The Experts below are selected from a list of 10194 Experts worldwide ranked by ideXlab platform
Karin Kast - One of the best experts on this subject based on the ideXlab platform.
-
ovarian and breast cancer risks associated with pathogenic variants in rad51c and rad51d
Journal of the National Cancer Institute, 2020Co-Authors: Xin Yang, Honglin Song, Goska Leslie, Eric Hahnen, Bernd Auber, Karin Kast, Judit Horvath, Christoph EngelAbstract:BACKGROUND: The purpose of this study was to estimate precise age-specific tubo-ovarian carcinoma (TOC) and breast cancer (BC) risks for carriers of pathogenic variants in RAD51C and RAD51D. METHODS: We analysed data from 6178 families, 125 with pathogenic variants in RAD51C; and 6690 families, 60 with pathogenic variants in RAD51D. TOC and BC relative and cumulative risks were estimated using Complex Segregation Analysis to model the cancer inheritance patterns in families, while adjusting for the mode of ascertainment of each family. All statistical tests were two-sided. RESULTS: Pathogenic variants in both RAD51C and RAD51D were associated with TOC (RAD51C RR = 7.55, 95%CI:5.60-10.19, p = 5 × 10-40; RAD51D RR = 7.60, 95%CI:5.61-10.30, p = 5 × 10-39) and BC (RAD51C RR = 1.99, 95%CI:1.39-2.85, p = 1.55 × 10-4; RAD51D RR = 1.83, 95%CI:1.24-2.72, p = 0.002). For both RAD51C and RAD51D, there was a suggestion that the TOC RRs increased with age until around age 60 years and decreased thereafter. The estimated cumulative risks of developing TOC to age 80 were 11% (95%CI:6-21%) for RAD51C and 13% (95%CI:7-23%) for RAD51D pathogenic variant carriers. The estimated cumulative risks of developing BC to 80 were 21% (95%CI:15-29%) for RAD51C and 20% (95%CI:14-28%) for RAD51D pathogenic variant carriers. Both TOC and BC risks for RAD51C/D pathogenic variant carriers varied by cancer family history, and could be as high as 32-36% for TOC, for carriers with two first degree relatives diagnosed with TOC; or 44-46% for BC, for carriers with two first degree relatives diagnosed with BC. CONCLUSIONS: These estimates will facilitate the genetic counselling of RAD51C and RAD51D pathogenic variant carriers and justify the incorporation of RAD51C and RAD51D into cancer risk prediction models.
Thomas R Famula - One of the best experts on this subject based on the ideXlab platform.
-
heritability and Complex Segregation Analysis of naturally occurring diabetes in australian terrier dogs
PLOS ONE, 2020Co-Authors: Mei Lun Mui, Thomas R Famula, Paula S Henthorn, Rebecka S HessAbstract:The Australian Terrier breed is the breed at highest risk for naturally-occurring diabetes mellitus in the United States, where it is 32 times more likely to develop diabetes compared to mixed breed dogs. However, the heritability and mode of inheritance of spontaneous diabetes in Australian Terriers has not been reported. The aim of this study was therefore to investigate the heritability and mode of inheritance of diabetes in Australian Terriers. A cohort of related Australian Terriers including 383 Australian Terriers without diabetes, 86 Australian Terriers with spontaneous diabetes, and 14 Australian Terriers with an unknown phenotype, was analyzed. A logistic regression model including the effects of sex was formulated to evaluate the heritability of diabetes. The inheritance pattern of spontaneous diabetes in Australian Terriers was investigated by use of Complex Segregation Analysis. Six possible inheritance models were studied, and the Akaike Information Criterion was used to determine the best model for diabetes inheritance in Australian Terriers, among the models deemed biologically feasible. Heritability of diabetes in Australian Terriers was estimated at 0.18 (95% confidence interval 0.0–0.67). There was no significant difference in the effect of males and females on disease outcome. Complex Segregation Analysis suggested that the mode of diabetes inheritance in Australian Terriers is polygenic, with no evidence for a large effect single gene influencing diabetes. It is concluded that in the population of Australian Terriers bred in the United States, a relatively small degree of genetic variation contributes to spontaneous diabetes. A genetic uniformity for diabetes-susceptible genes within the population of Australian Terriers bred in the Unites States could increase the risk of diabetes in this cohort. These findings hold promise for future genetic studies of canine diabetes focused on this particular breed.
