Meta-analysis of gene-level associations for rare variants based on single-variant statistics

Yi Juan Hu, Sonja I. Berndt, Stefan Gustafsson, Andrea Ganna, Joel Hirschhorn, Kari E. North, Erik Ingelsson, Dan Yu Lin, Francis S. Collins, Sonja I. Berndt, Stefan Gustafsson, Reedik Ma¨gi, Andrea Ganna, Eleanor Wheeler, Mary F. Feitosa, Anne E. Justice, Keri L. Monda, Damien C. Croteau-Chonka, Felix R. Day, To˜nu Esko & 310 others Tove Fall, Teresa Ferreira, Davide Gentilini, Anne U. Jackson, Jian’an Luan, Joshua C. Randall, Sailaja Vedantam, Cristen J. Willer, Thomas W. Winkler, Andrew R. Wood, Tsegaselassie Workalemahu, Yi Juan Hu, Sang Hong Lee, Liming Liang, Dan Yu Lin, Josine L. Min, Benjamin M. Neale, Gudmar Thorleifsson, Jian Yang, Eva Albrecht, Najaf Amin, Jennifer L. Bragg-Gresham, Gemma Cadby, Martin den Heijer, Niina Eklund, Krista Fischer, Anuj Goel, Jouke Jan Hottenga, Jennifer E. Huffman, Ivonne Jarick, Asa Johansson, Toby Johnson, Stavroula Kanoni, Marcus E. Kleber, Inke R. Ko¨nig, Kati Kristiansson, Zolta´n Kutalik, Claudia Lamina, Cecile Lecoeur, Guo Li, Massimo Mangino, Wendy L. McArdle, Carolina Medina-Gomez, Martina Mu¨ller-Nurasyid, Julius S. Ngwa, Ilja M. Nolte, Lavinia Paternoster, Sonali Pechlivanis, Markus Perola, Marjolein J. Peters, Michael Preuss, Lynda M. Rose, Jianxin Shi, Dmitry Shungin, Albert Vernon Smith, Rona J. Strawbridge, Ida Surakka, Alexander Teumer, Mieke D. Trip, Jonathan Tyrer, Jana V.Van Vliet-Ostaptchouk, Liesbeth Vandenput, Lindsay L. Waite, Jing Hua Zhao, Devin Absher, Folkert W. Asselbergs, Mustafa Atalay, Antony P. Attwood, Anthony J. Balmforth, Hanneke Basart, John Beilby, Lori L. Bonnycastle, Paolo Brambilla, Marcel Bruinenberg, Harry Campbell, Daniel I. Chasman, Peter S. Chines, Francis S. Collins, John M. Connell, William Cookson, Ulf de Faire, Femmie de Vegt, Mariano Dei, Maria Dimitriou, Sarah Edkins, Karol Estrada, David M. Evans, Martin Farrall, Marco M. Ferrario, Jean Ferrie`res, Lude Franke, Francesca Frau, Pablo V. Gejman, Harald Grallert, Henrik Gro¨nberg, Vilmundur Gudnason, Alistair S. Hall, Per Hall, Anna Liisa Hartikainen, Caroline Hayward, Nancy L. Heard-Costa, Andrew C. Heath, Johannes Hebebrand, Georg Homuth, Frank B. Hu, Sarah E. Hunt, Elina Hyppo¨nen, Carlos Iribarren, Kevin B. Jacobs, John Olov Jansson, Antti Jula, Mika Ka¨ho¨nen, Sekar Kathiresan, Frank Kee, Kay Tee Khaw, Mika Kivimaki, Wolfgang Koenig, Aldi T. Kraja, Meena Kumari, Kari Kuulasmaa, Johanna Kuusisto, Jaana H. Laitinen, Timo A. Lakka, Claudia Langenberg, Lenore J. Launer, Lars Lind, Jaana Lindstro¨m, Jianjun Liu, Antonio Liuzzi, Marja Liisa Lokki, Mattias Lorentzon, Pamela A.Madden Magnusson, P. A.M. Magnusson, Paolo Manunta, Diana Marek, Winfried Ma¨rz, Irene Mateo Leach, Barbara McKnight, Sarah E. Medland, Evelin Mihailov, Lili Milani, Grant W. Montgomery, Vincent Mooser, Thomas W. Mu¨hleisen, Patricia B. Munroe, Arthur W. Musk, Narisu Narisu, Gerjan Navis, George Nicholson, Ellen A. Nohr, Ken K. Ong, Ben A. Oostra, Colin N.A. Palmer, Aarno Palotie, John F. Peden, Nancy Pedersen, Annette Peters, Ozren Polasek, Anneli Pouta, Peter P. Pramstaller, Inga Prokopenko, Carolin Pu¨tter, Aparna Radhakrishnan, Olli Raitakari, Augusto Rendon, Fernando Rivadeneira, Igor Rudan, Timo E. Saaristo, Jennifer G. Sambrook, Alan R. Sanders, Serena Sanna, Jouko Saramies, Sabine Schipf, Stefan Schreiber, Heribert Schunkert, So Youn Shin, Stefano Signorini, Juha Sinisalo, Boris Skrobek, Nicole Soranzo, Alena Stanca´kova´, Klaus Stark, Jonathan C. Stephens, Kathleen Stirrups, Ronald P. Stolk, Michael Stumvoll, Amy J. Swift, Eirini V. Theodoraki, Barbara Thorand, David Alexandre Tregouet, Elena Tremoli, Melanie M.Van der Klauw, Joyce B.J.van Meurs, Sita H. Vermeulen, Jorma Viikari, Jarmo Virtamo, Veronique Vitart, Ge´rard Waeber, Zhaoming Wang, Elisabeth Wide´n, Sarah H. Wild, Gonneke Willemsen, Bernhard R. Winkelmann, Jacqueline C.M. Witteman, Bruce H.R. Wolffenbuttel, Andrew Wong, Alan F. Wright, M. Carola Zillikens, Philippe Amouyel, Bernhard O. Boehm, Eric Boerwinkle, Dorret I. Boomsma, Mark J. Caulfield, Stephen J. Chanock, L. Adrienne Cupples, Daniele Cusi, George V. Dedoussis, Jeanette Erdmann, Johan G. Eriksson, Paul W. Franks, Philippe Froguel, Christian Gieger, Ulf Gyllensten, Anders Hamsten, Tamara B. Harris, Christian Hengstenberg, Andrew A. Hicks, Aroon Hingorani, Anke Hinney, Albert Hofman, Kees G. Hovingh, Kristian Hveem, Thomas Illig, Marjo Riitta Jarvelin, Karl Heinz Jo¨ckel, Sirkka M. Keinanen-Kiukaanniemi, Lambertus A. Kiemeney, Diana Kuh, Markku Laakso, Terho Lehtima¨ki, Douglas F. Levinson, Nicholas G. Martin, Andres Metspalu, Andrew D. Morris, Markku S. Nieminen, Inger Njølstad, Claes Ohlsson, Albertine J. Oldehinkel, Willem H. Ouwehand, Lyle J. Palmer, Brenda Penninx, Chris Power, Michael A. Province, Bruce M. Psaty, Lu Qi, Rainer Rauramaa, Paul M. Ridker, Samuli Ripatti, Veikko Salomaa, Nilesh J. Samani, Harold Snieder, Thorkild I.A. Sørensen, Timothy D. Spector, Kari Stefansson, Anke To¨njes, Jaakko Tuomilehto, Andre´ G. Uitterlinden, Matti Uusitupa, Pim van der Harst, Peter Vollenweider, Henri Wallaschofski, Nicholas J. Wareham, Hugh Watkins, H. Erich Wichmann, James F. Wilson, Goncalo R. Abecasis, Themistocles L. Assimes, Ineˆs Barroso, Michael Boehnke, Ingrid B. Borecki, Panos Deloukas, Caroline S. Fox, Timothy Frayling, Leif C. Groop, Talin Haritunian, Robert C. Kaplan, David Hunter, Robert C. Kaplan, Fredrik Karpe,MiriamMoffatt, Karen L. Mohlke, Jeffrey R. O’Connell, Yudi Pawitan, Eric E. Schadt, David Schlessinger, Valgerdur Steinthorsdottir, David P. Strachan, Unnur Thorsteinsdottir, Cornelia M.van Duijn, Peter M. Visscher, Anna Maria Di Blasio, Joel N. Hirschhorn, Cecilia M. Lindgren, Andrew P. Morris, David Meyre, Andre´ Scherag, Mark I. McCarthy, Elizabeth K. Speliotes, Kari E. North, Ruth J.F. Loos, Erik Ingelsson

