Meta-analysis of Gene-Level Associations for Rare Variants Based on Single-Variant Statistics Academic Article uri icon

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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.

authors

  • Hu, Yi-Juan
  • Berndt, Sonja I
  • Gustafsson, Stefan
  • Ganna, Andrea
  • Hirschhorn, Joel
  • North, Kari E
  • Ingelsson, Erik
  • Lin, Dan-Yu
  • Berndt, Sonja I
  • Gustafsson, Stefan
  • Mägi, Reedik
  • Ganna, Andrea
  • Wheeler, Eleanor
  • Feitosa, Mary F
  • Justice, Anne E
  • Monda, Keri L
  • Croteau-Chonka, Damien C
  • Day, Felix R
  • Esko, Tõnu
  • 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
  • den Heijer, Martin
  • Eklund, Niina
  • Fischer, Krista
  • Goel, Anuj
  • Hottenga, Jouke-Jan
  • Huffman, Jennifer E
  • Jarick, Ivonne
  • Johansson, Åsa
  • Johnson, Toby
  • Kanoni, Stavroula
  • Kleber, Marcus E
  • König, Inke R
  • Kristiansson, Kati
  • Kutalik, Zoltán
  • Lamina, Claudia
  • Lecoeur, Cecile
  • Li, Guo
  • Mangino, Massimo
  • McArdle, Wendy L
  • Medina-Gomez, Carolina
  • Müller-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
  • Van Vliet-Ostaptchouk, Jana V
  • 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
  • de Faire, Ulf
  • de Vegt, Femmie
  • Dei, Mariano
  • Dimitriou, Maria
  • Edkins, Sarah
  • Estrada, Karol
  • Evans, David M
  • Farrall, Martin
  • Ferrario, Marco M
  • Ferrières, Jean
  • Franke, Lude
  • Frau, Francesca
  • Gejman, Pablo V
  • Grallert, Harald
  • Grönberg, 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
  • Hyppönen, Elina
  • Iribarren, Carlos
  • Jacobs, Kevin B
  • Jansson, John-Olov
  • Jula, Antti
  • Kähönen, 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
  • Lindström, Jaana
  • Liu, Jianjun
  • Liuzzi, Antonio
  • Lokki, Marja-Liisa
  • Lorentzon, Mattias
  • Madden, Pamela A
  • Magnusson, Patrik K
  • Manunta, Paolo
  • Marek, Diana
  • März, Winfried
  • Leach, Irene Mateo
  • McKnight, Barbara
  • Medland, Sarah E
  • Mihailov, Evelin
  • Milani, Lili
  • Montgomery, Grant W
  • Mooser, Vincent
  • Mühleisen, 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 NA
  • Palotie, Aarno
  • Peden, John F
  • Pedersen, Nancy
  • Peters, Annette
  • Polasek, Ozren
  • Pouta, Anneli
  • Pramstaller, Peter P
  • Prokopenko, Inga
  • Pütter, 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
  • Stančáková, 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
  • Van der Klauw, Melanie M
  • van Meurs, Joyce BJ
  • Vermeulen, Sita H
  • Viikari, Jorma
  • Virtamo, Jarmo
  • Vitart, Veronique
  • Waeber, Gérard
  • Wang, Zhaoming
  • Widén, Elisabeth
  • Wild, Sarah H
  • Willemsen, Gonneke
  • Winkelmann, Bernhard R
  • Witteman, Jacqueline CM
  • Wolffenbuttel, Bruce HR
  • 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
  • Jöckel, Karl-Heinz
  • Keinanen-Kiukaanniemi, Sirkka M
  • Kiemeney, Lambertus A
  • Kuh, Diana
  • Laakso, Markku
  • Lehtimäki, 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 IA
  • Spector, Timothy D
  • Stefansson, Kari
  • Tönjes, Anke
  • Tuomilehto, Jaakko
  • Uitterlinden, André G
  • Uusitupa, Matti
  • van der Harst, Pim
  • Vollenweider, Peter
  • Wallaschofski, Henri
  • Wareham, Nicholas J
  • Watkins, Hugh
  • Wichmann, H-Erich
  • Wilson, James F
  • Abecasis, Goncalo R
  • Assimes, Themistocles L
  • Barroso, Inês
  • Boehnke, Michael
  • Borecki, Ingrid B
  • Deloukas, Panos
  • Fox, Caroline S
  • Frayling, Timothy
  • Groop, Leif C
  • Haritunian, Talin
  • Heid, Iris M
  • Hunter, David
  • Kaplan, Robert C
  • Karpe, Fredrik
  • Moffatt, Miriam
  • Mohlke, Karen L
  • O’Connell, Jeffrey R
  • Pawitan, Yudi
  • Schadt, Eric E
  • Schlessinger, David
  • Steinthorsdottir, Valgerdur
  • Strachan, David P
  • Thorsteinsdottir, Unnur
  • van Duijn, Cornelia M
  • Visscher, Peter M
  • Di Blasio, Anna Maria
  • Hirschhorn, Joel N
  • Lindgren, Cecilia M
  • Morris, Andrew P
  • Meyre, David Jean-Claude
  • Scherag, André
  • McCarthy, Mark I
  • Speliotes, Elizabeth K
  • North, Kari E
  • Loos, Ruth JF
  • Ingelsson, Erik

publication date

  • August 2013