The sumLINK statistic for genetic linkage analysis in the presence of heterogeneity

Abstract

We present the "sumLINK" statistic--the sum of multipoint LOD scores for the subset of pedigrees with nominally significant linkage evidence at a given locus--as an alternative to common methods to identify susceptibility loci in the presence of heterogeneity. We also suggest the "sumLOD" statistic (the sum of positive multipoint LOD scores) as a companion to the sumLINK. sumLINK analysis identifies genetic regions of extreme consistency across pedigrees without regard to negative evidence from unlinked or uninformative pedigrees. Significance is determined by an innovative permutation procedure based on genome shuffling that randomizes linkage information across pedigrees. This procedure for generating the empirical null distribution may be useful for other linkage-based statistics as well. Using 500 genome-wide analyses of simulated null data, we show that the genome shuffling procedure results in the correct type 1 error rates for both the sumLINK and sumLOD. The power of the statistics was tested using 100 sets of simulated genome-wide data from the alternative hypothesis from GAW13. Finally, we illustrate the statistics in an analysis of 190 aggressive prostate cancer pedigrees from the International Consortium for Prostate Cancer Genetics, where we identified a new susceptibility locus. We propose that the sumLINK and sumLOD are ideal for collaborative projects and meta-analyses, as they do not require any sharing of identifiable data between contributing institutions. Further, loci identified with the sumLINK have good potential for gene localization via statistical recombinant mapping, as, by definition, several linked pedigrees contribute to each peak.

Figure 1

Shuffling procedure for creating null distribution. A) Raw test statistic is calculated across un-shuffled data at regular intervals throughout the genome. Figure shows five pedigrees (rows) and four chromosomes (columns). B) Chromosomes are connected end-to-end in random order within each pedigree, and the resulting loop is broken at a random location to create a new starting point. C) The new starting points are aligned, and null statistics can be calculated along the shuffled genome.

Figure 2

Simplistic illustration of the calculation of the sumLINK statistic. The linkage evidence for three pedigrees (broken lines) are shown across 6 loci. The sumLINK calculated from these three pedigrees in shown by the heavy black line. Pedigree LOD scores that are marked with a diamond meet the threshold for inclusion and these are summed to produce the sumLINK. Pedigree LOD scores marked with a cross do not meet the threshold for inclusion and do not contribute to the sumLINK.

Figure 3

Genome-wide multipoint sumLINK results (dominant model) and sumLOD results (recessive model) for the ICPCG aggressive prostate cancer data.

Figure 4

LOD traces for each pedigree contributing to the linkage results on chromosomes A) 20-dominant, B) 11-recessive, and C) 2-dominant. Black bars indicate the two-recombinant localization regions.