Research output: Contribution to journalArticle

36 Citations (Scopus)

Abstract

Meta-analysis of genome-wide association studies (GWASs) has led to the discoveries of many common variants associated with complex human diseases. There is a growing recognition that identifying "causal" rare variants also requires large-scale meta-analysis. The fact that association tests with rare variants are performed at the gene level rather than at the variant level poses unprecedented challenges in the meta-analysis. First, different studies may adopt different gene-level tests, so the results are not compatible. Second, gene-level tests require multivariate statistics (i.e., components of the test statistic and their covariance matrix), which are difficult to obtain. To overcome these challenges, we propose to perform gene-level tests for rare variants by combining the results of single-variant analysis (i.e., p values of association tests and effect estimates) from participating studies. This simple strategy is possible because of an insight that multivariate statistics can be recovered from single-variant statistics, together with the correlation matrix of the single-variant test statistics, which can be estimated from one of the participating studies or from a publicly available database. We show both theoretically and numerically that the proposed meta-analysis approach provides accurate control of the type I error and is as powerful as joint analysis of individual participant data. This approach accommodates any disease phenotype and any study design and produces all commonly used gene-level tests. An application to the GWAS summary results of the Genetic Investigation of ANthropometric Traits (GIANT) consortium reveals rare and low-frequency variants associated with human height. The relevant software is freely available.

Original languageEnglish (US)
Pages (from-to)236-248
Number of pages13
JournalAmerican Journal of Human Genetics
Volume93
Issue number2
DOIs
StatePublished - Aug 8 2013
Externally publishedYes

Fingerprint

Meta-Analysis
Genes
Genome-Wide Association Study
Software
Databases
Phenotype

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

Hu, Y. J., Berndt, S. I., Gustafsson, S., Ganna, A., Hirschhorn, J., North, K. E., ... Ingelsson, E. (2013). Meta-analysis of gene-level associations for rare variants based on single-variant statistics. American Journal of Human Genetics, 93(2), 236-248. https://doi.org/10.1016/j.ajhg.2013.06.011

Meta-analysis of gene-level associations for rare variants based on single-variant statistics. / Hu, Yi Juan; Berndt, Sonja I.; Gustafsson, Stefan; Ganna, Andrea; Hirschhorn, Joel; North, Kari E.; Ingelsson, Erik; Lin, Dan Yu; Collins, Francis S.; Berndt, Sonja I.; Gustafsson, Stefan; Ma¨gi, Reedik; Ganna, Andrea; Wheeler, Eleanor; Feitosa, Mary F.; Justice, Anne E.; Monda, Keri L.; Croteau-Chonka, Damien C.; Day, Felix R.; Esko, To˜nu; Fall, Tove; Ferreira, Teresa; Gentilini, Davide; Jackson, Anne U.; Luan, Jian’an; Randall, Joshua C.; Vedantam, Sailaja; Willer, Cristen J.; Winkler, Thomas W.; Wood, Andrew R.; Workalemahu, Tsegaselassie; Hu, Yi Juan; Lee, Sang Hong; Liang, Liming; Lin, Dan Yu; Min, Josine L.; Neale, Benjamin M.; Thorleifsson, Gudmar; Yang, Jian; Albrecht, Eva; Amin, Najaf; Bragg-Gresham, Jennifer L.; Cadby, Gemma; Heijer, Martin den; Eklund, Niina; Fischer, Krista; Goel, Anuj; Hottenga, Jouke Jan; Huffman, Jennifer E.; Jarick, Ivonne; Johansson, Asa; Johnson, Toby; Kanoni, Stavroula; Kleber, Marcus E.; Ko¨nig, Inke R.; Kristiansson, Kati; Kutalik, Zolta´n; Lamina, Claudia; Lecoeur, Cecile; Li, Guo; Mangino, Massimo; McArdle, Wendy L.; Medina-Gomez, Carolina; Mu¨ller-Nurasyid, Martina; Ngwa, Julius S.; Nolte, Ilja M.; Paternoster, Lavinia; Pechlivanis, Sonali; Perola, Markus; Peters, Marjolein J.; Preuss, Michael; Rose, Lynda M.; Shi, Jianxin; Shungin, Dmitry; Smith, Albert Vernon; Strawbridge, Rona J.; Surakka, Ida; Teumer, Alexander; Trip, Mieke D.; Tyrer, Jonathan; Vliet-Ostaptchouk, Jana V.Van; Vandenput, Liesbeth; Waite, Lindsay L.; Zhao, Jing Hua; Absher, Devin; Asselbergs, Folkert W.; Atalay, Mustafa; Attwood, Antony P.; Balmforth, Anthony J.; Basart, Hanneke; Beilby, John; Bonnycastle, Lori L.; Brambilla, Paolo; Bruinenberg, Marcel; Campbell, Harry; Chasman, Daniel I.; Chines, Peter S.; Collins, Francis S.; Connell, John M.; Cookson, William; Faire, Ulf de; Vegt, Femmie de; Dei, Mariano; Dimitriou, Maria; Edkins, Sarah; Estrada, Karol; Evans, David M.; Farrall, Martin; Ferrario, Marco M.; Ferrie`res, Jean; Franke, Lude; Frau, Francesca; Gejman, Pablo V.; Grallert, Harald; Gro¨nberg, Henrik; Gudnason, Vilmundur; Hall, Alistair S.; Hall, Per; Hartikainen, Anna Liisa; Hayward, Caroline; Heard-Costa, Nancy L.; Heath, Andrew C.; Hebebrand, Johannes; Homuth, Georg; Hu, Frank B.; Hunt, Sarah E.; Hyppo¨nen, Elina; Iribarren, Carlos; Jacobs, Kevin B.; Jansson, John Olov; Jula, Antti; Ka¨ho¨nen, Mika; Kathiresan, Sekar; Kee, Frank; Khaw, Kay Tee; Kivimaki, Mika; Koenig, Wolfgang; Kraja, Aldi T.; Kumari, Meena; Kuulasmaa, Kari; Kuusisto, Johanna; Laitinen, Jaana H.; Lakka, Timo A.; Langenberg, Claudia; Launer, Lenore J.; Lind, Lars; Lindstro¨m, Jaana; Liu, Jianjun; Liuzzi, Antonio; Lokki, Marja Liisa; Lorentzon, Mattias; Magnusson, Pamela A.Madden; Magnusson, P. A.M.; Manunta, Paolo; Marek, Diana; Ma¨rz, Winfried; Leach, Irene Mateo; McKnight, Barbara; Medland, Sarah E.; Mihailov, Evelin; Milani, Lili; Montgomery, Grant W.; Mooser, Vincent; Mu¨hleisen, Thomas W.; Munroe, Patricia B.; Musk, Arthur W.; Narisu, Narisu; Navis, Gerjan; Nicholson, George; Nohr, Ellen A.; Ong, Ken K.; Oostra, Ben A.; Palmer, Colin N.A.; Palotie, Aarno; Peden, John F.; Pedersen, Nancy; Peters, Annette; Polasek, Ozren; Pouta, Anneli; Pramstaller, Peter P.; Prokopenko, Inga; Pu¨tter, Carolin; Radhakrishnan, Aparna; Raitakari, Olli; Rendon, Augusto; Rivadeneira, Fernando; Rudan, Igor; Saaristo, Timo E.; Sambrook, Jennifer G.; Sanders, Alan R.; Sanna, Serena; Saramies, Jouko; Schipf, Sabine; Schreiber, Stefan; Schunkert, Heribert; Shin, So Youn; Signorini, Stefano; Sinisalo, Juha; Skrobek, Boris; Soranzo, Nicole; Stanca´kova´, Alena; Stark, Klaus; Stephens, Jonathan C.; Stirrups, Kathleen; Stolk, Ronald P.; Stumvoll, Michael; Swift, Amy J.; Theodoraki, Eirini V.; Thorand, Barbara; Tregouet, David Alexandre; Tremoli, Elena; Klauw, Melanie M.Van der; Meurs, Joyce B.J.van; Vermeulen, Sita H.; Viikari, Jorma; Virtamo, Jarmo; Vitart, Veronique; Waeber, Ge´rard; Wang, Zhaoming; Wide´n, Elisabeth; Wild, Sarah H.; Willemsen, Gonneke; Winkelmann, Bernhard R.; Witteman, Jacqueline C.M.; Wolffenbuttel, Bruce H.R.; Wong, Andrew; Wright, Alan F.; Zillikens, M. Carola; Amouyel, Philippe; Boehm, Bernhard O.; Boerwinkle, Eric; Boomsma, Dorret I.; Caulfield, Mark J.; Chanock, Stephen J.; Cupples, L. Adrienne; Cusi, Daniele; Dedoussis, George V.; Erdmann, Jeanette; Eriksson, Johan G.; Franks, Paul W.; Froguel, Philippe; Gieger, Christian; Gyllensten, Ulf; Hamsten, Anders; Harris, Tamara B.; Hengstenberg, Christian; Hicks, Andrew A.; Hingorani, Aroon; Hinney, Anke; Hofman, Albert; Hovingh, Kees G.; Hveem, Kristian; Illig, Thomas; Jarvelin, Marjo Riitta; Jo¨ckel, Karl Heinz; Keinanen-Kiukaanniemi, Sirkka M.; Kiemeney, Lambertus A.; Kuh, Diana; Laakso, Markku; Lehtima¨ki, Terho; Levinson, Douglas F.; Martin, Nicholas G.; Metspalu, Andres; Morris, Andrew D.; Nieminen, Markku S.; Njølstad, Inger; Ohlsson, Claes; Oldehinkel, Albertine J.; Ouwehand, Willem H.; Palmer, Lyle J.; Penninx, Brenda; Power, Chris; Province, Michael A.; Psaty, Bruce M.; Qi, Lu; Rauramaa, Rainer; Ridker, Paul M.; Ripatti, Samuli; Salomaa, Veikko; Samani, Nilesh J.; Snieder, Harold; Sørensen, Thorkild I.A.; Spector, Timothy D.; Stefansson, Kari; To¨njes, Anke; Tuomilehto, Jaakko; Uitterlinden, Andre´ G.; Uusitupa, Matti; Harst, Pim van der; Vollenweider, Peter; Wallaschofski, Henri; Wareham, Nicholas J.; Watkins, Hugh; Wichmann, H. Erich; Wilson, James F.; Abecasis, Goncalo R.; Assimes, Themistocles L.; Barroso, Ineˆs; Boehnke, Michael; Borecki, Ingrid B.; Deloukas, Panos; Fox, Caroline S.; Frayling, Timothy; Groop, Leif C.; Haritunian, Talin; Kaplan, Robert C.; Hunter, David; Kaplan, Robert C.; Karpe,MiriamMoffatt, Fredrik; Mohlke, Karen L.; O’Connell, Jeffrey R.; Pawitan, Yudi; Schadt, Eric E.; Schlessinger, David; Steinthorsdottir, Valgerdur; Strachan, David P.; Thorsteinsdottir, Unnur; Duijn, Cornelia M.van; Visscher, Peter M.; Blasio, Anna Maria Di; Hirschhorn, Joel N.; Lindgren, Cecilia M.; Morris, Andrew P.; Meyre, David; Scherag, Andre´; McCarthy, Mark I.; Speliotes, Elizabeth K.; North, Kari E.; Loos, Ruth J.F.; Ingelsson, Erik.

