BMI as a Modifiable Risk Factor for Type 2 Diabetes: Refining and Understanding Causal Estimates Using Mendelian Randomization

被引:119
作者
Corbin, Laura J. [1 ]
Richmond, Rebecca C. [1 ]
Wade, Kaitlin H. [1 ]
Burgess, Stephen [1 ,2 ]
Bowden, Jack [1 ,3 ]
Smith, George Davey [1 ]
Timpson, Nicholas J. [1 ]
机构
[1] Univ Bristol, MRC Integrat Epidemiol Unit, Bristol, Avon, England
[2] Univ Cambridge, Dept Publ Hlth & Primary Care, Cambridge, England
[3] Cambridge Inst Publ Hlth, MRC Biostat Unit, Cambridge, England
基金
英国医学研究理事会; 英国惠康基金;
关键词
BODY-MASS INDEX; INSTRUMENTS; INSIGHTS; TRAITS;
D O I
10.2337/db16-0418
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
This study focused on resolving the relationship between BMI and type 2 diabetes. The availability of multiple variants associated with BMI offers a new chance to resolve the true causal effect of BMI on type 2 diabetes; however, the properties of these associations and their validity as genetic instruments need to be considered alongside established and new methods for undertaking Mendelian randomization (MR). We explore the potential for pleiotropic genetic variants to generate bias, revise existing estimates, and illustrate value in new analysis methods. A two-sample MR approach with 96 genetic variants was used with three different analysis methods, two of which (MR-Egger and the weighted median) have been developed specifically to address problems of invalid instrumental variables. We estimate an odds ratio for type 2 diabetes per unit increase in BMI (kg/m(2)) of between 1.19 and 1.38, with the most stable estimate using all instruments and a weighted median approach (1.26 [95% CI 1.17, 1.34]). TCF7L2(rs7903146) was identified as a complex effect or pleiotropic instrument, and removal of this variant resulted in convergence of causal effect estimates from different causal analysis methods. This indicated the potential for pleiotropy to affect estimates and differences in performance of alternative analytical methods. In a real type 2 diabetes-focused example, this study demonstrates the potential impact of invalid instruments on causal effect estimates and the potential for new approaches to mitigate the bias caused.
引用
收藏
页码:3002 / 3007
页数:6
相关论文
共 33 条
[11]   DETECTION OF INFLUENTIAL OBSERVATION IN LINEAR-REGRESSION [J].
COOK, RD .
TECHNOMETRICS, 1977, 19 (01) :15-18
[12]   Mendelian randomization: genetic anchors for causal inference in epidemiological studies [J].
Davey Smith, George ;
Hemani, Gibran .
HUMAN MOLECULAR GENETICS, 2014, 23 :R89-R98
[13]   Mendelian randomization as an instrumental variable approach to causal inference [J].
Didelez, Vanessa ;
Sheehan, Nuala .
STATISTICAL METHODS IN MEDICAL RESEARCH, 2007, 16 (04) :309-330
[14]   Impact of Type 2 Diabetes Susceptibility Variants on Quantitative Glycemic Traits Reveals Mechanistic Heterogeneity [J].
Dimas, Antigone S. ;
Lagou, Vasiliki ;
Barker, Adam ;
Knowles, Joshua W. ;
Maegi, Reedik ;
Hivert, Marie-France ;
Benazzo, Andrea ;
Rybin, Denis ;
Jackson, Anne U. ;
Stringham, Heather M. ;
Song, Ci ;
Fischer-Rosinsky, Antje ;
Boesgaard, Trine Wellov ;
Grarup, Niels ;
Abbasi, Fahim A. ;
Assimes, Themistocles L. ;
Hao, Ke ;
Yang, Xia ;
Lecoeur, Cecile ;
Barroso, Ines ;
Bonnycastle, Lori L. ;
Boettcher, Yvonne ;
Bumpstead, Suzannah ;
Chines, Peter S. ;
Erdos, Michael R. ;
Graessler, Jurgen ;
Kovacs, Peter ;
Morken, Mario A. ;
Narisu, Narisu ;
Payne, Felicity ;
Stancakova, Alena ;
Swift, Amy J. ;
Toenjes, Anke ;
Bornstein, Stefan R. ;
Cauchi, Stephane ;
Froguel, Philippe ;
Meyre, David ;
Schwarz, Peter E. H. ;
Haering, Hans-Ulrich ;
Smith, Ulf ;
Boehnke, Michael ;
Bergman, Richard N. ;
Collins, Francis S. ;
Mohlke, Karen L. ;
Tuomilehto, Jaakko ;
Quertemous, Thomas ;
Lind, Lars ;
Hansen, Torben ;
Pedersen, Oluf ;
Walker, Mark .
