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Biomedical subjects

Y Y Shugart

Publications and source records attributed to Y Y Shugart.

At least 19 recordsLinked to original sources
PubMed2006

Trends in incidence and mortality of nasopharyngeal carcinoma over a 20-25 year period (1978/1983-2002) in Sihui and Cangwu counties in southern China.

BACKGROUND: Nasopharyngeal carcinoma (NPC) is a rare malignancy in most parts of the world but is common in southern China. A recent report from the Hong Kong Cancer Registry, a high-risk area for NPC in southern China, showed that incidence rate decreased by 29% for males and by 30% for females from 1980-1999, while mortality rate decreased by 43% for males and 50% for females. Changing environmental risk factors and improvements in diagnosis and treatment were speculated to be the major factors contributing to the downward trend of the incidence and mortality rates of NPC. To investigate the secular trends in different Cantonese populations with different socio-economic backgrounds and lifestyles, we report the incidences and mortality rates from two population-based cancer registries in Sihui and Cangwu counties from 1978-2002. METHODS: Incidence and mortality rates were aggregated by 5-year age groups and 5 calendar years. To adjust for the effect of difference in age composition for different periods, the total and age-specific rates of NPC incidence and mortality rate were adjusted by direct standardization according to the World Standard Population (1960). The Estimated Annual Percentage Change (EAPC) was used as an estimate of the trend. RESULTS: The incidence rate of NPC has remained stable during the recent two decades in Sihui and in females in Cangwu, with a slight increase observed in males in Cangwu from 17.81 to 19.76 per 100,000. The incidence rate in Sihui is 1.4-2.0 times higher during the corresponding years than in Cangwu, even though the residents of both areas are of Cantonese ethnicity. A progressive decline in mortality rate was observed in females only in Sihui, with an average reduction of 6.3% (p = 0.016) per five-year period. CONCLUSION: To summarize, there is great potential to work in the area of NPC prevention and treatment in southern China to decrease NPC risk and improve survival risk rates in order to reduce M:I ratios. Future efforts on effective prevention, early detection and treatment strategies were also discussed in this paper. Furthermore, the data quality and completeness also need to be improved.

Adult↗
PubMed2006

Genomewide linkage scan for obsessive-compulsive disorder: evidence for susceptibility loci on chromosomes 3q, 7p, 1q, 15q, and 6q.

Obsessive-compulsive disorder (OCD) is the tenth most disabling medical condition worldwide. Twin and family studies implicate a genetic etiology for this disorder, although specific genes have yet to be identified. Here, we present the first large-scale model-free linkage analysis of both extended and nuclear families using both 'broad' (definite and probable diagnoses) and 'narrow' (definite only) definitions of OCD. We conducted a genome-scan analysis of 219 families collected as part of the OCD Collaborative Genetics Study. Suggestive linkage signals were revealed by multipoint analysis on chromosomes 3q27-28 (P=0.0003), 6q (P=0.003), 7p (P=0.001), 1q (P=0.003), and 15q (P=0.006). Using the 'broad' OCD definition, we observed the strongest evidence for linkage on chromosome 3q27-28. The maximum overall Kong and Cox LODall score (2.67) occurred at D3S1262 and D3S2398, and simulation based P-values for these two signals were 0.0003 and 0.0004, respectively, although for both signals, the simulation-based genome-wide significance levels were 0.055. Covariate-linkage analyses implicated a possible role of gene(s) on chromosome 1 in increasing the risk for an earlier onset form of OCD. We are currently pursuing fine mapping in the five regions giving suggestive signals, with a particular focus on 3q27-28. Given probable etiologic heterogeneity in OCD, mapping gene(s) involved in the disorder may be enhanced by replication studies, large-scale family-based linkage studies, and the application of novel statistical methods.

Chromosomes, Human↗
PubMed2005

Possible association of the MAG locus with schizophrenia in a Chinese Han cohort of family trios.