In: American Journal of Human Genetics, Vol. 93, No. 2, 08.08.2013, p. 236-248.

Research output: Contribution to journalArticle

Hu, YJ, Berndt, SI, Gustafsson, S, Ganna, A, Hirschhorn, J, North, KE, Ingelsson, E, Lin, DY, Collins, FS, Berndt, SI, Gustafsson, S, Ma¨gi, R, Ganna, A, Wheeler, E, Feitosa, MF, Justice, AE, Monda, KL, Croteau-Chonka, DC, Day, FR, Esko, T, Fall, T, Ferreira, T, Gentilini, D, Jackson, AU, Luan, J, Randall, JC, Vedantam, S, Willer, CJ, Winkler, TW, Wood, AR, Workalemahu, T, Hu, YJ, Lee, SH, Liang, L, Lin, DY, Min, JL, Neale, BM, Thorleifsson, G, Yang, J, Albrecht, E, Amin, N, Bragg-Gresham, JL, Cadby, G, Heijer, MD, Eklund, N, Fischer, K, Goel, A, Hottenga, JJ, Huffman, JE, Jarick, I, Johansson, A, Johnson, T, Kanoni, S, Kleber, ME, Ko¨nig, IR, Kristiansson, K, Kutalik, Z, Lamina, C, Lecoeur, C, Li, G, Mangino, M, McArdle, WL, Medina-Gomez, C, Mu¨ller-Nurasyid, M, Ngwa, JS, Nolte, IM, Paternoster, L, Pechlivanis, S, Perola, M, Peters, MJ, Preuss, M, Rose, LM, Shi, J, Shungin, D, Smith, AV, Strawbridge, RJ, Surakka, I, Teumer, A, Trip, MD, Tyrer, J, Vliet-Ostaptchouk, JVV, Vandenput, L, Waite, LL, Zhao, JH, Absher, D, Asselbergs, FW, Atalay, M, Attwood, AP, Balmforth, AJ, Basart, H, Beilby, J, Bonnycastle, LL, Brambilla, P, Bruinenberg, M, Campbell, H, Chasman, DI, Chines, PS, Collins, FS, Connell, JM, Cookson, W, Faire, UD, Vegt, FD, Dei, M, Dimitriou, M, Edkins, S, Estrada, K, Evans, DM, Farrall, M, Ferrario, MM, Ferrie`res, J, Franke, L, Frau, F, Gejman, PV, Grallert, H, Gro¨nberg, H, Gudnason, V, Hall, AS, Hall, P, Hartikainen, AL, Hayward, C, Heard-Costa, NL, Heath, AC, Hebebrand, J, Homuth, G, Hu, FB, Hunt, SE, Hyppo¨nen, E, Iribarren, C, Jacobs, KB, Jansson, JO, Jula, A, Ka¨ho¨nen, M, Kathiresan, S, Kee, F, Khaw, KT, Kivimaki, M, Koenig, W, Kraja, AT, Kumari, M, Kuulasmaa, K, Kuusisto, J, Laitinen, JH, Lakka, TA, Langenberg, C, Launer, LJ, Lind, L, Lindstro¨m, J, Liu, J, Liuzzi, A, Lokki, ML, Lorentzon, M, Magnusson, PAM, Magnusson, PAM, Manunta, P, Marek, D, Ma¨rz, W, Leach, IM, McKnight, B, Medland, SE, Mihailov, E, Milani, L, Montgomery, GW, Mooser, V, Mu¨hleisen, TW, Munroe, PB, Musk, AW, Narisu, N, Navis, G, Nicholson, G, Nohr, EA, Ong, KK, Oostra, BA, Palmer, CNA, Palotie, A, Peden, JF, Pedersen, N, Peters, A, Polasek, O, Pouta, A, Pramstaller, PP, Prokopenko, I, Pu¨tter, C, Radhakrishnan, A, Raitakari, O, Rendon, A, Rivadeneira, F, Rudan, I, Saaristo, TE, Sambrook, JG, Sanders, AR, Sanna, S, Saramies, J, Schipf, S, Schreiber, S, Schunkert, H, Shin, SY, Signorini, S, Sinisalo, J, Skrobek, B, Soranzo, N, Stanca´kova´, A, Stark, K, Stephens, JC, Stirrups, K, Stolk, RP, Stumvoll, M, Swift, AJ, Theodoraki, EV, Thorand, B, Tregouet, DA, Tremoli, E, Klauw, MMVD, Meurs, JBJV, Vermeulen, SH, Viikari, J, Virtamo, J, Vitart, V, Waeber, G, Wang, Z, Wide´n, E, Wild, SH, Willemsen, G, Winkelmann, BR, Witteman, JCM, Wolffenbuttel, BHR, Wong, A, Wright, AF, Zillikens, MC, Amouyel, P, Boehm, BO, Boerwinkle, E, Boomsma, DI, Caulfield, MJ, Chanock, SJ, Cupples, LA, Cusi, D, Dedoussis, GV, Erdmann, J, Eriksson, JG, Franks, PW, Froguel, P, Gieger, C, Gyllensten, U, Hamsten, A, Harris, TB, Hengstenberg, C, Hicks, AA, Hingorani, A, Hinney, A, Hofman, A, Hovingh, KG, Hveem, K, Illig, T, Jarvelin, MR, Jo¨ckel, KH, Keinanen-Kiukaanniemi, SM, Kiemeney, LA, Kuh, D, Laakso, M, Lehtima¨ki, T, Levinson, DF, Martin, NG, Metspalu, A, Morris, AD, Nieminen, MS, Njølstad, I, Ohlsson, C, Oldehinkel, AJ, Ouwehand, WH, Palmer, LJ, Penninx, B, Power, C, Province, MA, Psaty, BM, Qi, L, Rauramaa, R, Ridker, PM, Ripatti, S, Salomaa, V, Samani, NJ, Snieder, H, Sørensen, TIA, Spector, TD, Stefansson, K, To¨njes, A, Tuomilehto, J, Uitterlinden, AG, Uusitupa, M, Harst, PVD, Vollenweider, P, Wallaschofski, H, Wareham, NJ, Watkins, H, Wichmann, HE, Wilson, JF, Abecasis, GR, Assimes, TL, Barroso, I, Boehnke, M, Borecki, IB, Deloukas, P, Fox, CS, Frayling, T, Groop, LC, Haritunian, T, Kaplan, RC, Hunter, D, Kaplan, RC, Karpe,MiriamMoffatt, F, Mohlke, KL, O’Connell, JR, Pawitan, Y, Schadt, EE, Schlessinger, D, Steinthorsdottir, V, Strachan, DP, Thorsteinsdottir, U, Duijn, CMV, Visscher, PM, Blasio, AMD, Hirschhorn, JN, Lindgren, CM, Morris, AP, Meyre, D, Scherag, A, McCarthy, MI, Speliotes, EK, North, KE, Loos, RJF & Ingelsson, E 2013, 'Meta-analysis of gene-level associations for rare variants based on single-variant statistics', American Journal of Human Genetics, vol. 93, no. 2, pp. 236-248. https://doi.org/10.1016/j.ajhg.2013.06.011