DIABETES, 2014, 63 (06) :2158-2171
[15]   Measuring inconsistency in meta-analyses [J].
Higgins, JPT ;
Thompson, SG ;
Deeks, JJ ;
Altman, DG .
BMJ-BRITISH MEDICAL JOURNAL, 2003, 327 (7414) :557-560
[16]   Causal Effects of Body Mass Index on Cardiometabolic Traits and Events: A Mendelian Randomization Analysis [J].
Holmes, Michael V. ;
Lange, Leslie A. ;
Palmer, Tom ;
Lanktree, Matthew B. ;
North, Kari E. ;
Almoguera, Berta ;
Buxbaum, Sarah ;
Chandrupatla, Hareesh R. ;
Elbers, Clara C. ;
Guo, Yiran ;
Hoogeveen, Ron C. ;
Li, Jin ;
Li, Yun R. ;
Swerdlow, Daniel I. ;
Cushman, Mary ;
Price, Tom S. ;
Curtis, Sean P. ;
Fornage, Myriam ;
Hakonarson, Hakon ;
Patel, Sanjay R. ;
Redline, Susan ;
Siscovick, David S. ;
Tsai, Michael Y. ;
Wilson, James G. ;
van der Schouw, Yvonne T. ;
FitzGerald, Garret A. ;
Hingorani, Aroon D. ;
Casas, Juan P. ;
de Bakker, Paul I. W. ;
Rich, Stephen S. ;
Schadt, Eric E. ;
Asselbergs, Folkert W. ;
Reiner, Alex P. ;
Keating, Brendan J. .
AMERICAN JOURNAL OF HUMAN GENETICS, 2014, 94 (02) :198-208
[17]   Mendelian randomization: Using genes as instruments for making causal inferences in epidemiology [J].
Lawlor, Debbie A. ;
Harbord, Roger M. ;
Sterne, Jonathan A. C. ;
Timpson, Nic ;
Smith, George Davey .
STATISTICS IN MEDICINE, 2008, 27 (08) :1133-1163
[18]   Genetic studies of body mass index yield new insights for obesity biology [J].
Locke, Adam E. ;
Kahali, Bratati ;
Berndt, Sonja I. ;
Justice, Anne E. ;
Pers, Tune H. ;
Day, Felix R. ;
Powell, Corey ;
Vedantam, Sailaja ;
Buchkovich, Martin L. ;
Yang, Jian ;
Croteau-Chonka, Damien C. ;
Esko, Tonu ;
Fall, Tove ;
Ferreira, Teresa ;
Gustafsson, Stefan ;
Kutalik, Zoltan ;
Luan, Jian'an ;
Maegi, Reedik ;
Randall, Joshua C. ;
Winkler, Thomas W. ;
Wood, Andrew R. ;
Workalemahu, Tsegaselassie ;
Faul, Jessica D. ;
Smith, Jennifer A. ;
Zhao, Jing Hua ;
Zhao, Wei ;
Chen, Jin ;
Fehrmann, Rudolf ;
Hedman, Asa K. ;
Karjalainen, Juha ;
Schmidt, Ellen M. ;
Absher, Devin ;
Amin, Najaf ;
Anderson, Denise ;
Beekman, Marian ;
Bolton, Jennifer L. ;
Bragg-Gresham, L. ;
Buyske, Steven ;
Demirkan, Ayse ;
Deng, Guohong ;
Ehret, Georg B. ;
Feenstra, Bjarke ;
Feitosa, Mary F. ;
Fischer, Krista ;
Goel, Anuj ;
Gong, Jian ;
Jackson, Anne U. ;
Kanoni, Stavroula ;
Kleber, Marcus E. ;
Kristiansson, Kati .
