title: Identifying genomic regions for fine-mapping using genome scan meta-analysis (GSMA) to identify the minimum regions of maximum significance (MRMS) across populations.
abstract: In order to detect linkage of the simulated complex disease Kofendrerd Personality Disorder across studies from multiple populations, we performed a genome scan meta-analysis (GSMA). Using the 7-cM microsatellite map, nonparametric multipoint linkage analyses were performed separately on each of the four simulated populations independently to determine p-values. The genome of each population was divided into 20-cM bin regions, and each bin was rank-ordered based on the most significant linkage p-value for that population in that region. The bin ranks were then averaged across all four studies to determine the most significant 20-cM regions over all studies. Statistical significance of the averaged bin ranks was determined from a normal distribution of randomly assigned rank averages. To narrow the region of interest for fine-mapping, the meta-analysis was repeated two additional times, with each of the 20-cM bins offset by 7 cM and 13 cM, respectively, creating regions of overlap with the original method. The 6-7 cM shared regions, where the highest averaged 20-cM bins from each of the three offsets overlap, designated the minimum region of maximum significance (MRMS). Application of the GSMA-MRMS method revealed genome wide significance (p-values refer to the average rank assigned to the bin) at regions including or adjacent to all of the simulated disease loci: chromosome 1 (p < 0.0001 for 160-167 cM, including D1), chromosome 3 (p-value < 0.0000001 for 287-294 cM, including D2), chromosome 5 (p-value < 0.001 for 0-7 cM, including D3), and chromosome 9 (p-value < 0.05 for 7-14 cM, the region adjacent to D4). This GSMA analysis approach demonstrates the power of linkage meta-analysis to detect multiple genes simultaneously for a complex disorder. The MRMS method enhances this powerful tool to focus on more localized regions of linkage.
authors.affiliation: Center for Craniofacial and Dental Genetics, School of Dental Medicine, University of Pittsburgh, Pittsburgh, PA 15219, USA. cooperm@sdmgenetics.pitt.edu
authors.forename: Margaret E
authors.initials: ME
authors.lastname: Cooper
authors.forename: Toby H
authors.initials: TH
authors.lastname: Goldstein
authors.forename: Brion S
authors.initials: BS
authors.lastname: Maher
authors.forename: Mary L
authors.initials: ML
authors.lastname: Marazita
mesh_terms: D002877:Chromosomes, Human / Q000235:genetics*; D008040:Genetic Linkage; D005828:Genetics, Population; D015894:Genome, Human / Q000235:genetics*; D055106:Genome-Wide Association Study; D006801:Humans; D020161:Physical Chromosome Mapping; D018709:Statistics, Nonparametric