Bias in two-sample Mendelian randomization when using heritable covariable-adjusted summary associations.
Bias in two-sample Mendelian randomization when using heritable covariable-adjusted summary associations.
复制标题
使用遗传协变量调整汇总关联时双样本孟德尔随机化的偏倚。
DOI：
10.1093/ije/dyaa266
复制
发表时间：
2021-11-10
影响因子：
7.7
通讯作者：
Borges MC
中科院分区：
文献类型：
--
作者：
Hartwig FP;Tilling K;Davey Smith G;Lawlor DA;Borges MC
两个样本孟德尔随机化 (MR) 允许使用来自全基因组关联研究 (GWAS) 的可免费获取的汇总关联结果来估计可修改暴露对结果的因果影响。一些 GWAS 对可遗传的协变量进行调整，试图估计遗传变异对感兴趣性状的直接影响。暴露 GWAS 和结果 GWAS 之一、两者或两者均未针对协变量进行调整。我们进行了一项模拟研究，其中包括可能激发 GWAS 中协变量调整的不同场景，并分析了真实数据，以评估在两样本 MR 中使用协变量调整汇总关联结果的影响。在暴露与协变量之间、暴露与结果之间以及协变量与结果之间不存在残余混杂的情况下，使用两样本 MR 的协变量调整汇总关联消除了水平多效性导致的偏差。然而，即使在不存在水平多效性的情况下（当遗传变异在没有协变量调整的情况下是有效工具时），协变量调整也会在存在残余混杂（尤其是协变量和结果之间）的情况下导致偏差。在使用来自人体测量特征遗传研究 (GIANT) 联盟和英国生物银行的真实数据进行的分析中，腰围对血压的因果效应估计在根据体重指数调整腰围后改变了方向。我们的研究结果表明，通常应避免在 MR 中使用协变量调整的汇总关联。如果不可能，则需要仔细考虑数据背后的因果关系（包括潜在的未测量的混杂因素），以指导敏感性分析并适当谨慎地解释结果。
Two-sample Mendelian randomization (MR) allows the use of freely accessible summary association results from genome-wide association studies (GWAS) to estimate causal effects of modifiable exposures on outcomes. Some GWAS adjust for heritable covariables in an attempt to estimate direct effects of genetic variants on the trait of interest. One, both or neither of the exposure GWAS and outcome GWAS may have been adjusted for covariables. We performed a simulation study comprising different scenarios that could motivate covariable adjustment in a GWAS and analysed real data to assess the influence of using covariable-adjusted summary association results in two-sample MR. In the absence of residual confounding between exposure and covariable, between exposure and outcome, and between covariable and outcome, using covariable-adjusted summary associations for two-sample MR eliminated bias due to horizontal pleiotropy. However, covariable adjustment led to bias in the presence of residual confounding (especially between the covariable and the outcome), even in the absence of horizontal pleiotropy (when the genetic variants would be valid instruments without covariable adjustment). In an analysis using real data from the Genetic Investigation of ANthropometric Traits (GIANT) consortium and UK Biobank, the causal effect estimate of waist circumference on blood pressure changed direction upon adjustment of waist circumference for body mass index. Our findings indicate that using covariable-adjusted summary associations in MR should generally be avoided. When that is not possible, careful consideration of the causal relationships underlying the data (including potentially unmeasured confounders) is required to direct sensitivity analyses and interpret results with appropriate caution.
