Biomedical subjects

J Blangero

Publications and source records attributed to J Blangero.

At least 127 records · Page 7Linked to original sources

PubMed1997

GAW10: simulated family data for a common oligogenic disease with quantitative risk factors.

GAW10 Problem 2 involves a simulated common disease defined by imposing a threshold, T, on a quantitative trait, Q1. Every individual with a value of Q1 > or = T (where T = 40) is defined as affected. Also thought to be associated with the disease as intervening variables are four other quantitative traits (Q2, Q3, Q4, and Q5) and an environmental factor (EF). Each individual has genotypes for 367 highly polymorphic markers on 10 chromosomes. The tasks for GAW10 were to characterize the genetic and environmental contribution to Q1 (and the disease), Q2, Q3, Q4, and Q5, and to localize any single genes that have detectable effects. Multiple replicates provided an opportunity to address questions of power and false positive rates.

Chromosome Mapping↗

PubMed1997

Bivariate quantitative trait linkage analysis: pleiotropy versus co-incident linkages.

Power to detect linkage and localization of a major gene were compared in univariate and bivariate variance components linkage analysis of three related quantitative traits in general pedigrees. Although both methods demonstrated adequate power to detect loci of moderate effect, bivariate analysis improved both power and localization for correlated quantitative traits mapping to the same chromosomal region, regardless of whether co-localization was the result of pleiotropy. Additionally, a test of pleiotropy versus co-incident linkage was shown to have adequate power and a low error rate.

Chromosome Mapping↗

PubMed1997

Multipoint oligogenic linkage analysis of quantitative traits.

We present an overview of pedigree-based variance component linkage methods and discuss their extension to oligogenic inheritance. As an example, oligogenic linkage analyses were performed using the quantitative trait Q4 from the GAW10 simulated data set. A strategy involving sequential oligogenic analyses was found to have increased power to detect the three quantitative trait loci (QTL) influencing Q4 when compared to the classical marginal approach of requiring each locus to have a lod score > or = 3. However, it is shown that requiring conditional lod scores > or = 3 in the sequential analyses may be overly conservative and alternative criteria for the acceptance of multilocus models are discussed.

Analysis of Variance↗

PubMed1997

Exploiting pleiotropy to map genes for oligogenic phenotypes using extended pedigree data.

We investigated the utility of two approaches for exploiting pleiotropy to search for genes influencing related traits. To do this we first assessed the genetic correlations among a set of five closely related quantitative traits (Q1, Q2, Q3, Q4, Q5). We then used the genetic correlations among these five traits both to remove the common genetic effects of the four remaining traits, thereby identifying the unique genetic contribution to each trait, and to extract a synthetic phenotype which exploits the shared genetic information (pleiotropy) among these five traits. After obtaining these conditional traits, we then searched for evidence of quantitative trait loci (QTLs) (using variance component linkage) influencing the unique residual genetic component for each trait as well as those influencing the expression of the synthetic traits. From this work, we conclude that the removal of the common genetic effects of other traits in a group may be of greater utility when the majority of the pleiotropy initially detected between traits is attributable to the shared additive effects of polygenes, rather than to those of major loci. By contrast, decomposition of the genetic covariance matrix to its principal components is a greater utility when the majority of pleiotropy is attributable to major loci.

Chromosome Mapping↗

PubMed1997

A variance component approach to dichotomous trait linkage analysis using a threshold model.

We developed and utilized a multipoint variance components method to test for linkage between a disease trait and markers on chromosome 5 in the simulated data provided in GAW10 Problem 2. We demonstrated that the discrete trait variance components method recovers unbiased estimates of quantitative trait locus (QTL) location and reasonable estimates of effect size. We also showed that dichotomization of (a continuous trait such as) Q1 diminished the power to detect linkage compared to direct analysis of Q1, and that extended pedigree analyses provided superior power to detect linkage compared to those in nuclear families.

Analysis of Variance↗

PubMed1997

Genetics of adult body mass and maintenance of adult body mass in captive baboons (Papio hamadryas subspecies).

