Pleiotropic Relationships between Cortisol Levels and Adiposity: The HERITAGE Family Study

Objective: To investigate familial basis for the relationship between cortisol adiposity at baseline and their training responses. Research Methods and Procedures: Bivariate correlation and segregation analyses were employed between cortisol and several adiposity measures [body mass index, fat mass (FM), fat-free mass, percentage of body fat (% BF), abdominal visceral fat (AVF), abdominal subcutaneous fat (ASF), and abdominal total fat (ATF)] from 99 white families and 105 black families. Results: In both races, significant inverse phenotypic correlations were generally observed between cortisol and adiposity measures at baseline but not for training responses. Significant cross-trait familial correlations were found for cortisol with abdominal fat (ASF, AVF, ATF) and overall body adiposity (FM, % BF) measures at baseline, which accounted for 14% to 20% of the phenotypic variance in whites. The cross-trait correlations were not significant for baseline phenotypes in blacks, perhaps because of the small sample size. A bivariate segregation analysis showed evidence of polygenic pleiotropy for cortisol with both abdominal fat and overall adiposity measures that accounted for 14% to 17% of the phenotypic covariance, but major gene pleiotropy was not suggested in whites. However, when ASF, AVF, and ATF were additionally adjusted for FM, no familial cross-trait correlations or polygenic pleiotropy between cortisol and the abdominal fat measures remained. Discussion: Evidence was found for polygenic pleiotropy but not for pleiotropic major gene effects between cortisol and overall adiposity in whites. However, the covariation of cortisol with abdominal fat phenotypes is dependent on concomitant polygenic factors for total-body fat.     

Familial Clustering of Abdominal Visceral Fat and Total Fat Mass: The Québec Family Study

The evidence for common familial factors underlying total fat mass (estimated from underwater weighing) and abdominal visceral fat (assessed from CT scan) was examined in families participating in phase 2 of the Québec Family Study (QFS) using a bivariate familial correlation model. Previous QFS investigations suggest that both genetic (major and polygenic) and familial environmental factors influence each phenotype, accounting for between 55% to 71% of the phenotypic variance in fat mass, and between 55% to 72% for abdominal visceral fat The current study suggests that the bivariate familial effect ranges from 29% to 50%. This pattern suggests that there may be common familial determinants for abdominal visceral fat and total fat mass, as well as additional familial factors which are specific to each. The relatively high spouse cross-trait correlations usually suggest that a large percent of the bivariate familial effect may be environmental in origin. However, if mating is not random, then the spouse resemblance may reflect either genetic or environmental causes, depending on the source [i.e., through similar genes or cohabitation (environmental) effects]. Finally, there are significant sex differences in the magnitude of the familial cross-trait correlations involving parents, but not offspring, suggesting complex generation (i.e., age) and sex effects. For example, genes may turn on or off as a function of age and sex, and/or there may be an accumulation over time of effects due to the environment which may vary by sex. Whether the common familial factors are genetic (major and/or polygenic), environmental, or some combination of both, and whether the familial expression depends on sex and/or age warrants further investigation using more complex models.     

Genetic Pleiotropy for Resting Metabolic Rate with Fat-Free Mass and Fat Mass: The Québec Family Study

Shared genetic and familial environmental causes for the associations among resting metabolic rate (RMR), fat-free mass (FFM), and fat mass (FM) were investigated in families participating in phase 2 of the Québec Family Study. A multivariate familial correlation model assessing the pattern of significant cross-trait correlations between family members (e.g., RMR in parents with FFM in offspring) was used to infer the etiology of the associations. For each of FM and FFM with RMR, significant sibling, parent-offspring, and intraindividual cross-trait correlations suggest the associations are familial. Furthermore, the lack of significant spouse cross-trait correlations suggests that the familial aggregation is primarily genetic. Bivariate heritability estimates suggest that as much as 45% to 50% of the shared variance between FFM and RMR may be genetic, and as much as 28% to 34% for FM and RMR. This study supports the notion that the gene(s) affecting each of FFM and FM also influence the RMR. Moreover, the lack of any familial associations between FFM and FM suggests that the effects of each body size component on RMR are independent, i.e., more than one genetic source on the RMR-body size association. The possibility that RMR is an oligogenic trait (i.e., more than one underlying genetic etiology) should be further investigated using more complex multivariate segregation methods until specific genes can be tested.     