-
heritability and Complex Segregation Analysis of diabetes mellitus in american eskimo dogs
Journal of Veterinary Internal Medicine, 2019Co-Authors: Stephen V Cai, Thomas R Famula, Anita M. Oberbauer, Rebecka S HessAbstract:Author(s): Cai, Stephen V; Famula, Thomas R; Oberbauer, Anita M; Hess, Rebecka S | Abstract: BackgroundHeritability and mode of inheritance of spontaneous diabetes mellitus (DM) in American Eskimo Dogs (AED) are unknown.ObjectiveInvestigate the heritability and mode of inheritance of DM in AED.AnimalsAn extended family of AED including 71 AED without DM, 47 AED with an unknown phenotype, and 38 AED with spontaneous DM.MethodsRetrospective evaluation of inheritance. A logistic regression model was formulated to evaluate the heritability of DM, including effects of sex and neuter status. Subsequently, Complex Segregation Analysis was employed to investigate the inheritance pattern of DM in AED. Six plausible models were considered, and the Akaike Information Criterion was used to determine the best of the biologically feasible models of inheritance of DM in AED.ResultsHeritability of DM in AED is estimated at 0.62 (95% posterior interval 0.01-0.99). Predicted DM probabilities for neutered females (NF), intact females (IF), neutered males (NM), and intact males (IM) were 0.76, 0.11, 0.63, and 0.12, respectively. There was no overlap between the 95% posterior intervals of disease probabilities in NF and IF or in NF and IM. Complex Segregation Analysis suggested that the mode of inheritance of DM in AED is polygenic, with no evidence for a single gene of large effect.Conclusions and clinical importanceThe estimated heritability of DM in AED is high but has low precision. Diabetes mellitus transmission in AED appears to follow a polygenic inheritance. Breeders could successfully implement a breeding program to decrease the incidence of DM in AED.
-
inheritance of cerebellar abiotrophy in arabians
American Journal of Veterinary Research, 2011Co-Authors: Leah S Brault, Thomas R Famula, Cecilia M T PenedoAbstract:Objective—To determine the mode of inheritance for cerebellar abiotrophy (CA), a neurologic disease in Arabians. Animals—804 Arabians, including 29 horses (15 males and 14 females) with CA. Procedures—Most horses (n = 755) belonged to 1 of 4 paternal families. Among the 29 CA-affected horses, all had clinical signs consistent with the disease; the disease was confirmed histologically following euthanasia in 8 horses. From the pedigree information, inbreeding coefficients were calculated for 16 affected horses and compared with coefficients for a subgroup of 16 unaffected horses. Complex Segregation Analysis was used to determine the effect of a putative Mendelian locus on the development of the disease and the probable mode of inheritance of CA. Results—The mean inbreeding coefficient was 0.0871 for CA-affected and unaffected horses, suggesting that all of the Arabians were inbred to the same degree and that affected horses were not more inbred than were unaffected horses. Results of the Complex segregati...
-
Inheritance of cataracts and primary lens luxation in Jack Russell Terriers.
