A genome-wide association study identifies 5 loci associated with frozen shoulder and implicates diabetes as a causal risk factor.
A genome-wide association study identifies 5 loci associated with frozen shoulder and implicates diabetes as a causal risk factor.
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DOI：
10.1371/journal.pgen.1009577
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发表时间：
2021-06
期刊：
影响因子：
4.5
通讯作者：
Weedon MN
中科院分区：
文献类型：
--
作者：
Green HD;Jones A;Evans JP;Wood AR;Beaumont RN;Tyrrell J;Frayling TM;Smith C;Weedon MN
肩部冻结是一种痛苦的疾病，经常需要手术，40-60岁的人中有5%的人会受到影响。人们对这种疾病的原因知之甚少，但糖尿病是一个很大的风险因素。为了开始了解相关的生物学机制，我们的目标是识别与肩部冻结相关的遗传变异，并使用孟德尔随机化方法来测试糖尿病的因果作用。我们使用来自住院、外科和初级保健代码的10,104例患者的数据，在英国生物库中对冻结的肩进行了全基因组关联研究(GWAS)。我们使用来自FinnGen的数据进行复制和荟萃分析。我们使用单样本和双样本孟德尔随机化方法来测试糖尿病与肩周炎的因果关系。我们确定了五个全基因组有意义的基因座。最显著的基因座(先导SNP rs2897第1325；OR=1.20，95%CI：1.16-1.24，p=5x10-29)含有WNT7B。该变异还与Dupuytren病有关(OR=2.31[2.24，2.39]，p<；1x10-300)，另外两个与肩部冻结相关的变异也是如此。孟德尔随机化结果提供了证据，表明1型糖尿病是导致肩周炎的原因风险因素(OR=1.03[1.02-1.05]，p=3x10-6)。没有证据表明肥胖与肩部冻结有因果关系，这表明糖尿病是通过血糖而不是机械效应来影响这种疾病的风险。我们已经确定了与肩部冻结有关的遗传基因。这与Dupuytren病相关基因有很大的重叠。糖尿病可能是一个致病风险因素。我们的结果为这种常见的疼痛情况提供了生物学机制的证据。肩部冻结是一种痛苦的疾病，经常需要手术，40-60岁的人中有5%的人会受到影响。人们对其病因知之甚少，但已知其在糖尿病患者中更为常见。在50万人的数据集中，我们使用了全基因组关联研究来寻找遗传原因，并使用了一种名为孟德尔随机化的遗传技术来测试糖尿病是否会导致肩部冻结。我们发现了五个与肩部冻结有关的新基因变异，并显示出与杜普伊特伦病的基因重叠，杜普伊特伦病是一种影响手指的类似疾病。我们发现了糖尿病和肥胖之间的联系，但当我们考虑到糖尿病的状况时，肥胖的联系就消失了，这表明这种情况是血糖升高而不是机械性的。我们的孟德尔随机研究显示，有证据表明，1型糖尿病对肩周炎的发生有因果影响，可能是通过一种涉及长期高血糖水平的途径。
Frozen shoulder is a painful condition that often requires surgery and affects up to 5% of individuals aged 40–60 years. Little is known about the causes of the condition, but diabetes is a strong risk factor. To begin to understand the biological mechanisms involved, we aimed to identify genetic variants associated with frozen shoulder and to use Mendelian randomization to test the causal role of diabetes. We performed a genome-wide association study (GWAS) of frozen shoulder in the UK Biobank using data from 10,104 cases identified from inpatient, surgical and primary care codes. We used data from FinnGen for replication and meta-analysis. We used one-sample and two-sample Mendelian randomization approaches to test for a causal association of diabetes with frozen shoulder. We identified five genome-wide significant loci. The most significant locus (lead SNP rs28971325; OR = 1.20, [95% CI: 1.16–1.24], p = 5x10-29) contained WNT7B. This variant was also associated with Dupuytren’s disease (OR = 2.31 [2.24, 2.39], p<1x10-300) as were a further two of the frozen shoulder associated variants. The Mendelian randomization results provided evidence that type 1 diabetes is a causal risk factor for frozen shoulder (OR = 1.03 [1.02–1.05], p = 3x10-6). There was no evidence that obesity was causally associated with frozen shoulder, suggesting that diabetes influences risk of the condition through glycemic rather than mechanical effects. We have identified genetic loci associated with frozen shoulder. There is a large overlap with Dupuytren’s disease associated loci. Diabetes is a likely causal risk factor. Our results provide evidence of biological mechanisms involved in this common painful condition. Frozen shoulder is a painful condition that often requires surgery and affects up to 5% of individuals aged 40–60 years. Little is known about the causes but it is known to be more common in people with diabetes. In a dataset of 500,000 people, we used a genome-wide association study to find genetic causes and a genetic technique called Mendelian randomisation to test if diabetes causes frozen shoulder. We found five new genetic variants that associate with frozen shoulder, and showed genetic overlap with Dupuytren’s Disease, a similar condition that affects the fingers. We found an association with diabetes and obesity, but that the obesity association disappeared when we accounted for diabetes status, suggesting the condition is glycaemic rather than mechanical. Our Mendelian randomisation study showed evidence that type 1 diabetes has a causal effect on development of frozen shoulder, likely through a pathway involving long-term high blood glucose levels.
