A Selection Operator for Summary Association Statistics Reveals Allelic Heterogeneity of Complex Traits.
A Selection Operator for Summary Association Statistics Reveals Allelic Heterogeneity of Complex Traits.
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DOI：
10.1016/j.ajhg.2017.09.027
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发表时间：
2017-12-07
影响因子：
9.8
通讯作者：
Shen X
中科院分区：
文献类型：
--
作者：
Ning Z;Lee Y;Joshi PK;Wilson JF;Pawitan Y;Shen X
近年来，作为全基因组关联研究（GWASs）的二级分析，条件和联合多snp分析（GCTA-COJO）已经成功地允许在检测位点内发现额外的关联信号。这表明GWASs中许多基因座包含不止一个因果变异。为了解释在每个发现的基因座中调节复杂性状的潜在机制，研究人员必须评估基因座内等位基因异质性的大小。在LASSO（最小绝对收缩和选择算子）回归的基础上，我们开发了一个惩罚选择算子，用于联合分析每个映射位点内的多变体（SOJO）。我们发现，与逐步条件多snp分析相比，SOJO在预测每个位点与复杂性状相关的等位基因数量方面具有更好的敏感性和特异性。SOJO提出了GCTA-COJO可能遗漏的因果变异。与使用GWAS中全基因组显著位点的顶级变异相比，使用SOJO在不需要额外的发现样本或基因组中额外的位点的情况下，将身高方差预测的比例提高了65%。我们的实证结果表明，人类身高不仅是一个高度的多基因性状，而且在其已建立的数百个位点内具有高度的等位基因异质性。
In recent years, as a secondary analysis in genome-wide association studies (GWASs), conditional and joint multiple-SNP analysis (GCTA-COJO) has been successful in allowing the discovery of additional association signals within detected loci. This suggests that many loci mapped in GWASs harbor more than a single causal variant. In order to interpret the underlying mechanism regulating a complex trait of interest in each discovered locus, researchers must assess the magnitude of allelic heterogeneity within the locus. We developed a penalized selection operator for jointly analyzing multiple variants (SOJO) within each mapped locus on the basis of LASSO (least absolute shrinkage and selection operator) regression derived from summary association statistics. We found that, compared to stepwise conditional multiple-SNP analysis, SOJO provided better sensitivity and specificity in predicting the number of alleles associated with complex traits in each locus. SOJO suggested causal variants potentially missed by GCTA-COJO. Compared to using top variants from genome-wide significant loci in GWAS, using SOJO increased the proportion of variance prediction for height by 65% without additional discovery samples or additional loci in the genome. Our empirical results indicate that human height is not only a highly polygenic trait, but also has high allelic heterogeneity within its established hundreds of loci.
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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.
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
30.8
作者：
Barrett, Jeffrey C.;Clayton, David G.;Concannon, Patrick;Akolkar, Beena;Cooper, Jason D.;Erlich, Henry A.;Julier, Cecile;Morahan, Grant;Nerup, Jorn;Nierras, Concepcion;Plagnol, Vincent;Pociot, Flemming;Schuilenburg, Helen;Smyth, Deborah J.;Stevens, Helen;Todd, John A.;Walker, Neil M.;Rich, Stephen S.
通讯作者：
Rich, Stephen S.
影响因子：
30.8
作者：
Yang, Jian;Ferreira, Teresa;Morris, Andrew P.;Medland, Sarah E.;Madden, Pamela A. F.;Heath, Andrew C.;Martin, Nicholas G.;Montgomery, Grant W.;Weedon, Michael N.;Loos, Ruth J.;Frayling, Timothy M.;McCarthy, Mark I.;Hirschhorn, Joel N.;Goddard, Michael E.;Visscher, Peter M.
通讯作者：
Visscher, Peter M.
影响因子：
30.8
作者：
Bulik-Sullivan, Brendan K.;Loh, Po-Ru;Finucane, Hilary K.;Ripke, Stephan;Yang, Jian;Patterson, Nick;Daly, Mark J.;Price, Alkes L.;Neale, Benjamin M.
通讯作者：
Neale, Benjamin M.