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Association Testing of Clustered Rare Causal Variants in Case-Control Studies

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  • Wan-Yu Lin

Abstract

Biological evidence suggests that multiple causal variants in a gene may cluster physically. Variants within the same protein functional domain or gene regulatory element would locate in close proximity on the DNA sequence. However, spatial information of variants is usually not used in current rare variant association analyses. We here propose a clustering method (abbreviated as “CLUSTER”), which is extended from the adaptive combination of P-values. Our method combines the association signals of variants that are more likely to be causal. Furthermore, the statistic incorporates the spatial information of variants. With extensive simulations, we show that our method outperforms several commonly-used methods in many scenarios. To demonstrate its use in real data analyses, we also apply this CLUSTER test to the Dallas Heart Study data. CLUSTER is among the best methods when the effects of causal variants are all in the same direction. As variants located in close proximity are more likely to have similar impact on disease risk, CLUSTER is recommended for association testing of clustered rare causal variants in case-control studies.

Suggested Citation

  • Wan-Yu Lin, 2014. "Association Testing of Clustered Rare Causal Variants in Case-Control Studies," PLOS ONE, Public Library of Science, vol. 9(4), pages 1-6, April.
  • Handle: RePEc:plo:pone00:0094337
    DOI: 10.1371/journal.pone.0094337
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    Cited by:

    1. Elodie Persyn & Richard Redon & Lise Bellanger & Christian Dina, 2018. "The impact of a fine-scale population stratification on rare variant association test results," PLOS ONE, Public Library of Science, vol. 13(12), pages 1-17, December.
    2. Rachel Marceau West & Wenbin Lu & Daniel M Rotroff & Melaine A Kuenemann & Sheng-Mao Chang & Michael C Wu & Michael J Wagner & John B Buse & Alison A Motsinger-Reif & Denis Fourches & Jung-Ying Tzeng, 2019. "Identifying individual risk rare variants using protein structure guided local tests (POINT)," PLOS Computational Biology, Public Library of Science, vol. 15(2), pages 1-24, February.

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