Stratification of Type 2 Diabetes by Age of Diagnosis in the UK Biobank Reveals Subgroup-Specific Genetic Associations and Causal Risk Profiles.
Stratification of Type 2 Diabetes by Age of Diagnosis in the UK Biobank Reveals Subgroup-Specific Genetic Associations and Causal Risk Profiles.
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DOI：
10.2337/db20-0602
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发表时间：
2021-08
期刊：
影响因子：
7.7
通讯作者：
Estonian Biobank Research Team:
中科院分区：
文献类型：
--
作者：
Noordam R;Läll K;Smit RAJ;Laisk T;Estonian Biobank Research Team;Metspalu A;Esko T;Milani L;Loos RJF;Mägi R;Willems van Dijk K;van Heemst D;Estonian Biobank Research Team:
2型糖尿病（T2 D）的发病机制可能随着年龄的增长而改变。在这里，我们使用基于诊断年龄的分层来深入了解不同年龄组T2 D的遗传学和因果风险因素。我们对T2 D和基于诊断年龄（<50岁，50-60岁，60-70岁和>70岁）的T2 D亚组进行了全基因组关联研究（GWAS）（共24，986例病例）。作为对照组，参与者在随访结束时至少70岁，未发生T2 D（N = 187，130）。GWAS确定了208个独立的前导单核苷酸多态性（SNP），映射到与T2 D相关的69个位点（P < 1.0e−8）。其中，定位于CDKN 2B-AS 1的SNP和定位于TCF 7 L2的多个独立SNP与70岁以后诊断的病例比与50岁以前诊断的病例更密切相关。根据不同的病例组，我们进行了双样本孟德尔随机化。最值得注意的是，我们观察到，在研究的风险因素中，BMI和T2 D之间的关联随着诊断年龄的增加而减弱。总的来说，我们的研究结果表明，基于诊断年龄的T2 D分层揭示了亚组特异性遗传学和因果决定因素，支持T2 D发病机制随年龄增长而变化的假设。
The pathogenesis of type 2 diabetes (T2D) might change with increasing age. Here, we used a stratification based on age of diagnosis to gain insight into the genetics and causal risk factors of T2D across different age-groups. We performed genome-wide association studies (GWAS) on T2D and T2D subgroups based on age of diagnosis (<50, 50–60, 60–70, and >70 years) (total of 24,986 cases). As control subjects, participants were at least 70 years of age at the end of follow-up without developing T2D (N =187,130). GWAS identified 208 independent lead single nucleotide polymorphism (SNPs) mapping to 69 loci associated with T2D (P < 1.0e−8). Among others, SNPs mapped to CDKN2B-AS1 and multiple independent SNPs mapped to TCF7L2 were more strongly associated with cases diagnosed after age 70 years than with cases diagnosed before age 50 years. Based on the different case groups, we performed two-sample Mendelian randomization. Most notably, we observed that of the investigated risk factors, the association between BMI and T2D attenuated with increasing age of diagnosis. Collectively, our results indicate that stratification of T2D based on age of diag-nosis reveals subgroup-specific genetics and causal determinants, supporting the hypothesis that the pathogenesis of T2D changes with increasing age.
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影响因子：
2.1
作者：
Bowden J;Davey Smith G;Haycock PC;Burgess S
通讯作者：
Burgess S
影响因子：
30.8
作者：
Mahajan A;Taliun D;Thurner M;Robertson NR;Torres JM;Rayner NW;Payne AJ;Steinthorsdottir V;Scott RA;Grarup N;Cook JP;Schmidt EM;Wuttke M;Sarnowski C;Mägi R;Nano J;Gieger C;Trompet S;Lecoeur C;Preuss MH;Prins BP;Guo X;Bielak LF;Below JE;Bowden DW;Chambers JC;Kim YJ;Ng MCY;Petty LE;Sim X;Zhang W;Bennett AJ;Bork-Jensen J;Brummett CM;Canouil M;Ec Kardt KU;Fischer K;Kardia SLR;Kronenberg F;Läll K;Liu CT;Locke AE;Luan J;Ntalla I;Nylander V;Schönherr S;Schurmann C;Yengo L;Bottinger EP;Brandslund I;Christensen C;Dedoussis G;Florez JC;Ford I;Franco OH;Frayling TM;Giedraitis V;Hackinger S;Hattersley AT;Herder C;Ikram MA;Ingelsson M;Jørgensen ME;Jørgensen T;Kriebel J;Kuusisto J;Ligthart S;Lindgren CM;Linneberg A;Lyssenko V;Mamakou V;Meitinger T;Mohlke KL;Morris AD;Nadkarni G;Pankow JS;Peters A;Sattar N;Stančáková A;Strauch K;Taylor KD;Thorand B;Thorleifsson G;Thorsteinsdottir U;Tuomilehto J;Witte DR;Dupuis J;Peyser PA;Zeggini E;Loos RJF;Froguel P;Ingelsson E;Lind L;Groop L;Laakso M;Collins FS;Jukema JW;Palmer CNA;Grallert H;Metspalu A;Dehghan A;Köttgen A;Abecasis GR;Meigs JB;Rotter JI;Marchini J;Pedersen O;Hansen T;Langenberg C;Wareham NJ;Stefansson K;Gloyn AL;Morris AP;Boehnke M;McCarthy MI
通讯作者：
McCarthy MI
影响因子：
37.8
作者：
Dale CE;Fatemifar G;Palmer TM;White J;Prieto-Merino D;Zabaneh D;Engmann JEL;Shah T;Wong A;Warren HR;McLachlan S;Trompet S;Moldovan M;Morris RW;Sofat R;Kumari M;Hyppönen E;Jefferis BJ;Gaunt TR;Ben-Shlomo Y;Zhou A;Gentry-Maharaj A;Ryan A;UCLEB Consortium; METASTROKE Consortium;Mutsert R;Noordam R;Caulfield MJ;Jukema JW;Worrall BB;Munroe PB;Menon U;Power C;Kuh D;Lawlor DA;Humphries SE;Mook-Kanamori DO;Sattar N;Kivimaki M;Price JF;Davey Smith G;Dudbridge F;Hingorani AD;Holmes MV;Casas JP
通讯作者：
Casas JP
影响因子：
30.8
作者：
Loh, Po-Ru;Tucker, George;Bulik-Sullivan, Brendan K.;Vilhjalmsson, Bjarni J.;Finucane, Hilary K.;Salem, Rany M.;Chasman, Daniel I.;Ridker, Paul M.;Neale, Benjamin M.;Berger, Bonnie;Patterson, Nick;Price, Alkes L.
通讯作者：
Price, Alkes L.
影响因子：
44.5
作者：
Ahlqvist, Emma;Storm, Petter;Groop, Leif
通讯作者：
Groop, Leif