a new testing strategy to identify rare variants with either risk or protective effect on disease一个新的测试策略来识别罕见变异与疾病风险或保护作用.pdfVIP

A New Testing Strategy to Identify Rare Variants with Either Risk or Protective Effect on Disease 1 2 3. 3,4,5. Iuliana Ionita-Laza *, Joseph D. Buxbaum , Nan M. Laird , Christoph Lange 1 Department of Biostatistics, Columbia University, New York, New York, United States of America, 2 Department of Psychiatry, Mount Sinai School of Medicine, New York, New York, United States of America, 3 Department of Biostatistics, Harvard University, Boston, Massachusetts, United States of America, 4 Institute for Genomic Mathematics, University of Bonn, Bonn, Germany, 5 German Center for Neurodegenerative Diseases, Bonn, Germany Abstract Rapid advances in sequencing technologies set the stage for the large-scale medical sequencing efforts to be performed in the near future, with the goal of assessing the importance of rare variants in complex diseases. The discovery of new disease susceptibility genes requires powerful statistical methods for rare variant analysis. The low frequency and the expected large number of such variants pose great difficulties for the analysis of these data. We propose here a robust and powerful testing strategy to study the role rare variants may play in affecting susceptibility to complex traits. The strategy is based on assessing whether rare variants in a genetic region collectively occur at significantly higher frequencies in cases compared with controls (or vice versa). A main feature of the proposed methodology is that, although it is an overall test assessing a possibly large number of rare variants simultaneously, the disease variants can be both protective and risk variants, with moderate decreases in statistical power when both types of variants are present. Using simulat