NATURE, 2015, 518 (7538) :197-+
[19]   A genome-wide approach accounting for body mass index identifies genetic variants influencing fasting glycemic traits and insulin resistance [J].
Manning, Alisa K. ;
Hivert, Marie-France ;
Scott, Robert A. ;
Grimsby, Jonna L. ;
Bouatia-Naji, Nabila ;
Chen, Han ;
Rybin, Denis ;
Liu, Ching-Ti ;
Bielak, Lawrence F. ;
Prokopenko, Inga ;
Amin, Najaf ;
Barnes, Daniel ;
Cadby, Gemma ;
Hottenga, Jouke-Jan ;
Ingelsson, Erik ;
Jackson, Anne U. ;
Johnson, Toby ;
Kanoni, Stavroula ;
Ladenvall, Claes ;
Lagou, Vasiliki ;
Lahti, Jari ;
Lecoeur, Cecile ;
Liu, Yongmei ;
Martinez-Larrad, Maria Teresa ;
Montasser, May E. ;
Navarro, Pau ;
Perry, John R. B. ;
Rasmussen-Torvik, Laura J. ;
Salo, Perttu ;
Sattar, Naveed ;
Shungin, Dmitry ;
Strawbridge, Rona J. ;
Tanaka, Toshiko ;
van Duijn, Cornelia M. ;
An, Ping ;
de Andrade, Mariza ;
Andrews, Jeanette S. ;
Aspelund, Thor ;
Atalay, Mustafa ;
Aulchenko, Yurii ;
Balkau, Beverley ;
Bandinelli, Stefania ;
Beckmann, Jacques S. ;
Beilby, John P. ;
Bellis, Claire ;
Bergman, Richard N. ;
Blangero, John ;
Boban, Mladen ;
Boehnke, Michael ;
Boerwinkle, Eric .
NATURE GENETICS, 2012, 44 (06) :659-U81
[20]   Large-scale association analysis provides insights into the genetic architecture and pathophysiology of type 2 diabetes [J].
Morris, Andrew P. ;
Voight, Benjamin F. ;
Teslovich, Tanya M. ;
Ferreira, Teresa ;
Segre, Ayellet V. ;
Steinthorsdottir, Valgerdur ;
Strawbridge, Rona J. ;
Khan, Hassan ;
Grallert, Harald ;
Mahajan, Anubha ;
Prokopenko, Inga ;
Kang, Hyun Min ;
Dina, Christian ;
Esko, Tonu ;
Fraser, Ross M. ;
Kanoni, Stavroula ;
Kumar, Ashish ;
Lagou, Vasiliki ;
Langenberg, Claudia ;
Luan, Jian'an ;
Lindgren, Cecilia M. ;
Mueller-Nurasyid, Martina ;
Pechlivanis, Sonali ;
Rayner, N. William ;
Scott, Laura J. ;
Wiltshire, Steven ;
Yengo, Loic ;
Kinnunen, Leena ;
Rossin, Elizabeth J. ;
Raychaudhuri, Soumya ;
Johnson, Andrew D. ;
Dimas, Antigone S. ;
Loos, Ruth J. F. ;
Vedantam, Sailaja ;
Chen, Han ;
Florez, Jose C. ;
Fox, Caroline ;
Liu, Ching-Ti ;
Rybin, Denis ;
Couper, David J. ;
Kao, Wen Hong L. ;
Li, Man ;
Cornelis, Marilyn C. ;
Kraft, Peter ;
Sun, Qi ;
van Dam, Rob M. ;
Stringham, Heather M. ;
Chines, Peter S. ;
Fischer, Krista ;
Fontanillas, Pierre .
NATURE GENETICS, 2012, 44 (09) :981-+