Evidence for Multiple Determinants of the Body Mass Index: The National Heart,Lung, and Blood Institute Family Heart Study

The body mass index (BMI) is a complex phenotype representing the amount of fat mass, lean mass, body build and proportions, and it is likely to be affected by various metabolic processes, hormonal effects, energy intake and expenditure, and interactions within and among these broad categories of etiologic factors. Nonetheless, several previous studies have reported evidence for major gene segregation for the BMI in various populations. Data on a random sample of Caucasian families participating in the National Heart, Lung, and Blood Institute (NHLBI) Family Heart Study were analyzed to document the extent of familial resemblance and to investigate whether a similar monogenic inheritance pattern could be detected. Genetic analysis was carried out on age- and sex-adjusted BMI values. Familial correlations were significant implying a maximal heritability, including all genetic and environmentally inherited additive factors, of 41% to 59%. Segregation analysis revealed the presence of two maximum likelihood solutions, one characterized as a recessive Mendelian gene and the other as a major effect with an ambiguous transmission pattern. The presence of two such solutions is consistent with detection of two separate factors, each influencing the BMI distribution in a substantive manner. The evidence also supports a multifactorial background for BMI and suggests that the frequencies of these two factors, one of which appears to be a gene, may vary among diverse populations in the United States.     

Cross-trait familial resemblance for body fat and blood pressure: familial correlations in the Québec Family Study.

Cross-trait resemblance between body fat and blood pressure (BP) was examined among families in the Québec Family Study by using a bivariate familial correlation model assessing both intraindividual (e.g., comparison of father's body fat with his own BP) and interindividual (e.g., comparison of father's body fat with son's BP) cross-trait correlations. Each of six body-fat measures-(i) percent body fat, (ii) body-mass index, (iii) the sum of six skinfolds, (iv) the ratio of the sum of six skinfolds to total fat mass, (v) the ratio of the trunk skinfold sum to the extremity skinfold sum, and (vi) the regression of the trunk-extremity skinfold ratio on the sum of six skinfolds--was analyzed separately with systolic BP and with diastolic BP. Results showed that (1) upper-body fat was the strongest interindividual correlate of BP (especially the correlation of trunk-extremity ratio with diastolic BP), suggesting shared pleiotropic genetic and/or common familial environmental effects; (2) summary body-fat measures either were inconsistent (in the case of both percent body fat and sum of six skinfolds) or gave no evidence of interindividual cross-trait resemblance with BP (in the case of body-mass index); and (3) intraindividual resemblance between the sum of six skinfolds and BP largely vanished once the skinfold sum was adjusted for fat mass, suggesting that the intraindividual association may be mediated largely by the absolute amount of subcutaneous fat rather than by the subcutaneous proportion. Finally, the magnitude of the spouse resemblance for the trunk-extremity ratio with diastolic BP suggests that a significant proportion of the resemblance may be due to environmental influences. In summary, our investigation confirms a heritable link between BP and truncal-abdominal fat as predicted by the metabolic-syndrome hypothesis. That this result is obtained in primarily normotensive, nonobese families, suggests the connection involves normal metabolic paths.     

Maximum-likelihood estimation of familial correlations from multivariate quantitative data on pedigrees: a general method and examples

A general method for maximum-likelihood estimation of familial correlations from pedigree data is presented. The method is applicable to any type of data structure, including pedigrees in which variable numbers of individuals are present within classes of relatives, data in which multiple phenotypic measures are obtained on each individual, and multiple group analyses in which some correlations are equated across groups. The method is applied to data on high-density lipoprotein cholesterol and total cholesterol levels obtained from participants in the Swedish Twin Family Study. Results indicate that there is strong familial resemblance for both traits but little cross-trait resemblance.     

