Biomedical subjects

Yin Y Shugart

Publications and source records attributed to Yin Y Shugart.

11 recordsLinked to original sources

PubMed2007

Dopaminergic polymorphisms in Tourette syndrome: association with the DAT gene (SLC6A3).

Tourette syndrome (TS) is a chronic neuropsychiatric disorder characterized by involuntary motor and phonic tics. The pattern of inheritance and associated genetic abnormality has yet to be fully characterized. A dopaminergic abnormality in this disorder is supported by response to specific therapies, nuclear imaging, and postmortem studies. In this protocol, dopaminergic polymorphisms were examined for associations with TS and attention-deficit hyperactivity disorder (ADHD). Polymorphisms investigated included the dopamine transporter (DAT1 DdeI and DAT1 VNTR), dopamine receptor (D4 Upstream Repeat and D4 VNTR), dopamine converting enzyme (dopamine beta-hydroxylase), and the acid phosphatase locus 1 (ACP1) gene. DNA was obtained from 266 TS individuals +/- ADHD and 236 controls that were ethnicity-matched. A significant association, using a genotype-based association analysis, was identified for the TS-total and TS-only versus control groups for the DAT1 DdeI polymorphism (AG vs. AA, P = 0.004 and P = 0.01, respectively). Population structure, estimated by the genotyping of 27 informative SNP markers, identified 3 subgroups. A statistical re-evaluation of the DAT1 DdeI polymorphism following population stratification confirmed the association for the TS-total and TS-only groups, but the degree of significance was reduced (P = 0.017 and P = 0.016, respectively). This study has identified a significant association between the presence of TS and a DAT polymorphism. Since abnormalities of the dopamine transporter have been hypothesized in the pathophysiology of TS, it is possible that this could be a functional allele associated with clinical expression.

Adolescent↗

PubMed2006

Hoarding in obsessive-compulsive disorder: results from the OCD Collaborative Genetics Study.

Hoarding behavior occurs frequently in obsessive-compulsive disorder (OCD). Results from previous studies suggest that individuals with OCD who have hoarding symptoms are clinically different than non-hoarders and may represent a distinct clinical group. In the present study, we compared 235 hoarding to 389 non-hoarding participants, all of whom had OCD, collected in the course of the OCD Collaborative Genetics Study. We found that, compared to non-hoarding individuals, hoarders were more likely to have symmetry obsessions and repeating, counting, and ordering compulsions; poorer insight; more severe illness; difficulty initiating or completing tasks; and indecision. Hoarders had a greater prevalence of social phobia and generalized anxiety disorder. Hoarders also had a greater prevalence of obsessive-compulsive and dependent personality disorders. Five personality traits were independently associated with hoarding: miserliness, preoccupation with details, difficulty making decisions, odd behavior or appearance, and magical thinking. Hoarding and indecision were more prevalent in the relatives of hoarding than of non-hoarding probands. Hoarding in relatives was associated with indecision in probands, independently of proband hoarding status. The findings suggest that hoarding behavior may help differentiate a distinct clinical subgroup of people with OCD and may aggregate in some OCD families. Indecision may be a risk factor for hoarding in these families.

Adolescent↗

PubMed2006

Covariate-based linkage analysis: application of a propensity score as the single covariate consistently improves power to detect linkage.

Successful identification of genetic risk loci for complex diseases has relied on the ability to minimize disease and genetic heterogeneity to increase the power to detect linkage. One means to account for disease heterogeneity is by incorporating covariate data. However, the inclusion of each covariate will add one degree of freedom to the allele sharing based linkage test, which may in fact decrease power. We explore the application of a propensity score, which is typically used in causal inference to combine multiple covariates into a single variable, as a means of allowing for multiple covariates with the addition of only one degree of freedom. In this study, binary trait data, simulated under various models involving genetic and environmental effects, were analyzed using a nonparametric linkage statistic implemented in LODPAL. Power and type I error rates were evaluated. Results suggest that the use of the propensity score to combine multiple covariates as a single covariate consistently improves the power compared to an analysis including no covariates, each covariate individually, or all covariates simultaneously. Type I error rates were inflated for analyses with covariates and increased with increasing number of covariates, but reduced to nominal rates with sample sizes of 1000 families. Therefore, we recommend using the propensity score as a single covariate in the linkage analysis of a trait suspected to be influenced by multiple covariates because of its potential to increase the power to detect linkage, while controlling for the increase in the type I error.