Neurotransmitter-based hypotheses have so far led to only moderate success in predicting new pathogenetic findings in etiology of schizophrenia. On the other hand, the more recent oligodendroglia hypotheses of this disorder have been supported by an increasing body of evidence. For example, the expression level of the myelin associated glycoprotein (MAG) gene has been shown to be significantly lower in schizophrenia patient groups compared to control groups. Such an effect might be a result of genetic variations of the MAG gene. In order to test this hypothesis, we genotyped four markers within the MAG locus in 413 trios sample of the Han Chinese using allele-specific PCR. None of the four markers revealed noticeable allelic significance. However, the four-marker and two-marker haplotypes covering components rs720309 and rs720308 were observed to be significantly associated with schizophrenia (P < 0.0001) in this study. In addition, we identified one common risk haplotype TA (rs720309-rs720308, present in 78.5% of the general population) that showed increased evidence of overtransmission from parents to affected offspring (P = 0.0001). The results demonstrated MAG might play a role in genetic susceptibility to schizophrenia. Furthermore, our finding of a possible association between the MAG locus and schizophrenia is in agreement with the hypotheses of oligodendrltic and myelination dysfunction.

Adult↗
PubMed2005

Filamin A mutations cause periventricular heterotopia with Ehlers-Danlos syndrome.

OBJECTIVE: To define the clinical, radiologic, and genetic features of periventricular heterotopia (PH) with Ehlers-Danlos syndrome (EDS). METHODS: Exonic sequencing and single stranded conformational polymorphism (SSCP) analysis was performed on affected individuals. Linkage analysis using microsatellite markers on the X-chromosome was performed on a single pedigree. Western blotting evaluated for loss of filamin A (FLNA) protein and Southern blotting assessed for any potential chromosome rearrangement in this region. RESULTS: The authors report two familial cases and nine additional sporadic cases of the EDS-variant form of PH, which is characterized by nodular brain heterotopia, joint hypermobility, and development of aortic dilatation in early adulthood. MRI typically demonstrated bilateral nodular PH, indistinguishable from PH due to FLNA mutations. Exonic sequencing or SSCP analyses of FLNA revealed a 2762 delG single base pair deletion in one affected female. Another affected female harbored a C116 single point mutation, resulting in an A39G change. A third affected female had a 4147 delG single base pair deletion. One pedigree with no detectable exonic mutation demonstrated positive linkage to the FLNA locus Xq28, an affected individual in this family also had no detectable FLNA protein, but no chromosomal rearrangement was detected. CONCLUSION: These results suggest that the Ehlers-Danlos variant of periventricular heterotopia (PH), in part, represents an overlapping syndrome with X-linked dominant PH due to filamin A mutations.

Adolescent↗
PubMed2003

A novel form of pontocerebellar hypoplasia maps to chromosome 7q11-21.

OBJECTIVE: To describe a novel form of pontocerebellar hypoplasia (PCH) and map its genetic locus. BACKGROUND: PCH is a heterogeneous group of disorders that are characterized by abnormally small cerebellum and brainstem. Autosomal recessive inheritance has been implied in many cases, but no genetic loci have been mapped to date. METHODS: The authors studied a consanguineous family from the Sultanate of Oman with three siblings with a novel form of PCH. The authors performed clinical studies and linkage analysis of this pedigree. RESULTS: The clinical features of the affected children include developmental delay, progressive microcephaly with brachycephaly, seizures during the first year of life, hypotonia with hyperreflexia, short stature, and optic atrophy. Imaging studies showed a small pons and cerebellum, prominent sulci and lateral ventricles, and decreased cerebral white matter volume. A lack of dyskinesias distinguishes this pedigree from PCH type 2. Genetic studies of this family revealed evidence of significant linkage to chromosome 7q11-21 (maximum multipoint lod score 3.23). CONCLUSIONS: This pedigree represents a novel form of autosomal recessive PCH, which the authors propose to call cerebellar atrophy with progressive microcephaly (CLAM). This disorder maps to chromosome 7q11-21, and this locus was named CLAM. This report represents the first identification of a genetic locus for PCH.

Abnormalities, Multiple↗
PubMed2003

Autosomal recessive form of periventricular heterotopia.