American journal of veterinary research, 2008Co-Authors: Anita M. Oberbauer, Steven R. Hollingsworth, Janelle M. Belanger, Kelly R. Regan, Thomas R FamulaAbstract:Objective—To characterize heritability and mode of inheritance of cataracts and primary lens luxation in Jack Russell Terriers. Animals—872 Jack Russell Terriers from which buccal epithelial cells were collected and phenotypes for cataracts and lens luxation were determined and an additional 1,898 Jack Russell Terriers without phenotypic information used to complete pedigree relationships and that were included in the analyses. Procedures—Narrow-sense heritabilities and genetic correlation for cataracts and lens luxation were modeled by use of threshold Analysis, whereas Complex Segregation Analysis was used to characterize mode of inheritance. For the analyses, dogs < 6 years old, unless confirmed as having cataracts or lens luxation, were classified as an unknown phenotype. The possible involvement of an HSF4 mutation in cataracts was determined by DNA sequencing. Results—Cataracts and primary lens luxation were highly heritable and genetically correlated, and neither was controlled by a single gene. Ca...
-
inheritance of resistance to xylella fastidiosa within a vitis rupestris vitis arizonica hybrid population
Theoretical and Applied Genetics, 2005Co-Authors: A F Krivanek, Thomas R Famula, Alan C Tenscher, M A WalkerAbstract:The inheritance of resistance to Xylella fastidiosa (Xf), the bacterium which causes Pierce’s disease (PD) in grapevines, was evaluated within a factorial mating design consisting of 16 full-sib families with resistance derived from Vitis arizonica interspecific hybrids. Measurements of disease progression under greenhouse conditions were based on quantitative assessment of Xf populations in stem tissues and on three phenotypic scores: leaf scorch, a cane maturation index (CMI) and an index that incorporated shoot stunting into the cane maturation index (CMSSI). Measurement of bacterial populations yielded the highest broad-sense heritability for resistance on a genotype mean basis (0.97), indicating that this measure of resistance was the least effected by environmental variation. Narrow-sense heritability of PD resistance was moderately high and measured 0.52, 0.60, 0.63 and 0.37 for Xf populations, CMI scores, CMSSI scores and leaf scorch values, respectively. Complex Segregation Analysis using the computer program Statistical Analysis for Genetic Epidemiology (sage) strongly indicated the existence of a major gene for PD resistance, which accounted for 91% of the total genetic variance. Conversion of the quantitative data into qualitative resistance levels and evaluation via a chi-square Analysis showed that 15 of the 16 families segregated in accordance with a single gene hypothesis with a dominant allele controlling PD resistance. These data indicate that the trait should be relatively easy to pass on from parents to progeny in a breeding program for the development of PD-resistant grape cultivars, particularly when selection is based on cane maturation scores or stem Xf populations.
Rebecka S Hess - One of the best experts on this subject based on the ideXlab platform.
-
heritability and Complex Segregation Analysis of naturally occurring diabetes in australian terrier dogs
PLOS ONE, 2020Co-Authors: Mei Lun Mui, Thomas R Famula, Paula S Henthorn, Rebecka S HessAbstract:The Australian Terrier breed is the breed at highest risk for naturally-occurring diabetes mellitus in the United States, where it is 32 times more likely to develop diabetes compared to mixed breed dogs. However, the heritability and mode of inheritance of spontaneous diabetes in Australian Terriers has not been reported. The aim of this study was therefore to investigate the heritability and mode of inheritance of diabetes in Australian Terriers. A cohort of related Australian Terriers including 383 Australian Terriers without diabetes, 86 Australian Terriers with spontaneous diabetes, and 14 Australian Terriers with an unknown phenotype, was analyzed. A logistic regression model including the effects of sex was formulated to evaluate the heritability of diabetes. The inheritance pattern of spontaneous diabetes in Australian Terriers was investigated by use of Complex Segregation Analysis. Six possible inheritance models were studied, and the Akaike Information Criterion was used to determine the best model for diabetes inheritance in Australian Terriers, among the models deemed biologically feasible. Heritability of diabetes in Australian Terriers was estimated at 0.18 (95% confidence interval 0.0–0.67). There was no significant difference in the effect of males and females on disease outcome. Complex Segregation Analysis suggested that the mode of diabetes inheritance in Australian Terriers is polygenic, with no evidence for a large effect single gene influencing diabetes. It is concluded that in the population of Australian Terriers bred in the United States, a relatively small degree of genetic variation contributes to spontaneous diabetes. A genetic uniformity for diabetes-susceptible genes within the population of Australian Terriers bred in the Unites States could increase the risk of diabetes in this cohort. These findings hold promise for future genetic studies of canine diabetes focused on this particular breed.
