Analysis of family- and population-based samples using multiple linkage disequilibrium mapping.

We report two methods for linkage disequilibrium mapping that involve incorporation of covariates through parametric modeling to utilize combined case-parent trios and unrelated case and/or control data. The proposed two combined methods were used to map the disease locus of hypertension in the angiotensin-converting enzyme (ACE) gene with incorporation of ACE activity. The efficiencies in estimating the disease locus increased by 351- and 100-fold in the hybrid study with respect to the two proposed methods when compared to the estimates from the trios study; and they changed by 1.4- and 0.4-fold, respectively, when compared to the case-control study. Efficiency of disease locus estimates was greatly improved in both simulations and hypertension studies based on the hybrid data, compared to case-parent trio studies only. These newly developed methods preserve the advantages of the previous methods, including flexible modeling and assessment of gene-gene and gene-covariate effects, while providing more power by using all the data combined. The computing program for analysis using the separate and hybrid data sets is freely available on the author's website.

Developing a Chinese quality of life in dementia instrument for patients with early-to-moderate dementia: an exploratory test of validity.

AIMS: The purpose of this study was to examine the psychometric properties of the Chinese Dementia Quality of Life instrument, which included testing the different pathways through theoretical quality of life domains (self-esteem, feelings of belonging and sense of aesthetics) to reach outcomes of positive and negative affect. BACKGROUND: Perceived quality of life in dementia has been conceptualised based on dementia stages. However, the relationships among quality of life domains are unclear in patients with dementia with a Mini-Mental State Examination >10. DESIGN: Cross-sectional study. METHODS: Older people (n = 110) were consecutively recruited from memory disorder clinics and community wellness centres (controls). Of these participants, 27 were controls, 39 were diagnosed with questionable dementia and 44 with mild-to-moderate Alzheimer's disease. The instrument was back translated and validated. RESULTS: The instrument has good overall internal consistency (Cronbach's alpha = 0.84-0.94). Item-total correlation coefficients, indicating construct validity, were all significant, except for one item. anova showed that controls, patients with questionable dementia and those with mild-to-moderate Alzheimer's disease differed significantly in scores on Sense of Aesthetics subscale. Instrument total score and scores on three of five subscales (not Feelings of Belonging) differed significantly between control and dementia groups, but not between patients with questionable dementia and those with mild-to-moderate Alzheimer's disease. Factor analyses showed two inconsistencies with the instrument's prior conceptualisation, namely the Self-Esteem and Negative Affect subscales. The Positive Affect path model was supported but not the Negative Affect path model. CONCLUSIONS: This patient-reported Dementia Quality of Life instrument has acceptable psychometric properties in Taiwanese patients with dementia with a Mini-Mental State Examination score >10. Relevance to clinical practice. The Chinese Dementia Quality of Life instrument can be used to assess subjective quality of life in Taiwanese patients with dementia with a Mini-Mental State Examination score >10.

Identification of rare variants for hypertension with incorporation of linkage information.

We conducted linkage analysis using the genome-wide association study data on chromosome 3, and then assessed association between hypertension and rare variants of genes located in the regions showing evidence of linkage. The rare variants were collapsed if their minor allele frequencies were less than or equal to the thresholds: 0.01, 0.03, or 0.05. In the collapsing process, they were either unweighted or weighted by the nonparametric linkage log of odds scores in 2 different schemes: exponential weighting and cumulative weighting. Logistic regression models using the generalized estimating equations approach were used to assess association between the collapsed rare variants and hypertension adjusting for age and gender. Evidence of association from the weighted and unweighted collapsing schemes with minor allele frequencies ≤0.01, after accounting for multiple testing, was found for genes DOCK3 (p = 0.0090), ARMC8 (p = 1.29E-5), KCNAB1 (p = 5.8E-4), and MYRIP (p = 5.79E-6). DOCK3 and MYRIP are newly discovered. Incorporating linkage scores as weights was found to help identify rare causal variants with a large effect size.

Taiwanese vegetarians and omnivores: dietary composition, prevalence of diabetes and IFG.

INTRODUCTION: Vegetarian diets have been shown to improve glucose metabolism and reduce risk for diabetes in Westerners but whether Chinese vegetarian diets have the same benefits is unknown. METHODS: We evaluated the association between diet and diabetes/impaired fasting glucose (IFG) among 4384 Taiwanese Buddhist volunteers and identified diabetes/IFG cases from a comprehensive review of medical history and fasting plasma glucose. RESULTS: Vegetarians had higher intakes of carbohydrates, fiber, calcium, magnesium, total and non-heme iron, folate, vitamin A, and lower intakes of saturated fat, cholesterol, and vitamin B12. Besides avoiding meat and fish, vegetarians had higher intakes of soy products, vegetables, whole grains, but similar intakes of dairy and fruits, compared with omnivores. The crude prevalence of diabetes in vegetarians versus omnivores is 0.6% versus 2.3% in pre-menopausal women, 2.8% versus 10% in menopausal women, and 4.3% versus 8.1% in men. Polytomous logistic regression adjusting for age, body mass index, family history of diabetes, education, leisure time physical activity, smoking and alcohol, showed that this vegetarian diet was negatively associated with diabetes and IFG in men (OR for diabetes: 0.49, 95% CI: 0.28-0.89; OR for IFG: 0.66, 95% CI: 0.46-0.95); in pre-menopausal women (OR for diabetes: 0.26, 95% CI: 0.06-1.21; OR for IFG: 0.60, 95% CI: 0.35-1.04); and in menopausal women (OR for diabetes: 0.25, 95% CI: 0.15-0.42; OR for IFG: 0.73, 95% CI: 0.56-0.95). CONCLUSION: We found a strong protective association between Taiwanese vegetarian diet and diabetes/IFG, after controlling for various potential confounders and risk factors.

