Pedigree and genotype errors in the Framingham Heart Study

The pedigree and genotype data from the Framingham Heart Study were examined for errors. Errors in 21 of 329 pedigrees were detected with the program PREST, and of these the errors in 16 pedigrees were resolved. Genotyping errors were then detected with SIMWALK2. Five Mendelian errors were found following the pedigree corrections. Double-recombinant errors were more common, with 142 being detected at mistyping probabilities of 0.25 or greater.     

A model-integrated multipoint Bayesian analysis of hypertension in the Framingham Heart Study data finds little evidence of linkage

This Genetic Analysis Workshop 13 contribution presents a linkage analysis of hypertension in the Framingham data based on the posterior probability of linkage, or PPL. We dichotomized the phenotype, coding individuals who had been treated for hypertension at any time, as well as those with repeated high blood pressure measurements, as affected. Here we use a new variation on the multipoint PPL that incorporates integration over the genetic model. PPLs were computed for chromosomes 1 through 5, 11, 14, and 17 and remained below the 2% assumed prior probability of linkage for 73% of the locations examined. The maximum PPL of 4.5% was obtained on chromosome 1 at 178 cM. Although this is more than twice the assumed prior probability of linkage, it is well below a level at which we would recommend committing substantial additional resources to molecular follow-up. While the PPL analysis of this data remains inconclusive, Bayesian methodology gives us a clear mechanism for using the information gained here in further studies.     

HDL cholesterol in females in the Framingham Heart Study is linked to a region of chromosome 2q

BACKGROUND: Despite strong evidence for a genetic component to variation in high-density lipoprotein cholesterol levels (HDL-C), specific polymorphisms associated with normal variation in HDL-C have not been identified. It is known, however, that HDL-C levels are influenced in complex ways by factors related to age and sex. In this paper, we examined the evidence for age- and sex-specific linkage of HDL-C in a longitudinal sample of participants from the Framingham Heart Study. To determine if aging could influence our ability to detect linkage, we explored the evidence for linkage of HDL-C at three time points, t1, t2, and t3, spaced approximately 8 years apart and corresponding respectively to visits 11, 15, and 20 for the original cohort and 1, 2, and 4 for the offspring and spouses. Additionally, to examine the effects of sex on linkage at each time point, we estimated the heritability and genetic correlation of HDL-C, performed linkage analysis of HDL-C, tested for genotype-by-sex interaction at a QTL, and performed linkage analysis of HDL-C in males and females separately. RESULTS AND CONCLUSION: In women, we found evidence for a QTL on chromosome 2q influencing HDL-C variation. Although the QTL could be detected in the combined sample of males and females at the first time point, the linkage was not significant at subsequent time points.     

Multivariate variance-components analysis of longitudinal blood pressure measurements from the Framingham Heart Study

Multivariate variance-components analysis provides several advantages over univariate analysis when studying correlated traits. It can test for pleiotropy or (in the longitudinal context) gene x age interaction. It can also have more power than univariate analyses to detect a quantitative trait locus influencing several traits. We apply multivariate variance components to longitudinal systolic blood pressure data from the Framingham Heart Study. We find evidence for a polygenic influence on blood pressure (heritabilities at different ages range from 27% to 38%). Tests based on a factor-analytic parameterization of the polygenic variance find significant (p < 2 x 10(-3)) evidence that different genes affect blood pressure at different ages. Still, estimates for the proportion of polygenic variance due to shared genes ran as high as 85% for some trait pairs. Univariate and multivariate linkage analyses replicate previous linkage results on chromosome 17 (maximum LOD scores of 2.2 and 2.4, respectively). In this study, multivariate analysis provides no increase in power; this is likely due to the strong positive correlation in systolic blood pressure measured at different ages.     