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影响因子：
30.8
作者：
DIAbetes Genetics Replication And Meta-analysis (DIAGRAM) Consortium;Asian Genetic Epidemiology Network Type 2 Diabetes (AGEN-T2D) Consortium;South Asian Type 2 Diabetes (SAT2D) Consortium;Mexican American Type 2 Diabetes (MAT2D) Consortium;Type 2 Diabetes Genetic Exploration by Nex-generation sequencing in muylti-Ethnic Samples (T2D-GENES) Consortium;Mahajan A;Go MJ;Zhang W;Below JE;Gaulton KJ;Ferreira T;Horikoshi M;Johnson AD;Ng MC;Prokopenko I;Saleheen D;Wang X;Zeggini E;Abecasis GR;Adair LS;Almgren P;Atalay M;Aung T;Baldassarre D;Balkau B;Bao Y;Barnett AH;Barroso I;Basit A;Been LF;Beilby J;Bell GI;Benediktsson R;Bergman RN;Boehm BO;Boerwinkle E;Bonnycastle LL;Burtt N;Cai Q;Campbell H;Carey J;Cauchi S;Caulfield M;Chan JC;Chang LC;Chang TJ;Chang YC;Charpentier G;Chen CH;Chen H;Chen YT;Chia KS;Chidambaram M;Chines PS;Cho NH;Cho YM;Chuang LM;Collins FS;Cornelis MC;Couper DJ;Crenshaw AT;van Dam RM;Danesh J;Das D;de Faire U;Dedoussis G;Deloukas P;Dimas AS;Dina C;Doney AS;Donnelly PJ;Dorkhan M;van Duijn C;Dupuis J;Edkins S;Elliott P;Emilsson V;Erbel R;Eriksson JG;Escobedo J;Esko T;Eury E;Florez JC;Fontanillas P;Forouhi NG;Forsen T;Fox C;Fraser RM;Frayling TM;Froguel P;Frossard P;Gao Y;Gertow K;Gieger C;Gigante B;Grallert H;Grant GB;Grrop LC;Groves CJ;Grundberg E;Guiducci C;Hamsten A;Han BG;Hara K;Hassanali N;Hattersley AT;Hayward C;Hedman AK;Herder C;Hofman A;Holmen OL;Hovingh K;Hreidarsson AB;Hu C;Hu FB;Hui J;Humphries SE;Hunt SE;Hunter DJ;Hveem K;Hydrie ZI;Ikegami H;Illig T;Ingelsson E;Islam M;Isomaa B;Jackson AU;Jafar T;James A;Jia W;Jöckel KH;Jonsson A;Jowett JB;Kadowaki T;Kang HM;Kanoni S;Kao WH;Kathiresan S;Kato N;Katulanda P;Keinanen-Kiukaanniemi KM;Kelly AM;Khan H;Khaw KT;Khor CC;Kim HL;Kim S;Kim YJ;Kinnunen L;Klopp N;Kong A;Korpi-Hyövälti E;Kowlessur S;Kraft P;Kravic J;Kristensen MM;Krithika S;Kumar A;Kumate J;Kuusisto J;Kwak SH;Laakso M;Lagou V;Lakka TA;Langenberg C;Langford C;Lawrence R;Leander K;Lee JM;Lee NR;Li M;Li X;Li Y;Liang J;Liju S;Lim WY;Lind L;Lindgren CM;Lindholm E;Liu CT;Liu JJ;Lobbens S;Long J;Loos