Factorial Mendelian randomization: using genetic variants to assess interactions.
Factorial Mendelian randomization: using genetic variants to assess interactions.
复制标题
DOI：
10.1093/ije/dyz161
复制
发表时间：
2020-08-01
影响因子：
7.7
通讯作者：
Burgess S
中科院分区：
文献类型：
--
作者：
Rees JMB;Foley CN;Burgess S
因子孟德尔随机化是使用遗传变异来回答有关相互作用的问题。尽管该方法已用于应用研究，但关于如何设计或执行析因孟德尔随机化分析的方法学建议却很少。以前的分析采用了2 × 2的方法，使用二分法遗传评分将人群分为四个亚组，如析因随机试验。我们描述了两种不同的情况下因子孟德尔随机化：调查风险因素之间的相互作用，并调查药物干预对风险因素之间的相互作用。我们提出了两阶段最小二乘方法，使用所有可用的遗传变异及其相互作用作为工具变量，并使用连续遗传评分而不是二分评分作为工具变量。我们使用英国生物银行的数据来说明我们的方法，以研究体重指数和饮酒对收缩压的影响。模拟和真实的数据表明，使用遗传变体之间的全套相互作用作为工具，效率最大化。在应用示例中，与2 × 2方法相比，效率提高了4到10倍。使用连续遗传分数的分析比使用二分法分数的分析更有效。通过寻找遗传变异来提高效率，这些遗传变异可以在风险因素分布的自然中断处将人口划分为更均等的群体。先前的析因孟德尔随机化分析可能效力不足。通过使用所有遗传变异及其相互作用作为工具变量，而不是2 × 2方法，可以提高效率。
Factorial Mendelian randomization is the use of genetic variants to answer questions about interactions. Although the approach has been used in applied investigations, little methodological advice is available on how to design or perform a factorial Mendelian randomization analysis. Previous analyses have employed a 2 × 2 approach, using dichotomized genetic scores to divide the population into four subgroups as in a factorial randomized trial. We describe two distinct contexts for factorial Mendelian randomization: investigating interactions between risk factors, and investigating interactions between pharmacological interventions on risk factors. We propose two-stage least squares methods using all available genetic variants and their interactions as instrumental variables, and using continuous genetic scores as instrumental variables rather than dichotomized scores. We illustrate our methods using data from UK Biobank to investigate the interaction between body mass index and alcohol consumption on systolic blood pressure. Simulated and real data show that efficiency is maximized using the full set of interactions between genetic variants as instruments. In the applied example, between 4- and 10-fold improvement in efficiency is demonstrated over the 2 × 2 approach. Analyses using continuous genetic scores are more efficient than those using dichotomized scores. Efficiency is improved by finding genetic variants that divide the population at a natural break in the distribution of the risk factor, or else divide the population into more equal-sized groups. Previous factorial Mendelian randomization analyses may have been underpowered. Efficiency can be improved by using all genetic variants and their interactions as instrumental variables, rather than the 2 × 2 approach.
登录
查看更多内容
影响因子：
24
作者：
Ference BA;Majeed F;Penumetcha R;Flack JM;Brook RD
通讯作者：
Brook RD
影响因子：
5
作者：
Labrecque, Jeremy A.;Swanson, Sonja A.
通讯作者：
Swanson, Sonja A.
影响因子：
7.7
作者：
Burgess, Stephen;Thompson, Simon G.
通讯作者：
Thompson, Simon G.
影响因子：
64.8
作者：
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;Lim, Unhee;Lotay, Vaneet;Mangino, Massimo;Leach, Irene Mateo;Medina-Gomez, Carolina;Medland, Sarah E.;Nalls, Michael A.;Palmer, Cameron D.;Pasko, Dorota;Pechlivanis, Sonali;Peters, Marjolein J.;Prokopenko, Inga;Shungin, Dmitry;Stancakova, Alena;Strawbridge, Rona J.;Sung, Yun Ju;Tanaka, Toshiko;Teumer, Alexander;Trompet, Stella;van der Laan, Sander W.;van Settee, Jessica;Van Vliet-Ostaptchouk, Jana V.;Wang, Zhaoming;Yengo, Loic;Zhang, Weihua;Isaacs, Aaron;Albrecht, Eva;Arnlov, Johan;Arscott, Gillian M.;Attwood, Antony P.;Bandinelli, Stefania;Barrett, Amy;Bas, Isabelita