves, Christopher J.;Guiducci, Candace;Hansen, Torben;Herder, Christian;Hitman, Graham A.;Hughes, Thomas E.;Isomaa, Bo;Jackson, Anne U.;Jorgensen, Torben;Kong, Augustine;Kubalanza, Kari;Kuruvilla, Finny G.;Kuusisto, Johanna;Langenberg, Claudia;Lango, Hana;Lauritzen, Torsten;Li, Yun;Lindgren, Cecilia M.;Lyssenko, Valeriya;Marvelle, Amanda F.;Meisinger, Christa;Midthjell, Kristian;Mohlke, Karen L.;Morken, Mario A.;Morris, Andrew D.;Narisu, Narisu;Nilsson, Peter;Owen, Katharine R.;Palmer, Colin N. A.;Payne, Felicity;Perry, John R. B.;Pettersen, Elin;Platou, Carl;Prokopenko, Inga;Qi, Lu;Qin, Li;Rayner, Nigel W.;Rees, Matthew;Roix, Jeffrey J.;Sandbaek, Anelli;Shields, Beverley;Sjogren, Marketa;Steinthorsdottir, Valgerdur;Stringham, Heather M.;Swift, Amy J.;Thorleifsson, Gudmar;Thorsteinsdottir, Unnur;Timpson, Nicholas J.;Tuomi, Tiinamaija;Tuomilehto, Jaakko;Walker, Mark;Watanabe, Richard M.;Weedon, Michael N.;Willer, Cristen J.;Illig, Thomas;Hveem, Kristian;Hu, Frank B.;Laakso, Markku;Stefansson, Kari;Pedersen, Oluf;Wareham, Nicholas J.;Barroso, Ines;Hattersley, Andrew T.;Collins, Francis S.;Groop, Leif;McCarthy, Mark I.;Boehnke, Michael;Altshuler, David
通讯作者：
Altshuler, David
影响因子：
30.8
作者：
Arking, Dan E.;Pfeufer, Arne;Chakravarti, Aravinda
通讯作者：
Chakravarti, Aravinda
影响因子：
9.8
作者：
Dudbridge, F;Koeleman, BPC
通讯作者：
Koeleman, BPC
影响因子：
4.2
作者：
McCarthy, Mark I
通讯作者：
McCarthy, Mark I