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Association Analysis and Meta-Analysis of Multi-allelic Variants for Large Scale Sequence Data

Xiaowei Zhan, Sai Chen, Yu Jiang, Mengzhen Liu, William G. Iacono, John K. Hewitt, John E Hokanson, Kenneth Krauter, Markku Laakso, Kevin W. Li, Sharon M Lutz, Matthew McGue, Anita Pandit, Gregory JM Zajac, Michael Boehnke, Goncalo R. Abecasis, Bibo Jiang, Scott I. Vrieze, Dajiang J. Liu
doi: https://doi.org/10.1101/197913
Xiaowei Zhan
1Department of Clinical Science, Quantitative Biomedical Research Center, University of Texas Southwestern Medical Center, Dallas, TX 75390
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  • For correspondence: xiaowei.zhan@utsouthwestern.edu dajiang.liu@psu.edu
Sai Chen
2Illumina Inc. 5200 Illuminay Way, San Diego, CA 92122
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Yu Jiang
3Department of Public Health Sciences, Penn State College of Medicine, Hershey, PA, 17033
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Mengzhen Liu
4Department of Psychology, University of Minnesota, Minneapolis, MN 55454
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William G. Iacono
5Department of Psychiatry, University of Minnesota, Minneapolis, MN 55454
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John K. Hewitt
6Institute for Behavioral Genetics, University of Colorado Boulder
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John E Hokanson
7Department of Epidemiology, School of Public Health, University of Colorado Denver, Aurora, Colorado 80045
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Kenneth Krauter
6Institute for Behavioral Genetics, University of Colorado Boulder
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Markku Laakso
8Department of Medicine, University of Eastern Finland and Kuopio University Hospital, Kuopio, Finland
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Kevin W. Li
9Center of Statistical Genetics, Department of Biostatistcs, University of Michigan, Ann Arbor, MI, 48109
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Sharon M Lutz
10Department of Biostatistics and Informatics, University of Colorado, Anschutz Medical Campus, Aurora, CO
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Matthew McGue
5Department of Psychiatry, University of Minnesota, Minneapolis, MN 55454
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Anita Pandit
9Center of Statistical Genetics, Department of Biostatistcs, University of Michigan, Ann Arbor, MI, 48109
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Gregory JM Zajac
9Center of Statistical Genetics, Department of Biostatistcs, University of Michigan, Ann Arbor, MI, 48109
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Michael Boehnke
9Center of Statistical Genetics, Department of Biostatistcs, University of Michigan, Ann Arbor, MI, 48109
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Goncalo R. Abecasis
9Center of Statistical Genetics, Department of Biostatistcs, University of Michigan, Ann Arbor, MI, 48109
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Bibo Jiang
3Department of Public Health Sciences, Penn State College of Medicine, Hershey, PA, 17033
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Scott I. Vrieze
4Department of Psychology, University of Minnesota, Minneapolis, MN 55454
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Dajiang J. Liu
3Department of Public Health Sciences, Penn State College of Medicine, Hershey, PA, 17033
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  • For correspondence: xiaowei.zhan@utsouthwestern.edu dajiang.liu@psu.edu
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Abstract

Motivation: There is great interest to understand the impact of rare variants in human diseases using large sequence datasets. In deep sequences datasets of >10,000 samples, ∼10% of the variant sites are observed to be multi-allelic. Many of the multi-allelic variants have been shown to be functional and disease relevant. Proper analysis of multi-allelic variants is critical to the success of a sequencing study, but existing methods do not properly handle multi-allelic variants and can produce highly misleading association results.

Results: We propose novel methods to encode multi-allelic sites, conduct single variant and gene-level association analyses, and perform meta-analysis for multi-allelic variants. We evaluated these methods through extensive simulations and the study of a large meta-analysis of ∼18,000 samples on the cigarettes-per-day phenotype. We showed that our joint modeling approach provided an unbiased estimate of genetic effects, greatly improved the power of single variant association tests, and enhanced gene-level tests over existing approaches.

Availability: Software packages implementing these methods are available at (https://github.com/zhanxw/rvtests http://genome.sph.umich.edu/wiki/RareMETAL).

Contact: xiaowei.zhan@utsouthwestem.edu; dajiang.liu@psu.edu

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Posted October 03, 2017.
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Association Analysis and Meta-Analysis of Multi-allelic Variants for Large Scale Sequence Data
Xiaowei Zhan, Sai Chen, Yu Jiang, Mengzhen Liu, William G. Iacono, John K. Hewitt, John E Hokanson, Kenneth Krauter, Markku Laakso, Kevin W. Li, Sharon M Lutz, Matthew McGue, Anita Pandit, Gregory JM Zajac, Michael Boehnke, Goncalo R. Abecasis, Bibo Jiang, Scott I. Vrieze, Dajiang J. Liu
bioRxiv 197913; doi: https://doi.org/10.1101/197913
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Association Analysis and Meta-Analysis of Multi-allelic Variants for Large Scale Sequence Data
Xiaowei Zhan, Sai Chen, Yu Jiang, Mengzhen Liu, William G. Iacono, John K. Hewitt, John E Hokanson, Kenneth Krauter, Markku Laakso, Kevin W. Li, Sharon M Lutz, Matthew McGue, Anita Pandit, Gregory JM Zajac, Michael Boehnke, Goncalo R. Abecasis, Bibo Jiang, Scott I. Vrieze, Dajiang J. Liu
bioRxiv 197913; doi: https://doi.org/10.1101/197913

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