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影响因子：
64.8
作者：
Horikoshi, Momoko;Beaumont, Robin N.;Day, Felix R.;Warrington, Nicole M.;Kooijman, Marjolein N.;Fernandez-Tajes, Juan;Feenstra, Bjarke;van Zuydam, Natalie R.;Gaulton, Kyle J.;Grarup, Niels;Bradfield, Jonathan P.;Strachan, David P.;Li-Gao, Ruifang;Ahluwalia, Tarunveer S.;Kreiner, Eskil;Rueedi, Rico;Lyytikainen, Leo-Pekka;Cousminer, Diana L.;Wu, Ying;Thiering, Elisabeth;Wang, Carol A.;Have, Christian T.;Hottenga, Jouke-Jan;Vilor-Tejedor, Natalia;Joshi, Peter K.;Boh, Eileen Tai Hui;Ntalla, Ioanna;Pitkanen, Niina;Mahajan, Anubha;van Leeuwen, Elisabeth M.;Joro, Raimo;Lagou, Vasiliki;Nodzenski, Michael;Diver, Louise A.;Zondervan, Krina T.;Bustamante, Mariona;Marques-Vidal, Pedro;Mercader, Josep M.;Bennett, Amanda J.;Rahmioglu, Nilufer;Nyholt, Dale R.;Ma, Ronald C. W.;Tam, Claudia H. T.;Tam, Wing Hung;Ganesh, Santhi K.;van Rooij, Frank J. A.;Jones, Samuel E.;Loh, Po-Ru;Ruth, Katherine S.;Tuke, Marcus A.;Tyrrell, Jessica;Wood, Andrew R.;Yaghootkar, Hanieh;Scholtens, Denise M.;Paternoster, Lavinia;Prokopenko, Inga;Kovacs, Peter;Atalay, Mustafa;Willems, Sara M.;Panoutsopoulou, Kalliope;Wang, Xu;Carstensen, Lisbeth;Geller, Frank;Schraut, Katharina E.;Murcia, Mario;van Beijsterveldt, Catharina E. M.;Willemsen, Gonneke;Appel, Emil V. R.;Fonvig, Cilius E.;Trier, Caecilie;Tiesler, Carla M. T.;Standl, Marie;Kutalik, Zoltan;Bonas-Guarch, Silvia;Hougaard, David M.;Sanchez, Friman;Torrents, David;Waage, Johannes;Hollegaard, Mads V.;de Haan, Hugoline G.;Rosendaal, Frits R.;Medina-Gomez, Carolina;Ring, Susan M.;Hemani, Gibran;McMahon, George;Robertson, Neil R.;Groves, Christopher J.;Langenberg, Claudia;Luan, Jian'an;Scott, Robert A.;Zhao, Jing Hua;Mentch, Frank D.;MacKenzie, Scott M.;Reynolds, Rebecca M.;Lowe, William L.;Toenjes, Anke;Stumvoll, Michael;Lindi, Virpi;Lakka, Timo A.;van Duijn, Cornelia M.;Kiess, Wieland;Koerner, Antje;Sorensen, Thorkild I. A.;Niinikoski, Harri;Pahkala, Katja;Raitakari, Olli T.;Zeggini, Eleftheria;Dedoussis, George V.;Teo, Yik-Ying;Saw, Seang-Mei;Melbye, Mads;Campbell, Harry;Wilson, James F.;Vrijheid, Martine;de Geus, Eco J. C. N.;Boomsma, Dorret I.;Kadarmideen, Haja N.;Holm, Jens-Christian;Hansen, Torben;Sebert, Sylvain;Hattersley, Andrew T.;Beilin, Lawrence J.;Newnham, John P.;Pennell, Craig E.;Heinrich, Joachim;Adair, Linda S.;Borja, Judith B.;Mohlke, Karen L.;Eriksson, Johan G.;Widen, Elisabeth;Kahonen, Mika;Viikari, Jorma S.;Lehtimaki, Terho;Vollenweider, Peter;Bonnelykke, Klaus;Bisgaard, Hans;Mook-Kanamori, Dennis O.;Hofman, Albert;Rivadeneira, Fernando;Uitterlinden, Andre G.;Pisinger, Charlotta;Pedersen, Oluf;Power, Christine;Hyppoenen, Elina;Wareham, Nicholas J.;Hakonarson, Hakon;Davies, Eleanor;Walker, Brian R.;Jaddoe, Vincent W. V.;Jaervelin, Marjo-Riitta;Grant, Struan F. A.;Vaag, Allan A.;Lawlor, Debbie A.;Frayling, Timothy M.;Smith, George Davey;Morris, Andrew P.;Ong, Ken K.;Felix, Janine F.;Timpson, Nicholas J.;Perry, John R. B.;Evans, David M.;McCarthy, Mark I.;Freathy, Rachel M.
通讯作者：
Freathy, Rachel M.