Hu, Yi Juan ; Berndt, Sonja I. ; Gustafsson, Stefan ; Ganna, Andrea ; Hirschhorn, Joel ; North, Kari E. ; Ingelsson, Erik ; Lin, Dan Yu ; Collins, Francis S. ; Berndt, Sonja I. ; Gustafsson, Stefan ; Ma¨gi, Reedik ; Ganna, Andrea ; Wheeler, Eleanor ; Feitosa, Mary F. ; Justice, Anne E. ; Monda, Keri L. ; Croteau-Chonka, Damien C. ; Day, Felix R. ; Esko, To˜nu ; Fall, Tove ; Ferreira, Teresa ; Gentilini, Davide ; Jackson, Anne U. ; Luan, Jian’an ; Randall, Joshua C. ; Vedantam, Sailaja ; Willer, Cristen J. ; Winkler, Thomas W. ; Wood, Andrew R. ; Workalemahu, Tsegaselassie ; Hu, Yi Juan ; Lee, Sang Hong ; Liang, Liming ; Lin, Dan Yu ; Min, Josine L. ; Neale, Benjamin M. ; Thorleifsson, Gudmar ; Yang, Jian ; Albrecht, Eva ; Amin, Najaf ; Bragg-Gresham, Jennifer L. ; Cadby, Gemma ; Heijer, Martin den ; Eklund, Niina ; Fischer, Krista ; Goel, Anuj ; Hottenga, Jouke Jan ; Huffman, Jennifer E. ; Jarick, Ivonne ; Johansson, Asa ; Johnson, Toby ; Kanoni, Stavroula ; Kleber, Marcus E. ; Ko¨nig, Inke R. ; Kristiansson, Kati ; Kutalik, Zolta´n ; Lamina, Claudia ; Lecoeur, Cecile ; Li, Guo ; Mangino, Massimo ; McArdle, Wendy L. ; Medina-Gomez, Carolina ; Mu¨ller-Nurasyid, Martina ; Ngwa, Julius S. ; Nolte, Ilja M. ; Paternoster, Lavinia ; Pechlivanis, Sonali ; Perola, Markus ; Peters, Marjolein J. ; Preuss, Michael ; Rose, Lynda M. ; Shi, Jianxin ; Shungin, Dmitry ; Smith, Albert Vernon ; Strawbridge, Rona J. ; Surakka, Ida ; Teumer, Alexander ; Trip, Mieke D. ; Tyrer, Jonathan ; Vliet-Ostaptchouk, Jana V.Van ; Vandenput, Liesbeth ; Waite, Lindsay L. ; Zhao, Jing Hua ; Absher, Devin ; Asselbergs, Folkert W. ; Atalay, Mustafa ; Attwood, Antony P. ; Balmforth, Anthony J. ; Basart, Hanneke ; Beilby, John ; Bonnycastle, Lori L. ; Brambilla, Paolo ; Bruinenberg, Marcel ; Campbell, Harry ; Chasman, Daniel I. ; Chines, Peter S. ; Collins, Francis S. ; Connell, John M. ; Cookson, William ; Faire, Ulf de ; Vegt, Femmie de ; Dei, Mariano ; Dimitriou, Maria ; Edkins, Sarah ; Estrada, Karol ; Evans, David M. ; Farrall, Martin ; Ferrario, Marco M. ; Ferrie`res, Jean ; Franke, Lude ; Frau, Francesca ; Gejman, Pablo V. ; Grallert, Harald ; Gro¨nberg, Henrik ; Gudnason, Vilmundur ; Hall, Alistair S. ; Hall, Per ; Hartikainen, Anna Liisa ; Hayward, Caroline ; Heard-Costa, Nancy L. ; Heath, Andrew C. ; Hebebrand, Johannes ; Homuth, Georg ; Hu, Frank B. ; Hunt, Sarah E. ; Hyppo¨nen, Elina ; Iribarren, Carlos ; Jacobs, Kevin B. ; Jansson, John Olov ; Jula, Antti ; Ka¨ho¨nen, Mika ; Kathiresan, Sekar ; Kee, Frank ; Khaw, Kay Tee ; Kivimaki, Mika ; Koenig, Wolfgang ; Kraja, Aldi T. ; Kumari, Meena ; Kuulasmaa, Kari ; Kuusisto, Johanna ; Laitinen, Jaana H. ; Lakka, Timo A. ; Langenberg, Claudia ; Launer, Lenore J. ; Lind, Lars ; Lindstro¨m, Jaana ; Liu, Jianjun ; Liuzzi, Antonio ; Lokki, Marja Liisa ; Lorentzon, Mattias ; Magnusson, Pamela A.Madden ; Magnusson, P. A.M. ; Manunta, Paolo ; Marek, Diana ; Ma¨rz, Winfried ; Leach, Irene Mateo ; McKnight, Barbara ; Medland, Sarah E. ; Mihailov, Evelin ; Milani, Lili ; Montgomery, Grant W. ; Mooser, Vincent ; Mu¨hleisen, Thomas W. ; Munroe, Patricia B. ; Musk, Arthur W. ; Narisu, Narisu ; Navis, Gerjan ; Nicholson, George ; Nohr, Ellen A. ; Ong, Ken K. ; Oostra, Ben A. ; Palmer, Colin N.A. ; Palotie, Aarno ; Peden, John F. ; Pedersen, Nancy ; Peters, Annette ; Polasek, Ozren ; Pouta, Anneli ; Pramstaller, Peter P. ; Prokopenko, Inga ; Pu¨tter, Carolin ; Radhakrishnan, Aparna ; Raitakari, Olli ; Rendon, Augusto ; Rivadeneira, Fernando ; Rudan, Igor ; Saaristo, Timo E. ; Sambrook, Jennifer G. ; Sanders, Alan R. ; Sanna, Serena ; Saramies, Jouko ; Schipf, Sabine ; Schreiber, Stefan ; Schunkert, Heribert ; Shin, So Youn ; Signorini, Stefano ; Sinisalo, Juha ; Skrobek, Boris ; Soranzo, Nicole ; Stanca´kova´, Alena ; Stark, Klaus ; Stephens, Jonathan C. ; Stirrups, Kathleen ; Stolk, Ronald P. ; Stumvoll, Michael ; Swift, Amy J. ; Theodoraki, Eirini V. ; Thorand, Barbara ; Tregouet, David Alexandre ; Tremoli, Elena ; Klauw, Melanie M.Van der ; Meurs, Joyce B.J.van ; Vermeulen, Sita H. ; Viikari, Jorma ; Virtamo, Jarmo ; Vitart, Veronique ; Waeber, Ge´rard ; Wang, Zhaoming ; Wide´n, Elisabeth ; Wild, Sarah H. ; Willemsen, Gonneke ; Winkelmann, Bernhard R. ; Witteman, Jacqueline C.M. ; Wolffenbuttel, Bruce H.R. ; Wong, Andrew ; Wright, Alan F. ; Zillikens, M. Carola ; Amouyel, Philippe ; Boehm, Bernhard O. ; Boerwinkle, Eric ; Boomsma, Dorret I. ; Caulfield, Mark J. ; Chanock, Stephen J. ; Cupples, L. Adrienne ; Cusi, Daniele ; Dedoussis, George V. ; Erdmann, Jeanette ; Eriksson, Johan G. ; Franks, Paul W. ; Froguel, Philippe ; Gieger, Christian ; Gyllensten, Ulf ; Hamsten, Anders ; Harris, Tamara B. ; Hengstenberg, Christian ; Hicks, Andrew A. ; Hingorani, Aroon ; Hinney, Anke ; Hofman, Albert ; Hovingh, Kees G. ; Hveem, Kristian ; Illig, Thomas ; Jarvelin, Marjo Riitta ; Jo¨ckel, Karl Heinz ; Keinanen-Kiukaanniemi, Sirkka M. ; Kiemeney, Lambertus A. ; Kuh, Diana ; Laakso, Markku ; Lehtima¨ki, Terho ; Levinson, Douglas F. ; Martin, Nicholas G. ; Metspalu, Andres ; Morris, Andrew D. ; Nieminen, Markku S. ; Njølstad, Inger ; Ohlsson, Claes ; Oldehinkel, Albertine J. ; Ouwehand, Willem H. ; Palmer, Lyle J. ; Penninx, Brenda ; Power, Chris ; Province, Michael A. ; Psaty, Bruce M. ; Qi, Lu ; Rauramaa, Rainer ; Ridker, Paul M. ; Ripatti, Samuli ; Salomaa, Veikko ; Samani, Nilesh J. ; Snieder, Harold ; Sørensen, Thorkild I.A. ; Spector, Timothy D. ; Stefansson, Kari ; To¨njes, Anke ; Tuomilehto, Jaakko ; Uitterlinden, Andre´ G. ; Uusitupa, Matti ; Harst, Pim van der ; Vollenweider, Peter ; Wallaschofski, Henri ; Wareham, Nicholas J. ; Watkins, Hugh ; Wichmann, H. Erich ; Wilson, James F. ; Abecasis, Goncalo R. ; Assimes, Themistocles