1. A new strategy for enhancing imputation quality of rare variants from next-generation sequencing data via combining SNP and exome chip data
- Author
-
Anna Gloyn, Eric Gamazon, Benjamin Glaser, Adam Locke, E Shyong Tai, Jennifer Asimit, Inga Prokopenko, John Blangero, Dan Nicolae, Christian Fuchsberger, Jennifer Below, Mark Seielstad, Mark McCarthy, Cecilia Lindgren, Xueling Sim, Mohammad Kamran Ikram, and Other departments
- Subjects
Genotype ,Bioinformatics ,LOCI ,Computational biology ,Biology ,GENOTYPE IMPUTATION ,Polymorphism, Single Nucleotide ,DNA sequencing ,03 medical and health sciences ,CODING VARIANTS ,Missing heritability problem ,Genetics ,SNP ,Exome ,GENOME-WIDE ASSOCIATION ,COMMON ,Genotyping ,Exome sequencing ,Imputation ,Oligonucleotide Array Sequence Analysis ,030304 developmental biology ,Genetics & Heredity ,AFRICAN-AMERICANS ,08 Information And Computing Sciences ,0303 health sciences ,Science & Technology ,Methodology Article ,030305 genetics & heredity ,Rare variant ,GENETIC-VARIATION ,High-Throughput Nucleotide Sequencing ,T2D-Genes Consortium ,11 Medical And Health Sciences ,06 Biological Sciences ,Exome chip ,SNP genotyping ,Biotechnology & Applied Microbiology ,DISEASES ,POPULATIONS ,Life Sciences & Biomedicine ,Combined approach ,PROJECT ,Imputation (genetics) ,Biotechnology - Abstract
Background: Rare variants have gathered increasing attention as a possible alternative source of missing heritability. Since next generation sequencing technology is not yet cost-effective for large-scale genomic studies, a widely used alternative approach is imputation. However, the imputation approach may be limited by the low accuracy of the imputed rare variants. To improve imputation accuracy of rare variants, various approaches have been suggested, including increasing the sample size of the reference panel, using sequencing data from study-specific samples (i.e., specific populations), and using local reference panels by genotyping or sequencing a subset of study samples. While these approaches mainly utilize reference panels, imputation accuracy of rare variants can also be increased by using exome chips containing rare variants. The exome chip contains 250 K rare variants selected from the discovered variants of about 12,000 sequenced samples. If exome chip data are available for previously genotyped samples, the combined approach using a genotype panel of merged data, including exome chips and SNP chips, should increase the imputation accuracy of rare variants. Results: In this study, we describe a combined imputation which uses both exome chip and SNP chip data simultaneously as a genotype panel. The effectiveness and performance of the combined approach was demonstrated using a reference panel of 848 samples constructed using exome sequencing data from the T2D-GENES consortium and 5,349 sample genotype panels consisting of an exome chip and SNP chip. As a result, the combined approach increased imputation quality up to 11 %, and genomic coverage for rare variants up to 117.7 % (MAF
- Published
- 2015