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Genome-wide association tests of inversions with application to psoriasis

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Abstract

Although inversions have occasionally been found to be associated with disease susceptibility through interrupting a gene or its regulatory region, or by increasing the risk for deleterious secondary rearrangements, no association study has been specifically conducted for risks associated with inversions, mainly because existing approaches to detecting and genotyping inversions do not readily scale to a large number of samples. Based on our recently proposed approach to identifying and genotyping inversions using principal components analysis (PCA), we herein develop a method of detecting association between inversions and disease in a genome-wide fashion. Our method uses genotype data for single nucleotide polymorphisms (SNPs), and is thus cost-efficient and computationally fast. For an inversion polymorphism, local PCA around the inversion region is performed to infer the inversion genotypes of all samples. For many inversions, we found that some of the SNPs inside an inversion region are fixed in the two lineages of different orientations and thus can serve as surrogate markers. Our method can be applied to case–control and quantitative trait association studies to identify inversions that may interrupt a gene or the connection between a gene and its regulatory agents. Our method also offers a new venue to identify inversions that are responsible for disease-causing secondary rearrangements. We illustrated our proposed approach to case–control data for psoriasis and identified novel associations with a few inversion polymorphisms.

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Acknowledgments

This work has been supported by NIH grant R01CA134682. JM also acknowledge the support provided by the Biostatistics/Epidemiology/Research Design (BERD) component of the Center for Clinical and Translational Sciences (CCTS) for this project. CCTS is mainly funded by the NIH Centers for Translational Science Award (NIH CTSA) grant (UL1 RR024148), awarded to University of Texas Health Science Center at Houston in 2006 by the National Center for Research Resources (NCRR) and its renewal (UL1 TR000371) by the National Center for Advancing Translational Sciences (NCATS).

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Authors and Affiliations

  1. Biostatistics/Epidemiology/Research Design Core, Center for Clinical and Translational Sciences, The University of Texas Health Science Center at Houston, Houston, TX, 77030, USA

    Jianzhong Ma

  2. Division of Epidemiology, Human Genetics, and Environmental Sciences, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX, 77030, USA

    Jianzhong Ma

  3. Division of Biostatistics, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX, 77030, USA

    Momiao Xiong

  4. Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, WI, 53226, USA

    Ming You

  5. Department of Genetics, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA

    Guillermina Lozano

  6. Department of Community and Family Medicine, Geisel School of Medicine, Dartmouth College, 46 Centerra Parkway, Suite 330, Lebanon, NH, 03766, USA

    Christopher I. Amos

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  1. Jianzhong Ma
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  2. Momiao Xiong
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  3. Ming You
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  4. Guillermina Lozano
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  5. Christopher I. Amos
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Corresponding authors

Correspondence to Jianzhong Ma or Christopher I. Amos.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplemental Data.

Supplemental Data include eight tables.

Online Resource 1: Table S1. List of inversions with surrogate SNPs including known inversions from the DGV and those predicted using the PCA-based approach.

Online Resource 2: Table S2. Inversions significantly associated with psoriasis observed from the original data set.

Online Resource 3: Table S3. Inversions significantly associated with psoriasis observed from the replicate data set.

Online Resource 4: Table S4-S8. Inversion-genotype frequencies for the five inversions identified to be significantly associated with psoriasis.

Supplementary material 1 (XLSX 186 kb)

Supplementary material 2 (XLSX 15 kb)

Supplementary material 3 (XLSX 14 kb)

Supplementary material 4 (PDF 29 kb)

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Ma, J., Xiong, M., You, M. et al. Genome-wide association tests of inversions with application to psoriasis. Hum Genet 133, 967–974 (2014). https://doi.org/10.1007/s00439-014-1437-1

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