| Autor: |
Ionita-Laza I; Department of Biostatistics, Columbia University, New York, New York, United States of America., Capanu M; Memorial Sloan-Kettering Cancer Center, New York, New York, United States of America., De Rubeis S; 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., McCallum K; Department of Biostatistics, Columbia University, New York, New York, United States of America., Buxbaum JD; 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. |
| Abstrakt: |
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. |
