Meta-analysis of Gene-Level Associations for Rare Variants Based on Single-Variant Statistics

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., component... Mehr ...

Verfasser: Hu, Y.J.
Berndt, S.I.
Gustafsson, S.
Ganna, A.
Hirschhorn, J.N.
North, K.E.
Ingelsson, E.
Lin, D.-Y.
Hottenga, J.J.
Willemsen, G.
Boomsma, D.I.
Penninx, B.W.J.H.
van Duijn, C.M.
Dokumenttyp: Artikel
Erscheinungsdatum: 2013
Reihe/Periodikum: Hu , Y J , Berndt , S I , Gustafsson , S , Ganna , A , Hirschhorn , J N , North , K E , Ingelsson , E , Lin , D-Y , Hottenga , J J , Willemsen , G , Boomsma , D I , Penninx , B W J H & van Duijn , C M 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
Schlagwörter: /dk/atira/pure/keywords/cohort_studies/netherlands_twin_register_ntr_ / name=Netherlands Twin Register (NTR)
Sprache: Englisch
Permalink: https://search.fid-benelux.de/Record/base-29214277
Datenquelle: BASE; Originalkatalog
Powered By: BASE
Link(s) : https://research.vu.nl/en/publications/961e883e-4c46-4791-91ca-5654125f6c7d

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.