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Identification of Genes Underlying Polygenic Obesity in Animal Models
Published in Claude Bouchard, The Genetics of Obesity, 2020
Craig H. Warden, Janis S. Fisler
The ability to analyze phenotype and genotype information for QTLs in model systems is combined in the Mapmaker29 and Mapmaker/QTL programs.22 The QTL analysis requires the construction of genetic linkage maps of ordered markers which can be constructed from primary data using the Mapmaker program.29 This program is interactive and relatively easy to use; the linkage maps constructed can be used directly by the Mapmaker/QTL program. Mapmaker/QTL uses genetic linkage maps along with quantitative phenotype data to locate QTLs by an efficient interval mapping method that calculates log-of-the-odds (LOD) scores for each quantitative trait at 1- to 2-centimorgan (cM) intervals between each marker.23 This gives Mapmaker/QTL the ability to detect QTLs in between linked markers. LOD scores provide a measure of the significance of linkage of trait and genotype. A LOD score of 3.0 or greater is a statistically significant evidence of linkage. While Mapmaker/QTL is an easy-to-use interactive program, it nevertheless should be used with some care. For instance, since the program uses a missing data algorithm to estimate the genotypes between markers, in some cases the estimated genotypes may give false positive LOD score results. Thus, the Mapmaker/QTL program cannot be used to prove the existence of a QTL between two linked markers, but rather guides one in the selection of additional markers to genotype in a cross at the sites of putative QTLs.
Molecular Genetic Diagnosis of Human Malignant Hyperthermia
Published in S. Tsuyoshi Ohnishi, Tomoko Ohnishi, Malignant Hyperthermia, 1994
The first step in linkage analysis is to isolate DNA from each family member’s white blood cells. Restriction enzymes are used to digest the DNA that is then separated by size and Southern blotted. A LOD score is calculated for each marker and the disease phenotype at various recombination frequencies. Computer programs (LIPED, LINKAGE) perform the requisite calculations after the mechanism of inheritance, and estimates of penetrance and mutation rate are specified.46 As the search narrows, higher LOD scores at lower recombination fractions may be generated by selection of other markers in the region.
Prevalence and Genetic Epidemiology of Developmental Disabilities
Published in Merlin G. Butler, F. John Meaney, Genetics of Developmental Disabilities, 2019
Coleen A. Boyle, Kim Van Naarden Braun, Marshalyn Yeargin-Allsopp
While no specific genes for autism have been identified to date, chromosomal regions have been identified based on genome-wide scans and linkage studies. Log-odds, more commonly known as LOD scores, represent the statistical method used in linkage studies to determine whether two loci are linked (i.e., in close enough proximity to be inherited together). Traditionally a LOD score of 2.0 or greater is suggestive of a potential association (123). Table 3 presents studies that have identified regions on chromosomes 1, 2, 7, 13, 16, and X as yielding multipoint maximum LOD scores of greater than or equal to 2.0 suggestive of potential associations. While none of the identified regions have been replicated by other studies, regions identified by different investigators have overlapped. This provides further support for the importance of a particular region. For example, the finding by the International Molecular Genetic Study of Autism Consortium (IMGSAC) of linkage on chromosome 7q (124) was found at a different, but overlapping region by Barrett et al. (125). Similar scenarios occurred for the 2q chromosomal region between Buxbaum et al. (126) and the IMGSAC and regions on the 16p chromosome by Lui et al. (127) and the IMGSAC. As previously mentioned, the phenotypic heterogeneity of study populations between studies may be significant and may account for the lack of replication of findings. Therefore, it is quite powerful when different studies identify overlapping regions on the same chromosome. The validity of these and other findings from linkage analyses will be strengthened in future research by controlling for the bias introduced by clinical heterogeneity.
Linkage analysis identifies novel genetic modifiers of microbiome traits in families with inflammatory bowel disease
Published in Gut Microbes, 2022
Arunabh Sharma, Silke Szymczak, Malte Rühlemann, Sandra Freitag-Wolf, Carolin Knecht, Janna Enderle, Stefan Schreiber, Andre Franke, Wolfgang Lieb, Michael Krawczak, Astrid Dempfle
A LOD score >3 classically has been considered indicative of statistically significant linkage because it implies that the likelihood ratio of two loci being linked rather than unlinked is at least 1000. Yet, two randomly chosen loci in the human genome are about 50 times more probable to be unlinked so that the prior odds of linkage equal 1:50. Taken together, a LOD score >3 thus corresponds to posterior odds of linkage >20, so that p < .05.55 The classical approach of adopting a one-unit support interval as a surrogate 95% confidence intervals for the location of a peak LOD signal is based upon the theory of maximum likelihood (ML) estimation, equating sampling variance of the ML estimate to the steepness of the likelihood curve around the ML estimate.56 This approach has been criticized before for providing too narrow an interval at times so that we chose to adopt a two-unit support interval instead.
Whole exome sequencing in a large pedigree with DCM identifies a novel mutation in RBM20
Published in Acta Cardiologica, 2020
Tomas Robyns, Rik Willems, Johan Van Cleemput, Shalini Jhangiani, Donna Muzny, Richard Gibbs, James R. Lupski, Jeroen Breckpot, Koenraad Devriendt, Anniek Corveleyn
WES was performed on 2 distant affected family members (III-2 and III-6 in the pedigree). Filtering of variants is illustrated in Figure 2. After filtering, 19 variants were scored using the pre-specified protocol. Of these, 9 were classified as variants of unknown significance and 1 as likely pathogenic. These 10 variants were further evaluated with co-segregation analysis (Table 2). Only the variant in RBM20 was present in all affected or borderline affected patients and not present in the unaffected individuals. The variant was classified as likely pathogenic according to the ACMG-AMP criteria due to strong co-segregation, absence from controls (1000 G, ESP and ExAC) and the fact that missense variants in this gene cause disease. The LOD score for this variant was 2.1, the maximum score obtainable in this pedigree. A variant in CPN1 was present in all tested individuals apart from one who did not have DCM. CPN1 encodes kininase, which is not linked to cardiac phenotypes or expressed in cardiac tissue and therefore presumably has no effect on the DCM observed in this pedigree.
A new perspective on the genetics of keratoconus: why have we not been more successful?
Published in Ophthalmic Genetics, 2018
Hanne Valgaeren, Carina Koppen, Guy Van Camp
KC is a disease characterized by reduced penetrance and variable expression, so more than 10 individuals need to be included in linkage analysis to obtain a LOD-score of three. Such large families are very rare. Often linkage analysis has been performed on smaller KC families, where this LOD-score of three cannot be reached, and only suggestive linkage can be observed. Multiple loci linked to KC have been reported in literature (Table 1). It is apparent that many of the loci only reach suggestive linkage (LOD < 3) and that most of the loci were not replicated by another independent study. Even if some of these loci with suggestive linkage are in fact false positive results, several loci with LOD score above three have been described (Table 1). This implicates that KC is a heterogeneous disorder, with multiple genes underlying the pathogenesis.