'Location, Location, Location': A Spatial Approach for Rare-Variant Analysis and an Application to a Study on Nonsyndromic Cleft Lip with or Without Cleft Palate

• Activity Number: 664
• Type: Invited
• Date/Time: Thursday, August 8, 2013 : 10:30 AM to 12:20 PM
• Sponsor: WNAR
• Author(s): Heide Fier and Sungho Won and Dmitry Prokopenko and Kerstin Ludwig and Rolf Fimmers and Edwin Silverman and Marcello Pagano and Elisabeth Mangold and Christoph Lange*+
• Companies: Department of Genomic Mathematics, University of Bonn and Chung-Ang University and University of Bonn and Department of Genomics, Life and Brain Center, University of Bonn, Bonn, Germany and Institute for Medical Biometry, Informatics and Epidemiology, University of Bonn and Harvard Medical School and Harvard University and University of Bonn and Department of Biostatistics, Harvard School of Public Health
• Keywords: rare variants ; sequence data ; spatial clustering ; clustering approach ; spatial approach ; nonsyndromic cleft lip

Abstract

For the analysis of rare variants in sequence data, existing approaches provide powerful tests that can incorporate information on allele frequencies and prior biological knowledge, differences in the spatial clustering of rare variants between cases and controls cannot be incorporated. Based on the assumption that deleterious variants and protective variants cluster or occur in different parts of the genomic region of interest, we propose a testing strategy for rare variants that builds on spatial-cluster methodology and that guide the identifications of the biological relevant segments of the region. Our approach does not require assumptions about the directions of the genetic effects. In simulations, we assess the power of the clustering approach and compare it to existing methodology. Our simulation results suggest that the clustering-approach for rare variants is well powered. The efficiency of our spatial-clustering approach is not affected by the presence of rare variants that have opposite effect size directions. An application to a sequencing study for nonsyndromic cleft lip with or without cleft palate demonstrates its practical relevance.