Evaluation and application of summary statistic imputation to discover new height-associated loci.

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Ressource 1Download: BIB_DE5541571092- Kutalik 2018.pdf (5920.13 [Ko])
State: Public
Version: Final published version
Serval ID
serval:BIB_DE5541571092
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Evaluation and application of summary statistic imputation to discover new height-associated loci.
Journal
PLoS genetics
Author(s)
Rüeger S., McDaid A., Kutalik Z.
ISSN
1553-7404 (Electronic)
ISSN-L
1553-7390
Publication state
Published
Issued date
05/2018
Peer-reviewed
Oui
Volume
14
Number
5
Pages
e1007371
Language
english
Notes
Publication types: Evaluation Studies ; Journal Article ; Research Support, Non-U.S. Gov't
Publication Status: epublish
Abstract
As most of the heritability of complex traits is attributed to common and low frequency genetic variants, imputing them by combining genotyping chips and large sequenced reference panels is the most cost-effective approach to discover the genetic basis of these traits. Association summary statistics from genome-wide meta-analyses are available for hundreds of traits. Updating these to ever-increasing reference panels is very cumbersome as it requires reimputation of the genetic data, rerunning the association scan, and meta-analysing the results. A much more efficient method is to directly impute the summary statistics, termed as summary statistics imputation, which we improved to accommodate variable sample size across SNVs. Its performance relative to genotype imputation and practical utility has not yet been fully investigated. To this end, we compared the two approaches on real (genotyped and imputed) data from 120K samples from the UK Biobank and show that, genotype imputation boasts a 3- to 5-fold lower root-mean-square error, and better distinguishes true associations from null ones: We observed the largest differences in power for variants with low minor allele frequency and low imputation quality. For fixed false positive rates of 0.001, 0.01, 0.05, using summary statistics imputation yielded a decrease in statistical power by 9, 43 and 35%, respectively. To test its capacity to discover novel associations, we applied summary statistics imputation to the GIANT height meta-analysis summary statistics covering HapMap variants, and identified 34 novel loci, 19 of which replicated using data in the UK Biobank. Additionally, we successfully replicated 55 out of the 111 variants published in an exome chip study. Our study demonstrates that summary statistics imputation is a very efficient and cost-effective way to identify and fine-map trait-associated loci. Moreover, the ability to impute summary statistics is important for follow-up analyses, such as Mendelian randomisation or LD-score regression.
Keywords
Algorithms, Biostatistics/methods, Exome/genetics, Gene Frequency, Genetic Association Studies/methods, Genome-Wide Association Study/methods, Genotype, Humans, Linkage Disequilibrium, Oligonucleotide Array Sequence Analysis, Phenotype, Polymorphism, Single Nucleotide, Quantitative Trait Loci/genetics, Reproducibility of Results
Pubmed
Web of science
Open Access
Yes
Create date
24/05/2018 17:05
Last modification date
20/08/2019 16:02
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