-
heritability and Complex Segregation Analysis of diabetes mellitus in american eskimo dogs
Journal of Veterinary Internal Medicine, 2019Co-Authors: Stephen V Cai, Thomas R Famula, Anita M. Oberbauer, Rebecka S HessAbstract:Author(s): Cai, Stephen V; Famula, Thomas R; Oberbauer, Anita M; Hess, Rebecka S | Abstract: BackgroundHeritability and mode of inheritance of spontaneous diabetes mellitus (DM) in American Eskimo Dogs (AED) are unknown.ObjectiveInvestigate the heritability and mode of inheritance of DM in AED.AnimalsAn extended family of AED including 71 AED without DM, 47 AED with an unknown phenotype, and 38 AED with spontaneous DM.MethodsRetrospective evaluation of inheritance. A logistic regression model was formulated to evaluate the heritability of DM, including effects of sex and neuter status. Subsequently, Complex Segregation Analysis was employed to investigate the inheritance pattern of DM in AED. Six plausible models were considered, and the Akaike Information Criterion was used to determine the best of the biologically feasible models of inheritance of DM in AED.ResultsHeritability of DM in AED is estimated at 0.62 (95% posterior interval 0.01-0.99). Predicted DM probabilities for neutered females (NF), intact females (IF), neutered males (NM), and intact males (IM) were 0.76, 0.11, 0.63, and 0.12, respectively. There was no overlap between the 95% posterior intervals of disease probabilities in NF and IF or in NF and IM. Complex Segregation Analysis suggested that the mode of inheritance of DM in AED is polygenic, with no evidence for a single gene of large effect.Conclusions and clinical importanceThe estimated heritability of DM in AED is high but has low precision. Diabetes mellitus transmission in AED appears to follow a polygenic inheritance. Breeders could successfully implement a breeding program to decrease the incidence of DM in AED.
Lennart Iselius - One of the best experts on this subject based on the ideXlab platform.
-
Segregation Analysis of prostate cancer in sweden support for dominant inheritance
American Journal of Epidemiology, 1997Co-Authors: Henrik Gronberg, Lena Damber, Janerik Damber, Lennart IseliusAbstract:Several epidemiologic studies have shown familial aggregation of prostate cancer. To assess the nature of familial clustering of prostate cancer, a Complex Segregation Analysis was performed on a population-based sample of 2,857 nuclear families ascertained through an affected father diagnosed with prostate cancer in Sweden during 1959-1963. The Segregation Analysis, using a large, unselected population of prostate cancer families, revealed that the observed clustering of prostate cancer was best explained by a high risk allele inherited in a dominant mode, with a high population frequency (1.67%) and a moderate lifetime penetrance (63%). This study confirms the result from one earlier published Segregation Analysis and provides the context for interpreting the recently published linkage of hereditary prostate cancer families to chromosome 1q 24-25 (HPC1).
-
cluster headache is an autosomal dominantly inherited disorder in some families a Complex Segregation Analysis
Journal of Medical Genetics, 1995Co-Authors: M B Russell, P G Andersson, L L Thomsen, Lennart IseliusAbstract:We investigated the mode of inheritance of cluster headache in 370 families. The probands were from a neurological clinic in Jutland and two departments of neurology in Copenhagen County, Denmark. The criteria of the International Headache Society were used. The patterns of Segregation of cluster headache were assessed by Complex Segregation Analysis performed with the computer program POINTER. Of the 370 probands with cluster headache, 25 had 36 relatives with cluster headache. The Segregation Analysis suggests that cluster headache has an autosomal dominant gene (p < 0.10) with a penetrance of 0.30-0.34 in males and 0.17-0.21 in females. The gene is present in 3 to 4% of males and 7 to 10% of females with cluster headache. An autosomal dominant gene has a role in cluster headache in some families.
