title: Identification of rare causal variants in sequence-based studies: methods and applications to VPS13B, a gene involved in Cohen syndrome and autism.
abstract: Pinpointing the small number of causal variants among the abundant naturally occurring genetic variation is a difficult challenge, but a crucial one for understanding precise molecular mechanisms of disease and follow-up functional studies. We propose and investigate two complementary statistical approaches for identification of rare causal variants in sequencing studies: a backward elimination procedure based on groupwise association tests, and a hierarchical approach that can integrate sequencing data with diverse functional and evolutionary conservation annotations for individual variants. Using simulations, we show that incorporation of multiple bioinformatic predictors of deleteriousness, such as PolyPhen-2, SIFT and GERP++ scores, can improve the power to discover truly causal variants. As proof of principle, we apply the proposed methods to VPS13B, a gene mutated in the rare neurodevelopmental disorder called Cohen syndrome, and recently reported with recessive variants in autism. We identify a small set of promising candidates for causal variants, including two loss-of-function variants and a rare, homozygous probably-damaging variant that could contribute to autism risk.
authors.affiliation: Department of Biostatistics, Columbia University, New York, New York, United States of America.
authors.forename: Iuliana
authors.initials: I
authors.lastname: Ionita-Laza
authors.affiliation: Memorial Sloan-Kettering Cancer Center, New York, New York, United States of America.
authors.forename: Marinela
authors.initials: M
authors.lastname: Capanu
authors.affiliation: Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America; Departments of Psychiatry, Mount Sinai School of Medicine, New York, New York, United States of America.
authors.forename: Silvia
authors.initials: S
authors.lastname: De Rubeis
authors.affiliation: Department of Biostatistics, Columbia University, New York, New York, United States of America.
authors.forename: Kenneth
authors.initials: K
authors.lastname: McCallum
authors.affiliation: Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America; Departments of Psychiatry, Mount Sinai School of Medicine, New York, New York, United States of America; Departments of Genetics and Genomic Sciences, and Neuroscience, and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America; Mindich Child Health and Development Institute, Mount Sinai School of Medicine, New York, New York, United States of America.
authors.forename: Joseph D
authors.initials: JD
authors.lastname: Buxbaum
mesh_terms: D000075803:Angiopoietin-Like Protein 4; D042682:Angiopoietins / Q000235:genetics; D001321:Autistic Disorder / Q000175:diagnosis / Q000235:genetics*; D019295:Computational Biology; D003198:Computer Simulation; D002658:Developmental Disabilities / Q000175:diagnosis / Q000235:genetics; D019143:Evolution, Molecular; D005385:Fingers / Q000002:abnormalities*; D005787:Gene Frequency; D014644:Genetic Variation; D055106:Genome-Wide Association Study; D006801:Humans; D008607:Intellectual Disability / Q000175:diagnosis / Q000235:genetics*; D008831:Microcephaly / Q000175:diagnosis / Q000235:genetics*; D008957:Models, Genetic; D009123:Muscle Hypotonia / Q000175:diagnosis / Q000235:genetics*; D009216:Myopia / Q000175:diagnosis / Q000235:genetics*; D009765:Obesity / Q000175:diagnosis / Q000235:genetics*; D012162:Retinal Degeneration; D012984:Software; D033921:Vesicular Transport Proteins / Q000235:genetics*
chemical_list: C474772:ANGPTL4 protein, human; D000075803:Angiopoietin-Like Protein 4; D042682:Angiopoietins; C475722:VPS13B protein, human; D033921:Vesicular Transport Proteins