Abstract
Recent advances in high-throughput sequencing technologies make it increasingly more efficient to sequence large cohorts for many complex traits. We discuss here a class of sequence-based association tests for family-based designs that corresponds naturally to previously proposed population-based tests, including the classical Burden and variance-component tests. This framework allows for a direct comparison between the powers of sequence-based association tests with family- vs population-based designs. We show that for dichotomous traits using family-based controls results in similar power levels as the population-based design (although at an increased sequencing cost for the family-based design), while for continuous traits (in random samples, no ascertainment) the population-based design can be substantially more powerful. A possible disadvantage of population-based designs is that they can lead to increased false-positive rates in the presence of population stratification, while the family-based designs are robust to population stratification. We show also an application to a small exome-sequencing family-based study on autism spectrum disorders. The tests are implemented in publicly available software.
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Acknowledgements
The research was partially supported by National Science Foundation grant DMS-1100279 and National Institutes of Health grants R01MH095797 and 1R03HG005908 (to II-L), a Seaver Foundation grant and National Institutes of Health grants MH089025 and (to JDB) and National Institutes of Health grants R37 CA076404 and P01CA134294 (to SL and XL).
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Ionita-Laza, I., Lee, S., Makarov, V. et al. Family-based association tests for sequence data, and comparisons with population-based association tests. Eur J Hum Genet 21, 1158–1162 (2013). https://doi.org/10.1038/ejhg.2012.308
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DOI: https://doi.org/10.1038/ejhg.2012.308
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