Adult body mass and changes in mass during an individual's life are important indicators of general health and reproductive fitness. Therefore, characterization of the factors that influence normal variation in body mass has important implications for colony management and husbandry. The main objective of this study was to quantify the genetic contribution to adult body mass and its maintenance in baboons. Intra-individual mean and variance in body mass were calculated from multiple weight measures available for each of 1,614 animals at least 10 years of age. Heritabilities were estimated using maximum likelihood methods. Mean adult body mass had a significant heritability (50%) as did variance in adult body mass (12%). The sexes differed in several respects: on average females were smaller than males and had greater variability in adult body mass; mean and variance in body mass increased with age in females only; and number of offspring showed a significant positive relationship with body mass in females only. There were significant differences between subspecies in body mass as well as ability to maintain body mass. These results indicate that there is a significant genetic influence on body mass and its maintenance, and suggest that different factors influence changes in body mass with age as well as body mass maintenance in male and female baboons.

Animals↗

PubMed1997

Quantitative genetics of serum sex hormone-binding globulin levels in participants in the San Antonio Family Heart Study.

Sex hormone-binding globulin (SHBG) is a steroid-binding plasma protein with a high affinity for testosterone that has been inversely associated with cardiovascular disease risk in many populations. SHBG may also act as a receptor in some tissues. Although the function of SHBG is relatively well understood, comparatively little is known about genetic factors contributing to the normal variation of serum SHBG levels. We estimated the heritability (h2) of serum SHBG levels in 717 related Mexican-Americans participating in the San Antonio Family Heart Study (SAFHS). We found a significant heritability (h2 = 0.31, P < .0001) for serum SHBG levels; age, exogenous hormones, smoking status, diabetic status, and adiposity showed significant associations (P < .05) with mean levels of SHBG. Sex was associated with mean SHBG levels but not with genetic or environmental variance in SHBG levels; heritability estimates were the same for males and females. These results indicate a significant genetic influence on SHBG in Mexican-Americans. Thus, SHBG may prove to be an important indicator of genetic risk for cardiovascular disease in this population, as well as others.

Adolescent↗

PubMed1997

A major quantitative trait locus determining serum leptin levels and fat mass is located on human chromosome 2.

Obesity is a major predisposing factor for the development of several chronic diseases including non-insulin dependent diabetes mellitus (NIDDM) and coronary heart disease (CHD). Leptin is a serum protein which is secreted by adipocytes and thought to play a role in the regulation of body fat. Leptin levels in humans have been found to be highly correlated with an individual's total adiposity. We performed a genome-wide scan and conducted multipoint linkage analysis using a general pedigree-based variance component approach to identify genes with measurable effects on quantitative variation in leptin levels in Mexican Americans. A microsatellite polymorphism, D2S1788, mapped to chromosome 2p21 (approximately 74 cM from the tip of the short arm) and showed strong evidence of linkage with serum leptin levels with a lod score of 4.95 (P = 9 x 10(-7)). This locus accounted for 47% of the variation in serum leptin levels, with a residual additive genetic component contributing an additional 24%. This region contains several potential candidate genes for obesity, including glucokinase regulatory protein (GCKR) and pro-opiomelanocortin (POMC). Our results show strong evidence of linkage of this region of chromosome 2 with serum leptin levels and indicate that this region could contain an important human obesity gene.

Adipose Tissue↗

PubMed1997

Genetic contribution of the endothelial constitutive nitric oxide synthase gene to plasma nitric oxide levels.

Nitric oxide (NO) has an important physiological role in regulating vascular tone and is also relevant to many pathological processes including hypertension and atherosclerosis. Endothelial constitutive nitric oxide synthase (ecNOS) is the key enzyme in determining basal vascular wall NO production. We used a combination of maximum-likelihood-based statistical genetic methods to explore the contributions of the ecNOS gene and other unmeasured genes to basal NO production measured by its metabolites (NOx: nitrite and nitrate) in 428 members of 108 nuclear families. Our initial quantitative genetic analysis estimated that approximately 30% of the variance in fasting NOx levels is due to genes (chi 2(1) = 16.04, P = .000062). Complex segregation analysis detected the effects of both a single locus and residual polygenes on NOx levels, and measured genotype analysis showed that plasma NOx levels in those homozygous for the rare allele (64.9 +/- 7.8 mumol/L) were significantly higher (P = .000242) than those homozygous for the common allele (30.2 +/- 3.1 mumol/L). The results of the variance component linkage analysis were consistent with linkage of a quantitative trait locus in or near the ecNOS gene to variation in plasma NOx levels (P = .0066). While many environmental factors have been shown to alter transiently plasma NOx levels, our study is the first to identify a substantial effect of the ecNOS locus on the variance of plasma NOx, i.e. basal NO production. This finding may be relevant to atherogenesis and NO-related disorders.

