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Kung-Yee Liang

Publications and source records attributed to Kung-Yee Liang.

30 records · Page 2Linked to original sources
PubMed2003

Genomewide linkage scan for schizophrenia susceptibility loci among Ashkenazi Jewish families shows evidence of linkage on chromosome 10q22.

Previous linkage studies in schizophrenia have been discouraging due to inconsistent findings and weak signals. Genetic heterogeneity has been cited as one of the primary culprits for such inconsistencies. We have performed a 10-cM autosomal genomewide linkage scan for schizophrenia susceptibility regions, using 29 multiplex families of Ashkenazi Jewish descent. Although there is no evidence that the rate of schizophrenia among the Ashkenazim differs from that in other populations, we have focused on this population in hopes of reducing genetic heterogeneity among families and increasing the detectable effects of any particular locus. We pursued both allele-sharing and parametric linkage analyses as implemented in Genehunter, version 2.0. Our strongest signal was achieved at chromosome 10q22.3 (D10S1686), with a nonparametric linkage score (NPL) of 3.35 (genomewide empirical P=.035) and a dominant heterogeneity LOD score (HLOD) of 3.14. Six other regions gave NPL scores >2.00 (on chromosomes 1p32.2, 4q34.3, 6p21.31, 7p15.2, 15q11.2, and 21q21.2). Upon follow-up with an additional 23 markers in the chromosome 10q region, our peak NPL score increased to 4.27 (D10S1774; empirical P=.00002), with a 95% confidence interval of 12.2 Mb for the location of the trait locus (D10S1677 to D10S1753). We find these results encouraging for the study of schizophrenia among Ashkenazi families and suggest further linkage and association studies in this chromosome 10q region.

Adolescent↗
PubMed2003

The identification of OCD-related subgroups based on comorbidity.

BACKGROUND: Individuals with obsessive-compulsive disorder (OCD) frequently have other psychiatric disorders. This study employed latent class analysis (LCA) to explore whether there are underlying clinical constructs that distinguish "OCD-related" subgroups. METHODS: The study included 450 subjects, case and control probands and their first-degree relatives, and LCA was used to derive empirically based subgroups of 10 disorders: OCD, obsessive-compulsive personality disorder (OCPD), recurrent major depressive disorder (RMDD), separation anxiety disorder, panic disorder or agoraphobia (PD/AG), tic disorders (TD), generalized anxiety disorder (GAD), somatoform disorders (hypochondriasis or body dysmorphic disorder), pathologic skin picking or nail biting (PSP/NB), and eating disorders (EDs). The derived classes were compared on several clinical variables. RESULTS: The best fitting model is a four-class structure: minimal disorder, predominant RMDD and GAD, "highly comorbid," and PD/AG and TD. The nature and number of disorders represented suggests that the first classes are distributed ordinarily on a dimension of severity, and the fourth class is qualitatively distinct. Support for this structure is based on the number of disorders, age at onset of OCD, neuroticism, and extraversion. CONCLUSIONS: In this OCD enriched sample, LCA identified four classes of disorder. These classes appear to conform to two subgroups that may prove useful in investigating the etiology of OCD.

Age of Onset↗
PubMed2003

Multipoint affected sibpair linkage methods for localizing susceptibility genes of complex diseases.

Recently, Liang et al. ([2001] Hum. Hered. 51:64-78) proposed a general multipoint linkage method for estimating the chromosomal position of a putative susceptibility locus. Their technique is computationally simple and does not require specification of penetrance or a mode of inheritance. In complex genetic diseases, covariate data may be available which reflect etiologic or locus heterogeneity. We developed approaches to incorporating covariates into the method of Liang et al. ([2001] Hum. Hered. 51:64-78) with particular attention to exploiting age-at-onset information. The results of simulation studies, and a worked data example using a family data set ascertained through probands with schizophrenia, suggest that utilizing covariate information can yield substantial efficiency gains in localizing susceptibility genes.

Age of Onset↗
PubMed2003

Multipoint linkage disequilibrium mapping approach: incorporating evidence of linkage and linkage disequilibrium from unlinked region.

Gene mapping for complex diseases is still a challenge in genetic studies. For family-based studies, the single-locus methods for detecting linkage and linkage disequilibrium (LD) one at a time may not capture the assumed interaction between multiple causal genes efficiently. We propose a multipoint LD approach for assessing the evidence of linkage and LD in a targeted chromosomal region by incorporating evidence from an unlinked region using the case-parent trio design. The paternal and maternal preferential transmission statistics defined in Liang et al. ([2001] Am. J. Hum. Genet. 68:937-950) are the primary statistics for this approach. Our generalized estimating equation (GEE) method builds on a model using the expected preferential transmission statistic from the targeted region conditional on this same statistic from the unlinked region. The major assumption is that there is no more than one trait locus in both the targeted region and unlinked region. The map position of an unobserved trait locus and its confidence interval can be calculated. Finally, we apply this approach to the African-American families drawn from the Collaborative Study on the Genetics of Asthma (CSGA). Previous analysis using this GEE approach developed by Liang et al. ([2001] Am. J. Hum. Genet. 68:937-950) suggested strong evidence of linkage and LD on chromosome 11, but only marginal evidence on chromosome 8. While conditioning on marker D11S937 on chromosome 11, a separate trait locus on chromosome 8 was estimated at tau(2) empty set = 11.67 cM, with a 95% confidence interval of (8.75, 14.59), and the test statistic shows significant evidence of linkage and LD (P-value=0.0198) in this region of chromosome 8.

