Meta-analysis of gene-level associations for rare variants based on single-variant statistics
Academic Article
Publication Date:
2013
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. © 2013 The American Society of Human Genetics.
Iris type:
1.1 Articolo in rivista
List of contributors:
Hu, Y. -J.; Berndt, S. I.; Gustafsson, S.; Ganna, A.; Ingelsson, E.; Hirschhorn, J.; North, K. E.; Lin, D. -Y.; Berndt, S. I.; Gustafsson, S.; Magi, R.; Ganna, A.; Wheeler, E.; Feitosa, M. F.; Justice, A. E.; Monda, K. L.; Croteau-Chonka, D. C.; Day, F. R.; Esko, T.; Fall, T.; Ferreira, T.; Gentilini, D.; Jackson, A. U.; Luan, J.; Randall, J. C.; Vedantam, S.; Willer, C. J.; Winkler, T. W.; Wood, A. R.; Workalemahu, T.; Hu, Y. -J.; Lee, S. H.; Liang, L.; Lin, D. -Y.; Min, J. L.; Neale, B. M.; Thorleifsson, G.; Yang, J.; Albrecht, E.; Amin, N.; Bragg-Gresham, J. L.; Cadby, G.; Heijer, M.; Eklund, N.; Fischer, K.; Goel, A.; Hottenga, J. -J.; Huffman, J. E.; Jarick, I.; Johansson, A.; Johnson, T.; Kanoni, S.; Kleber, M. E.; Konig, I. R.; Kristiansson, K.; Kutalik, Z.; Lamina, C.; Lecoeur, C.; Li, G.; Mangino, M.; Mcardle, W. L.; Medina-Gomez, C.; Muller-Nurasyid, M.; Ngwa, J. S.; Nolte, I. M.; Paternoster, L.; Pechlivanis, S.; Perola, M.; Peters, M. J.; Preuss, M.; Rose, L. M.; Shi, J.; Shungin, D.; Smith, A. V.; Strawbridge, R. J.; Surakka, I.; Teumer, A.; Trip, M. D.; Tyrer, J.; Vliet-Ostaptchouk, J. V.; Vandenput, L.; Waite, L. L.; Zhao, J. H.; Absher, D.; Asselbergs, F. W.; Atalay, M.; Attwood, A. P.; Balmforth, A. J.; Basart, H.; Beilby, J.; Bonnycastle, L. L.; Brambilla, P.; Bruinenberg, M.; Campbell, H.; Chasman, D. I.; Chines, P. S.; Connell, J. M.; Cookson, W.; Faire, U.; Vegt, F.; Dei, M.; Dimitriou, M.; Edkins, S.; Estrada, K.; Evans, D. M.; Farrall, M.; Ferrario, M. M.; Ferrieres, J.; Franke, L.; Frau, F.; Gejman, P. V.; Grallert, H.; Gronberg, H.; Gudnason, V.; Hall, A. S.; Hall, P.; Hartikainen, A. -L.; Hayward, C.; Heard-Costa, N. L.; Heath, A. C.; Hebebrand, J.; Homuth, G.; Hu, F. B.; Hunt, S. E.; Hypponen, E.; Iribarren, C.; Jacobs, K. B.; Jansson, J. -O.; Jula, A.; Kahonen, M.; Kathiresan, S.; Kee, F.; Khaw, K. -T.; Kivimaki, M.; Koenig, W.; Kraja, A. T.; Kumari, M.; Kuulasmaa, K.; Kuusisto, J.; Laitinen, J. H.; Lakka, T. A.; Langenberg, C.; Launer, L. J.; Lind, L.; Lindstrom, J.; Liu, J.; Liuzzi, A.; Lokki, M. -L.; Lorentzon, M.; Magnusson, P. A. M.; Magnusson, P. A. M.; Manunta, P.; Marek, D.; Marz, W.; Leach, I. M.; Mcknight, B.; Medland, S. E.; Mihailov, E.; Milani, L.; Montgomery, G. W.; Mooser, V.; Muhleisen, T. W.; Munroe, P. B.; Musk, A. W.; Narisu, N.; Navis, G.; Nicholson, G.; Nohr, E. A.; Ong, K. K.; Oostra, B. A.; Palmer, C. N. A.; Palotie, A.; Peden, J. F.; Pedersen, N.; Peters, A.; Polasek, O.; Pouta, A.; Pramstaller, P. P.; Prokopenko, I.; Putter, C.; Radhakrishnan, A.; Raitakari, O.; Rendon, A.; Rivadeneira, F.; Rudan, I.; Saaristo, T. E.; Sambrook, J. G.; Sanders, A. R.; Sanna, S.; Saramies, J.; Schipf, S.; Schreiber, S.; Schunkert, H.; Shin, S. -Y.; Signorini, S.; Sinisalo, J.; Skrobek, B.; Soranzo, N.; Stancakova, A.; Stark, K.; Stephens, J. C.; Stirrups, K.; Stolk, R. P.; Stumvoll, M.; Swift, A. J.; Theodoraki, E. V.; Thorand, B.; Tregouet, D. -A.; Tremoli, E.; Klauw, M. M.; Meurs, J. B.; Vermeulen, S. H.; Viikari, J.; Virtamo, J.; Vitart, V.; Waeber, G.; Wang, Z.; Widen, E.; Wild, S. H.; Willemsen, G.; Winkelmann, B. R.; Witteman, J. C. M.; Wolffenbuttel, B. H. R.; Wong, A.; Wright, A. F.; Zillikens, M. C.; Amouyel, P.; Boehm, B. O.; Boerwinkle, E.; Boomsma, D. I.; Caulfield, M. J.; Chanock, S. J.; Cupples, L. A.; Cusi, D.; Dedoussis, G. V.; Erdmann, J.; Eriksson, J. G.; Franks, P. W.; Froguel, P.; Gieger, C.; Gyllensten, U.; Hamsten, A.; Harris, T. B.; Hengstenberg, C.; Hicks, A. A.; Hingorani, A.; Hinney, A.; Hofman, A.; Hovingh, K. G.; Hveem, K.; Illig, T.; Jarvelin, M. -R.; Jockel, K. -H.; Keinanen-Kiukaanniemi, S. M.; Kiemeney, L. A.; Kuh, D.; Laakso, M.; Lehtimaki, T.; Levinson, D. F.; Martin, N. G.; Metspalu, A.; Morris, A. D.; Nieminen, M. S.; Njolstad, I.; Ohlsson, C.; Oldehinkel, A. J.; Ouwehand, W. H.; Palmer, L. J.; Penninx, B.; Power, C.; Province, M. A.; Psaty, B. M.; Qi, L.; Rauramaa, R.; Ridker, P. M.; Ripatti, S.; Salomaa, V.; Samani, N. J.; Snieder, H.; Sorensen, T. I. A.;
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