Familial Resemblance in Eating Behaviors in Men and Women from the Quebec Family Study

Objective: It is commonly recognized that genetic, environmental, behavioral, and social factors are involved in the development of obesity. The family environment may play a key role in shaping children's eating behaviors. The purpose of this study was to estimate the degree of familial resemblance in eating behavioral traits (cognitive dietary restraint, disinhibition, and susceptibility to hunger). Research Methods and Procedures: Eating behavioral traits were assessed with the Three‐Factor Eating Questionnaire in 282 men and 402 women (202 families) from the Quebec Family Study. Familial resemblance for each trait (adjusted for age, sex, and BMI) was investigated using a familial correlation model. Results: The pattern of familial correlation showed significant spouse correlation for the three eating behavior phenotypes, as well as significant parent‐offspring and sibling correlations for disinhibition and susceptibility to hunger. According to the most parsimonious model, generalized heritability estimates (including genetic and shared familial environmental effects) reached 6%, 18%, and 28% for cognitive dietary restraint, disinhibition, and susceptibility to hunger, respectively. Discussion: These results suggest that there is a significant familial component to eating behavioral traits but that the additive genetic component appears to be small, with generalized heritability estimates ranging from 6% to 28%. Thus, non‐familial environmental factors and gene‐gene and gene‐environmental interactions seem to be the major determinants of the eating/behavioral traits.     

Evidence, from combined segregation and linkage analysis, that a variant of the angiotensin I-converting enzyme (ACE) gene controls plasma ACE levels.

The hypothesis of a genetic control of plasma angiotensin I-converting enzyme (ACE) level has been suggested both by segregation analysis and by the identification of an insertion/deletion (I/D) polymorphism of the ACE gene, a polymorphism contributing much to the variability of ACE level. To elucidate whether the I/D polymorphism was directly involved in the genetic regulation, plasma ACE activity and genotype for the I/D polymorphism were both measured in a sample of 98 healthy nuclear families. The pattern of familial correlations of ACE level was compatible with a zero correlation between spouses and equal parent-offspring and sib-sib correlations (.24 +/- .04). A segregation analysis indicated that this familial resemblance could be entirely explained by the transmission of a codominant major gene. The I/D polymorphism was associated with marked differences of ACE levels, although these differences were less pronounced than those observed in the segregation analysis. After adjustment for the polymorphism effects, the residual heritability (.280 +/- .096) was significant. Finally, a combined segregation and linkage analysis provided evidence that the major-gene effect was due to a variant of the ACE gene, in strong linkage disequilibrium with the I/D polymorphism. The marker allele I appeared always associated with the major-gene allele s characterized by lower ACE levels. The frequency of allele I was .431 +/- .025, and that of major allele s was .557 +/- .041. The major gene had codominant effects equal to 1.3 residual SDs and accounted for 44% of the total variability of ACE level, as compared with 28% for the I/D polymorphism.(ABSTRACT TRUNCATED AT 250 WORDS)     

A family study of dermatoglyphic traits in India: a search for major gene effects on palmar pattern ridge counts

Palmar pattern ridge counts were subjected to segregation analysis in an attempt to identify possible major gene effects on these dermatoglyphic traits. The phenotypes considered were total palmar pattern ridge count, and ridge counts for the right interdigital III and IV and left interdigital IV individual palmar areas (sample sizes were too small for the other palmar areas). Evidence of familial resemblance was found for all of the phenotypes studied, and initial evidence for a major effect was found for all but the right palm interdigital III ridge count. However, this initial evidence could be attributed to nongenetic effects in each case, including skewness in the trait distribution. Tests for agreement with Mendelian transmission frequencies were found to be very useful in discriminating between a non-Mendelian major effect and a major gene. We concluded against a major gene effect for any of these traits, and multifactorial inheritance remains a plausible alternative explanation for the familial resemblance.     