N.;Bellis, Claire;Bennett, Amanda J.;Berne, Christian;Blagieva, Roza;Blueher, Matthias;Bohringer, Stefan;Bonnycastle, Lori L.;Boettcher, Yvonne;Boyd, Heather A.;Bruinenberg, Marcel;Caspersen, Ida H.;Chen, Yii-Der Ida;Clarke, Robert;Daw, E. Warwick;de Craen, Anton J. M.;Delgado, Graciela;Dimitriou, Maria;Doney, Alex S. F.;Eklund, Niina;Estrada, Karol;Eury, Elodie;Folkersen, Lasse;Fraser, Ross M.;Garcia, Melissa E.;Geller, Frank;Giedraitis, Vilmantas;Gigante, Bruna;Go, Alan S.;Golay, Alain;Goodall, Alison H.;Gordon, Scott D.;Gorski, Mathias;Grabe, Hans-Joergen;Grallert, Harald;Grammer, Tanja B.;Graessler, Jurgen;Gronberg, Henrik;Groves, Christopher J.;Gusto, Gaeelle;Haessler, Jeffrey;Hall, Per;Haller, Toomas;Hallmans, Goran;Hartman, Catharina A.;Hassinen, Maija;Hayward, Caroline;Heard-Costa, Nancy L.;Helmer, Qinta;Hengstenberg, Christian;Holmen, Oddgeir;Hottenga, Jouke-Jan;James, Alan L.;Jeff, Janina M.;Johansson, Asa;Jolley, Jennifer;Juliusdottir, Thorhildur;Kinnunen, Leena;Koenig, Wolfgang;Koskenvuo, Markku;Kratzer, Wolfgang;Laitinen, Jaana;Lamina, Claudia;Leander, Karin;Lee, Nanette R.;Lichtner, Peter;Lind, Lars;Lindstrom, Jaana;Lo, Ken Sin;Lobbens, Stephane;Lorbeer, Roberto;Lu, Yingchang;Mach, Francois;Magnusson, Patrik K. E.;Mahajan, Anubha;McArdle, Wendy L.;McLachlan, Stela;Menni, Cristina;Merger, Sigrun;Mihailov, Evelin;Milani, Lili;Moayyeri, Alireza;Monda, Keri L.;Morken, Mario A.;Mulas, Antonella;Mueller, Gabriele;Mueller-Nurasyid, Martina;Musk, Arthur W.;Nagaraja, Ramaiah;Noethen, Markus M.;Nolte, Ilja M.;Pilz, Stefan;Rayner, Nigel W.;Renstrom, Frida;Rettig, Rainer;Ried, Janina S.;Ripke, Stephan;Robertson, Neil R.;Rose, Lynda M.;Sanna, Serena;Scharnagl, Hubert;Scholtens, Salome;Schumacher, Fredrick R.;Scott, William R.;Seufferlein, Thomas;Shi, Jianxin;Smith, Albert Vernon;Smolonska, Joanna;Stanton, Alice V.;Steinthorsdottir, Valgerdur;Stirrups, Kathleen;Stringham, Heather M.;Sundstrom, Johan;Swertz, Morris A.;Swift, Amy J.;Syvanen, Ann-Christine;Tan, Sian-Tsung;Tayo, Bamidele O.;Thorand, Barbara;Thorleifsson, Gudmar;Tyrer, Jonathan P.;Uh, Hae-Won;Vandenput, Liesbeth;Verhulst, Frank C.;Vermeulen, Sita H.;Verweij, Niek;Vonk, Judith M.;Waite, Lindsay L.;Warren, Helen R.;Waterworth, Dawn;Weedon, Michael N.;Wilkens, Lynne R.;Willenborg, Christina;Wilsgaard, Tom;Wojczynski, Mary K.;Wong, Andrew;Wrightl, Alan F.;Zhang, Qunyuan;Brennan, Eoin P.;Choi, Murim;Dastani, Zari;Drong, Alexander W.;Eriksson, Per;Franco-Cereceda, Anders;Gadin, Jesper R.;Gharavi, Ali G.;Goddard, Michael E.;Handsaker, Robert E.;Huang, Jinyan;Karpe, Fredrik;Kathiresan, Sekar;Keildson, Sarah;Kiryluk, Krzysztof;Kubo, Michiaki;Lee, Jong-Young;Liang, Liming;Lifton, Richard P.;Ma, Baoshan;McCarroll, Steven A.;McKnight, Amy J.;Min, Josine L.;Moffatt, Miriam F.;Montgomery, Grant W.;Murabito, Joanne M.;Nicholson, George;Nyholt, Dale R.;Okada, Yukinori;Perry, John R. B.;Dorajoo, Rajkumar;Reinmaa, Eva;Salem, Rany M.;Sandholm, Niina;Scott, Robert A.;Stolk, Lisette;Takahashi, Atsushi;Tanaka, Toshihiro;van 't Hooft, Ferdinand M.;Vinkhuyzen, Anna A. E.;Westra, Harm-Jan;Zheng, Wei;Zondervan, Krina T.;Heath, Andrew C.;Arveiler, Dominique;Bakker, Stephan J. L.;Beilby, John;Bergman, Richard N.;Blangero, John;Bovet, Pascal;Campbell, Harry;Caulfield, Mark J.;Cesana, Giancarlo;Chakravarti, Aravinda;Chasman, Daniel I.;Chines, Peter S.;Collins, Francis S.;Crawford, Dana C.;Cupples, L. Adrienne;Cusi, Daniele;Danesh, John;de Faire, Ulf;den