Linkage analysis of alcohol dependence using both affected and discordant sib pairs

Abstract

The basic idea of affected-sib-pair (ASP) linkage analysis is to test whether the inheritance pattern of a marker deviates from Mendelian expectation in a sample of ASPs. The test depends on an assumed Mendelian control distribution of the number of marker alleles shared identical by descent (IBD), i.e., 1/4, 1/2, and 1/4 for 2, 1, and 0 allele(s) IBD, respectively. However, Mendelian transmission may not always hold, for example because of inbreeding or meiotic drive at the marker or a nearby locus. A more robust and valid approach is to incorporate discordant-sib-pairs (DSPs) as controls to avoid possible false-positive results. To be robust to deviation from Mendelian transmission, here we analyzed Collaborative Study on the Genetics of Alcoholism data by modifying the ASP LOD score method to contrast the estimated distribution of the number of allele(s) shared IBD by ASPs with that by DSPs, instead of with the expected distribution under the Mendelian assumption. This strategy assesses the difference in IBD sharing between ASPs and the IBD sharing between DSPs. Further, it works better than the conventional LOD score ASP linkage method in these data in the sense of avoiding false-positive linkage evidence.

High-Density Single Nucleotide Polymorphism Genome-Wide Linkage Scan for Susceptibility Genes for Diabetic Nephropathy in Type 1 Diabetes

“…Such consistency would not be expected were the results due to genotyping errors. Inclusion of diabetic nephropathy ASPs would have been another way to mitigate the risk of misgenotyping, and methods to analyze DSPs and ASPs together exist (28,29). However, as documented (7), collection of diabetic nephropathy ASPs is extremely difficult and, being concordant for both diabetic nephropathy and type 1 diabetes, these siblings would present an additional challenge in terms of interpretation.…”

Advances in statistical human genetics over the last 25 years

“…Analogous to the use of the original HE regression for binary traits, this formulation has been extended to compare the allele sharing between concordant and discordant sib pairs [131], making it robust to segregation distortion. However, there is a difference in how covariates are to be interpreted in the two models [107], which we can expect will be reflected in the relative power of the two models to detect linkage in different situations.…”

Linkage mapping methods applied to the COGA data set: Presentation Group 4 of Genetic Analysis Workshop 14

“…Doan et al [2005] used all affected relative pairs. Xu et al [2005] used nonoverlapping affected relative pairs, Yoon et al [2005] used all sib pairs, and Shih et al [2005] used affected and discordant sib pairs. There were also differences in the genetic markers examined.…”

“…Two groups [Daw et al, 2005;Hinrichs et al, 2005] sought to compare SNP markers with microsatellite markers on chromosome 7. Four groups [Doan et al, 2005;Shih et al, 2005;Xu et al, 2005;Yoon et al, 2005] focused on the genome-wide microsatellite marker data. Williams et al [2005] used the genome-wide microsatellite data and SNP data on chromosomes where linkage was found to the microsatellites.…”

“…A complete description of the data used here can be found in Edenberg et al [2005]. Six of the papers in our group analyzed linkage to an alcoholism diagnosis: four chose the ALDX1 diagnosis, which was based on criteria from DSM-III-R and Feighner [Doan et al, 2005;Shih et al, 2005;Williams et al, 2005;Yoon et al, 2005, Feighner et al, 1972DSM-III-R, 1987]; one chose the ALDX2 diagnosis, which was based on DSM-IV alcohol dependence criteria [Xu et al, 2005]; and one used a combined ALDX1 and ALDX2 phenotype [Libiger and Schork, 2005]. One paper analyzed linkage to one of the electrophysiological endophenotypes, ttth1, the response at the FP1 electrode to the target case of the Visual Oddball Experiment [Daw et al, 2005].…”