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Affected Offspring (affected + offspring)
Selected AbstractsInformative-Transmission Disequilibrium Test (i-TDT): combined linkage and association mapping that includes unaffected offspring as well as affected offspringGENETIC EPIDEMIOLOGY, Issue 2 2007Chao-Yu Guo Abstract To date, there is no test valid for the composite null hypothesis of no linkage or no association that utilizes transmission information from heterozygous parents to their unaffected offspring as well as the affected offspring from ascertained nuclear families. Since the unaffected siblings also provide information about linkage and association, we introduce a new strategy called the informative-transmission disequilibrium test (i-TDT), which uses transmission information from heterozygous parents to all of the affected and unaffected offspring in ascertained nuclear families and provides a valid chi-square test for both linkage and association. The i-TDT can be used in various study designs and can accommodate all types of independent nuclear families with at least one affected offspring. We show that the transmission/disequilibrium test (TDT) (Spielman et al. [1993] Am. J. Hum. Genet. 52:506,516) is a special case of the i-TDT, if the study sample contains only case-parent trios. If the sample contains only affected and unaffected offspring without parental genotypes, the i-TDT is equivalent to the sibship disequilibrium test (SDT) (Horvath and Laird [1998] Am. J. Hum. Genet. 63:1886,1897. In addition, the test statistic of i-TDT is simple, explicit and can be implemented easily without intensive computing. Through computer simulations, we demonstrate that power of the i-TDT can be higher in many circumstances compared to a method that uses affected offspring only. Applying the i-TDT to the Framingham Heart Study data, we found that the apolipoprotein E (APOE) gene is significantly linked and associated with cross-sectional measures and longitudinal changes in total cholesterol. Genet. Epidemiol. © 2006 Wiley-Liss, Inc. [source] Properties of the transmission-disequilibrium test in the presence of inbreedingGENETIC EPIDEMIOLOGY, Issue 2 2002Emmanuelle Génin Abstract Family-based association tests such as the transmission-disequilibrium test (TDT), which compare alleles transmitted and non-transmitted from parents to affected offspring, are widely used to detect the role of genetic risk factors in diseases. These methods have the advantage of being robust to population stratification and are thus believed to be valid whatever the population context. In different studies of the statistical properties of the TDT, parents of affected offspring are typically assumed to be neither inbred nor related. In many human populations, however, this assumption is false and parental alleles are then no longer independent. It is thus of interest to determine whether the TDT is a valid test of linkage and association in the presence of inbreeding. We present a method to derive the expected value of the TDT statistic under different disease models and for any relationship between the parents of affected offspring. Using this method, we show that in the presence of inbreeding, the TDT is still a valid test for linkage but not for association. The power of the test to detect linkage may, however, be increased in the presence of inbreeding under different modes of inheritance. Genet. Epidemiol. 22:116,127, 2002. © 2002 Wiley-Liss, Inc. [source] Tests for genetic association using family dataGENETIC EPIDEMIOLOGY, Issue 2 2002Mei-Chiung Shih Abstract We use likelihood-based score statistics to test for association between a disease and a diallelic polymorphism, based on data from arbitrary types of nuclear families. The Nonfounder statistic extends the transmission disequilibrium test (TDT) to accommodate affected and unaffected offspring, missing parental genotypes, phenotypes more general than qualitative traits, such as censored survival data and quantitative traits, and residual correlation of phenotypes within families. The Founder statistic compares observed or inferred parental genotypes to those expected in the general population. Here the genotypes of affected parents and those with many affected offspring are weighted more heavily than unaffected parents and those with few affected offspring. We illustrate the tests by applying them to data on a polymorphism of the SRD5A2 gene in nuclear families with multiple cases of prostate cancer. We also use simulations to compare the power of these family-based statistics to that of the score statistic based on Cox's partial likelihood for censored survival data, and find that the family-based statistics have considerably more power when there are many untyped parents. The software program FGAP for computing test statistics is available at http://www.stanford.edu/dept/HRP/epidemiology/FGAP. Genet. Epidemiol. 