影响因子：
64.8
作者：
Shungin, Dmitry;Winkler, Thomas W.;Croteau-Chonka, Damien C.;Ferreira, Teresa;Lockes, Adam E.;Maegi, Reedik;Strawbridge, Rona J.;Pers, Tune H.;Fischer, Krista;Justice, Anne E.;Workalemahu, Tsegaselassie;Wu, Joseph M. W.;Buchkovich, Martin L.;Heard-Costa, Nancy L.;Roman, Tamara S.;Drong, Alexander W.;Song, Ci;Gustafsson, Stefan;Day, Felix R.;Esko, Tonu;Fall, Tove;Kutalik, Zoltan;Luan, Jian'an;Randall, Joshua C.;Scherag, Andre;Vedantam, Sailaja;Wood, Andrew R.;Chen, Jin;Fehrmann, Rudolf;Karjalainen, Juha;Kahali, Bratati;Liu, Ching-Ti;Schmidt, Ellen M.;Absher, Devin;Amin, Najaf;Anderson, Denise;Beekman, Marian;Bragg-Gresham, Jennifer L.;Buyske, Steven;Demirkan, Ayse;Ehret, Georg B.;Feitosa, Mary F.;Goel, Anuj;Jackson, Anne U.;Johnson, Toby;Kleber, Marcus E.;Kristiansson, Kati;Mangino, Massimo;Leach, Irene Mateo;Medina-Gomez, Carolina;Palmer, Cameron D.;Pasko, Dorota;Pechlivaniss, Sonali;Peters, Marjolein J.;Prokopenko, Inga;Stancakova, Alena;Sung, Yun Ju;Tanakam, Toshiko;Teumer, Alexander;Van Vliet-Ostaptchouk, Jana V.;Yengo, Loic;Zhang, Weihua;Albrecht, Eva;Arnlov, Johan;Arscott, Gillian M.;Bandinelli, Stefania;Barrett, Amy;Bellis, Claire;Bennett, Amanda J.;Berne, Christian;Blueher, Matthias;Buhringer, Stefan;Bonnet, Fabrice;Boettcher, Yvonne;Bruinenberg, Marcel;Carba, Delia B.;Caspersen, Ida H.;Clarke, Robert;Daw, E. Warwick;Deelen, Joris;Deelman, Ewa;Delgado, Graciela;Doney, Alex S. F.;Eklund, Niina;Erdos, Michael R.;Estrada, Karol;Eury, Elodie;Friedrichs, Nele;Garcia, Melissa E.;Giedraitis, Vilmantas;Gigante, Bruna;Go, Alan S.;Golay, Alain;Grallert, Harald;Grammer, Tanja B.;Graessler, Juergen;Grewal, Jagvir;Groves, Christopher J.;Haller, Toomas;Hallmans, Goran;Hartman, Catharina A.;Hassinen, Maija;Hayward, Caroline;Heikkila, Kauko;Herzig, Karl-Heinz;Helmer, Quinta;Hillege, Hans L.;Holmen, Oddgeir;Hunt, Steven C.;Isaacs, Aaron;Ittermann, Till;James, Alan L.;Johansson, Ingegerd;Juliusdottir, Thorhildur;Kalafati, Ioanna-Panagiota;Kinnunen, Leena;Koenig, Wolfgang;Kooner, Ishminder K.;Kratzer, Wolfgang;Lamina, Claudia;Leander, Karin;Lee, Nanette R.;Lichtner, Peter;Lind, Lars;Lindstrom, Jaana;Lobbens, Stephane;Lorentzon, Mattias;Mach, Francois;Magnusson, Patrik K. E.;Mahajan, Anubha;McArdle, Wendy L.;Menni, Cristina;Merger, Sigrun;Mihailov, Evelin;Milani, Lili;Mills, Rebecca;Moayyeri, Alireza;Monda, Ken L.;Mooijaart, Simon P.;Muehleisen, Thomas W.;Mulas, Antonella;Mueller, Gabriele;Mueller-Nurasyid, Martina;Nagaraja, Ramaiah;Nalls, Michael A.;Narisu, Narisu;Glorioso, Nicola;Nolte, Ilja M.;Olden, Matthias;Rayner, Nigel W.;Renstrom, Frida;Ried, Janina S.;Robertson, Neil R.;Rose, Lynda M.;Sanna, Serena;Scharnagl, Hubert;Scholtens, Salome;Sennblad, Bengt;Seufferlein, Thomas;Sitlani, Colleen M.;Smith, Albert