John A Eisman - One of the best experts on this subject based on the ideXlab platform.
-
genetics of bone mineral density evidence for a major pleiotropic effect from an intercontinental study
Journal of Bone and Mineral Research, 2004Co-Authors: Gregory Livshits, Tuan V Nguyen, K Yakovenko, Hongwen Deng, Robert R Recker, John A EismanAbstract:BMD is a primary predictor of osteoporotic fracture, and its genetic determination is still unclear. This study showed that the correlation between BMD at different skeletal sites is caused by an underlying genetic structure of common genetic effects. In addition to possible shared (pleiotropic) genetic and environmental effects, each of the BMD variables may also be determined by site-specific genetic factors. Introduction: BMD is a primary predictor of osteoporotic fracture and a key phenotype for the genetic study of osteoporosis. The interindividual variation in BMD measured at a given skeletal site is largely regulated by genetic factors. A strong phenotypic covariation exists for BMD at different skeletal sites. This study tests the hypothesis that the covariation is in fact caused by an underlying genetic structure of common genetic effects and that, in addition to possible shared (pleiotropic) genetic effects, each of the BMD variables may also be determined by site-specific genetic factors Materials and Methods: A bivariate Complex Segregation Analysis as implemented in statistical package PAP was conducted to explore various models of pleiotropic genetic and environmental transmission in lumbar spine and femoral neck BMD, as well as in compact and spongious segments of hand phalanges. The BMD was obtained in three ethnically, culturally, and socially heterogeneous samples of white pedigrees, with 2549 individuals between 18 and 100 years of age, from Australia, Europe, and North America. Results and Conclusions: The genetic correlation between BMD measures ranged between 0.50 0.09 and 0.79 0.04 in the three samples. In each sample, the model incorporated a major locus pleiotropic effect, and residual correlation was found to be the most parsimonious model. Estimated parameters from the model indicated a significant pleiotropic major gene effect on both lumbar spine and femoral neck BMD, with the existence of a significant residual correlation (0.51 0.07 to 0.66 0.04). These results suggest that the covariation in BMD at different skeletal sites, and between mostly compact versus mostly trabecular bone, was largely determined by common genetic factors that are pleiotropic or in close linkage and linkage disequilibirum, while at the same time, exhibiting considerable evidence of shared environmental effects. The results, for the first time, suggest that the possibility of pleiotropic genetic effect may be controlled by a major genetic locus. Identification of the major locus could open new opportunity to understanding the liability and pathogenic processes in which they are involved in the determination of fracture risk. J Bone Miner Res 2004;19:914 -923. Published online on January 27, 2004; doi: 10.1359/JBMR.040132
-
genetic determination of bone mineral density evidence for a major gene
The Journal of Clinical Endocrinology and Metabolism, 2003Co-Authors: Tuan V Nguyen, Gregory Livshits, K Yakovenko, John A EismanAbstract:This study was designed to test the hypothesis of a major gene influence on the variation in bone mineral density (BMD). BMD and bone mineral content at the lumbar spine and femoral neck were measured in 330 men and 413 women, aged 18-90 yr, from 107 nuclear and Complex families (including 5 large pedigrees with 194 individuals who were identified through an index case with moderately high BMD at the femoral neck (z-score, >or=1.28)). After adjusting for age and body weight, familial factors accounted for up to 72% of the total variation in BMD. In Complex Segregation Analysis, for all variables examined the best-fitting most parsimonious model consistently suggested the Mendelian transmission of a major gene locus with significant residual correlations among siblings. This genetic model suggested that the proportion of a total variance (adjusted for significant covariates) attributable to a putative major gene effect ranged between 0.30 +/- 0.09 for femoral neck BMD and 0.53 +/- 0.07 for the principal component obtained on BMD and corresponding bone mineral content measures. These findings clearly support the hypothesis that a large component of the variance in BMD is under genetic control, with strong evidence for a major gene locus influencing BMD transmission.