L. ; Barroso, Ineˆs ; Boehnke, Michael ; Borecki, Ingrid B. ; Deloukas, Panos ; Fox, Caroline S. ; Frayling, Timothy ; Groop, Leif C. ; Haritunian, Talin ; Kaplan, Robert C. ; Hunter, David ; Kaplan, Robert C. ; Karpe,MiriamMoffatt, Fredrik ; Mohlke, Karen L. ; O’Connell, Jeffrey R. ; Pawitan, Yudi ; Schadt, Eric E. ; Schlessinger, David ; Steinthorsdottir, Valgerdur ; Strachan, David P. ; Thorsteinsdottir, Unnur ; Duijn, Cornelia M.van ; Visscher, Peter M. ; Blasio, Anna Maria Di ; Hirschhorn, Joel N. ; Lindgren, Cecilia M. ; Morris, Andrew P. ; Meyre, David ; Scherag, Andre´ ; McCarthy, Mark I. ; Speliotes, Elizabeth K. ; North, Kari E. ; Loos, Ruth J.F. ; Ingelsson, Erik. / Meta-analysis of gene-level associations for rare variants based on single-variant statistics. In: American Journal of Human Genetics. 2013 ; Vol. 93, No. 2. pp. 236-248.
@article{a20e350a16624b829c4570fbd96a847b,
title = "Meta-analysis of gene-level associations for rare variants based on single-variant statistics",
abstract = "Meta-analysis of genome-wide association studies (GWASs) has led to the discoveries of many common variants associated with complex human diseases. There is a growing recognition that identifying {"}causal{"} rare variants also requires large-scale meta-analysis. The fact that association tests with rare variants are performed at the gene level rather than at the variant level poses unprecedented challenges in the meta-analysis. First, different studies may adopt different gene-level tests, so the results are not compatible. Second, gene-level tests require multivariate statistics (i.e., components of the test statistic and their covariance matrix), which are difficult to obtain. To overcome these challenges, we propose to perform gene-level tests for rare variants by combining the results of single-variant analysis (i.e., p values of association tests and effect estimates) from participating studies. This simple strategy is possible because of an insight that multivariate statistics can be recovered from single-variant statistics, together with the correlation matrix of the single-variant test statistics, which can be estimated from one of the participating studies or from a publicly available database. We show both theoretically and numerically that the proposed meta-analysis approach provides accurate control of the type I error and is as powerful as joint analysis of individual participant data. This approach accommodates any disease phenotype and any study design and produces all commonly used gene-level tests. An application to the GWAS summary results of the Genetic Investigation of ANthropometric Traits (GIANT) consortium reveals rare and low-frequency variants associated with human height. The relevant software is freely available.",
author = "Hu, {Yi Juan} and Berndt, {Sonja I.} and Stefan Gustafsson and Andrea Ganna and Joel Hirschhorn and North, {Kari E.} and Erik Ingelsson and Lin, {Dan Yu} and Collins, {Francis S.} and Berndt, {Sonja I.} and Stefan Gustafsson and Reedik Ma¨gi and Andrea Ganna and Eleanor Wheeler and Feitosa, {Mary F.} and Justice, {Anne E.} and Monda, {Keri L.} and Croteau-Chonka, {Damien C.} and Day, {Felix R.} and To˜nu Esko and Tove Fall and Teresa Ferreira and Davide Gentilini and Jackson, {Anne U.} and Jian’an Luan and Randall, {Joshua C.} and Sailaja Vedantam and Willer, {Cristen J.} and Winkler, {Thomas W.} and Wood, {Andrew R.} and Tsegaselassie Workalemahu and Hu, {Yi Juan} and Lee, {Sang Hong} and Liming Liang and Lin, {Dan Yu} and Min, {Josine L.} and Neale, {Benjamin M.} and Gudmar Thorleifsson and Jian Yang and Eva Albrecht and Najaf Amin and Bragg-Gresham, {Jennifer L.} and Gemma Cadby and Heijer, {Martin den} and Niina Eklund and Krista Fischer and Anuj Goel and Hottenga, {Jouke Jan} and Huffman, {Jennifer E.} and Ivonne Jarick and Asa Johansson and Toby Johnson and Stavroula Kanoni and Kleber, {Marcus E.} and Ko¨nig, {Inke R.} and Kati Kristiansson and Zolta´n Kutalik and Claudia Lamina and Cecile Lecoeur and Guo Li and Massimo Mangino and McArdle, {Wendy L.} and Carolina Medina-Gomez and Martina Mu¨ller-Nurasyid and Ngwa, {Julius S.} and Nolte, {Ilja M.} and Lavinia Paternoster and Sonali Pechlivanis and Markus Perola and Peters, {Marjolein J.} and Michael Preuss and Rose, {Lynda M.} and Jianxin Shi and Dmitry Shungin and Smith, {Albert Vernon} and Strawbridge, {Rona J.} and Ida Surakka and Alexander Teumer and Trip, {Mieke D.} and Jonathan Tyrer and Vliet-Ostaptchouk, {Jana V.Van} and Liesbeth Vandenput and Waite, {Lindsay L.} and Zhao, {Jing Hua} and Devin Absher and Asselbergs, {Folkert W.} and Mustafa Atalay and Attwood, {Antony P.} and Balmforth, {Anthony J.} and Hanneke Basart and John Beilby and Bonnycastle, {Lori L.} and Paolo Brambilla and Marcel Bruinenberg and Harry Campbell and Chasman, {Daniel I.} and Chines, {Peter S.} and Collins, {Francis S.} and Connell, {John M.} and William Cookson and Faire, {Ulf de} and Vegt, {Femmie de} and Mariano Dei and Maria Dimitriou and Sarah Edkins and Karol Estrada and Evans, {David M.} and Martin Farrall and Ferrario, {Marco M.