Black or African American↗
PubMed2003

Multipoint linkage disequilibrium mapping for complex diseases.

Linkage disequilibrium (LD) or association studies using case-parent trios have become a common approach to locate unobserved susceptibility genes underlying complex diseases. With the availability of ever more dense marker maps, how to utilize the information carried by multiple markers simultaneously remains challenging. Recently, Liang et al. ([2001a] Am. J. Hum. Genet. 68: 937-950) proposed a multipoint LD method to estimate the location of a susceptibility gene within a framework map along with its sampling uncertainty. Two important features of this method are that 1) it uses all trios whether parents are heterozygous for a given marker or not, and 2) it provides a single test statistic for the null hypothesis of no linkage or no LD to the region, avoiding the multiple testing problem encountered when performing individual transmission disequilibrium tests (TDT) for each marker individually. In this paper, we discuss how this method can be expanded to address important issues pertaining to complex diseases in a unified fashion. These issues include, among others, gene-gene and gene-environment interactions, genetic heterogeneity, phenotypic refinement, and paternal vs. maternal transmission. We applied this method to asthmatic case-parent trios from the Collaborative Study on the Genetics of Asthma (CSGA), and found that the previous evidence for linkage and LD in a 13.6 cM region of chromosome 11 can be attributed to maternal transmission, while there was no evidence of excess paternal transmission. Furthermore, such discrepancy in preferential transmission was most evident among probands with early onset age (6 years old or younger).

Algorithms↗
PubMed2002

Sports ability in young men and the incidence of cardiovascular disease.

PURPOSE: For physical activity to reduce the risk of cardiovascular disease, it must be sustained throughout life. We sought to determine the relation between the ability of young adults in different sports and their continued physical activity in midlife, and subsequent cardiovascular disease. SUBJECTS AND METHODS: Baseline self-reported ability in tennis, golf, football, baseball, and basketball was assessed in a cohort study involving 1019 male medical students (median age, 22 years). Physical activity and sports participation were assessed 22 years later. The incidence of cardiovascular disease was assessed during a median follow-up of 40 years, using annual questionnaires, medical records, and death certificates. RESULTS: Subjects with high ability in tennis as young adults had the highest participation in the sport in midlife (median age, 48 years). In the midlife questionnaire administered in 1978, 33% reported playing tennis within the past week and 51% within the past year. Tennis was the only sport in which a higher ability during medical school was associated with a lower risk of cardiovascular disease. After adjustment for father's occupation, parental incidence of cardiovascular disease, serum cholesterol level, cigarette smoking, body mass index, and hypertension during follow-up, the relative hazard of developing cardiovascular disease was 0.56 (95% confidence interval [CI]: 0.35 to 0.89) in the high-ability group and 0.67 (95% CI: 0.47 to 0.96) in the low-ability group, compared with the no-ability group. CONCLUSION: Our results support the association between sustained activity in aerobic sports and a lower risk of cardiovascular disease. Sustainability of activity should be considered when developing physical education programs for young adults.

Adult↗
PubMed2002

Coffee intake and risk of hypertension: the Johns Hopkins precursors study.

BACKGROUND: Whether the increase in blood pressure with coffee drinking seen in clinical trials persists over time and translates into an increased incidence of hypertension is not known. METHODS: We assessed coffee intake in a cohort of 1017 white male former medical students (mean age, 26 years) in graduating classes from 1948 to 1964 up to 11 times over a median follow-up of 33 years. Blood pressure and incidence of hypertension were determined annually by self-report, demonstrated to be accurate in this cohort. RESULTS: Consumption of 1 cup of coffee a day raised systolic blood pressure by 0.19 mm Hg (95% confidence interval, 0.02-0.35) and diastolic pressure by 0.27 mm Hg (95% confidence interval, 0.15-0.39) after adjustment for parental incidence of hypertension and time-dependent body mass index, cigarette smoking, alcohol drinking, and physical activity in analyses using generalized estimating equations. Compared with nondrinkers at baseline, coffee drinkers had a greater incidence of hypertension during follow-up (18.8% vs. 28.3%; P =.03). Relative risk (95% confidence interval) of hypertension associated with drinking 5 or more cups a day was 1.35 (0.87-2.08) for baseline intake and 1.60 (1.06-2.40) for intake over follow-up. After adjustment for the variables listed above, however, these associations were not statistically significant. CONCLUSION: Over many years of follow-up, coffee drinking is associated with small increases in blood pressure, but appears to play a small role in the development of hypertension.

