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RAISS: robust and accurate imputation from summary statistics.

ABSTRACT: MOTIVATION:Multi-trait analyses using public summary statistics from genome-wide association studies (GWASs) are becoming increasingly popular. A constraint of multi-trait methods is that they require complete summary data for all traits. Although methods for the imputation of summary statistics exist, they lack precision for genetic variants with small effect size. This is benign for univariate analyses where only variants with large effect size are selected a posteriori. However, it can lead to strong p-value inflation in multi-trait testing. Here we present a new approach that improve the existing imputation methods and reach a precision suitable for multi-trait analyses. RESULTS:We fine-tuned parameters to obtain a very high accuracy imputation from summary statistics. We demonstrate this accuracy for variants of all effect sizes on real data of 28 GWAS. We implemented the resulting methodology in a python package specially designed to efficiently impute multiple GWAS in parallel. AVAILABILITY AND IMPLEMENTATION:The python package is available at: https://gitlab.pasteur.fr/statistical-genetics/raiss, its accompanying documentation is accessible here http://statistical-genetics.pages.pasteur.fr/raiss/. SUPPLEMENTARY INFORMATION:Supplementary data are available at Bioinformatics online.

SUBMITTER: Julienne H

PROVIDER: S-EPMC6853677 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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RAISS: robust and accurate imputation from summary statistics.

Julienne Hanna H Shi Huwenbo H Pasaniuc Bogdan B Aschard Hugues H

Bioinformatics (Oxford, England) 20191101 22

<h4>Motivation</h4>Multi-trait analyses using public summary statistics from genome-wide association studies (GWASs) are becoming increasingly popular. A constraint of multi-trait methods is that they require complete summary data for all traits. Although methods for the imputation of summary statistics exist, they lack precision for genetic variants with small effect size. This is benign for univariate analyses where only variants with large effect size are selected a posteriori. However, it ca ...[more]

PMID: 31173064

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Project description:MotivationImputation using external reference panels (e.g. 1000 Genomes) is a widely used approach for increasing power in genome-wide association studies and meta-analysis. Existing hidden Markov models (HMM)-based imputation approaches require individual-level genotypes. Here, we develop a new method for Gaussian imputation from summary association statistics, a type of data that is becoming widely available.ResultsIn simulations using 1000 Genomes (1000G) data, this method recovers 84% (54%) of the effective sample size for common (>5%) and low-frequency (1-5%) variants [increasing to 87% (60%) when summary linkage disequilibrium information is available from target samples] versus the gold standard of 89% (67%) for HMM-based imputation, which cannot be applied to summary statistics. Our approach accounts for the limited sample size of the reference panel, a crucial step to eliminate false-positive associations, and it is computationally very fast. As an empirical demonstration, we apply our method to seven case-control phenotypes from the Wellcome Trust Case Control Consortium (WTCCC) data and a study of height in the British 1958 birth cohort (1958BC). Gaussian imputation from summary statistics recovers 95% (105%) of the effective sample size (as quantified by the ratio of [Formula: see text] association statistics) compared with HMM-based imputation from individual-level genotypes at the 227 (176) published single nucleotide polymorphisms (SNPs) in the WTCCC (1958BC height) data. In addition, for publicly available summary statistics from large meta-analyses of four lipid traits, we publicly release imputed summary statistics at 1000G SNPs, which could not have been obtained using previously published methods, and demonstrate their accuracy by masking subsets of the data. We show that 1000G imputation using our approach increases the magnitude and statistical evidence of enrichment at genic versus non-genic loci for these traits, as compared with an analysis without 1000G imputation. Thus, imputation of summary statistics will be a valuable tool in future functional enrichment analyses.Availability and implementationPublicly available software package available at http://bogdan.bioinformatics.ucla.edu/software/.Contactbpasaniuc@mednet.ucla.edu or aprice@hsph.harvard.eduSupplementary informationSupplementary materials are available at Bioinformatics online.

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RAISS: robust and accurate imputation from summary statistics.

Publications

RAISS: robust and accurate imputation from summary statistics.

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