RJ;Lu W;Luan J;Lyssenko V;Ma RC;Maeda S;Mägi R;Männisto S;Matthews DR;Meigs JB;Melander O;Metspalu A;Meyer J;Mirza G;Mihailov E;Moebus S;Mohan V;Mohlke KL;Morris AD;Mühleisen TW;Müller-Nurasyid M;Musk B;Nakamura J;Nakashima E;Navarro P;Ng PK;Nica AC;Nilsson PM;Njølstad I;Nöthen MM;Ohnaka K;Ong TH;Owen KR;Palmer CN;Pankow JS;Park KS;Parkin M;Pechlivanis S;Pedersen NL;Peltonen L;Perry JR;Peters A;Pinidiyapathirage JM;Platou CG;Potter S;Price JF;Qi L;Radha V;Rallidis L;Rasheed A;Rathman W;Rauramaa R;Raychaudhuri S;Rayner NW;Rees SD;Rehnberg E;Ripatti S;Robertson N;Roden M;Rossin EJ;Rudan I;Rybin D;Saaristo TE;Salomaa V;Saltevo J;Samuel M;Sanghera DK;Saramies J;Scott J;Scott LJ;Scott RA;Segrè AV;Sehmi J;Sennblad B;Shah N;Shah S;Shera AS;Shu XO;Shuldiner AR;Sigurđsson G;Sijbrands E;Silveira A;Sim X;Sivapalaratnam S;Small KS;So WY;Stančáková A;Stefansson K;Steinbach G;Steinthorsdottir V;Stirrups K;Strawbridge RJ;Stringham HM;Sun Q;Suo C;Syvänen AC;Takayanagi R;Takeuchi F;Tay WT;Teslovich TM;Thorand B;Thorleifsson G;Thorsteinsdottir U;Tikkanen E;Trakalo J;Tremoli E;Trip MD;Tsai FJ;Tuomi T;Tuomilehto J;Uitterlinden AG;Valladares-Salgado A;Vedantam S;Veglia F;Voight BF;Wang C;Wareham NJ;Wennauer R;Wickremasinghe AR;Wilsgaard T;Wilson JF;Wiltshire S;Winckler W;Wong TY;Wood AR;Wu JY;Wu Y;Yamamoto K;Yamauchi T;Yang M;Yengo L;Yokota M;Young R;Zabaneh D;Zhang F;Zhang R;Zheng W;Zimmet PZ;Altshuler D;Bowden DW;Cho YS;Cox NJ;Cruz M;Hanis CL;Kooner J;Lee JY;Seielstad M;Teo YY;Boehnke M;Parra EJ;Chambers JC;Tai ES;McCarthy MI;Morris AP
通讯作者：
Morris AP
影响因子：
64.8
作者：
Bycroft C;Freeman C;Petkova D;Band G;Elliott LT;Sharp K;Motyer A;Vukcevic D;Delaneau O;O'Connell J;Cortes A;Welsh S;Young A;Effingham M;McVean G;Leslie S;Allen N;Donnelly P;Marchini J
通讯作者：
Marchini J
影响因子：
2.1
作者：
Bowden J;Davey Smith G;Haycock PC;Burgess S
通讯作者：
Burgess S
BMI是2型糖尿病的可修改风险因素：使用门德利随机化的炼油和理解因果估计。
影响因子：
7.7
作者：
Corbin LJ;Richmond RC;Wade KH;Burgess S;Bowden J;Smith GD;Timpson NJ
通讯作者：
Timpson NJ
DOI：
10.1136/bmj.k601
发表时间：
2018-07-12
期刊：
BMJ (Clinical research ed.)
影响因子：
--
作者：
Davies NM;Holmes MV;Davey Smith G
通讯作者：
Davey Smith G