BACKGROUND: Familial periventricular heterotopia (PH) represents a disorder of neuronal migration resulting in multiple gray matter nodules along the lateral ventricular walls. Prior studies have shown that mutations in the filamin A (FLNA) gene can cause PH through an X-linked dominant inheritance pattern. OBJECTIVE: To classify cortical malformation syndromes associated with PH. METHODS: Analyses using microsatellite markers directed toward genomic regions of FLNA and to a highly homologous autosomal gene, FLNB, were performed on two pedigrees to evaluate for linkage with either filamin gene. RESULTS: Two consanguineous pedigrees with PH that suggest an autosomal recessive inheritance pattern are reported. MRI of the brain revealed periventricular nodules of cerebral gray matter intensity, typical for PH. Seizures or developmental delay appeared to be a common presenting feature. Microsatellite analysis suggested no linkage to FLNA or FLNB. CONCLUSIONS: Autosomal recessive PH is another syndromic migrational disorder, distinct from X-linked dominant PH. Further classification of these different syndromes will provide an approach for genetic evaluation.

Adult↗
PubMed2002

Genetic susceptibility to Hodgkin's lymphoma and to secondary cancer: workshop report.

Although the occurrence of familial Hodgkin's lymphoma (HL) is a rare event, genetic susceptibility as a cause of HL and its influence on treatment outcome may not be rare. However, results obtained from the analysis of HL families will probably have broad implications with regard to understanding common pathogenic factors leading to the development of the disease. The description of anticipation among the affected offspring of HL patients further strengthens the view that heritable factors contribute to development of HL. Moreover, the finding that particular human leukocyte antigen (HLA) alleles are associated with susceptibility to HL may be regarded as a hint to the presence of an as yet undefined infectious agent, leading to the growth of a malignant lymphoma cell clone in those patients that are more susceptible to this agent due to their HLA genotype. In addition, since an intrinsic genomic instability was observed in a proportion of HL patients, it is plausible that these patients are not only susceptible to the causation of HL, but are also at a higher risk of developing therapy-related (TR) secondary cancers following treatment. Estimation of sister chromatid exchange was established as a tool to identify patients at higher risk of TR cancer. In this context the use of therapeutic agents known to increase genomic instability should be carefully considered prior to determing the best treatment. The future identification of heritable factors contributing to HL will be of importance both with regard to diagnosis as well as treatment of HL patients.

Age of Onset↗
PubMed2001

Comparison of sib pair-based approaches for identifying quantitative trait loci underlying asthma in the Busselton families.

The goal of this study is to determine the linkage relationship between IgE levels and the 269 microsatellite markers using the Genetic Analysis Workshop 12 Busselton data set. Analyses were carried out using both traditional and new Haseman-Elston methods, the maximum likelihood quantitative trait locus estimation (MLE QTL) method and the nonparametric (NP QTL) method. Our analyses confirmed some of the signals reported by Daniels et al. [Nature 383:247-50, 1996]. We also observed that several significant signals reported in the original report became insignificant (D6S76 and D11S96) and several new signals showed up after the data were reanalyzed using the new Haseman-Elston method, the MLE QTL method, and the NP QTL method. Based on the original and the current analyses, we recommend that follow-up studies of three regions including D7S2250, FCER1B, D11S901, and six markers on chromosome 16 be given higher priority.

Adult↗
PubMed2001

Apparent anticipation and heterogeneous transmission patterns in familial Hodgkin's and non-Hodgkin's lymphoma: report from a study based on Swedish cancer database.

The goal of this study was to test whether there is genetic anticipation in Hodgkin's disease (HD) and non-Hodgkin's lymphoma (NHL). We analyzed 102 parent-child pairs with HD or NHL, based upon the Swedish Cancer Database. We identified 18 sib-pairs (2 HD and 16 NHL) and 102 parent-child pairs (13 HD/HD, 56 NHL/NHL, 25 HD/NHL, and 8 NHL/HD). The mean anticipation score was 27.6 years for all 102 parent-child pairs. The anticipation means were 13.8, 28.4, 19.8 and 35.8 years for these pair-type groups, respectively. These differences between the age of onset for each affected parent-child pair type were statistically significant. The anticipation level was more pronounced among the NHUNHL pairs than in the HD/HD pairs (difference = 12.6 years, p = 0.0003). These results allow us to conclude with confidence that there is an apparent genetic anticipation in familial HD and NHL in the Swedish population.

Anticipation, Genetic↗
PubMed2000

Complex segregation analysis provides compelling evidence for a major gene underlying obsessive-compulsive disorder and for heterogeneity by sex.

