Rapid and Accurate Haplotype Phasing and Missing-data Inference for Whole-genome Association Studies by Use of Localized Haplotype Clustering

Overview

Journal Am J Hum Genet

Publisher Cell Press

Specialty Genetics

Date 2007 Oct 10

PMID 17924348

Citations 1718

Authors

Sharon R Browning

Brian L Browning

Affiliations

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Abstract

Whole-genome association studies present many new statistical and computational challenges due to the large quantity of data obtained. One of these challenges is haplotype inference; methods for haplotype inference designed for small data sets from candidate-gene studies do not scale well to the large number of individuals genotyped in whole-genome association studies. We present a new method and software for inference of haplotype phase and missing data that can accurately phase data from whole-genome association studies, and we present the first comparison of haplotype-inference methods for real and simulated data sets with thousands of genotyped individuals. We find that our method outperforms existing methods in terms of both speed and accuracy for large data sets with thousands of individuals and densely spaced genetic markers, and we use our method to phase a real data set of 3,002 individuals genotyped for 490,032 markers in 3.1 days of computing time, with 99% of masked alleles imputed correctly. Our method is implemented in the Beagle software package, which is freely available.

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References

Stephens M, Scheet P . Accounting for decay of linkage disequilibrium in haplotype inference and missing-data imputation. Am J Hum Genet. 2005; 76(3):449-62. PMC: 1196397. DOI: 10.1086/428594. View

Kong A, Gudbjartsson D, Sainz J, Jonsdottir G, Gudjonsson S, Richardsson B . A high-resolution recombination map of the human genome. Nat Genet. 2002; 31(3):241-7. DOI: 10.1038/ng917. View

Hawley M, Kidd K . HAPLO: a program using the EM algorithm to estimate the frequencies of multi-site haplotypes. J Hered. 1995; 86(5):409-11. DOI: 10.1093/oxfordjournals.jhered.a111613. View

Browning S . Multilocus association mapping using variable-length Markov chains. Am J Hum Genet. 2006; 78(6):903-13. PMC: 1474089. DOI: 10.1086/503876. View

Qin Z, Niu T, Liu J . Partition-ligation-expectation-maximization algorithm for haplotype inference with single-nucleotide polymorphisms. Am J Hum Genet. 2002; 71(5):1242-7. PMC: 385113. DOI: 10.1086/344207. View

Eronen L, Geerts F, Toivonen H . HaploRec: efficient and accurate large-scale reconstruction of haplotypes. BMC Bioinformatics. 2006; 7:542. PMC: 1766938. DOI: 10.1186/1471-2105-7-542. View

Scheet P, Stephens M . A fast and flexible statistical model for large-scale population genotype data: applications to inferring missing genotypes and haplotypic phase. Am J Hum Genet. 2006; 78(4):629-44. PMC: 1424677. DOI: 10.1086/502802. View

Tregouet D, Escolano S, Tiret L, Mallet A, Golmard J . A new algorithm for haplotype-based association analysis: the Stochastic-EM algorithm. Ann Hum Genet. 2004; 68(Pt 2):165-77. DOI: 10.1046/j.1529-8817.2003.00085.x. View

Halperin E, Eskin E . Haplotype reconstruction from genotype data using Imperfect Phylogeny. Bioinformatics. 2004; 20(12):1842-9. DOI: 10.1093/bioinformatics/bth149. View

10.

Marchini J, Cutler D, Patterson N, Stephens M, Eskin E, Halperin E . A comparison of phasing algorithms for trios and unrelated individuals. Am J Hum Genet. 2006; 78(3):437-50. PMC: 1380287. DOI: 10.1086/500808. View

11.

Schaffner S, Foo C, Gabriel S, Reich D, Daly M, Altshuler D . Calibrating a coalescent simulation of human genome sequence variation. Genome Res. 2005; 15(11):1576-83. PMC: 1310645. DOI: 10.1101/gr.3709305. View

12.

. Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature. 2007; 447(7145):661-78. PMC: 2719288. DOI: 10.1038/nature05911. View

13.

Stephens M, Donnelly P . A comparison of bayesian methods for haplotype reconstruction from population genotype data. Am J Hum Genet. 2003; 73(5):1162-9. PMC: 1180495. DOI: 10.1086/379378. View

14.

Kimmel G, Shamir R . GERBIL: Genotype resolution and block identification using likelihood. Proc Natl Acad Sci U S A. 2004; 102(1):158-62. PMC: 544046. DOI: 10.1073/pnas.0404730102. View

15.

Browning B, Browning S . Efficient multilocus association testing for whole genome association studies using localized haplotype clustering. Genet Epidemiol. 2007; 31(5):365-75. DOI: 10.1002/gepi.20216. View

16.

Stephens M, Smith N, Donnelly P . A new statistical method for haplotype reconstruction from population data. Am J Hum Genet. 2001; 68(4):978-89. PMC: 1275651. DOI: 10.1086/319501. View

17.

Barrett J, Cardon L . Evaluating coverage of genome-wide association studies. Nat Genet. 2006; 38(6):659-62. DOI: 10.1038/ng1801. View

18.

Carlson C, Eberle M, Rieder M, Yi Q, Kruglyak L, Nickerson D . Selecting a maximally informative set of single-nucleotide polymorphisms for association analyses using linkage disequilibrium. Am J Hum Genet. 2003; 74(1):106-20. PMC: 1181897. DOI: 10.1086/381000. View

19.

Excoffier L, Laval G, Balding D . Gametic phase estimation over large genomic regions using an adaptive window approach. Hum Genomics. 2004; 1(1):7-19. PMC: 3525008. DOI: 10.1186/1479-7364-1-1-7. View

20.

Plagnol V, Cooper J, Todd J, Clayton D . A method to address differential bias in genotyping in large-scale association studies. PLoS Genet. 2007; 3(5):e74. PMC: 1868951. DOI: 10.1371/journal.pgen.0030074. View