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Fang-Chi Hsu

Publications and source records attributed to Fang-Chi Hsu.

9 recordsLinked to original sources
PubMed2026

Genomic insights into stroke recovery: cross-phenotype associations.

Stroke is a major cause of long-term disability with variable recovery. While clinical factors such as initial severity play a role, genetic factors are increasingly recognized as important contributors to stroke recovery. Genotype studies are generally focused on a single post-stroke behavioural domain, but some genes might relate to broad mechanisms of plasticity. This study therefore aimed to identify cross-phenotypic genetic variants associated across two or more stroke recovery domains. DNA from Stroke, Stress, Rehabilitation, and Genetics study participants was genotyped, resulting in 9 814 610 variants. In order to examine cross-phenotypic results, we first conducted genome-wide association studies on the six recovery domains: motor (grip force), cognition (Telephone Montreal Cognitive Assessment), depression (Patient Health Questionnaire-8), stress (Primary Care Post-Traumatic Stress Disorder Screen), functional status (Stroke Impact Scale-Activities of Daily Living), and disability (modified Rankin Scale 0-2 versus 3-6), some of which were tested longitudinally, yielding nine phenotypes. Models were adjusted for age, sex, initial severity (NIH Stroke Scale score), and ancestry. Cross-phenotype associations were identified by evaluating single nucleotide polymorphisms (SNPs) associated (P < 5e-5) with multiple phenotypes. To determine how these genetic variants may relate to biological mechanisms of recovery, we conducted gene enrichment analyses. Participants (n = 565, 59% male) had mild-moderate initial stroke severity (median acute NIH Stroke Scale score = 4). After accounting for the correlation structure among the nine phenotypes, we observed 319 cross-phenotypic SNPs, 3.45 times the expected number. Five of the cross-phenotypic SNPs were linked to genes relevant to neural development, function and plasticity, e.g. ERICH1 (rs11778883-C), FOX3 (rs55726768-G), LIFR-AS1 (rs76401391-T), RPS6KA2 (rs113518460-C) and TUBGCP2 (rs147150392-C), as were enrichments in RAB5-EEA1, CTNNA1-CTNNB1, CIN85-SH3GL2 and ELMO1-DOCK2 complexes. Multiple gene enrichments were found, e.g. Stroke Impact Scale-Activities of Daily Living and Patient Health Questionnaire 8 at 3 months were enriched for CREB phosphorylation, which is important for long-term potentiation. We identified cross-phenotypic SNPs associated with multiple behavioural domains of stroke recovery. Some of these genes encode, or regulate, druggable proteins. These genetic factors are not well captured by clinical or neuroimaging assessments and so provide a unique window into stroke recovery. These findings, if validated, suggest that some genes may be broadly important to stroke recovery.

GWAS↗
PubMed2004

Renal artery calcified plaque associations with subclinical renal and cardiovascular disease.

BACKGROUND: The prognostic significance of renal artery calcified plaque (RAC) and its relationship with renal function, albuminuria, and systemic atherosclerosis are unknown. METHODS: Calcified atherosclerotic plaque was measured in the renal arteries of 96 unrelated Caucasian subjects with type 2 diabetes mellitus (DM) using four-channel multidetector-row computed tomography (MDCT4). Renal artery calcium was measured as the sum of ostial and main renal artery calcium scores. Participants also underwent MDCT scanning to measure coronary artery calcium (CAC), carotid artery calcium, common iliac artery calcium, infra-renal aorta calcium, and B-mode ultrasound to measure carotid artery intima-medial thickness (IMT). Spearman's rank correlation coefficients were used to assess associations between RAC and measures of subclinical renal and cardiovascular disease. Partial correlation coefficients were computed to adjust for the potential confounding effects of age, gender, body mass index (BMI), DM duration, smoking, and serum cholesterol and triglyceride levels. RESULTS: Characteristics of the study group were 54% (52/96) female with a mean +/- SD (median) age 62.8 +/- 8.4 (62.5) years, DM duration 10.6 +/- 6.3 (8.0) years, hemoglobin A1C 7.5 +/- 1.5 (7.2)%, BMI 32.1 +/- 6.3 (31.1) kg/m(2), serum creatinine concentration 1.11 +/- 0.18 (1.10) mg/dL, urine albumin:creatinine ratio (ACR) 105.3 +/- 423.1 (17.6) mg/g, modified MDRD equation glomerular filtration rate (GFR) 64.3 +/- 12.6 (63.6) mL/min, RAC 372 +/- 799 (101), CAC 1819 +/- 2594 (622), carotid artery calcium 264 +/- 451 (72), and B-mode ultrasound carotid IMT 0.70 +/- 0.12 (0.69) mm. Sixty-five percent of subjects (62/96) had detectable RAC. Renal artery calcium was significantly associated with CAC (r= 0.50, P < 0.0001), carotid artery calcium (r= 0.58, P < 0.0001), common iliac artery calcium (r= 0.45, P < 0.0001), infra-renal aorta calcium (r= 0.70, P < 0.0001), IMT (r= 0.40, P= 0.0004), diastolic blood pressure (r=-0.33, P= 0.0009), BMI (r=-0.19, P= 0.0573), and age (r= 0.54, P < 0.0001). There was no association between RAC and GFR (r=-0.15, P= 0.1637) or between RAC and urine ACR (r= 0.07, P= 0.5083). CONCLUSION: Renal artery calcium is strongly associated with older age, diastolic blood pressure, BMI, carotid artery IMT, and coronary, carotid, common iliac artery, and infra-renal aorta calcium in Caucasians with type 2 diabetes mellitus. Renal artery calcium, similar to CAC and IMT, appears to be a useful noninvasive marker of subclinical atherosclerosis. However, RAC is not significantly associated with either GFR or albuminuria.

