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Chunk #14 — MATERIALS AND METHODS — Linkage Analyses

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Autosomal linkage scan for loci predisposing to comorbid dependence on multiple substances.
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Empirical thresholds for autosome-wide suggestive and significant linkages were determined by Monte Carlo simulations under the null hypothesis of random linkage via a gene-dropping algorithm in Merlin. We simulated 1,000 data sets conditional on the observed family structure, marker spacing, allele frequencies, and missing data pattern [Sawcer et al., 1997; Kruglyak and Daly, 1998]. A marker set with low LD of r2 < 0.1 was selected for each pair of markers (3,675 SNPs in AAs and 3,760 SNPs in EAs) to reduce computational burden. Regression-based linkage analysis, the same approach used for the observed data, was then carried out for each simulated dataset and the highest lod score for each chromosome was retained. The autosome-wide suggestive linkage threshold is defined as the maximum lod score expected once by chance per genome scan [Lander and Kruglyak, 1995], and is set as the 1,000th highest lod score out of 22,000 lod scores for each of the 22 autosomal chromosomes from the 1,000 simulations. The autosome-wide significant threshold is set as the 95th percentile of the 22,000 lod scores. The empirical “suggestive” and