title: A spectral approach integrating functional genomic annotations for coding and noncoding variants.
abstract: Over the past few years, substantial effort has been put into the functional annotation of variation in human genome sequences. Such annotations can have a critical role in identifying putatively causal variants for a disease or trait among the abundant natural variation that occurs at a locus of interest. The main challenges in using these various annotations include their large numbers and their diversity. Here we develop an unsupervised approach to integrate these different annotations into one measure of functional importance (Eigen) that, unlike most existing methods, is not based on any labeled training data. We show that the resulting meta-score has better discriminatory ability using disease-associated and putatively benign variants from published studies (in both coding and noncoding regions) than the recently proposed CADD score. Across varied scenarios, the Eigen score performs generally better than any single individual annotation, representing a powerful single functional score that can be incorporated in fine-mapping studies.
authors.affiliation: Department of Biostatistics, Columbia University, New York, New York, USA.
authors.forename: Iuliana
authors.initials: I
authors.lastname: Ionita-Laza
authors.affiliation: Department of Biostatistics, Columbia University, New York, New York, USA.
authors.forename: Kenneth
authors.initials: K
authors.lastname: McCallum
authors.affiliation: Department of Psychiatry, Columbia University, New York, New York, USA.
authors.forename: Bin
authors.initials: B
authors.lastname: Xu
authors.affiliation: Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, New York, USA.|Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, New York, USA.|Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA.|Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, New York, USA.|Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
authors.forename: Joseph D
authors.initials: JD
authors.lastname: Buxbaum
mesh_terms: D020022:Genetic Predisposition to Disease; D015894:Genome, Human; D006801:Humans; D009154:Mutation; D040641:Quantitative Trait Loci