22:128,145, 2002. © 2002 Wiley-Liss, Inc. [source] A Bayesian approach to the transmission/disequilibrium test for binary traitsGENETIC EPIDEMIOLOGY, Issue 1 2002Varghese George Abstract The transmission/disequilibrium test (TDT) for binary traits is a powerful method for detecting linkage between a marker locus and a trait locus in the presence of allelic association. The TDT uses information on the parent-to-offspring transmission status of the associated allele at the marker locus to assess linkage or association in the presence of the other, using one affected offspring from each set of parents. For testing for linkage in the presence of association, more than one offspring per family can be used. However, without incorporating the correlation structure among offspring, it is not possible to correctly assess the association in the presence of linkage. In this presentation, we propose a Bayesian TDT method as a complementary alternative to the classical approach. In the hypothesis testing setup, given two competing hypotheses, the Bayes factor can be used to weigh the evidence in favor of one of them, thus allowing us to decide between the two hypotheses using established criteria. We compare the proposed Bayesian TDT with a competing frequentist-testing method with respect to power and type I error validity. If we know the mode of inheritance of the disease, then the joint and marginal posterior distributions for the recombination fraction (,) and disequilibrium coefficient (,) can be obtained via standard MCMC methods, which lead naturally to Bayesian credible intervals for both parameters. Genet. Epidemiol. 22:41,51, 2002. © 2002 Wiley-Liss, Inc. [source] Study of four genes belonging to the folate pathway: transcobalamin 2 is involved in the onset of non-syndromic cleft lip with or without cleft palate,,HUMAN MUTATION, Issue 3 2006Marcella Martinelli Abstract Cleft lip with or without cleft palate (CL/P) is the most common inborn craniofacial anomaly. Affected individuals require extensive medical and psychosocial support. Although CL/P has a complex and poorly understood etiology, increasing evidence of folate pathway involvement has been collected. So far, only the MTHFR gene has been extensively investigated as a risk factor for CL/P, while little has been done to test genetic variations in the folate biosynthetic pathways that may influence the infant's susceptibility to these birth defects. To date, this paper presents the first attempt to verify the involvement of four genes belonging to the folate pathway in nonsyndromic cleft onset. We used a case-parent triad design to test for linkage disequilibrium in the case of seven SNPs mapping on four different genes: transcobalamin 1 and 2 (TCN1 and TCN2), methionine synthase (MTR), and MTR reductase (MTRR). Our finding suggests that TCN2 is involved in causing CL/P. Indeed, significant overtransmission of the C allele was observed at the polymorphism c.776C>G (p.Pro259Arg) to the affected offspring (P=0.01). Results obtained with additional TCN2 polymorphisms suggest that c.776C>G may be functionally related to CL/P. However, because conflicting data exist with regard to the effect of the polymorphism in transcobalamin 2 function or in perturbing plasma levels of key molecules in the folate pathway, further investigation is warranted to confirm our data. © 2006 Wiley-Liss, Inc. [source] Effects of a Novel Cognition-Enhancing Agent on Fetal Ethanol-Induced Learning DeficitsALCOHOLISM, Issue 10 2010Daniel D. Savage Background:, Drinking during pregnancy has been associated with learning disabilities in affected offspring. At present, there are no clinically effective pharmacotherapeutic interventions for these learning deficits. Here, we examined the effects of ABT-239, a histamine H3 receptor antagonist, on fetal ethanol-induced fear conditioning and spatial memory deficits. Methods and Results:, Long-Evans rat dams stably consumed a mean of 2.82 g ethanol/kg during a 4-hour period each day during pregnancy. This voluntary drinking pattern produced a mean peak serum ethanol level of 84 mg/dl. Maternal weight gain, litter size and birth weights were not different between the ethanol-consuming and control groups. Female adult offspring from the control and fetal alcohol-exposed (FAE) groups received saline or 1 mg ABT-239/kg 30 minutes prior to fear conditioning training. Three days later, freezing time to the context was significantly reduced in saline-treated FAE rats compared to control. Freezing time in ABT-239-treated FAE rats was not different than that in controls. In the spatial navigation study, adult male offspring received a single injection of saline or ABT-239 30 minutes prior to 12 training trials on a fixed platform version of the Morris Water Task. All rats reached the same performance asymptote on Trials 9 to 12 on Day 1. However, 4 days later, first-trial retention of platform location was significantly worse in the saline-treated FAE rats compared control offspring. Retention by ABT-239-treated FAE rats was similar to that by controls. ABT-239's effect on spatial memory retention in FAE rats was dose dependent. Conclusions:, These results suggest that ABT-239 administered prior to training can improve retention of acquired information by FAE offspring on more challenging versions of hippocampal-sensitive learning tasks. Further, the differential effects of ABT-239 in FAE offspring compared to controls raises questions about the impact of fetal ethanol exposure on histaminergic neurotransmission in affected offspring. [source] Inheritance of dermoid