} and Jean Ferrie`res and Lude Franke and Francesca Frau and Gejman, {Pablo V.} and Harald Grallert and Henrik Gro¨nberg and Vilmundur Gudnason and Hall, {Alistair S.} and Per Hall and Hartikainen, {Anna Liisa} and Caroline Hayward and Heard-Costa, {Nancy L.} and Heath, {Andrew C.} and Johannes Hebebrand and Georg Homuth and Hu, {Frank B.} and Hunt, {Sarah E.} and Elina Hyppo¨nen and Carlos Iribarren and Jacobs, {Kevin B.} and Jansson, {John Olov} and Antti Jula and Mika Ka¨ho¨nen and Sekar Kathiresan and Frank Kee and Khaw, {Kay Tee} and Mika Kivimaki and Wolfgang Koenig and Kraja, {Aldi T.} and Meena Kumari and Kari Kuulasmaa and Johanna Kuusisto and Laitinen, {Jaana H.} and Lakka, {Timo A.} and Claudia Langenberg and Launer, {Lenore J.} and Lars Lind and Jaana Lindstro¨m and Jianjun Liu and Antonio Liuzzi and Lokki, {Marja Liisa} and Mattias Lorentzon and Magnusson, {Pamela A.Madden} and Magnusson, {P. A.M.} and Paolo Manunta and Diana Marek and Winfried Ma¨rz and Leach, {Irene Mateo} and Barbara McKnight and Medland, {Sarah E.} and Evelin Mihailov and Lili Milani and Montgomery, {Grant W.} and Vincent Mooser and Mu¨hleisen, {Thomas W.} and Munroe, {Patricia B.} and Musk, {Arthur W.} and Narisu Narisu and Gerjan Navis and George Nicholson and Nohr, {Ellen A.} and Ong, {Ken K.} and Oostra, {Ben A.} and Palmer, {Colin N.A.} and Aarno Palotie and Peden, {John F.} and Nancy Pedersen and Annette Peters and Ozren Polasek and Anneli Pouta and Pramstaller, {Peter P.} and Inga Prokopenko and Carolin Pu¨tter and Aparna Radhakrishnan and Olli Raitakari and Augusto Rendon and Fernando Rivadeneira and Igor Rudan and Saaristo, {Timo E.} and Sambrook, {Jennifer G.} and Sanders, {Alan R.} and Serena Sanna and Jouko Saramies and Sabine Schipf and Stefan Schreiber and Heribert Schunkert and Shin, {So Youn} and Stefano Signorini and Juha Sinisalo and Boris Skrobek and Nicole Soranzo and Alena Stanca´kova´ and Klaus Stark and Stephens, {Jonathan C.} and Kathleen Stirrups and Stolk, {Ronald P.} and Michael Stumvoll and Swift, {Amy J.} and Theodoraki, {Eirini V.} and Barbara Thorand and Tregouet, {David Alexandre} and Elena Tremoli and Klauw, {Melanie M.Van der} and Meurs, {Joyce B.J.van} and Vermeulen, {Sita H.} and Jorma Viikari and Jarmo Virtamo and Veronique Vitart and Ge´rard Waeber and Zhaoming Wang and Elisabeth Wide´n and Wild, {Sarah H.} and Gonneke Willemsen and Winkelmann, {Bernhard R.} and Witteman, {Jacqueline C.M.} and Wolffenbuttel, {Bruce H.R.} and Andrew Wong and Wright, {Alan F.} and Zillikens, {M. Carola} and Philippe Amouyel and Boehm, {Bernhard O.} and Eric Boerwinkle and Boomsma, {Dorret I.} and Caulfield, {Mark J.} and Chanock, {Stephen J.} and Cupples, {L. Adrienne} and Daniele Cusi and Dedoussis, {George V.} and Jeanette Erdmann and Eriksson, {Johan G.} and Franks, {Paul W.} and Philippe Froguel and Christian Gieger and Ulf Gyllensten and Anders Hamsten and Harris, {Tamara B.} and Christian Hengstenberg and Hicks, {Andrew A.} and Aroon Hingorani and Anke Hinney and Albert Hofman and Hovingh, {Kees G.} and Kristian Hveem and Thomas Illig and Jarvelin, {Marjo Riitta} and Jo¨ckel, {Karl Heinz} and Keinanen-Kiukaanniemi, {Sirkka M.} and Kiemeney, {Lambertus A.} and Diana Kuh and Markku Laakso and Terho Lehtima¨ki and Levinson, {Douglas F.} and Martin, {Nicholas G.} and Andres Metspalu and Morris, {Andrew D.} and Nieminen, {Markku S.} and Inger Nj{\o}lstad and Claes Ohlsson and Oldehinkel, {Albertine J.} and Ouwehand, {Willem H.} and Palmer, {Lyle J.} and Brenda Penninx and Chris Power and Province, {Michael A.} and Psaty, {Bruce M.} and Lu Qi and Rainer Rauramaa and Ridker, {Paul M.} and Samuli Ripatti and Veikko Salomaa and Samani, {Nilesh J.} and Harold Snieder and S{\o}rensen, {Thorkild I.A.} and Spector, {Timothy D.} and Kari Stefansson and Anke To¨njes and Jaakko Tuomilehto and Uitterlinden, {Andre´ G.} and Matti Uusitupa and Harst, {Pim van der} and Peter Vollenweider and Henri Wallaschofski and Wareham, {Nicholas J.} and Hugh Watkins and Wichmann, {H. Erich} and Wilson, {James F.} and Abecasis, {Goncalo R.} and Assimes, {Themistocles L.} and Ineˆs Barroso and Michael Boehnke and Borecki, {Ingrid B.} and Panos Deloukas and Fox, {Caroline S.} and Timothy Frayling and Groop, {Leif C.} and Talin Haritunian and Kaplan, {Robert C.} and David Hunter and Kaplan, {Robert C.} and Fredrik Karpe,MiriamMoffatt and Mohlke, {Karen L.} and O’Connell, {Jeffrey R.} and Yudi Pawitan and Schadt, {Eric E.} and David Schlessinger and Valgerdur Steinthorsdottir and Strachan, {David P.} and Unnur Thorsteinsdottir and Duijn, {Cornelia M.van} and Visscher, {Peter M.} and Blasio, {Anna Maria Di} and Hirschhorn, {Joel N.} and Lindgren, {Cecilia M.} and Morris, {Andrew P.} and David Meyre and Andre´ Scherag and McCarthy, {Mark I.} and Speliotes, {Elizabeth K.} and North, {Kari E.} and Loos, {Ruth J.F.} and Erik Ingelsson",
year = "2013",
month = "8",
day = "8",
doi = "10.1016/j.ajhg.2013.06.011",
language = "English (US)",
volume = "93",
pages = "236--248",
journal = "American Journal of Human Genetics",
issn = "0002-9297",
publisher = "Cell Press",
number = "2",