Adolescent↗

PubMed1997

Shared and unique genetic effects among seven HDL phenotypes.

The purpose of this study was to investigate the genetic control of various HDL measures and to determine the proportion of genetic variance explained by shared genes (ie, pleiotropy) and the proportion unique to each trait. The data used were drawn from large, randomly ascertained pedigrees of Mexican Americans participating in the San Antonio Family Heart Study. Data were available for 655 individuals (258 men and 397 women) in 26 families. We performed a multivariate quantitative genetic analysis to simultaneously estimate both the additive genetic and random environmental correlations among seven HDL phenotypes. These seven HDL phenotypes can be divided into two categories: measures of concentration and estimates of particle size. Concentration was measured for apo A-I, apo A-II, esterified cholesterol, and unesterified cholesterol, and particle size was estimated for apo A-I, apo A-II, and esterified cholesterol. The heritabilities (h2) for each of the seven traits were significantly greater than zero (P<.05) and ranged from 0.2 to 0.6. When considered in a pairwise fashion, all combinations of these traits showed marked genetic correlations (rho(G)=0.33 to 0.87) and all were significantly greater than zero (P<.05), indicative of pleiotropic effects. However, we found substantial unique genetic variance for each of these traits even after accounting for the effects shared in common with all the remaining measures. We conclude that the genetic variation in these HDL phenotypes is a result of the action of common as well as unique genes.

Adult↗

PubMed1997

Genetic epidemiology of seropositivity for Trypanosoma cruzi infection in rural Goias, Brazil.

Chagas' disease is a zoonotic disease found throughout Latin America. Despite control programs in many of the affected countries, infection with Trypanosoma cruzi continues to be a major public health concern. In Brazil alone, approximately 53 million people live in endemic areas. Research with humans and with animal models indicates that there is variation in susceptibility to infection with T. cruzi. The reasons for this variation are not known although several studies have implicated genetic factors. An indirect immunofluorescence assay was used to assess seropositivity for T. cruzi infection in 716 adults from the municipality of Posse, Goias, Brazil. Detailed genealogic information was gathered at the time of sampling, which allowed assignment of 525 individuals to 146 pedigrees containing between two and 103 individuals; the remaining 191 unrelated individuals were retained as independents in the analysis. Using a maximum likelihood variance decomposition approach, we performed quantitative genetic analyses to determine if genetic factors could partially account for the observed pattern of seropositivity. The maximum likelihood estimate of the heritability of T. cruzi infection was 0.56 +/- 0.27 (mean +/- SE), indicating that genetic factors account for more than half of the observed variation in infection status. An additional 23% of the variation (c2 = 0.23 +/- 0.09) is attributable to the effects of shared environment, as assessed by common household. The results indicate that genetic factors play an important role in determining epidemiologic patterns of T. cruzi infection. Further characterization of these genetic factors may suggest new biologic areas to be targeted by prevention and intervention programs.

Adolescent↗

PubMed1997

Quantitative genetic analysis of susceptibility to hookworm infection in a population from rural Zimbabwe.

Overdispersion is a common feature of population distribution patterns for hookworm infection in humans. Genetic factors may be partially responsible for this observed increased susceptibility in a fraction of the exposed population. However, the hypothesis that there are genetic components to susceptibility to this infectious disease has not been tested explicitly. The purpose of this study is to quantify the influence of genetic factors on patterns of hookworm infection in a rural population in Zimbabwe. A quantitative measure of hookworm load, number of hookworm eggs per gram of feces, as determined by the Kato thick smear technique, was available for 289 individuals. Of these, 279 individuals were members of 62 nuclear families and 10 were independent individuals. We analyzed the hookworm data in combination with the pedigree structure of the sampled individuals using quantitative genetic analysis techniques. Using this variance decomposition approach, we estimated the heritability of hook worm load to be 0.37 +/- 0.09 (p < 0.0001). This significant heritability indicates that 37% of the variation (after correcting for the effects of covariates) in hookworm eggs per gram observed in this population is attributable to genetic factors. The results suggest that further investigation and characterization of the genetic components influencing susceptibility to hookworm infection are warranted.