Vernon;Stirrups, Kathleen;Stringham, Heather M.;Sundstrom, Johan;Swertz, Morris A.;Swift, Amy J.;Syvanen, Ann-Christine;Tayo, Bamidele O.;Thorand, Barbara;Thorleifsson, Gudmar;Tomaschitz, Andreas;Troffa, Chiara;van Oort, Floor V. A.;Verweij, Niek;Vonk, Judith M.;Waite, Lindsay L.;Wennauer, Roman;Wilsgaard, Tom;Wojczynski, Mary K.;Wong, Andrew;Zhang, Qunyuan;Zhao, Jing Hua;Brennan, Eoin P.;Choi, Murim;Eriksson, Per;Folkersen, Lasse;Franco-Cereceda, Anders;Gharavi, Ali G.;Hedman, Asa K.;Hivert, Marie-France;Huang, Jinyan;Kanoni, Stavroula;Karpe, Fredrik;Keildson, Sarah;Kiryluk, Krzysztof;Liang, Liming;Lifton, Richard P.;Ma, Baoshan;McKnight, Amy J.;McPherson, Ruth;Metspalu, Andres;Min, Josine L.;Moffatt, Miriam F.;Montgomery, Grant W.;Murabito, Joanne M.;Nicholson, George;Nyholt, Dale R.;Olsson, Christian;Perry, John R. B.;Reinmaa, Eva;Salem, Rany M.;Sandholm, Niina;Schadt, Eric E.;Scott, Robert A.;Stolk, Lisette;Vallejo, Edgar E.;Westra, Harm-Jan;Zondervan, Krina T.;Amouyel, Philippe;Arveiler, Dominique;Bakker, Stephan J. L.;Beilby, John;Bergman, Richard N.;Blangero, John;Brown, Morris J.;Burnier, Michel;Campbell, Harry;Chakravarti, Aravinda;Chiness, Peter S.;Claudi-Boehmi, Simone;Collins, Francis S.;Crawford, Dana C.;Danesh, John;de Faire, Ulf;de Geusl, Eco J. C.;Doerr, Marcus;Erbel, Raimund;Eriksson, Johan G.;Farrall, Martin;Ferrannini, Ele;Ferrieres, Jean;Forouhi, Nita G.;Forrester, Terrence;Franco, Oscar H.;Gansevoort, Ron T.;Gieger, Christian;Gudnason, Vilmundur;Haiman, Christopher A.;Harris, Tamara B.;Hattersley, Andrew T.;Heliovaara, Markku;Hicks, Andrew A.;Hingorani, Aroon D.;Hoffmann, Wolfgang;Hofman, Albert;Homuth, Georg;Humphries, Steve E.;Hyppoenen, Elina;Illig, Thomas;Jarvelin, Marjo-Riitta;Johansen, Berit;Jousilahti, Pekka;Jula, Antti M.;Kaprio, Jaakko;Kee, Frank;Keinanen-Kiukaanniemi, Sirkka M.;Kooner, Jaspal S.;Kooperberg, Charles;Kovacs, Peter;Kraja, Aldi T.;Kumari, Meena;Kuulasmaa, Kari;Kuusisto, Johanna;Lakka, Timo A.;Langenberg, Claudia;Le Marchand, Loic;Lehtimaki, Terho;Lyssenko, Valeriya;Mannisto, Satu;Marette, Andre;Matise, Tara C.;McKenzie, Colin A.;McKnight, Barbara;Musk, Arthur W.;Mohlenkamp, Stefan;Morris, Andrew D.;Nelis, Mari;Ohlsson, Claes;Oldehinkel, Albertine J.;Ong, Ken K.;Palmer, Lyle J.;Penninx, Brenda W.;Peters, Annette;Pramstaller, Peter P.;Raitakari, Olli T.;Rankinen, Tuomo;Rao, D. C.;Rice, Treva K.;Ridker, Paul M.;Ritchie, Marylyn D.;Rudan, Igor;Salomaa, Veikko;Samani, Nilesh J.;Saramies, Jouko;Sarzynski, Mark A.;Schwarz, Peter E. H.;Shuldiner, Alan R.;Staessen, Jan A.;Steinthorsdottir, Valgerdur;Stolk, Ronald P.;Strauch, Konstantin;Toenjes, Anke;Tremblay, Angelo;Tremoli, Elena;Vohl, Marie-Claude;Voelker, Uwe;Vollenweider, Peter;Wilson, James F.;Witteman, Jacqueline