}

TY - JOUR

T1 - Meta-analysis of gene-level associations for rare variants based on single-variant statistics

AU - Hu, Yi Juan

AU - Berndt, Sonja I.

AU - Gustafsson, Stefan

AU - Ganna, Andrea

AU - Hirschhorn, Joel

AU - North, Kari E.

AU - Ingelsson, Erik

AU - Lin, Dan Yu

AU - Collins, Francis S.

AU - Berndt, Sonja I.

AU - Gustafsson, Stefan

AU - Ma¨gi, Reedik

AU - Ganna, Andrea

AU - Wheeler, Eleanor

AU - Feitosa, Mary F.

AU - Justice, Anne E.

AU - Monda, Keri L.

AU - Croteau-Chonka, Damien C.

AU - Day, Felix R.

AU - Esko, To˜nu

AU - Fall, Tove

AU - Ferreira, Teresa

AU - Gentilini, Davide

AU - Jackson, Anne U.

AU - Luan, Jian’an

AU - Randall, Joshua C.

AU - Vedantam, Sailaja

AU - Willer, Cristen J.

AU - Winkler, Thomas W.

AU - Wood, Andrew R.

AU - Workalemahu, Tsegaselassie

AU - Hu, Yi Juan

AU - Lee, Sang Hong

AU - Liang, Liming

AU - Lin, Dan Yu

AU - Min, Josine L.

AU - Neale, Benjamin M.

AU - Thorleifsson, Gudmar

AU - Yang, Jian

AU - Albrecht, Eva

AU - Amin, Najaf

AU - Bragg-Gresham, Jennifer L.

AU - Cadby, Gemma

AU - Heijer, Martin den

AU - Eklund, Niina

AU - Fischer, Krista

AU - Goel, Anuj

AU - Hottenga, Jouke Jan

AU - Huffman, Jennifer E.

AU - Jarick, Ivonne

AU - Johansson, Asa

AU - Johnson, Toby

AU - Kanoni, Stavroula

AU - Kleber, Marcus E.

AU - Ko¨nig, Inke R.

AU - Kristiansson, Kati

AU - Kutalik, Zolta´n

AU - Lamina, Claudia

AU - Lecoeur, Cecile

AU - Li, Guo

AU - Mangino, Massimo

AU - McArdle, Wendy L.

AU - Medina-Gomez, Carolina

AU - Mu¨ller-Nurasyid, Martina

AU - Ngwa, Julius S.

AU - Nolte, Ilja M.

AU - Paternoster, Lavinia

AU - Pechlivanis, Sonali

AU - Perola, Markus

AU - Peters, Marjolein J.

AU - Preuss, Michael

AU - Rose, Lynda M.

AU - Shi, Jianxin

AU - Shungin, Dmitry

AU - Smith, Albert Vernon

AU - Strawbridge, Rona J.

AU - Surakka, Ida

AU - Teumer, Alexander

AU - Trip, Mieke D.

AU - Tyrer, Jonathan

AU - Vliet-Ostaptchouk, Jana V.Van

AU - Vandenput, Liesbeth

AU - Waite, Lindsay L.

AU - Zhao, Jing Hua

AU - Absher, Devin

AU - Asselbergs, Folkert W.

AU - Atalay, Mustafa

AU - Attwood, Antony P.

AU - Balmforth, Anthony J.

AU - Basart, Hanneke

AU - Beilby, John

AU - Bonnycastle, Lori L.

AU - Brambilla, Paolo

AU - Bruinenberg, Marcel

AU - Campbell, Harry

AU - Chasman, Daniel I.

AU - Chines, Peter S.

AU - Collins, Francis S.

AU - Connell, John M.

AU - Cookson, William

AU - Faire, Ulf de

AU - Vegt, Femmie de

AU - Dei, Mariano

AU - Dimitriou, Maria

AU - Edkins, Sarah

AU - Estrada, Karol

AU - Evans, David M.

AU - Farrall, Martin

AU - Ferrario, Marco M.

AU - Ferrie`res, Jean

AU - Franke, Lude

AU - Frau, Francesca

AU - Gejman, Pablo V.

AU - Grallert, Harald

AU - Gro¨nberg, Henrik

AU - Gudnason, Vilmundur

AU - Hall, Alistair S.

AU - Hall, Per

AU - Hartikainen, Anna Liisa

AU - Hayward, Caroline

AU - Heard-Costa, Nancy L.

AU - Heath, Andrew C.

AU - Hebebrand, Johannes

AU - Homuth, Georg

AU - Hu, Frank B.

AU - Hunt, Sarah E.

AU - Hyppo¨nen, Elina

AU - Iribarren, Carlos

AU - Jacobs, Kevin B.

AU - Jansson, John Olov

AU - Jula, Antti

AU - Ka¨ho¨nen, Mika

AU - Kathiresan, Sekar

AU - Kee, Frank

AU - Khaw, Kay Tee

AU - Kivimaki, Mika

AU - Koenig, Wolfgang

AU - Kraja, Aldi T.

AU - Kumari, Meena

AU - Kuulasmaa, Kari

AU - Kuusisto, Johanna

AU - Laitinen, Jaana H.

AU - Lakka, Timo A.

AU - Langenberg, Claudia

AU - Launer, Lenore J.

AU - Lind, Lars

AU - Lindstro¨m, Jaana

AU - Liu, Jianjun

AU - Liuzzi, Antonio

AU - Lokki, Marja Liisa

AU - Lorentzon, Mattias

AU - Magnusson, Pamela A.Madden

AU - Magnusson, P. A.M.

AU - Manunta, Paolo

AU - Marek, Diana

AU - Ma¨rz, Winfried

AU - Leach, Irene Mateo

AU - McKnight, Barbara

AU - Medland, Sarah E.

AU - Mihailov, Evelin

AU - Milani, Lili

AU - Montgomery, Grant W.

AU - Mooser, Vincent

AU - Mu¨hleisen, Thomas W.

AU - Munroe, Patricia B.

AU - Musk, Arthur W.

AU - Narisu, Narisu

AU - Navis, Gerjan

AU - Nicholson, George

AU - Nohr, Ellen A.

AU - Ong, Ken K.

AU - Oostra, Ben A.

AU - Palmer, Colin N.A.

AU - Palotie, Aarno

AU - Peden, John F.

AU - Pedersen, Nancy

AU - Peters, Annette

AU - Polasek, Ozren

AU - Pouta, Anneli

AU - Pramstaller, Peter P.

AU - Prokopenko, Inga

AU - Pu¨tter, Carolin

AU - Radhakrishnan, Aparna

AU - Raitakari, Olli

AU - Rendon, Augusto

AU - Rivadeneira, Fernando

AU - Rudan, Igor

AU - Saaristo, Timo E.

AU - Sambrook, Jennifer G.

AU - Sanders, Alan R.