The genetic and environmental sources of body mass index variability: the Muscatine Ponderosity Family Study.

The role of genetic and environmental factors in determining the variability in body mass index (BMI; kg/m2) was investigated in 1,302 relatives identified through 284 schoolchildren from Muscatine, IA. BMI levels were first adjusted for variability in age, by gender and by relative type. There was significant familial aggregation of adjusted BMI in the pedigrees, as indicated by inter- and intraclass correlation coefficients significantly different from zero. A mixture of two normal distributions fit the adjusted BMI data better than did a single normal distribution. Genetic and environmental models that could explain both the familial aggregation and the mixture of normal distributions were investigated using complex segregation analysis. There was strong support for a single recessive locus with a major effect that accounted for almost 35% of the adjusted variation in BMI. Polygenic loci accounted for an additional 42% of the variation. Approximately 23% of the adjusted variation was not explained by genetic factors. For spouses living in the same household, their shared environment accounted for 12% of their variation. For siblings living in the same household, their shared environment accounted for 10% of their variation. While shared environments contributed to variation in adjusted BMI, more than 75% of the variation was explained by genetic factors that include a single recessive locus. Approximately 6% of the individuals in the population from which these pedigrees were sampled are predicted to have two copies of the recessive gene, while 37% of the individuals are predicted to have one copy of the gene.     

Evidence for a dominant major gene conferring predisposition to hepatitis C virus infection in endemic conditions

Hepatitis C virus (HCV), infecting 170 million people worldwide, is a major public health problem. In developing countries, unsafe injections and blood transfusions are thought to be the major routes of transmission. However, our previous work in a population from Egypt, endemic for HCV, revealed highly significant familial correlations, strongly suggesting the existence of both familial transmission of the virus and genetic predisposition to HCV infection. We investigated the hypothesis of genetic predisposition by carrying out a segregation analysis of HCV infection in the same population. We used a logistic regression model simultaneously taking into account a major gene effect, familial correlations and relevant risk factors. We analyzed 312 pedigrees (3,703 subjects). Overall HCV seroprevalence was 11.8% and increased with age. The main associated risk factors were previous parenteral treatment for schistosomiasis and blood transfusions. We found strong evidence for a dominant major gene conferring a predisposition to HCV infection. The frequency of the predisposing allele was 0.013, reflecting a strong predisposition to HCV infection in 2.6% of the subjects, particularly those under the age of 20. This study provides evidence for the involvement of host genetic factors in susceptibility/resistance to HCV infection in endemic conditions.     

Evidence for a Shared Etiological Mechanism of Psychotic Symptoms and Obsessive-Compulsive Symptoms in Patients with Psychotic Disorders and Their Siblings

The prevalence of obsessive-compulsive disorder in subjects with psychotic disorder is much higher than in the general population. The higher than chance co-occurrence has also been demonstrated at the level of subclinical expression of both phenotypes. Both extended phenotypes have been shown to cluster in families. However, little is known about the origins of their elevated co-occurrence. In the present study, evidence for a shared etiological mechanism was investigated in 3 samples with decreasing levels of familial psychosis liability: 987 patients, 973 of their unaffected siblings and 566 healthy controls. The association between the obsessive-compulsive phenotype and the psychosis phenotype c.q. psychosis liability was investigated. First, the association was assessed between (subclinical) obsessive-compulsive symptoms and psychosis liability. Second, in a cross-sib cross-trait analysis, it was examined whether (subclinical) obsessive-compulsive symptoms in the patient were associated with (subclinical) psychotic symptoms in the related unaffected sibling. Evidence was found for both associations, which is compatible with a partially shared etiological pathway underlying obsessive-compulsive and psychotic disorder. This is the first study that used a cross-sib cross-trait design in patients and unaffected siblings, thus circumventing confounding by disease-related factors present in clinical samples.     

