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.

Genome‐wide linkage analysis of 1,233 prostate cancer pedigrees from the International Consortium for prostate cancer Genetics using novel sumLINK and sumLOD analyses

“…Two other loci (1q23 and 8q12) are near peaks that were reported in the first analysis [8]. The loci on chromosomes 6p21, 11q13, and 20p11-q11 correspond to susceptibility loci previously identified in the ICPCG data resource in linkage scans for aggressive PC [11,15]. The remaining loci have not previously been identified in pooled ICPCG data, though many of them correspond to findings reported elsewhere in linkage studies by individual institutions.…”

“…This value is computed at intervals of 1 cM throughout the genome. We assess the significance of the sumLINK empirically using a unique genome randomization and shuffling method that simulates the expected consistency of linked pedigrees under null conditions [11]. Briefly, for each pedigree, the vectors of LOD scores for each chromosome are connected in random order, with the first and last values connected to form a ''loop,'' and the loop is broken at a random position to create a randomized, shuffled ''genomewide'' vector of LOD scores.…”

“…Here, we present the results of a secondary analysis of the ICPCG pooled pedigree resource using new genome-wide linkage-based statistics, the sumLINK and sumLOD, to identify PC susceptibility loci. These new statistics have been shown in simulation studies to be powerful and robust tools for identifying susceptibility loci in the presence of genetic heterogeneity [11]. The sumLINK/sumLOD approach is well-suited to analysis of pooled data resources such as this, because it requires only summary data from each constituent group which is logistically easier to attain (there are often data privacy and confidentiality concerns associated with sharing individual raw genotype data and pedigree structures).…”

Accounting for genetic heterogeneity in homozygosity mapping: application to Mendelian susceptibility to mycobacterial disease

“…For each S, a GW empirical level of significance, EmpP, is subsequently obtained through permutations. The idea of focusing only on LOD scores greater than zero and evaluating significance levels by Monte Carlo methods has already been proposed for single-point linkage4 and multipoint linkage in the context of complex traits 5. Here, we demonstrate the usefulness of the approach to GWHM.…”

An Application of the Latent p Value Method to Assess Linkage in Asthma Pedigrees

“…Valid interpretation of the C-statistic requires empirical assessment since the statistic is a function of the number of pedigrees and hence a potentially large number of free parameters, ik . Recently, Christensen et al [15] proposed the sumlink statistic to account for the presence of linkage heterogeneity. The sumlink statistic is the summation over pedigrees of classic multipoint LOD scores ( = 0) at each locus that exceed a threshold of 0.588, which corresponds to a nominal p value of 0.05.…”