Cultural Specificity and Comparison in Psychiatric Epidemiology: Walking the Tightrope in American Indian Research

Increasingly, the mental health needs of populations are measured using large-sample surveys with standardized measures and methods. Such efforts, however, rarely include sufficient number of smaller, culturally defined populations to draw defensible conclusions about their needs. Furthermore, without some adaptation, the standardized methods and measures may yield invalid results in such populations. Using a recently completed psychiatric epidemiology and services study with American Indian populations as a case example, this paper outlines issues facing epidemiologists working in such culturally diverse contexts. The issues discussed include the following: (1) persuading the scientific community and potential sponsors that work with distinct or culturally defined populations is important; (2) framing research questions and activities to meet the needs of communities; (3) defining a population of inference; (4) balancing the needs for comparability and cultural specificity; (5) maximizing scientific validity in light of the challenges in sample acquisition; and (6) developing and implementing data collection methods that uphold scientific standards but are also realistic given the context. The authors draw on their experiences—most recently in the American Indian Service Utilization, Psychiatric Epidemiology, Risk and Protective Factors Project (AI-SUPERPFP)—to illustrate these issues and suggest ways to address each. A goal of this paper is to challenge those invested in conducting culturally valid epidemiologic work in such populations to better articulate the nature of these efforts.     

The uterine length in women with Turner syndrome reflects the postmenarcheal daily estrogen dose

AIM: To evaluate the effects of estrogen substitution on the uterine development in patients with Turner syndrome. METHOD: 57 women, aged 18.1-41.5 years, were treated with estrogen from puberty induction. RESULTS: In 21 women (37%), the uterus developed to >65 mm in length. The daily estrogen dose correlated with both uterine length (r = 0.29; p < 0.05) and Tanner breast stage (r = 0.44; p < 0.001). A negative correlation between age at artificial menarche and uterine length was found (r = -0.29; p < 0.05). The endometrium thickness was greater in women with an uterus length >65 mm (p < 0.05). In 50% of the women (18 were evaluated), an adult-shaped uterus developed. Previous growth hormone therapy (n = 32) had no impact on the uterus length. CONCLUSIONS: The uterine development was suboptimal in most patients. Further investigation is needed to optimize estrogen therapy for uterine development in patients with Turner syndrome.     

Increased frequency of islet cell antibodies in unaffected brothers of children with type 1 diabetes

AIM: To assess the relation between islet cell antibody (ICA) positivity and demographic characteristics in an extensive series of first-degree relatives of children with type 1 diabetes (T1D). METHODS: Family members of children diagnosed with T1D before the age of 16 years and attending one of 27 participating paediatric units in Finland taking care of children with diabetes were invited to volunteer for an ICA screening program aimed at identifying individuals eligible for inclusion in the European Nicotinamide Diabetes Intervention Trial (ENDIT). The final series comprised 2,522 first-degree relatives (1,107 males) with a mean age of 20.4 (range 0.1-51.9) years, out of whom 390 were fathers, 622 mothers, 717 brothers, and 793 sisters of affected cases. RESULTS: Two hundred and four family members (8.1%) tested positive for ICA with levels ranging from 3 to 564 (median 18) Juvenile Diabetes Foundation (JDF) units. One hundred and five relatives (4.2%) had an ICA level of 18 JDF units or more. Males had detectable ICA more often than females (9.6 vs. 6.9%; p = 0.02). Antibody-positive family members under the age of 20 years had higher ICA levels than the older ones [median 18 (range 3-514) JDF units vs. 10 (range 3-564) JDF units; p = 0.008]. Among the adult relatives (>or=20 years of age) antibody-positive females had higher ICA levels than the males [median 10 (range 5-564) JDF units vs. 9 (range 3-130) JDF units; p = 0.04]. Siblings had an increased frequency of high-titre ICA (>or=18 JDF units) when compared to the parents (4.8 vs. 3.2%; p = 0.05). Among siblings, we found a higher frequency of ICA positivity in brothers than in sisters (10.8 vs. 6.9%; p = 0.01), and this was also true for high-titre ICA (6.0 vs. 3.8 %; p = 0.04). Geographically, the highest ICA prevalence was seen among relatives living in the middle of Finland (10.4 vs. 7.2% in the other parts of Finland; p = 0.01). CONCLUSIONS: These results imply that male gender and young age favour positive ICA reactivity among family members of children with T1D. Siblings test positive for high ICA titres (>or=18 JDF units) more frequently than parents. Accordingly, judged from demographic characteristics, the yield of ICA screening in first-degree relatives would be maximized by targeting young brothers of affected cases.