Evidence from twin and family studies supports a genetic etiology for obsessive-compulsive disorder (OCD). The purpose of this study was to test whether a major gene is implicated in a proportion of families with OCD. Complex segregation analyses of 153 families (80 case and 73 control), ascertained in the Johns Hopkins OCD Family Study, provided strong evidence for a major gene. A Mendelian-dominant model, with significant sex effects and with residual familial effects, best explained the observed data. Stratification of the sample by the sex of probands provided further evidence of heterogeneity with respect to familial aggregation. Segregation analyses of 86 families with a female proband and of the 67 families with a male proband suggested that a Mendelian-dominant model with familial residual effects was the most parsimonious model explaining the inheritance of OCD in both subgroups.

Adolescent↗
PubMed2000

A genetic study of Hodgkin's lymphoma: an estimate of heritability and anticipation based on the familial cancer database in Sweden.

Hodgkin's lymphoma (HL) is a heterogeneous hemopoietic malignancy. Previous studies have implicated a genetic etiology responsible for familial HL. We have estimated the heritability of HL and tested the hypothesis of genetic anticipation by using a high quality cancer database of the Swedish population. Heritability was estimated by employing a threshold-liability model. To test the hypothesis of anticipation, the usual T-test procedure was used to test whether there was a difference in cancer age-of-onset between parents and children who were affected with HL. A randomization test was carried out to test the validity of the P-values. Additional analyses were performed after stratifying the data based on birth cohorts. This data set revealed that there was a difference between the age-of-onset of parents and of offspring who were affected with HL. We also estimated the heritability of HL in the Swedish population to be approximately 28.4%. Both findings provide further evidence for a genetic basis for HL.

Adult↗
PubMed2000

A new locus for dominant drusen and macular degeneration maps to chromosome 6q14.

PURPOSE: To report the localization of a gene causing drusen and macular degeneration in a previously undescribed North American family. METHODS: Genetic mapping studies were performed using linkage analysis in a single family with drusen and atrophic macular degeneration. RESULTS: The clinical manifestations in this family ranged from fine macular drusen in asymptomatic middle-aged individuals to atrophic macular lesions in two children and two elderly patients. We mapped the gene to chromosome 6q14 between markers D6S2258 and D6S1644. CONCLUSIONS: In a family with autosomal dominant drusen and atrophic macular degeneration, the gene maps to a 3.2-cM region on chromosome 6q14. This locus appears to be distinct from, but adjacent to, the loci for cone-rod dystrophy 7 (CORD7) and North Carolina macular dystrophy (MCDR1). Future identification of the gene responsible for the disease in this family will provide a better understanding of macular degeneration.

Adolescent↗
PubMed2000

Linkage exclusion and mutational analysis of the noggin gene in patients with fibrodysplasia ossificans progressiva (FOP).

Fibrodysplasia ossificans progressiva (FOP) is an extremely rare and disabling genetic disorder characterized by congenital malformation of the great toes and by progressive heterotopic endochondral ossification in predictable anatomical patterns. Although elevated levels of bone morphogenetic protein 4 (BMP4) occur in lymphoblastoid cells and in lesional cells of patients with FOP, mutations have not been identified in the BMP4 gene, suggesting that the mutation in FOP may reside in a BMP4-interacting factor or in another component of the BMP4 pathway. A powerful antagonist of BMP4 is the secreted polypeptide noggin. A recent case report described a heterozygous 42-bp deletion in the protein-coding region of the noggin gene in a patient with FOP. In order to determine if noggin mutations are a widespread finding in FOP, we examined 31 families with 1 or more FOP patients. Linkage analysis with an array of highly polymorphic microsatellite markers closely linked to the noggin gene was performed in four classically-affected multigenerational FOP families and excluded linkage of the noggin locus to FOP (the multipoint lod score was -2 or less throughout the entire range of markers). We sequenced the noggin gene in affected members of all four families, as well as in 18 patients with sporadic FOP, and failed to detect any mutations. Single-strand conformation polymorphism (SSCP) analysis of 4 of these patients plus an additional 9 patients also failed to reveal any mutations. Among the samples analyzed by SSCP and DNA sequencing was an independently obtained DNA sample from the identical FOP patient previously described with the 42-bp noggin deletion; no mutation was detected. Examination of the DNA sequences of 20 cloned noggin PCR products, undertaken to evaluate the possibility of a somatic mutation in the noggin gene which could be carried by a small subset of white blood cells, also failed to detect the presence of the reported 42-bp deletion. We conclude that mutations in the coding region of noggin are not associated with FOP.