AU - Sanna, Serena

AU - Saramies, Jouko

AU - Schipf, Sabine

AU - Schreiber, Stefan

AU - Schunkert, Heribert

AU - Shin, So Youn

AU - Signorini, Stefano

AU - Sinisalo, Juha

AU - Skrobek, Boris

AU - Soranzo, Nicole

AU - Stanca´kova´, Alena

AU - Stark, Klaus

AU - Stephens, Jonathan C.

AU - Stirrups, Kathleen

AU - Stolk, Ronald P.

AU - Stumvoll, Michael

AU - Swift, Amy J.

AU - Theodoraki, Eirini V.

AU - Thorand, Barbara

AU - Tregouet, David Alexandre

AU - Tremoli, Elena

AU - Klauw, Melanie M.Van der

AU - Meurs, Joyce B.J.van

AU - Vermeulen, Sita H.

AU - Viikari, Jorma

AU - Virtamo, Jarmo

AU - Vitart, Veronique

AU - Waeber, Ge´rard

AU - Wang, Zhaoming

AU - Wide´n, Elisabeth

AU - Wild, Sarah H.

AU - Willemsen, Gonneke

AU - Winkelmann, Bernhard R.

AU - Witteman, Jacqueline C.M.

AU - Wolffenbuttel, Bruce H.R.

AU - Wong, Andrew

AU - Wright, Alan F.

AU - Zillikens, M. Carola

AU - Amouyel, Philippe

AU - Boehm, Bernhard O.

AU - Boerwinkle, Eric

AU - Boomsma, Dorret I.

AU - Caulfield, Mark J.

AU - Chanock, Stephen J.

AU - Cupples, L. Adrienne

AU - Cusi, Daniele

AU - Dedoussis, George V.

AU - Erdmann, Jeanette

AU - Eriksson, Johan G.

AU - Franks, Paul W.

AU - Froguel, Philippe

AU - Gieger, Christian

AU - Gyllensten, Ulf

AU - Hamsten, Anders

AU - Harris, Tamara B.

AU - Hengstenberg, Christian

AU - Hicks, Andrew A.

AU - Hingorani, Aroon

AU - Hinney, Anke

AU - Hofman, Albert

AU - Hovingh, Kees G.

AU - Hveem, Kristian

AU - Illig, Thomas

AU - Jarvelin, Marjo Riitta

AU - Jo¨ckel, Karl Heinz

AU - Keinanen-Kiukaanniemi, Sirkka M.

AU - Kiemeney, Lambertus A.

AU - Kuh, Diana

AU - Laakso, Markku

AU - Lehtima¨ki, Terho

AU - Levinson, Douglas F.

AU - Martin, Nicholas G.

AU - Metspalu, Andres

AU - Morris, Andrew D.

AU - Nieminen, Markku S.

AU - Njølstad, Inger

AU - Ohlsson, Claes

AU - Oldehinkel, Albertine J.

AU - Ouwehand, Willem H.

AU - Palmer, Lyle J.

AU - Penninx, Brenda

AU - Power, Chris

AU - Province, Michael A.

AU - Psaty, Bruce M.

AU - Qi, Lu

AU - Rauramaa, Rainer

AU - Ridker, Paul M.

AU - Ripatti, Samuli

AU - Salomaa, Veikko

AU - Samani, Nilesh J.

AU - Snieder, Harold

AU - Sørensen, Thorkild I.A.

AU - Spector, Timothy D.

AU - Stefansson, Kari

AU - To¨njes, Anke

AU - Tuomilehto, Jaakko

AU - Uitterlinden, Andre´ G.

AU - Uusitupa, Matti

AU - Harst, Pim van der

AU - Vollenweider, Peter

AU - Wallaschofski, Henri

AU - Wareham, Nicholas J.

AU - Watkins, Hugh

AU - Wichmann, H. Erich

AU - Wilson, James F.

AU - Abecasis, Goncalo R.

AU - Assimes, Themistocles L.

AU - Barroso, Ineˆs

AU - Boehnke, Michael

AU - Borecki, Ingrid B.

AU - Deloukas, Panos

AU - Fox, Caroline S.

AU - Frayling, Timothy

AU - Groop, Leif C.

AU - Haritunian, Talin

AU - Kaplan, Robert C.

AU - Hunter, David

AU - Kaplan, Robert C.

AU - Karpe,MiriamMoffatt, Fredrik

AU - Mohlke, Karen L.

AU - O’Connell, Jeffrey R.

AU - Pawitan, Yudi

AU - Schadt, Eric E.

AU - Schlessinger, David

AU - Steinthorsdottir, Valgerdur

AU - Strachan, David P.

AU - Thorsteinsdottir, Unnur

AU - Duijn, Cornelia M.van

AU - Visscher, Peter M.

AU - Blasio, Anna Maria Di

AU - Hirschhorn, Joel N.

AU - Lindgren, Cecilia M.

AU - Morris, Andrew P.

AU - Meyre, David

AU - Scherag, Andre´

AU - McCarthy, Mark I.

AU - Speliotes, Elizabeth K.

AU - North, Kari E.

AU - Loos, Ruth J.F.

AU - Ingelsson, Erik

PY - 2013/8/8

Y1 - 2013/8/8

N2 - Meta-analysis of genome-wide association studies (GWASs) has led to the discoveries of many common variants associated with complex human diseases. There is a growing recognition that identifying "causal" rare variants also requires large-scale meta-analysis. The fact that association tests with rare variants are performed at the gene level rather than at the variant level poses unprecedented challenges in the meta-analysis. First, different studies may adopt different gene-level tests, so the results are not compatible. Second, gene-level tests require multivariate statistics (i.e., components of the test statistic and their covariance matrix), which are difficult to obtain. To overcome these challenges, we propose to perform gene-level tests for rare variants by combining the results of single-variant analysis (i.e., p values of association tests and effect estimates) from participating studies. This simple strategy is possible because of an insight that multivariate statistics can be recovered from single-variant statistics, together with the correlation matrix of the single-variant test statistics, which can be estimated from one of the participating studies or from a publicly available database. We show both theoretically and numerically that the proposed meta-analysis approach provides accurate control of the type I error and is as powerful as joint analysis of individual participant data. This approach accommodates any disease phenotype and any study design and produces all commonly used gene-level tests. An application to the GWAS summary results of the Genetic Investigation of ANthropometric Traits (GIANT) consortium reveals rare and low-frequency variants associated with human height. The relevant software is freely available.

AB - Meta-analysis of genome-wide association studies (GWASs) has led to the discoveries of many common variants associated with complex human diseases. There is a growing recognition that identifying "causal" rare variants also requires large-scale meta-analysis. The fact that association tests with rare variants are performed at the gene level rather than at the variant level poses unprecedented challenges in the meta-analysis. First, different studies may adopt different gene-level tests, so the results are not compatible. Second, gene-level tests require multivariate statistics (i.e., components of the test statistic and their covariance matrix), which are difficult to obtain. To overcome these challenges, we propose to perform gene-level tests for rare variants by combining the results of single-variant analysis (i.e., p values of association tests and effect estimates) from participating studies. This simple strategy is possible because of an insight that multivariate statistics can be recovered from single-variant statistics, together with the correlation matrix of the single-variant test statistics, which can be estimated from one of the participating studies or from a publicly available database. We show both theoretically and numerically that the proposed meta-analysis approach provides accurate control of the type I error and is as powerful as joint analysis of individual participant data. This approach accommodates any disease phenotype and any study design and produces all commonly used gene-level tests. An application to the GWAS summary results of the Genetic Investigation of ANthropometric Traits (GIANT) consortium reveals rare and low-frequency variants associated with human height. The relevant software is freely available.

UR - http://www.scopus.com/inward/record.url?scp=84881660693&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84881660693&partnerID=8YFLogxK

U2 - 10.1016/j.ajhg.2013.06.011

DO - 10.1016/j.ajhg.2013.06.011

M3 - Article

VL - 93

SP - 236

EP - 248

JO - American Journal of Human Genetics

JF - American Journal of Human Genetics

SN - 0002-9297

IS - 2

ER -