Adolescent↗

PubMed1997

Genetic drift and gene flow in post-famine Ireland.

This study examines the genetic impact of the Great Famine (1846-1851) on the regional genetic structure of Ireland. The Great Famine resulted in a rapid decrease in population size throughout Ireland in a short period of time, increasing the possibility of genetic drift. Our study is based on migration and anthropometric data collected originally in the 1930s from 7211 adult Irish males. These data were subdivided into three time periods defined by year of birth: 1861-1880, 1881-1900, and 1901-1920. Within each time period the data were further subdivided into six geographic regions of Ireland. Estimates of Wright's FST were calculated from parent-offspring migration data and from 17 anthropometric variables (10 head measures, 7 body measures). Over time, the average population size decreased, but average rates of migration increased. The estimates of FST at equilibrium from migration matrix analysis suggest that the net effect of these opposite effects is a reduction in among-group variation. Closer examination shows that within each time period the rate of convergence to equilibrium is slow, meaning that the expected levels of genetic homogeneity revealed from migration matrix analysis are not likely to be seen over short intervals of time. Estimates of FST from anthropometric data show either relatively little change in microdifferentiation or some increase, depending on which variables are analyzed. Investigation of a simple model of demographic and genetic change shows that, given the demographic changes in post-Famine Ireland, FST could in theory increase, decrease, or remain the same over short intervals of time. Overall, the Great Famine appears to have had minimal impact on the genetic structure of Ireland on a regional level. Comparison with studies focusing on local genetic structure shows the opposite. It appears that the level of genetic impact depends strongly on the level of analysis; local populations are affected to a greater extent by demographic shifts than regional populations. We also provide formulas for the standard errors of FST from metric traits and related statistics.

Adolescent↗

PubMed1997

Quantitative genetic analysis of arterial oxygen saturation in Tibetan highlanders.

This study was designed to test the hypothesis that genetic differences inferred from biological kinship relationships among individuals contribute to individual variation in percentage of oxygen saturation of arterial hemoglobin (SaO2) in a high-altitude native population. SaO2 data were obtained by pulse oximetry from 354 nonpregnant, healthy Tibetan residents of Pen-Dri, two rural agropastoral villages at 3800-4065 m altitude in Lhasa Municipal District, Tibet Autonomous Region, China. Statistical analyses of these data from 46 pedigrees tested the hypothesis of a significant genetic contribution to SaO2 variation. The average SaO2 was 89.4 +/- 0.2%, with a range of 76-97%. Additive genetic effects account for 44% of the interindividual phenotypic variation in SaO2 in the sample. Complex segregation analysis and variance decomposition analysis determined that 21% of the total phenotypic variation could be explained by a major gene influencing SaO2. Homozygotes for the low-SaO2 allele have a mean SaO2 of 83.6%, whereas heterozygotes and homozygotes for the high-SaO2 allele have means of 87.6% and 88.3%, respectively. This confirms findings in another Tibetan sample and extends the known geographic distribution of the major gene. These results suggest the hypothesis that individuals with the dominant allele for higher SaO2 have a selective advantage in their high-altitude hypoxic environment.

Adaptation, Physiological↗

PubMed1997

Ontogenetic changes in genetic regulation of fetal morphometrics in baboons (Papio hamadryas subspp.).

It is known that different genes are expressed during ontogeny; however, it is unclear how variation in that expression is associated with changes in growth patterns. The objective of this study is to assess how genetic variation in fetal morphology changes with ontogeny in baboons. Longitudinal measures of the head and femur (60 to 180 days gestation) were available for 892 pregnancies. We used a genetic model that allowed both the genetic and environmental variances (sigma 2G and sigma 2E) to change with age and estimated genetic and environmental correlations (rho G and rho E) between measurements at different ages. The results indicate a significant increase in the genetic variance for biparietal diameter and femur length but not for head circumference and fronto-occipital diameter. The rho G estimates for all measures decreased as the age between measures increased from 0 to 120 days, indicating that different groups of genes are expressed early in gestation and late in gestation. The rho E estimates dropped rapidly from 1 to 0 for all measures, indicating temporally localized environmental influences on fetal growth. Thus fetal morphometrics are significantly heritable and those genes that influence them show age-specific expression during ontogeny.