sinus in the Rhodesian ridgebackJOURNAL OF SMALL ANIMAL PRACTICE, Issue 2 2005N. H. C. Salmon Hillbertz Objectives: To define the mode of inheritance of dermoid sinus. Methods: A chi-squared analysis was performed on data from 46 litters produced between 1990 and 2001. Data were corrected to avoid bias in the segregation ratio. Results: In data from 57 litters (n=492), 82 dermoid sinus positive offspring were observed. The frequency of affected offspring in the Swedish Rhodesian ridgeback population is estimated to be between 8 and 10 per cent. Clinical Significance: Bias in heredity pattern may be caused by undetected dermoid sinus type V. Improved clinical diagnosis of all dermoid sinus types is therefore crucial. [source] Familial essential tremor with apparent autosomal dominant inheritance: Should we also consider other inheritance modes?MOVEMENT DISORDERS, Issue 9 2006Shaochun Ma MD Abstract A positive family history is present in many patients with essential tremor (ET), but twin studies and segregation analysis have suggested that ET is not entirely a genetic disorder. Two genetic loci have been identified in autosomal dominant (AD) ET and polymorphisms in the DRD3 and HS1-BP3 genes have been proposed as the possible susceptibility factors for ET. There is also evidence for further genetic heterogeneity. We evaluated 4 unrelated large kindreds with ET with an apparent AD mode of transmission. Each kindred spanned at least 3 generations and contained at least 13 living affected subjects who met criteria for definitive ET. None of the pedigrees had evidence for inheritance of ET from both parents. Known genetic ET loci were excluded in these families. We detected a preferential transmission of ET in every kindred and the proportion of affected offspring varied from 75% to 90% (P < 0.05) in the generations with complete ascertainment. Our data indicate that non-Mendelian preferential transmission of an affected allele is a feature in many ET kindreds with multiple affected members and an apparent AD mode of inheritance. ET may have a complex etiology. Additional genetic models need to be considered, including an interaction of susceptibility genes and environmental risk factors. © 2006 Movement Disorder Society [source] Rapid genetic analysis of oculocutaneous albinism (OCA1) using denaturing high performance liquid chromatography (DHPLC) systemPRENATAL DIAGNOSIS, Issue 5 2006Shin-Yu Lin Abstract Objectives To present the prenatal genetic diagnoses and counseling for two cases of oculocutaneous albinism (OCA) type I family by detection of mutations in the OCA1 gene by denaturing high performance liquid chromatography (DHPLC) system and a review of the literature. Methods All DNA samples were extracted from peripheral whole blood and amniocentesis-derived cells. Mutation analysis was performed for all five coding exons of the TYR gene, which were amplified by PCR. DHPLC was used for heteroduplex detection and sequence analysis was performed to demonstrate the mutation loci. Results Case 1: After sampling of blood from the family members and performing amniocentesis of the fetus, it was demonstrated that the affected boy and the female fetus were shown to be compound heterozygotes for mutations in the TYR gene. In addition, it was shown that the parents were carriers of the two mutations. However, the couple chose to keep the baby. Case 2: Mutation analysis of the DNA of the siblings revealed two heterozygous mutations in the TYR gene. Her husband is free of the disease. According to the principles of autosomal recessive inheritance, the incidence of affected offspring is very low. Conclusions Herein we introduce a novel application for molecular diagnostic of DHPLC coupled with direct sequencing, which can provide an effective and exact diagnosis in patients with albinism. Clinicians should be cognizant of the risk of OCA inheritance by the offspring through careful identification of genetic mutations and the inheritance mode, both important to ensure comprehensive genetic counseling. Copyright © 2006 John Wiley & Sons, Ltd. [source] Genetics of autosomal recessive non-syndromic mental retardation: recent advancesCLINICAL GENETICS, Issue 3 2007L Basel-Vanagaite The identification of the genes mutated in autosomal recessive non-syndromic mental retardation (ARNSMR) has been very active recently. This report presents an overview of the current knowledge on clinical data in ARNSMR and progress in research. To date, 12 ARNSMR loci have been mapped, and three genes identified. Mutations in known ARNSMR genes have been detected so far in only a small number of families; their contribution to mental retardation in the general population might be limited. The ARNSMR-causing genes belong to different protein families, including serine proteases, Adenosine 5,-triphosphate-dependent Lon proteases and calcium-regulated transcriptional repressors. All of the mutations in the ARNSMR-causing genes are protein truncating, indicating a putative severe loss-of-function effect. The future objective will be the development of diagnostic kits for molecular diagnosis in mentally retarded individuals in order to offer at-risk families pre-natal diagnosis to detect affected offspring. [source] | |||||||||||||