A multiple splitting approach to linkage analysis in large pedigrees identifies a linkage to asthma on chromosome 12

Abstract

Large genealogies are potentially very informative for linkage analysis. However, the software available for exact nonparametric multipoint linkage analysis is limited with respect to the complexity of the families it can handle. A solution is to split the large pedigrees into sub-families meeting complexity constraints. Different methods have been proposed to “best” split large genealogies. Here, we propose a new procedure in which linkage is performed on several carefully chosen sub-pedigree sets from the genealogy instead of using just a single sub-pedigree set. Our multiple splitting procedure capitalizes on the sensitivity of linkage results to family structure and has been designed to control computational feasibility and global type I error. We describe and apply this procedure to the extreme case of the highly complex Hutterite pedigree and use it to perform a genome-wide linkage analysis on asthma. The detection of a genome-wide significant linkage for asthma on chromosome 12q21 illustrates the potential of this multiple splitting approach.

Refining genome-wide linkage intervals using a meta-analysis of genome-wide association studies identifies loci influencing personality dimensions

“…However, they demonstrated similar profiles of LODs for all analyzed traits (Spearman's correlations varied from 0.6 (Po0.001) to 0.8 (Po0.001)), which allowed us to use the maximum of three values of LOD for each marker locus. 47 In accordance with Bonferroni correction, suggestive and significant thresholds were estimated as 2.34 and 3.75, respectively. The analysis was based on 2244 genotyped and phenotyped persons from ERF.…”

Linkage Analysis with Dense SNP Maps in Isolated Populations

“…Consequently, linkage with chromosome 12 using the microsatellite map was reanalyzed considering these individuals only (the results presented hereafter are thus slightly different from the results in Bellenguez et al [35] ). A maximum LOD score of 3.78 is detected at 95.17 cM (about 83 Mb) in a sub-pedigree set, which is comprised of 16 extended sub-pedigrees and includes 206 genotyped and 104 affected individuals.…”

“…In a previous study [35] , we used a multiple pedigree splitting approach to perform linkage analysis for asthma symptoms with the microsatellite markers. Several different sub-pedigree sets, resulting from breaking the 1,840-member Hutterite pedigree with GREFFA [18] , were analysed.…”

“…Our study is based on a sample of individuals phenotyped for asthma related traits and genotyped for both microsatellite markers and the 500K Affymetrix SNP chip. To evaluate the amount of linkage information that can be extracted from the SNP map when LD is minimized, we consider a 30 Mb region on chromosome 12 where we detected a linkage signal with microsatellite markers, using a novel multiple pedigree splitting approach [35] . We start by considering two methods based on a block description of the LD pattern, one modelling LD in the linkage analysis [6] and another selecting a subset of SNPs with minimum LD, SNPLINK [17] .…”

Genome-Wide Linkage Scan Maps ETINPH Gene to Chromosome 19q12–13.31

“…During the genome-wide scan, a model-dependent and a nonparametric linkage analysis of dense SNPs arrays were performed using sparse gene flow tree algorithms as implemented in Merlin [26] , with a splitting approach due to the large size of the pedigree [27] . For fine-mapping, with the parameters of an autosomal dominant trait with a rare disease frequency of 0.0001 and full penetrance [23] , a two-point modeldependent linkage analysis of the full pedigree was performed using the genotype/phase elimination algorithms implemented in LODLINK in the S.A.G.E.…”