Carrier Proteins↗
PubMed2000

Autosomal recessive lissencephaly with cerebellar hypoplasia is associated with human RELN mutations.

Normal development of the cerebral cortex requires long-range migration of cortical neurons from proliferative regions deep in the brain. Lissencephaly ("smooth brain," from "lissos," meaning smooth, and "encephalos," meaning brain) is a severe developmental disorder in which neuronal migration is impaired, leading to a thickened cerebral cortex whose normally folded contour is simplified and smooth. Two identified lissencephaly genes do not account for all known cases, and additional lissencephaly syndromes have been described. An autosomal recessive form of lissencephaly (LCH) associated with severe abnormalities of the cerebellum, hippocampus and brainstem maps to chromosome 7q22, and is associated with two independent mutations in the human gene encoding reelin (RELN). The mutations disrupt splicing of RELN cDNA, resulting in low or undetectable amounts of reelin protein. LCH parallels the reeler mouse mutant (Reln(rl)), in which Reln mutations cause cerebellar hypoplasia, abnormal cerebral cortical neuronal migration and abnormal axonal connectivity. RELN encodes a large (388 kD) secreted protein that acts on migrating cortical neurons by binding to the very low density lipoprotein receptor (VLDLR), the apolipoprotein E receptor 2 (ApoER2; refs 9-11 ), alpha3beta1 integrin and protocadherins. Although reelin was previously thought to function exclusively in brain, some humans with RELN mutations show abnormal neuromuscular connectivity and congenital lymphoedema, suggesting previously unsuspected functions for reelin in and outside of the brain.

Animals↗
PubMed2000

Combined segregation and linkage analysis of 59 Hodgkin's disease families indicates the role of HLA determinants.

Through a literature search, we identified a total of 59 nuclear families with Hodgkin's disease (HD). The affected individuals in these families were HLA haplotyped. To evaluate the role of HLA-linked determinants of HD and investigate the mode of inheritance of familial HD, a combined segregation and linkage analysis was performed, together with a semi-parametric analysis of sib pairs. Amongst single locus models, a general single locus model showed no improvement over an additive model. However, a two locus additive model gave the best overall fit and a lod score of 3.55. We conclude that HD is most likely to be determined by both an HLA-associated major gene and other non-HLA genetic factors together with environmental effects.

HLA Antigens↗
PubMed1999

An evaluation of affected-sib-pair methods and transmission/disequilibrium tests for detecting genes underlying a complex trait.

For the analysis of complex traits, it is of interest to compare a few nonparametric methods such as affected-sib-pair (ASP) analyses and transmission/disequilibrium tests (TDT). The affected-sib-pair approaches we have examined here are ASP and ALL-SP which are implemented in SIBPAIR program. We also applied the BETA program which has not so far been extensively compared with other methods. The study indicates that the ASP program and the BETA program give concordant results although BETA tends to give higher lod scores. However, when all sibs were included in the analysis (ALL-SP), linkage signals became weaker, compared with ASP and BETA. The TDT detected 66 positive signals at a significance level of 0.05 and identified a true locus. Overall, our results suggest that affected-sib-pair analysis has reasonable power (p < 0.0001) to detect linkage given the disease model and the family structure specified in the GAW11 Problem 2 data set.

Genetic Testing↗
PubMed1999

The impact of redefining affection status for alcoholism on affected-sib-pair analysis.

The analysis of a complex disease such as alcohol dependence requires a more precise definition of affection status. Collaborative Study on the Genetics of Alcoholism (COGA) provided a variety of qualitative and quantitative measures as well as genotype information, in addition to two criteria of affection status. To identify two groups of phenotypically "more homogeneous" individuals among alcoholics (COGA criterion), we redefined affection status by using cluster analysis and classification and regression tree, incorporating some important covariates such as event related potentials, monoamine oxidase B activity, status of smoking, age of onset, three variables of personality assessed with the Tridimensional Personality Questionnaire and three latent class variables. With redefined affection status, we repeated nonparametric analysis by three sib pair analysis programs (SIBPAL, SIBPAIR, and BETA) using nine candidate DNA markers identified by Reich et al. [1998] and Long et al. [1998]. The goals of our analysis are 1) to confirm previous results for these nine markers with redefined affection status and 2) to compare the performance from these three programs.

Adolescent↗