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Rare Variant Analysis for Family-Based Design

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  • Gourab De
  • Wai-Ki Yip
  • Iuliana Ionita-Laza
  • Nan Laird

Abstract

Genome-wide association studies have been able to identify disease associations with many common variants; however most of the estimated genetic contribution explained by these variants appears to be very modest. Rare variants are thought to have larger effect sizes compared to common SNPs but effects of rare variants cannot be tested in the GWAS setting. Here we propose a novel method to test for association of rare variants obtained by sequencing in family-based samples by collapsing the standard family-based association test (FBAT) statistic over a region of interest. We also propose a suitable weighting scheme so that low frequency SNPs that may be enriched in functional variants can be upweighted compared to common variants. Using simulations we show that the family-based methods perform at par with the population-based methods under no population stratification. By construction, family-based tests are completely robust to population stratification; we show that our proposed methods remain valid even when population stratification is present.

Suggested Citation

  • Gourab De & Wai-Ki Yip & Iuliana Ionita-Laza & Nan Laird, 2013. "Rare Variant Analysis for Family-Based Design," PLOS ONE, Public Library of Science, vol. 8(1), pages 1-9, January.
    • Handle: RePEc:plo:pone00:0048495
    DOI: 10.1371/journal.pone.0048495
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    References listed on IDEAS

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    1. Thomas J Hoffmann & Nicholas J Marini & John S Witte, 2010. "Comprehensive Approach to Analyzing Rare Genetic Variants," PLOS ONE, Public Library of Science, vol. 5(11), pages 1-9, November.
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    Cited by:

    1. Anshuman Sewda & A J Agopian & Elizabeth Goldmuntz & Hakon Hakonarson & Bernice E Morrow & Deanne Taylor & Laura E Mitchell & on behalf of the Pediatric Cardiac Genomics Consortium, 2019. "Gene-based genome-wide association studies and meta-analyses of conotruncal heart defects," PLOS ONE, Public Library of Science, vol. 14(7), pages 1-19, July.
    2. Wenjing Qi & Andrew S Allen & Yi-Ju Li, 2019. "Family-based association tests for rare variants with censored traits," PLOS ONE, Public Library of Science, vol. 14(1), pages 1-17, January.

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