Algorithms↗

PubMed2006

The OCD collaborative genetics study: methods and sample description.

Results from twin and family studies suggest that obsessive-compulsive disorder (OCD) may be transmitted in families but, to date, genes for the disorder have not been identified. The OCD Collaborative Genetics Study (OCGS) is a six-site collaborative genetic linkage study of OCD. Specimens and blinded clinical data will be made available through the National Institute of Mental Health (NIMH) cell repository. In this initial report, we describe the methods of the study and present clinical characteristics of affected individuals for researchers interested in this valuable resource for genetic studies of OCD. The project clinically evaluated and collected blood specimens from 238 families containing 299 OCD-affected sibling pairs and their parents, and additional affected relative pairs, for a genome-wide linkage study. Of the 999 individuals interviewed to date, 624 were diagnosed with "definite" OCD. The mean age of subjects was 36 years (range 7-95). The majority of affected individuals (66%) were female. The mean age at onset of obsessive-compulsive symptoms was 9.5 years. Specific mood disorders, anxiety disorders, eating disorders, and skin picking were more prevalent in female cases, whereas tics, Tourette disorder, and alcohol dependence were more prevalent in male cases. Compared to "definite" cases of OCD, "probable" cases (n = 82) had, on average, later age at onset of obsessive-compulsive symptoms, lower severity score, and fewer numbers of different categories of obsessions and compulsions, and they were less likely to have received treatment for their symptoms.

Adolescent↗

PubMed2005

Application of the propensity score in a covariate-based linkage analysis of the Collaborative Study on the Genetics of Alcoholism.

BACKGROUND: Covariate-based linkage analyses using a conditional logistic model as implemented in LODPAL can increase the power to detect linkage by minimizing disease heterogeneity. However, each additional covariate analyzed will increase the degrees of freedom for the linkage test, and therefore can also increase the type I error rate. Use of a propensity score (PS) has been shown to improve consistently the statistical power to detect linkage in simulation studies. Defined as the conditional probability of being affected given the observed covariate data, the PS collapses multiple covariates into a single variable. This study evaluates the performance of the PS to detect linkage evidence in a genome-wide linkage analysis of microsatellite marker data from the Collaborative Study on the Genetics of Alcoholism. Analytical methods included nonparametric linkage analysis without covariates, with one covariate at a time including multiple PS definitions, and with multiple covariates simultaneously that corresponded to the PS definitions. Several definitions of the PS were calculated, each with increasing number of covariates up to a maximum of five. To account for the potential inflation in the type I error rates, permutation based p-values were calculated. RESULTS: Results suggest that the use of individual covariates may not necessarily increase the power to detect linkage. However the use of a PS can lead to an increase when compared to using all covariates simultaneously. Specifically, PS3, which combines age at interview, sex, and smoking status, resulted in the greatest number of significant markers identified. All methods consistently identified several chromosomal regions as significant, including loci on chromosome 2, 6, 7, and 12. CONCLUSION: These results suggest that the use of a propensity score can increase the power to detect linkage for a complex disease such as alcoholism, especially when multiple important covariates can be used to predict risk and thereby minimize linkage heterogeneity. However, because the PS is calculated as a conditional probability of being affected, it does require the presence of observed covariate data on both affected and unaffected individuals, which may not always be available in real data sets.

Alcoholism↗

PubMed2005

Application of family-based association testing to assess the genotype-phenotype association involved in complex traits using single-nucleotide polymorphisms.

