Fast Linkage Analysis with MOD Scores Using Algebraic Calculation

Brügger, M.; Strauch, Konstantin

doi:10.1159/000369065

Cited by 6 publications

(14 citation statements)

References 45 publications

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“…While formal statistical analysis using MOD scores (Brugger & Strauch, ) did not show statistically significant associations between the OCA genes and CM risk, the trends were positive and suggestive of an effect, which requires validation in a larger series of families.…”

Section: Heterozygous Germline Variants In Oca Genes: Variants In Ocamentioning

confidence: 95%

Germline variants in oculocutaneous albinism genes and predisposition to familial cutaneous melanoma

Nathan

Johansson

Palmer

et al. 2019

Pigment Cell Melanoma Res

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Approximately 1%–2% of cutaneous melanoma (CM) is classified as strongly familial. We sought to investigate unexplained CM predisposition in families negative for the known susceptibility genes using next‐generation sequencing of affected individuals. Segregation of germline variants of interest within families was assessed by Sanger sequencing. Several heterozygous variants in oculocutaneous albinism (OCA) genes: TYR, OCA2, TYRP1 and SLC45A2, were present in our CM cohort. OCA is a group of autosomal recessive genetic disorders, resulting in pigmentation defects of the eyes, hair and skin. Missense variants classified as pathogenic for OCA were present in multiple families and some fully segregated with CM. The functionally compromised TYR p.T373K variant was present in three unrelated families. In OCA2, known pathogenic variants: p.V443I and p.N489D, were present in three families and one family, respectively. We identified a likely pathogenic SLC45A2 frameshift variant that fully segregated with CM in a family of four cases. Another four‐case family harboured cosegregating variants (p.A24T and p.R153C) of uncertain functional significance in TYRP1. We conclude that rare, heterozygous variants in OCA genes confer moderate risk for CM.

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Section: Heterozygous Germline Variants In Oca Genes: Variants In Ocamentioning

confidence: 95%

Germline variants in oculocutaneous albinism genes and predisposition to familial cutaneous melanoma

Nathan

Johansson

Palmer

et al. 2019

Pigment Cell Melanoma Res

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“…We used GHM version 3.1 [ 25 ] for MOD score calculation and trait-model parameter estimation. In particular, we used the GHM options “modcalc single,” “penetrance restriction off,” “allfreq restriction off,” “maximization dense,” and “dimensions 4” or “dimensions 5” for ni models and imprinting models, respectively.…”

Section: Methodsmentioning

confidence: 99%

“…Even if the conditions under which the MOD score provides unbiased estimates of the joint trait-marker inheritance parameters are fulfilled, the identifiability of these parameters is restricted by the type(s) of pedigrees in a given sample. In a model-based linkage analysis, such as a MOD score analysis, the penetrances, disease allele frequency, and the recombination fraction represent a reparametrization of the truly underlying allele-sharing classes [ 9 , 10 , 25 , 26 ]. In other words, allele-sharing probabilities (classes) of a given pedigree type can be expressed in terms of the joint trait-marker inheritance parameters.…”

Section: Introductionmentioning

confidence: 99%

“…Genomic imprinting implies dependence of an individual's liability to develop a disease on the parental origin of the mutated allele(s), leads to a deviation from the classic Mendelian assumption of equal contribution of parental genomes to the progeny and is, therefore, called a “parent-of-origin effect” [ 29 ]. In the context of a parametric linkage analysis, imprinting can be modelled using a 4-penetrance formulation distinguishing the heterozygotes according to the parental origin of the disease allele: f = ( f 0 , f 1 ,pat , f 1 ,mat , f 2 ), as implemented in the program GENEHUNTER-MODSCORE (GHM) [ 25 , 30 , 31 , 32 ], which is a further development of GENEHUNTER-IMPRINTING [ 33 ]. In the nonparametric context, the allele-sharing class z 1 of an ASP is split up into z 1 ,pat and z 1 ,mat according to the parental origin of the shared allele.…”

Section: Introductionmentioning

confidence: 99%

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Estimation of Trait-Model Parameters in a MOD Score Linkage Analysis

