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

PLoS Genetics
Sina RüegerZoltán Kutalik

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 posit...Continue Reading

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Citations

May 8, 2020·Journal of Medical Genetics·Chantal Babb de VilliersSowmiya Moorthie
Feb 13, 2021·American Journal of Medical Genetics. Part B, Neuropsychiatric Genetics : the Official Publication of the International Society of Psychiatric Genetics·Chris ChatzinakosSilviu-Alin Bacanu
Jan 7, 2021·Nature Communications·Vasiliki LagouUNKNOWN Meta-Analyses of Glucose and Insulin-related traits Consortium (MAGIC)
Mar 20, 2021·Calcified Tissue International·Ying-Qi LiuHong-Wen Deng
May 19, 2021·BMC Bioinformatics·Emily A KingJacob F Degner
Apr 18, 2020·American Journal of Human Genetics·Daniel I ChasmanMiriam S Udler
Oct 2, 2021·Nature Genetics·Saori SakaueYukinori Okada

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Methods Mentioned

BETA
genotyping
chips
exome array
chip
exome

Software Mentioned

SNPTEST
Phenoscanner
HAPGEN2
GTEx
IMPUTE
Minimac
IMPUTE2
R
SSIMP
GIANT

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