C.;Adair, Linda S.;Bochud, Murielle;Boehm, Bernhard O.;Bornstein, Stefan R.;Bouchard, Claude;Cauchi, Stephane;Caulfield, Mark J.;Chambers, John C.;Chasman, Daniel I.;Cooper, Richard S.;Dedoussis, George;Ferrucci, Luigi;Froguel, Philippe;Grabe, Hans-Joergen;Hamsten, Anders;Hui, Jennie;Hveem, Kristian;Joeckel, Karl-Heinz;Kivimaki, Mika;Kuh, Diana;Laakso, Markku;Liu, Yongmei;Maerz, Winfried;Munroe, Patricia B.;Njolstad, Inger;Oostra, Ben A.;Palmer, Colin N. A.;Pedersen, Nancy L.;Perola, Markus;Perusse, Louis;Peters, Ulrike;Power, Chris;Quertermous, Thomas;Rauramaa, Rainer;Rivadeneira, Fernando;Saaristo, Timo E.;Saleheen, Danish;Sinisalo, Juha;Slagboom, P. Eline;Snieder, Harold;Spector, Tim D.;Thorsteinsdottir, Unnur R.;Stumvoll, Michael;Tuomilehto, Jaakko;Uitterlinden, Andre G.;Uusitupa, Math;van der Harst, Pim;Veronesi, Giovanni;Walker, Mark;Wareham, Nicholas J.;Watkins, Hugh;Wichmann, H-Erich;Abecasis, Goncalo R.;Assimes, Themistocles L.;Berndt, Sonja I.;Boehnkes, Michael;Borecki, Ingrid B.;Deloukas, Panos;Franke, Lude;Frayling, Timothy M.;Groop, Leif C.;Hunter, David J.;Kaplan, Robert C.;O'Connell, Jeffrey R.;Qi, Lu;Schlessinger, David;Strachan, David P.;Stefansson, Kari;van Dujin, Cornelia M.;Willer, Cristen J.;Visscher, Peter M.;Yang, Jian;Hirschhorn, Joel N.;Zillikens, M. Carola;McCarthy, Mark I.;Speliotes, Elizabeth K.;North, Kari E.;Fox, Caroline S.;Barroso, Ines;Franks, Paul W.;Ingelsson, Erik;Heid, Iris M.;Loos, Ruth J. F.;Cupples, L. Adrienne;Morris, Andrew P.;Lindgren, Cecilia M.;Mohlke, Karen L.
通讯作者：
Mohlke, Karen L.
腰围比与心脏代谢性状，2型糖尿病和冠状动脉疾病的遗传关联。
DOI：
10.1001/jama.2016.21042
发表时间：
2017-02-14
期刊：
JAMA
影响因子：
--
作者：
Emdin CA;Khera AV;Natarajan P;Klarin D;Zekavat SM;Hsiao AJ;Kathiresan S
通讯作者：
Kathiresan S
影响因子：
16.6
作者：
Soler Artigas M;Wain LV;Miller S;Kheirallah AK;Huffman JE;Ntalla I;Shrine N;Obeidat M;Trochet H;McArdle WL;Alves AC;Hui J;Zhao JH;Joshi PK;Teumer A;Albrecht E;Imboden M;Rawal R;Lopez LM;Marten J;Enroth S;Surakka I;Polasek O;Lyytikäinen LP;Granell R;Hysi PG;Flexeder C;Mahajan A;Beilby J;Bossé Y;Brandsma CA;Campbell H;Gieger C;Gläser S;González JR;Grallert H;Hammond CJ;Harris SE;Hartikainen AL;Heliövaara M;Henderson J;Hocking L;Horikoshi M;Hutri-Kähönen N;Ingelsson E;Johansson Å;Kemp JP;Kolcic I;Kumar A;Lind L;Melén E;Musk AW;Navarro P;Nickle DC;Padmanabhan S;Raitakari OT;Ried JS;Ripatti S;Schulz H;Scott RA;Sin DD;Starr JM;UK BiLEVE;Viñuela A;Völzke H;Wild SH;Wright AF;Zemunik T;Jarvis DL;Spector TD;Evans DM;Lehtimäki T;Vitart V;Kähönen M;Gyllensten U;Rudan I;Deary IJ;Karrasch S;Probst-Hensch NM;Heinrich J;Stubbe B;Wilson JF;Wareham NJ;James AL;Morris AP;Jarvelin MR;Hayward C;Sayers I;Strachan DP;Hall IP;Tobin MD
通讯作者：
Tobin MD
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