Validation of genotype imputation in Southeast Asian populations and the effect of single nucleotide polymorphism annotation on imputation outcome

Springer Science and Business Media LLC - Tập 19 - Trang 1-10 - 2018
Worachart Lert-itthiporn1,2, Bhoom Suktitipat3,4, Harald Grove2,4, Anavaj Sakuntabhai5,6,7, Prida Malasit8,9, Nattaya Tangthawornchaikul8,9, Fumihiko Matsuda10, Prapat Suriyaphol2,4
1Molecular Medicine Graduate Program, Faculty of Science, Mahidol University, Bangkok, Thailand
2Division of Bioinformatics and Data Management for Research, Department of Research and Development, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand
3Integrative Computational BioScience Center, Department of Biochemistry, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok,, Thailand
4Center of Excellence in Bioinformatics and Clinical Data Management, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
5Unité de Génétique Fonctionnelle des Maladies Infectieuses, Department Genome and Genetics, Institut Pasteur, Paris, France
6Centre National de la Recherche Scientifique, URA3012, Paris, France
7Systems Biology of Diseases Research Unit, Faculty of Science, Mahidol University, Bangkok, Thailand
8Medical Biotechnology Research Unit, National Center for Genetic Engineering and Biotechnology, National Science and Technology Development Agency, Bangkok, Thailand
9Division of Dengue Hemorrhagic Fever Research, Department of Research and Development, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
10Center for Genomic Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan

Tóm tắt

Imputation involves the inference of untyped single nucleotide polymorphisms (SNPs) in genome-wide association studies. The haplotypic reference of choice for imputation in Southeast Asian populations is unclear. Moreover, the influence of SNP annotation on imputation results has not been examined. This study was divided into two parts. In the first part, we applied imputation to genotyped SNPs from Southeast Asian populations from the Pan-Asian SNP database. Five percent of the total SNPs were removed. The remaining SNPs were applied to imputation with IMPUTE2. The imputed outcomes were verified with the removed SNPs. We compared imputation references from Chinese and Japanese haplotypes from the HapMap phase II (HMII) and the complete set of haplotypes from the 1000 Genomes Project (1000G). The second part was imputation accuracy and yield in Thai patient dataset. Half of the autosomal SNPs was removed to create Set 1. Another dataset, Set 2, was then created where we switched which half of the SNPs were removed. Both Set 1 and Set 2 were imputed with HMII to create a complete imputed SNPs dataset. The dataset was used to validate association testing, SNPs annotation and imputation outcome. The accuracy was highest for all populations when using the HMII reference, but at the cost of a lower yield. Thai genotypes showed the highest accuracy over other populations in both HMII and 1000G panels, although accuracy and yield varied across chromosomes. Imputation was tested in a clinical dataset to compare accuracy in gene-related regions, and coding regions were found to have a higher accuracy and yield. This work provides the first evidence of imputation reference selection for Southeast Asian studies and highlights the effects of SNP locations respective to genes on imputation outcome. Researchers will need to consider the trade-off between accuracy and yield in future imputation studies.

Tài liệu tham khảo

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