A multi-dimensional integrative scoring framework for predicting functional variants in the human genome.

Attempts to identify and prioritize functional DNA elements in coding and non-coding regions, particularly through use of in silico functional annotation data, continue to increase in popularity. However, specific functional roles can vary widely from one variant to another, making it challenging to summarize different aspects of variant function with a one-dimensional rating. Here we propose multi-dimensional annotation-class integrative estimation (MACIE), an unsupervised multivariate mixed-model framework capable of integrating annotations of diverse origin to assess multi-dimensional functional roles for both coding and non-coding variants. Unlike existing one-dimensional scoring methods, MACIE views variant functionality as a composite attribute encompassing multiple characteristics and estimates the joint posterior functional probabilities of each genomic position. This estimate offers more comprehensive and interpretable information in the presence of multiple aspects of functionality. Applied to a variety of independent coding and non-coding datasets, MACIE demonstrates powerful and robust performance in discriminating between functional and non-functional variants. We also show an application of MACIE to fine-mapping and heritability enrichment analysis by using the lipids GWAS summary statistics data from the European Network for Genetic and Genomic Epidemiology Consortium.

A framework for detecting noncoding rare-variant associations of large-scale whole-genome sequencing studies.

Large-scale whole-genome sequencing studies have enabled analysis of noncoding rare-variant (RV) associations with complex human diseases and traits. Variant-set analysis is a powerful approach to study RV association. However, existing methods have limited ability in analyzing the noncoding genome. We propose a computationally efficient and robust noncoding RV association detection framework, STAARpipeline, to automatically annotate a whole-genome sequencing study and perform flexible noncoding RV association analysis, including gene-centric analysis and fixed window-based and dynamic window-based non-gene-centric analysis by incorporating variant functional annotations. In gene-centric analysis, STAARpipeline uses STAAR to group noncoding variants based on functional categories of genes and incorporate multiple functional annotations. In non-gene-centric analysis, STAARpipeline uses SCANG-STAAR to incorporate dynamic window sizes and multiple functional annotations. We apply STAARpipeline to identify noncoding RV sets associated with four lipid traits in 21,015 discovery samples from the Trans-Omics for Precision Medicine (TOPMed) program and replicate several of them in an additional 9,123 TOPMed samples. We also analyze five non-lipid TOPMed traits.

FAVOR: functional annotation of variants online resource and annotator for variation across the human genome.

Large biobank-scale whole genome sequencing (WGS) studies are rapidly identifying a multitude of coding and non-coding variants. They provide an unprecedented resource for illuminating the genetic basis of human diseases. Variant functional annotations play a critical role in WGS analysis, result interpretation, and prioritization of disease- or trait-associated causal variants. Existing functional annotation databases have limited scope to perform online queries and functionally annotate the genotype data of large biobank-scale WGS studies. We develop the Functional Annotation of Variants Online Resources (FAVOR) to meet these pressing needs. FAVOR provides a comprehensive multi-faceted variant functional annotation online portal that summarizes and visualizes findings of all possible nine billion single nucleotide variants (SNVs) across the genome. It allows for rapid variant-, gene- and region-level queries of variant functional annotations. FAVOR integrates variant functional information from multiple sources to describe the functional characteristics of variants and facilitates prioritizing plausible causal variants influencing human phenotypes. Furthermore, we provide a scalable annotation tool, FAVORannotator, to functionally annotate large-scale WGS studies and efficiently store the genotype and their variant functional annotation data in a single file using the annotated Genomic Data Structure (aGDS) format, making downstream analysis more convenient. FAVOR and FAVORannotator are available at https://favor.genohub.org.