Brügger

Rospleszcz²,

Strauch³

2016

Hum Hered

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Background/Aims: Theoretically, the trait-model parameters (disease allele frequency and penetrance function) can be estimated without bias in a MOD score linkage analysis. We aimed to practically evaluate the MOD score approach regarding its ability to provide unbiased trait-model parameters for various pedigree-type and trait-model scenarios. We further investigated the ability of the MOD score approach to detect imprinting using affected sib pairs (ASPs) and affected half-sib pairs (AHSPs) when all parental genotypes are missing. Methods: Simulated pedigree data were analyzed using the GENEHUNTER-MODSCORE software package. Parameter estimation performance in terms of bias and variability was evaluated with regard to trait-model type and pedigree complexity. Results: Generally, parameters were estimated with lower bias and variability with increasing pedigree complexity, especially for recessive and overdominant models. However, dominant and additive models could hardly be distinguished even when using 3-generation pedigrees. Imprinting could clearly be detected for mixtures of mainly ASPs and only few AHSPs with the common parent of the imprinted sex, even though no parental genotypes were available. Conclusion: Our results provide guidance to researchers regarding the possibility to estimate trait-model parameters by a MOD score analysis, including the degree of imprinting, with certain types of pedigrees.

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“…Since the asymptotic distribution of MOD scores is unknown in the general case, p values for the linkage test must be obtained by simulating the distribution of the MOD score under the null hypothesis of no linkage. Our group has implemented the MOD score approach, including a routine to perform simulations under the null hypothesis of no linkage, in the GENEHUNTER-MODSCORE (GHM) software (Brugger & Strauch, 2014;Dietter et al, 2007;Mattheisen et al, 2008;Strauch, 2003), which is based on the GENEHUNTER program (Kruglyak et al, 1996). Its application has led to the identification of a variety of genetic disease loci responsible for congenital heart defects (Flaquer et al, 2013), allergic rhinitis (Kruse et al, 2012), atopic dermatitis (Christensen et al, 2009), bipolar affective disorder (Schumacher et al, 2005), and house dust mite allergy (Kurz et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

Properties and Evaluation of the MOBIT – a novel Linkage-based Test Statistic and Quantification Method for Imprinting

Brügger¹,

Knapp

Strauch³

2019

Statistical Applications in Genetics and Molecular Biology

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Genomic imprinting is a parent-of-origin effect apparent in an appreciable number of human diseases. We have proposed the new imprinting test statistic MOBIT, which is based on MOD score analysis. We were interested in the properties of the MOBIT concerning its distribution under three hypotheses: (1) H0, a: no linkage, no imprinting; (2) H0, b: linkage, no imprinting; (3) H1: linkage and imprinting. More specifically, we assessed the confounding between imprinting and sex-specific recombination frequencies, which presents a major difficulty in linkage-based testing for imprinting, and evaluated the power of the test. To this end, we have performed a linkage simulation study of affected sib-pairs and a three-generation pedigree with two trait models, many two- and multipoint marker scenarios, three genetic map ratios, two sample sizes, and five imprinting degrees. We also investigated the ability of the MOBIT to quantify the degree of imprinting and applied the MOBIT using a real data example on house dust mite allergy. We further proposed and evaluated two approaches to obtain empiric p values for the MOBIT. Our results showed that twopoint analyses assuming a sex-averaged marker map led to an inflated type I error due to confounding, especially for a larger marker-trait locus distance. When the correct sex-specific marker map was assumed, twopoint analyses have a reduced power to detect imprinting, compared to sex-averaged analyses with an appropriate correction for the inflation of the test statistic. However, confounding was not an issue in multipoint analysis unless the map ratio was extreme and marker spacing was sparse. With multipoint analysis, power as well as the ability to quantify the imprinting degree were almost equally high when a sex-averaged or the correct sex-specific map was used in the analysis. We recommend to obtain empiric p values for the MOBIT using genotype simulations based on the best-fitting nonimprinting model of the real dataset analysis. In addition, an implementation of a method based on the permutation of parental sexes is also available. In summary, we propose to perform multipoint analyses using densely spaced markers to efficiently discover new imprinted loci and to reliably quantify the degree of imprinting.

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Fast Linkage Analysis with MOD Scores Using Algebraic Calculation

Cited by 6 publications

References 45 publications

Germline variants in oculocutaneous albinism genes and predisposition to familial cutaneous melanoma

Germline variants in oculocutaneous albinism genes and predisposition to familial cutaneous melanoma

Estimation of Trait-Model Parameters in a MOD Score Linkage Analysis

Properties and Evaluation of the MOBIT – a novel Linkage-based Test Statistic and Quantification Method for Imprinting

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