Adult↗
PubMed2002

Unified sampling approach for multipoint linkage disequilibrium mapping of qualitative and quantitative traits.

Rapid development in biotechnology has enhanced the opportunity to deal with multipoint gene mapping for complex diseases, and association studies using quantitative traits have recently generated much attention. Unlike the conventional hypothesis-testing approach for fine mapping, we propose a unified multipoint method to localize a gene controlling a quantitative trait. We first calculate the sample size needed to detect linkage and linkage disequilibrium (LD) for a quantitative trait, categorized by decile, under three different modes of inheritance. Our results show that sampling trios of offspring and their parents from either extremely low (EL) or extremely high (EH) probands provides greater statistical power than sampling in the intermediate range. We next propose a unified sampling approach for multipoint LD mapping, where the goal is to estimate the map position (tau) of a trait locus and to calculate a confidence interval along with its sampling uncertainty. Our method builds upon a model for an expected preferential transmission statistic at an arbitrary locus conditional on the sampling scheme, such as sampling from EL and EH probands. This approach is valid regardless of the underlying genetic model. The one major assumption for this model is that no more than one quantitative trait locus (QTL) is linked to the region being mapped. Finally we illustrate the proposed method using family data on total serum IgE levels collected in multiplex asthmatic families from Barbados. An unobserved QTL appears to be located at tau; = 41.93 cM with 95% confidence interval of (40.84, 43.02) through the 20-cM region framed by markers D12S1052 and D12S1064 on chromosome 12. The test statistic shows strong evidence of linkage and LD (chi-square statistic = 18.39 with 2 df, P-value = 0.0001).

Asthma↗
PubMed2002

Ascertainment adjustment in complex diseases.

Genetic studies of complex diseases must confront two statistically difficult issues simultaneously. First, in many settings, to minimize the number of individuals to be genotyped, families enriched for disease must be oversampled. Also, statistical models in family studies should allow for residual association. This association will represent unmeasured genetic and environmental factors influencing disease risk. Dealing with these features simultaneously is both compelling and challenging. Burton et al. [2000] (Am. J. Hum. Gen. 69: 1505-14) recently discussed this issue and suggested that ascertainment corrections may lead to problematic parameter estimation. We revisit the issues and examples of Burton et al. [2000] (Am. J. Hum. Genet. 69: 1505-14) and present a more optimistic assessment. Estimation in this context is conceptually straightforward, but may be more problematic in practice. Specifically, we find that even slight misspecification of the random effects distribution in ascertainment-adjusted likelihood can yield severely biased parameter estimates. This result should make scientists wary when interpreting results from ascertainment-adjusted variance-component models. .

Bias↗
PubMed2002

Multipoint linkage detection in the presence of heterogeneity.

Linkage heterogeneity is common for complex diseases. It is well known that loss of statistical power for detecting linkage will result if one assumes complete homogeneity in the presence of linkage heterogeneity. To this end, Smith (1963, Annals of Human Genetics 27, 175-182) proposed an admixture model to account for linkage heterogeneity. It is well known that for this model, the conventional chi-squared approximation to the likelihood ratio test for no linkage does not apply even when the sample size is large. By dealing with nuclear families and one marker at a time for genetic diseases with simple modes of inheritance, score-based test statistics (Liang and Rathouz, 1999, Biometrics 55, 65-74) and likelihood-ratio-based test statistics (Lemdani and Pons, 1995, Biometrics 51, 1033-1041) have been proposed which have a simple large-sample distribution under the null hypothesis of linkage. In this paper, we extend their work to more practical situations that include information from multiple markers and multi-generational pedigrees while allowing for a class of general genetic models. Three different approaches are proposed to eliminate the nuisance parameters in these test statistics. We show that all three approaches lead to the same asymptotic distribution under the null hypothesis of no linkage. Simulation results show that the proposed test statistics have adequate power to detect linkage and that the performances of these two classes of test statistics are quite comparable. We have applied the proposed method to a family study of asthma (Barnes et al., 1996), in which the score-based test shows evidence of linkage with p-value <0.0001 in the region of interest on chromosome 12. Additionally, we have implemented this score-based test within the frequently used computer package GENEHUNTER.

Journal Article↗
PubMed2002

Obsessive-compulsive disorder: defining the phenotype.

Characterizing the obsessive-compulsive disorder (OCD) phenotype is important for treatment and etiologic studies. This article describes a family-study approach for identifying the spectrum of conditions related to OCD and subtyping OCD cases into homogeneous subtypes.

Age of Onset↗