Ruijter, Hester M.;Dominiczak, Anna F.;Erbel, Raimund;Erdmann, Jeanette;Eriksson, Johan G.;Farrall, Martin;Felix, Stephan B.;Ferrannini, Ele;Ferrieres, Jean;Ford, Ian;Forouhi, Nita G.;Forrester, Terrence;Franco, Oscar H.;Gansevoort, Ron T.;Gejman, Pablo V.;Gieger, Christian;Gottesman, Omri;Gudnason, Vilmundur;Gyllensten, Ulf;Hall, Alistair S.;Harris, Tamara B.;Hattersley, Andrew T.;Hicks, Andrew A.;Hindorff, Lucia A.;Hingorani, Aroon D.;Hofman, Albert;Homuth, Georg;Hovingh, G. Kees;Humphries, Steve E.;Hunt, Steven C.;Hypponen, Elina;Illig, Thomas;Jacobs, Kevin B.;Jarvelin, Marjo-Riitta;Joeckel, Karl-Heinz;Johansen, Berit;Jousilahti, Pekka;Jukema, J. Wouter;Jula, Antti M.;Kaprio, Jaakko;Kastelein, John J. P.;Keinanen-Kiukaanniemi, Sirkka M.;Kiemeney, Lambertus A.;Knekt, Paul;Kooner, Jaspal S.;Kooperberg, Charles;Kovacs, Peter;Kraja, Aldi T.;Kumari, Meena;Kuusisto, Johanna;Lakka, Timo A.;Langenberg, Claudia;Le Marchand, Laic;Lehtimaki, Terho;Lyssenko, Valeriya;Mannisto, Satu;Marette, Andre;Matise, Tara C.;McKenzie, Colin A.;McKnight, Barbara;Moll, Frans L.;Morris, Andrew D.;Morris, Andrew P.;Murray, Jeffrey C.;Nelis, Mari;Ohlsson, Claes;Oldehinkel, Albertine J.;Ong, Ken K.;Madden, Pamela A. F.;Pasterkamp, Gerard;Peden, John F.;Peters, Annette;Postma, Dirkje S.;Pramstaller, Peter P.;Price, Jackie F.;Qi, Lu;Raitakari, Olli T.;Rankinen, Tuomo;Rao, D. C.;Rice, Treva K.;Ridker, Paul M.;Rioux, John D.;Ritchie, Marylyn D.;Rudan, Igor;Salomaa, Veikko;Samani, Nilesh J.;Saramines, Jouko;Sarzynski, Mark A.;Schunkert, Heribert;Schwarz, Peter E. H.;Sever, Peter;Shuldiner, Alan R.;Sinisalo, Juha;Stolk, Ronald P.;Strauch, Konstantin;Toenjes, Anke;Tregouet, David-Alexandre;Tremblay, Angelo;Tremoli, Elena;Virtamo, Jarmo;Vohl, Marie-Claude;Voelker, Uwe;Waeber, Gerard;Willemsen, Gonneke;Witteman, Jacqueline C.;Zillikens, M. Carola;Adair, Linda S.;Amouyel, Philippe;Asselbergs, Folkert W.;Assimes, Themistocles L.;Bochud, Murielle;Boehm, Bernhard O.;Boerwinkle, Eric;Bornstein, Stefan R.;Bottinger, Erwin P.;Bouchard, Claude;Cauchi, Stephane;Chambers, John C.;Chanock, Stephen J.;Cooper, Richard S.;de Bakker, Paul I. W.;Dedoussis, George;Ferrucci, Luigi;Franks, Paul W.;Froguel, Philippe;Groop, Leif C.;Haiman, Christopher A.;Hamsten, Anders;Hui, Jennie;Hunter, David J.;Hveem, Kristian;Kaplan, Robert C.;Kivimaki, Mika;Kuh, Diana;Laakso, Markku;Liu, Yongmei;Martin, Nicholas G.;Maerz, Winfried;Melbve, Mads;Metspalu, Andres;Moebus, Susanne;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;Sattar, Naveed;Schadt, Eric E.;Schlessinger, David;Slagboom, P. Eline;Snieder, Harold;Spector, Tim D.;Thorsteinsdottir, Unnu R.;Stumvoll, Michael;Tuomilehto, Jaakko;Uitterlinden, Andre G.;Uusitupa, Matti;van der Harst, Pim;Walker, Mark;Wallaschofski, Henri;Wareham, Nicholas J.;Watkins, Hugh;Weir, David R.;Wichmann, H-Erich;Wilson, James F.;Zanen, Pieter;Borecki, Ingrid B.;Deloukas, Panos;Fox, Caroline S.;Heid, Iris M.;O'Connell, Jeffrey R.;Strachan, David P.;Stefansson, Kari;van Duijri, Cornelia M.;Abecasis, Goncalo R.;Franke, Lude;Frayling, Timothy M.;McCarthy, Mark I.;Visscher, Peter M.;Scherag, Andre;Willer, Cristen J.;Boehnke, Michael;Mohlke, Karen L.;Lindgren, Cecilia M.;Beckmann, Jacques S.;Barroso, Ines;North, Kari E.;Ingelsson, Erik;Hirschhorn, Joel N.;Loos, Ruth J. F.;Speliotes, Elizabeth K.
通讯作者：
Speliotes, Elizabeth K.
影响因子：
158.5
作者：
Ference, Brian A.;Robinson, Jennifer G.;Sabatine, Marc S.
通讯作者：
Sabatine, Marc S.