Efficiency and power as a function of sequence coverage, SNP array density, and imputation.

PLoS Comput Biol
Authors
Keywords
Abstract

High coverage whole genome sequencing provides near complete information about genetic variation. However, other technologies can be more efficient in some settings by (a) reducing redundant coverage within samples and (b) exploiting patterns of genetic variation across samples. To characterize as many samples as possible, many genetic studies therefore employ lower coverage sequencing or SNP array genotyping coupled to statistical imputation. To compare these approaches individually and in conjunction, we developed a statistical framework to estimate genotypes jointly from sequence reads, array intensities, and imputation. In European samples, we find similar sensitivity (89%) and specificity (99.6%) from imputation with either 1× sequencing or 1 M SNP arrays. Sensitivity is increased, particularly for low-frequency polymorphisms (MAF 5%), when low coverage sequence reads are added to dense genome-wide SNP arrays--the converse, however, is not true. At sites where sequence reads and array intensities produce different sample genotypes, joint analysis reduces genotype errors and identifies novel error modes. Our joint framework informs the use of next-generation sequencing in genome wide association studies and supports development of improved methods for genotype calling.

Year of Publication
2012
Journal
PLoS Comput Biol
Volume
8
Issue
7
Pages
e1002604
Date Published
2012
ISSN
1553-7358
URL
DOI
10.1371/journal.pcbi.1002604
PubMed ID
22807667
PubMed Central ID
PMC3395607
Links
Grant list
T32 GM007748 / GM / NIGMS NIH HHS / United States
U01 HG005208 / HG / NHGRI NIH HHS / United States
5-T32-GM007748-33 / GM / NIGMS NIH HHS / United States
U01HG005208 / HG / NHGRI NIH HHS / United States