Rare variant genotype imputation with thousands of study-specific whole-genome sequences: implications for cost-effective study designs.

Details

Serval ID
serval:BIB_0147B0DB2A8B
Type
Article: article from journal or magazin.
Collection
Publications
Title
Rare variant genotype imputation with thousands of study-specific whole-genome sequences: implications for cost-effective study designs.
Journal
European journal of human genetics
Author(s)
Pistis G., Porcu E., Vrieze S.I., Sidore C., Steri M., Danjou F., Busonero F., Mulas A., Zoledziewska M., Maschio A., Brennan C., Lai S., Miller M.B., Marcelli M., Urru M.F., Pitzalis M., Lyons R.H., Kang H.M., Jones C.M., Angius A., Iacono W.G., Schlessinger D., McGue M., Cucca F., Abecasis G.R., Sanna S.
ISSN
1476-5438 (Electronic)
ISSN-L
1018-4813
Publication state
Published
Issued date
07/2015
Peer-reviewed
Oui
Volume
23
Number
7
Pages
975-983
Language
english
Notes
Publication types: Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
Abstract
The utility of genotype imputation in genome-wide association studies is increasing as progressively larger reference panels are improved and expanded through whole-genome sequencing. Developing general guidelines for optimally cost-effective imputation, however, requires evaluation of performance issues that include the relative utility of study-specific compared with general/multipopulation reference panels; genotyping with various array scaffolds; effects of different ethnic backgrounds; and assessment of ranges of allele frequencies. Here we compared the effectiveness of study-specific reference panels to the commonly used 1000 Genomes Project (1000G) reference panels in the isolated Sardinian population and in cohorts of European ancestry including samples from Minnesota (USA). We also examined different combinations of genome-wide and custom arrays for baseline genotypes. In Sardinians, the study-specific reference panel provided better coverage and genotype imputation accuracy than the 1000G panels and other large European panels. In fact, even gene-centered custom arrays (interrogating ~200 000 variants) provided highly informative content across the entire genome. Gain in accuracy was also observed for Minnesotans using the study-specific reference panel, although the increase was smaller than in Sardinians, especially for rare variants. Notably, a combined panel including both study-specific and 1000G reference panels improved imputation accuracy only in the Minnesota sample, and only at rare sites. Finally, we found that when imputation is performed with a study-specific reference panel, cutoffs different from the standard thresholds of MACH-Rsq and IMPUTE-INFO metrics should be used to efficiently filter badly imputed rare variants. This study thus provides general guidelines for researchers planning large-scale genetic studies.
Keywords
Cost-Benefit Analysis, European Continental Ancestry Group/genetics, Gene Frequency, Genetics, Population, Genome, Human/genetics, Genome-Wide Association Study/economics, Genome-Wide Association Study/methods, Genotype, Haplotypes, Humans, Italy, Minnesota, Polymorphism, Single Nucleotide, Research Design, Sequence Analysis, DNA/economics, Sequence Analysis, DNA/methods
Pubmed
Web of science
Open Access
Yes
Create date
18/01/2021 21:33
Last modification date
19/01/2021 6:26
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