Identifying individual risk rare variants using protein structure-guided local tests (POINT)

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 associated with low-density lipoprotein in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) clinical trial data. Author summaryWhile 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 May 23, 2018 2/31 . CC-BY 4.0 International license It is made available under a (which was not peer-reviewed) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.The copyright holder for this preprint . http://dx.doi.org/10.1101/333245 doi: bioRxiv preprint first posted online May. 29, 2018; from neighboring variants in the protein in a robust manner. We show how POINT improves selection performance over single variant tests and sliding window approaches.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 five promising variants within PCSK9 in association with low-density lipoprotein, including thr...

An association test of the spatial distribution of rare missense variants within protein structures identifies Alzheimer's disease–related patterns

“…We test the structure kernel approach implemented in POKEMON and compare it to two other structure-informed association methods, PSCAN and POINT (Tang et al 2020;Marceau West et al 2019) and a frequency-based kernel analogous to a SKAT analysis of missense variants (Figure 1). We evaluated the false positive rate (FPR) of POKEMON with the structure kernel and found that the averaged FPR is 0.0455 for all simulated configurations (Supplemental Fig…”