 Identifying individual risk rare variants using protein structure guided local tests (POINT)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 and Jung-Ying Tzeng PLOS Computational Biology, 2019, vol. 15, issue 2, 1-24 Abstract: Rare variants are of increasing interest to genetic association studies because of their etiological contributions to human complex diseases. Due to the rarity of the mutant events, rare variants are routinely analyzed on an aggregate level. While aggregation analyses improve the detection of global-level signal, they are not able to pinpoint causal variants within a variant set. To perform inference on a localized level, additional information, e.g., biological annotation, is often needed to boost the information content of a rare variant. Following the observation that important variants are likely to cluster together on functional domains, we propose a protein structure guided local test (POINT) to provide variant-specific association information using structure-guided aggregation of signal. Constructed under a kernel machine framework, POINT performs local association testing by borrowing information from neighboring variants in the 3-dimensional protein space in a data-adaptive fashion. Besides merely providing a list of promising variants, POINT assigns each variant a p-value to permit variant ranking and prioritization. We assess the selection performance of POINT using simulations and illustrate how it can be used to prioritize individual rare variants in PCSK9, ANGPTL4 and CETP in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) clinical trial data.Author summary: While it is known that rare variants play an important role in understanding associations between genotype and complex diseases, pinpointing individual rare variants likely to be responsible for association is still a daunting task. Due to their low frequency in the population and reduced signal, localizing causal rare variants often requires additional information, such as type of DNA change or location of variant along the sequence, to be incorporated in a biologically meaningful fashion that does not overpower the genotype data. In this paper, we use the observation that important variants tend to cluster together on functional domains to propose a new approach for prioritizing rare variants: the protein structure guided local test (POINT). POINT uses a gene’s 3-dimensional protein folding structure to guide aggregation of information from neighboring variants in the protein in a robust manner. We show how POINT improves selection performance over existing methods. We further illustrate how it can be used to prioritize individual rare variants using the Action to Control Cardiovascular Risk in Diabetes (ACCORD) clinical trial data, finding promising variants within genes in association with lipoprotein-related outcomes. Date: 2019 Downloads: (external link) Related works: Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text Persistent link: https://EconPapers.repec.org/RePEc:plo:pcbi00:1006722 DOI: 10.1371/journal.pcbi.1006722 Access Statistics for this article More articles in PLOS Computational Biology from Public Library of Science |
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