Testing groups of genomic locations for enrichment in disease loci using linkage scan data: a method for hypothesis testing.
Genes for complex disorders have proven hard to find using linkage analysis. The results rarely reach the desired level of significance and researchers often have failed to replicate positive findings. There is, however, a wealth of information from other scientific approaches which enables the formation of hypotheses on groups of genes or genomic regions likely to be enriched in disease loci. Examples include genes belonging to specific pathways or producing proteins interacting with known risk factors, genes that show altered expression levels in patients or even the group of top scoring locations in a linkage study. We show here that this hypothesis of enrichment for disease loci can be tested using genome-wide linkage data, provided that these data are independent from the data used to generate the hypothesis. Our method is based on the fact that non-parametric linkage analyses are expected to show increased scores at each one of the disease loci, although this increase might not rise above the noise of stochastic variation. By using a summary statistic and calculating its empirical significance, we show that enrichment hypotheses can be tested with power higher than the power of the linkage scan data to identify individual loci. Via simulated linkage scans for a number of different models, we gain insight in the interpretation of genome scan results and test the power of our proposed method. We present an application of the method to real data from a late-onset Alzheimer's disease linkage scan as a proof of principle.
Avramopoulos
Dimitrios
D
Department of Psychiatry, The Johns Hopkins University, School of Medicine, Broadway Research Building 509, 733 North Broadway, Baltimore, MD 21205, USA. adimitr1@jhmi.edu
Zandi
Peter
P
Gherman
Adrian
A
Fallin
M Daniele
MD
Bassett
Susan S
SS
D000544:Alzheimer Disease / Q000453:epidemiology; D008040:Genetic Linkage / Q000235:genetics*; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D015894:Genome, Human / Q000235:genetics*; D023281:Genomics; D006801:Humans; D008957:Models, Genetic; D010375:Pedigree; D035781:Siblings; D018709:Statistics, Nonparametric