4.7 Article

Simultaneous Genotype Calling and Haplotype Phasing Improves Genotype Accuracy and Reduces False-Positive Associations for Genome-wide Association Studies

期刊

AMERICAN JOURNAL OF HUMAN GENETICS
卷 85, 期 6, 页码 847-861

出版社

CELL PRESS
DOI: 10.1016/j.ajhg.2009.11.004

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资金

  1. Wellcome Trust [076113]
  2. New Zealand Marsden Fund [08-UOA-028]
  3. NIH [R01HG004960]
  4. National Human Genome Research Institute
  5. New Zealand Marsden Fund

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We present a novel method for Simultaneous genotype calling and haplotype-phase inference. Our method employs the computationally efficient BEAGLE haplotype-frequency model, which can be applied to large-scale studies with millions of markers and thousands of samples. We compare genotype calls made with our method to genotype calls made with the BIRDSEED, CHIAMO, GenCall, and ILLUMINUS genotype-calling methods, using genotype data from the Illumina 550K and Affymetrix 500K arrays. We show that our method has higher genotype-call accuracy and yields fewer uncalled genotypes than competing methods. We perform single-marker analysis of data from the Wellcome Trust Case Control Consortium bipolar disorder and type 2 diabetes Studies. I or bipolar disorder, the genotype calls in the original study yield 25 markers with apparent false-positive association with bipolar disorder at a p < 10(-7) significance level, whereas genotype calls made with our method yield no associated markers at this significance threshold. Conversely, for markers with replicated association with type 2 diabetes, there is good concordance between genotype calls used in the original study and calls made by our method. Results from single-marker and haplotypic analysis of our method's genotype calls for the bipolar disorder study indicate that our method is highly effective at eliminating genotyping artifacts that cause false-positive associations in genome-wide association Studies. Our new genotype-calling methods are implemented in the BEAGLE and BEAGLECALL software packages.

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