Animals↗

PubMed1996

Genetic and environmental contributions to cardiovascular risk factors in Mexican Americans. The San Antonio Family Heart Study.

BACKGROUND: The familial aggregation of coronary heart disease can be in large part accounted for by a clustering of cardiovascular disease risk factors. To elucidate the determinants of cardiovascular disease, many epidemiological studies have focused on the behavioral and lifestyle determinants of these risk factors, whereas others have examined whether specific candidate genes influence quantitative variation in these phenotypes. METHODS AND RESULTS: Among Mexican Americans from San Antonio (Tex), we quantified the relative contributions of both genetic and environmental influences to a large panel of cardiovascular risk factors, including serum levels of lipids, lipoproteins, glucose, hormones, adiposity, and blood pressure. Members of 42 extended families were studied, including 1236 first-, second-, and third-degree relatives of randomly ascertained probands and their spouses. In addition to the phenotypic assessments, information was obtained regarding usual dietary and physical activity patterns, medication use, smoking habits, alcohol consumption, and other lifestyle behaviors and medical factors. Maximum likelihood methods were used to partition the variance of each phenotype into components attributable to the measured covariates, additive genetic effects (heritability), household effects, and an unmeasured environmental residual. For the lipid and lipoprotein phenotypes, age, gender, and other environmental covariates accounted in general for < 15% of the total phenotypic variance, whereas genes accounted for 30% to 45% of the phenotypic variation. Similarly, genes accounted for 15% to 30% of the phenotypic variation in measures of glucose, hormones, adiposity, and blood pressure. CONCLUSIONS: These results highlight the importance of considering genetic factors in studies of risk factors for cardiovascular disease.

Adult↗

PubMed1996

Genetic correlations between lipoprotein phenotypes and indicators of sex hormone levels in Mexican Americans.

Previous studies have shown that the inverse relationship between HDL cholesterol (HDL-C) and triglyceride (TG) levels, risk factors for cardiovascular disease, is due largely to the effects of shared genes. HDL-C and TG are also known to be related to endogenous sex hormone levels, however the nature of the relationships is unclear. The objective of this study is to ascertain the extent to which these relationships are determined by shared genes. We conducted a multivariate quantitative genetic analysis of HDL-C, TG, dehydroepiandrosterone sulfate (DHEAS) and sex hormone-binding globulin (SHBG) in 635 people from 27 pedigrees participating in the San Antonio Family Heart Study. Heritabilities (h2) and genetic and environmental correlations (rho G and rho E) were estimated simultaneously by maximum likelihood methods. All four traits showed significant (P < 0.05) heritabilities: h2HDL-C = 0.38, h2TG = 0.54, h2DHEAS = 0.43, h2SHBG = 0.26. Significant genetic correlations were detected between HDL and each of the other traits: rho G(HDL-TG) = -0.56, rho G(HDL-DHEAS) = 0.23 and rho G(HDL-SHBG) = -0.56. However, there were no significant genetic correlations between TG and either measure of sex hormones. Thus, at least three separate groups of genes influence HDL-C levels in Mexican Americans: one group that has pleiotropic effects on HDL and TG, one group influences both HDL-C and SHBG and a third influences both HDL-C and DHEAS.

Adipose Tissue↗

PubMed1996

Genetic determinants of cutaneous malignant melanoma in Sinclair swine.

The role of genetic factors involved in the determination of risk of cutaneous malignant melanoma (CMM) in humans remains unclear owing to genetic heterogeneity and reliance on simplistic models of inheritance. Here, we report a statistical genetic analysis of cutaneous malignant melanoma in Sinclair swine (SSCM), a unique animal model for human CMM. Using complex segregation analysis a two-locus model involving an unknown major locus and a second locus that lies within or close to the swine leukocyte antigen (SLA) complex jointly determine risk of SSCM in pedigreed animals. These loci also influence severity of affection, accounting for approximately 20% of the phenotypic variation in quantitative tumour burden.

Animals↗