BACKGROUND: We used the FBAT (family-based association test) software to test for association between 300 individual single-nucleotide polymorphisms and P1 (a latent trait of Kofendred Personality Disorder) in 100 simulated replicates of the Aipotu population. Using the Genetic Analysis Workshop 14 dataset, we calculated the power of FBAT to detect linkage disequilibrium on chromosome 3 (D2). Also, we calculated the false-positive rate on chromosome 1, which contains a true locus (D1) but no linkage disequilibrium was simulated between the trait and all the surrounding single-nucleotide polymorphisms. RESULTS: We were able to detect the associations between phenotype P1 and three adjacent markers B03T3056 (average p-value = 0.0002), B03T3057 (average p-value = 0.00072), and B03T3058 (average p-value = 0.0038) with power of 98%, 87%, 71% on chromosome 3, respectively. The overall false positive rate to detect association was 0.06 on chromosome 1. CONCLUSION: The power to detect a significant association in 100 nuclear families affected with the latent trait of Kofendred Personality Disorder by using FBAT was reasonable (based on 100 replicates). In the future, we will compare the performance of FBAT with alternative approaches, such as using FBAT-generalized estimating equations methods to test for association in families affected with complex traits.

Chromosomes, Human, Pair 1↗

PubMed2004

Etiological heterogeneity of familial periventricular heterotopia and hydrocephalus.

Periventricular heterotopia (PH) represents a neuronal migration disorder that results in gray matter nodules along the lateral ventricles beneath an otherwise normal appearing cortex. While prior reports have shown that mutations in the filamin A (FLNA) gene can cause X-linked dominant PH, an increasing number of studies suggest the existence of additional PH syndromes. Further classification of these cortical malformation syndromes associated with PH allows for determination of the causal genes. Here we report three familial cases of PH with hydrocephalus. One pedigree has a known FLNA mutation with hydrocephalus occurring in the setting of valproic acid exposure. Another pedigree demonstrated possible linkage to the Xq28 locus including FLNA, although uncharacteristically a male was affected and sequencing of the FLNA gene in this individual revealed no mutation. However, in the third family with an autosomal mode of inheritance, microsatellite analysis ruled out linkage with the FLNA gene. Routine karyotyping and fluorescent in situ hybridization using BAC probes localized to FLNA also showed no evidence of genomic rearrangement. Western blot analysis of one of the affected individuals demonstrated normal expression of the FLNA protein. Lastly, sequencing of greater than 95% of the FLNA gene in an affected member failed to demonstrate a mutation. In conclusion, these findings demonstrate the etiological heterogeneity of PH with hydrocephalus. Furthermore, there likely exists an autosomal PH gene, distinct from the previously described X-linked and autosomal recessive forms. Affected individuals have severe developmental delay and may have radiographic findings of hydrocephalus.

Adult↗

PubMed2003

Suggestive linkage to chromosomal regions 13q31 and 22q12 in families with psychotic bipolar disorder.

OBJECTIVE: Linkage studies of bipolar disorder and schizophrenia have found overlapping evidence for susceptibility genes in four chromosomal regions-10p12-14, 13q32, 18p11.2, and 22q12-13. The authors previously demonstrated familial clustering of psychotic symptoms-defined as hallucinations and/or delusions-in some bipolar disorder pedigrees. In this study they used stratified linkage analysis to test the hypothesis that those bipolar disorder pedigrees most enriched for psychotic symptoms would show greater evidence of linkage to the regions of previous bipolar disorder/schizophrenia linkage overlap. METHOD: Nonparametric linkage analyses using GENEHUNTER and ASPEX were performed on 65 bipolar disorder families. Family subsets were defined by the number of family members with psychotic mood disorder. RESULTS: The 10 families in which three or more members had psychotic mood disorder showed suggestive evidence of linkage to 13q31 (nonparametric linkage score=3.56; LOD score=2.52) and 22q12 (nonparametric linkage score=3.32; LOD score=3.06). These results differed significantly from those for the entire study group of 65 families, which showed little or no linkage evidence in the two regions. The 10 families with three or more psychotic members did not show evidence of linkage to 10p12-14 or 18p11.2. The 95% confidence interval on 22q12 spanned 4.3 centimorgans (2.6 megabases) and was congruent with previous findings. CONCLUSIONS: Bipolar disorder families in which psychotic symptoms cluster may carry susceptibility genes on chromosomal regions 13q31 and 22q12. Replication should be attempted in similar families and perhaps in schizophrenia families in which mood symptoms cluster because these overlapping phenotypes may correlate most closely with the putative susceptibility genes. The localization of the 22q12 finding particularly encourages further study of this region.

