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Characterizing how variation at the level of individual nucleotides contributes to traits and diseases has been an area of growing interest since the completion of sequencing the first human genome. Our understanding of how a single nucleotide polymorphism (SNP) leads to a pathogenic phenotype on a genome-wide scale is a fruitful endeavor for anyone interested in developing diagnostic tests, therapeutics, or simply wanting to understand the etiology of a disease or trait. To this end, many datasets and algorithms have been developed as resources/tools to annotate SNPs. One of the most common practices is to annotate coding SNPs that affect the protein sequence. Synonymous variants are often grouped as one type of variant, however there are in fact many tools available to dissect their effects on gene expression. More recently, large consortiums like ENCODE and GTEx have made it possible to annotate non-coding regions. Although annotating variants is a common technique among human geneticists, the constant advances in tools and biology surrounding SNPs requires an updated summary of what is known and the trajectory of the field. This review will discuss the history behind SNP annotation, commonly used tools, and newer strategies for SNP annotation. Additionally, we will comment on the caveats that distinguish approaches from one another, along with gaps in the current state of knowledge, and potential future directions. We do not intend for this to be a comprehensive review for any specific area of SNP annotation, but rather it will be an excellent resource for those unfamiliar with computational tools used to functionally characterize SNPs. In summary, this review will help illustrate how each SNP annotation method impacts the way in which the genetic and molecular etiology of a disease is explored in-silico ., Competing Interests: Not applicable.Not applicable.The authors declare that they have no competing interests.Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Background: Machine learning methods have gained popularity and practicality in identifying linear and non-linear effects of variants associated with complex disease/traits. Detection of epistatic interactions still remains a challenge due to the large number of features and relatively small sample size as input, thus leading to the so-called "short fat data" problem. The efficiency of machine learning methods can be increased by limiting the number of input features. Thus, it is very important to perform variable selection before searching for epistasis. Many methods have been evaluated and proposed to perform feature selection, but no single method works best in all scenarios. We demonstrate this by conducting two separate simulation analyses to evaluate the proposed collective feature selection approach., Results: Through our simulation study we propose a collective feature selection approach to select features that are in the "union" of the best performing methods. We explored various parametric, non-parametric, and data mining approaches to perform feature selection. We choose our top performing methods to select the union of the resulting variables based on a user-defined percentage of variants selected from each method to take to downstream analysis. Our simulation analysis shows that non-parametric data mining approaches, such as MDR, may work best under one simulation criteria for the high effect size (penetrance) datasets, while non-parametric methods designed for feature selection, such as Ranger and Gradient boosting, work best under other simulation criteria. Thus, using a collective approach proves to be more beneficial for selecting variables with epistatic effects also in low effect size datasets and different genetic architectures. Following this, we applied our proposed collective feature selection approach to select the top 1% of variables to identify potential interacting variables associated with Body Mass Index (BMI) in ~ 44,000 samples obtained from Geisinger's MyCode Community Health Initiative (on behalf of DiscovEHR collaboration)., Conclusions: In this study, we were able to show that selecting variables using a collective feature selection approach could help in selecting true positive epistatic variables more frequently than applying any single method for feature selection via simulation studies. We were able to demonstrate the effectiveness of collective feature selection along with a comparison of many methods in our simulation analysis. We also applied our method to identify non-linear networks associated with obesity., Competing Interests: The authors declare that they have no competing interests.Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.