Adult↗
PubMed2004

Association analysis of the plasminogen activator inhibitor-1 4G/5G polymorphism in Hispanics and African Americans: the IRAS family study.

OBJECTIVE: Plasminogen activator inhibitor type-1 (PAI-1) plays a central role in fibrolysis and has recently been hypothesized to influence components of the insulin resistance syndrome. We consider whether the 4G/5G polymorphism influences components of insulin resistance and obesity solely through PAI-1 protein levels or also though a secondary pathway. In addition, we explore whether transforming growth factor (TGF-beta1), a key regulator of PAI-1 expression, modifies the influence of the PAI-1 4G/5G polymorphism on these traits. METHODS AND RESULTS: The Insulin Resistance and Atherosclerosis (IRAS) Family Study genotyped 287 African American (18 pedigrees) and 811 Hispanic American (45 pedigrees) individuals for the 4G/5G PAI-1 and two TGF-beta1 polymorphisms (R25P, C-509T). Individuals were recruited from three clinical centers located in San Antonio (urban Hispanic), San Luis Valley (rural Hispanic) and Los Angeles (African American). The presence of the 4G PAI-1 allele was positively associated with PAI-1 protein level (combined sample p < 0.0001). Hispanic Americans average 65% higher PAI-1 protein levels than African Americans (p < 0.0001). Consistently across ethnic groups, increased PAI-1 protein levels were associated with increased insulin resistance and overall and central obesity (p value < 0.0001, combined sample). Adjusting for PAI-1 protein levels, there was evidence of an association of PAI-1 genotype (4G) with insulin sensitivity (p < 0.002) and subcutaneous fat (p < 0.01). These associations were not influenced by TGF-beta1 genotypes. CONCLUSIONS: PAI-1 protein is a strong correlate of insulin resistance (IR) and obesity in Hispanics and African Americans. However, PAI-1 4G/5G polymorphism appears to influence insulin resistance and obesity beyond its direct influence on serum PAI-1 protein levels.

Black or African American↗
PubMed2003

Comparison of significance level at the true location using two linkage approaches: LODPAL and GENEFINDER.

BACKGROUND: We compare two new software packages for linkage analysis, LODPAL and GENEFINDER. Both allow for covariate adjustment. Replicates 1 to 3 of Genetic Analysis Workshop 13 simulated data sets were used for the analyses. We described the results of searching for evidence of loci contributing to a simulated quantitative trait related to systolic blood pressure (SBP). Individuals with SBP greater than 130 mm Hg were defined as affected individuals, and all others as unaffected. Total cholesterol was treated as a covariate. RESULTS: Using LODPAL, the power of detecting one of the three major genes related to SBP is 44.4% when a LOD score of 1 is used as the cut-off point. The power of GENEFINDER is lower than that of LODPAL. It is 22.2%. CONCLUSIONS: Based on the limited comparison, LODPAL provided the more reasonable power to detect linkage compared to GENEFINDER. After adjusting for the total cholesterol covariate, the current version of both programs appeared to give a high number of false positives.

Adult Children↗
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↗
PubMed2003

Effects of covariates: a summary of Group 5 contributions.

This report summarizes the contributions of Genetic Analysis Workshop 13 (GAW13) related to the use of covariates in genetic analysis. Seven papers are summarized, five of which analyzed the Framingham Heart Study Data, and two the simulated data. Five papers examined the role of covariates in linkage analysis, using a variety of statistical approaches including affected sibling pair analysis, conditional logistic regression, and variance components methods. One paper examined the impact of covariates on family-based association analysis. In each of these papers, the detection of genetic effects could be influenced by the incorporation of covariates. The final paper examined the role of transmission ratio distortion in the analysis of complex traits and the role of covariates in the variability in transmission ratio distortion. While each paper takes a different approach to the genetic analysis of complex traits, a common thread running through each is that the inclusion of covariates can have a substantial impact on the results of the analysis. Care must be taken to understand how the covariates are being used in each analysis, what assumptions are being made, and how these assumptions might affect the results and their interpretation. Finally, the results of Group 5 studies show that inclusion of covariates can increase the power to detect genes for complex traits, and has the potential to advance an understanding of the role of genes in these complex traits.

Cardiovascular Diseases↗
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↗