Affective Disorders, Psychotic↗

PubMed2002

CGH-targeted linkage analysis reveals a possible BRCA1 modifier locus on chromosome 5q.

Women with germline mutations in BRCA1 have a greatly elevated risk of breast and ovarian cancer. However, considerable variation in the degree of breast cancer risk associated with a BRCA1 mutation has been observed, suggesting that modifiers of BRCA1 penetrance may exist. We hypothesized that the modifier genes might be located in regions of allelic imbalance in the tumors of BRCA1 mutation carriers, as have been reported on chromosomes 4p, 4q and 5q. In order to determine whether novel genetic modifiers of BRCA1-associated breast cancer penetrance in these regions exist, we used non-parametric linkage analysis methods to determine whether allele sharing of chromosomes 4p, 4q and 5q was observed preferentially within BRCA1 mutation families in women with BRCA1 mutations and breast cancer. No significant linkage on chromosome 4p or 4q was observed associated with breast cancer risk in BRCA1 mutation carriers. However, we observed a significant linkage signal at D5S1471 on chromosome 5q (P = 0.009) in all the families analyzed together. The significance of this observation increased in the subset of families with an average of breast cancer diagnosis less than 45 years (P = 0.003). These results suggest the presence of one or more genes on chromosome 5q33-34 that modify breast cancer risk in BRCA1 mutation carriers. The approach described here may be utilized to identify penetrance modifiers in other autosomal dominant syndromes.

Adult↗

PubMed2002

Mutations in the RPGR gene cause X-linked cone dystrophy.

X-linked cone dystrophy is a type of hereditary retinal degeneration characterized by a progressive dysfunction of the day vision or photopic (cone) system with preservation of night vision or scotopic (rod) function. The disease presents with a triad of photophobia, loss of color vision and reduced central vision. This phenotype is distinct from retinitis pigmentosa (RP) in which there are prominent night and peripheral vision disturbances. X-linked cone dystrophy is a genetically heterogeneous disorder, with linkage to loci on Xp11.4--Xp21.1 (COD1, OMIM 304020) and Xq27 (COD2, OMIM 303800). COD1 maps to a region that harbors the RPGR gene, mutations in which account for >70% of patients with X-linked RP. The majority of these mutations reside in one purine-rich exon, ORF15, encoding 567 amino acids with a repetitive domain rich in glutamic acid residues. We mapped two families with X-linked cone dystrophy to the COD1 locus and identified two distinct mutations in ORF15 in the RPGR gene (ORF15+1343_1344delGG and ORF15+694_708del15) leading to a frame-shift and premature termination of translation in one case and a deletion of five amino acids in another. Consistent with expression of RPGR in rods and cones, our results show that mutations in RPGR, in addition to X-linked RP, can also cause cone-specific degeneration.

Amino Acid Sequence↗

PubMed2002

The power and statistical behaviour of allele-sharing statistics when applied to models with two disease loci.

We have evaluated the power for detecting a common trait determined by two loci, using seven statistics, of which five are implemented in the computer program SimWalk2, and two are implemented in GENEHUNTER. Unlike most previous reports which involve evaluations of the power of allele-sharing statistics for a single disease locus, we have used a simulated data set of general pedigrees in which a two-locus disease is segregating and evaluated several nonparametric linkage statistics implemented in the two programs. We found that the power for detecting linkage using the S(all) statistic in GENEHUNTER (GH, version 2.1), implemented as statistic E in SimWalk2 (version 2.82), is different in the two. The P values associated with statistic E output by SimWalk2 are consistently more conservative than those from GENEHUNTER except when the underlying model includes heterogeneity at a level of 50% where the P values output are very comparable. On the other hand, when the thresholds are determined empirically under the null hypothesis, S(all) in GENEHUNTER and statistic E have similar power.

Alleles↗