Genetic variation in the NOC gene is associated with body mass index in Chinese subjects.

UNLABELLED: Circadian clock genes are critical regulators of energy homeostasis and metabolism. However, whether variation in the circadian genes is associated with metabolic phenotypes in humans remains to be explored. In this study, we systemically genotyped 20 tag single nucleotide polymorphisms (SNPs) in 8 candidate genes involved in circadian clock, including CLOCK, BMAL1(ARNTL), PER1, PER2, CRY1, CRY2, CSNK1E,, and NOC(CCRN4L) in 1,510 non-diabetic Chinese subjects in Taipei and Yunlin populations in Taiwan. Their associations with metabolic phenotypes were analyzed. We found that genetic variation in the NOC gene, rs9684900 was associated with body mass index (BMI) (P = 0.0016, Bonferroni corrected P = 0.032). Another variant, rs135764 in the CSNK1E gene was associated with fasting glucose (P = 0.0023, Bonferroni corrected P = 0.046). These associations were consistent in both Taipei and Yunlin populations. Significant epistatic and joint effects between SNPs on BMI and related phenotypes were observed. Furthermore, NOC mRNA levels in human abdominal adipose tissue were significantly increased in obese subjects compared to non-obese controls. CONCLUSION: Genetic variation in the NOC gene is associated with BMI in Chinese subjects.

Assessment of gene-covariate interactions by incorporating covariates into association mapping.

The HLA region is considered to be the main genetic risk factor for rheumatoid arthritis. Previous research demonstrated that HLA-DRB1 alleles encoding the shared epitope are specific for disease that is characterized by antibodies to cyclic citrullinated peptides (anti-CCP). In the present study, we incorporated the shared epitope and either anti-CCP antibodies or rheumatoid factor into linkage disequilibrium mapping, to assess the association between the shared epitope or antibodies with the disease gene identified. Incorporating the covariates into the association mapping provides a mechanism 1) to evaluate gene-gene and gene-environment interactions and 2) to dissect the pathways underlying disease induction/progress in quantitative antibodies.

Assessing genotype x environment interaction in linkage mapping using affected sib pairs.

Rheumatoid arthritis (RA) is a complex disease that involves both environmental and genetic factors. Elucidation of the basic etiologic factors involved in RA is essential for preventing and treating this disease. However, the etiology of RA, like that of other complex diseases, is largely unknown. In the present study, we conducted autosomal multipoint linkage scans using affected sib pairs by incorporating the smoking status into analysis. We divided the affected sib pairs into three subgroups based on smoking status (ever, current, or never). Interactions between the susceptibility genes and smoking could then be assessed through linkage mapping. Results suggested that the genetic effect of chromosome 6p21.2-3 in concordant current smoker pairs was about two-fold greater than that of the concordant non-current smoker pairs or discordant pairs. With incorporation of smoking status, additional regions with evidence of linkage were identified, including chromosomes 4q and 20q; while evidence of linkage remained in the regions of chromosomes 6p, 8p, and 9p. The interaction effects varied in different regions. Results from our analyses suggested that incorporating smoking status into linkage analyses could increase the statistical power of the multipoint linkage approach applied here and help elucidate the etiology of RA.

Incorporating quantitative variables into linkage analysis using affected sib pairs.

Rheumatoid arthritis is a complex disease in which environmental factors interact with genetic factors that influence susceptibility. Incorporating information about related quantitative traits or environmental factors into linkage mapping could therefore greatly improve the efficiency and precision of identifying the disease locus. Using a multipoint linkage approach that allows the incorporation of quantitative variables into multipoint linkage mapping based on affected sib pairs, we incorporated data on anti-cyclic citrullinated peptide antibodies, immunoglobulin M rheumatoid factor and age at onset into genome-wide linkage scans. The strongest evidence of linkage was observed on chromosome 6p with a p-value of 3.8 x 10(-15) for the genetic effect. The trait locus is estimated at approximately 45.51-45.82 cM, with standard errors of the estimates range from 0.82 to 1.26 cM, depending on whether and which quantitative variable is incorporated. The standard error of the estimate of trait locus decreased about 28% to 35% after incorporating the additional information from the quantitative variables. This mapping technique helps to narrow down the regions of interest when searching for a susceptibility locus and to elucidate underlying disease mechanisms.