Familial resemblance of plasma angiotensin-converting enzyme level: the Nancy Study.

Plasma angiotensin I-converting enzyme (ACE) activity has been measured in a sample of 87 healthy families participating in a study of cardiovascular risk factors. The mean +/- SD levels of plasma ACE were 34.1 +/- 10.7, 30.7 +/- 10.4 and 43.1 +/- 17.2 units/liter in fathers (n = 87), mothers (n = 87) and offspring (n = 169), respectively. Plasma ACE was uncorrelated with age, height, weight, or blood pressure in the parents, but a negative correlation with age was observed in offspring (r = -.32). The age-adjusted familial correlations of plasma ACE were .038, .166, .323 and .303 for spouses, father-offspring, mother-offspring, and siblings, respectively. The results of the genetic analysis suggest that a major gene may affect the interindividual variability of plasma ACE, with different codominant effects in parents and offspring. According to this model, the major gene effect accounts for 4.8, 4.0, and 10.8 units/liter of the overall mean and for 29%, 29% and 75% of the variance of age-adjusted ACE in fathers, mothers, and offspring, respectively. The estimate of the probability of the less frequent allele is .26, and the major gene effect is approximately twice as great in high homozygotes than in heterozygotes and in offspring than in parents. The results of this study demonstrate the occurrence of a familial resemblance of plasma ACE activity in healthy families and suggest that this observation can be explained by the segregation of a major gene.     

Genetic determination of high-density lipoprotein-cholesterol and apolipoprotein A-1 plasma levels in a family study of cardiac catheterization patients.

Plasma levels of two lipoprotein risk factors, high-density lipoprotein-cholesterol (HDL-C) and apolipoprotein A-1 (apo A-1), have been shown to be negatively associated with the risk of developing coronary artery disease, and several reports have examined familial factors in HDL-C and apo A-1 levels. A number of studies suggest that shared genes influence familial resemblance of these lipoprotein levels far more than do shared environments. Possible mechanisms for the inheritance of these two risk factors (HDL-C and apo A-1 plasma levels) are explored using data from 390 individuals in 69 families ascertained through probands undergoing diagnostic cardiac catheterization. Segregation analysis was used to test a series of specific models of inheritance. Evidence for single-locus control of apo A-1 levels, with Mendelian transmission of a dominant allele leading to elevated apo A-1 levels, was seen in these families, although there was additional correlation among sibs present. This locus accounted for 48.6% and 37.2% of the total variation in apo A-1 levels in males and females, respectively. Similar evidence of segregation at a single locus controlling HDL-C levels was not seen in these families.     

Influence of genotype-dependent effects of covariates on the outcome of segregation analysis of the body mass index.

Several recent studies of the body mass index (BMI) have provided support for a recessive major gene influencing heaviness in humans. Segregation analysis of the BMI was carried out recently in a series of randomly sampled French-Canadian families to determine whether we could replicate the major gene finding by using a residual phenotype adjusted for the effects of age and sex. The best model included a recessive major effect for high BMI values with residual familial resemblance; however, Mendelian transmission could not be confirmed, and the no-transmission hypothesis (where all the tau's are constrained to be equal) was not rejected. Considering that the BMI is a complex phenotype affected by many factors and that there are known variations in body composition during growth and aging, we undertook a reanalysis of the data, using a model that allowed the estimation of genotype-specific age and gender effects. New tests on the transmission parameters satisfy the criteria for interfering Mendelian segregation. The results suggest that individuals with the "high" recessive genotype show the greatest degree of heaviness at birth, with a subsequent trend toward lower values throughout life, while individuals with the dominant "normal" genotypes show no appreciable trends with age. In addition, the "high" genotype appears to confer a greater degree of heaviness in females as compared with males. These results, along with other observations from the data, suggest that, while a recessive single gene influence may be discernible, the phenotypic expression of the BMI is likely to be complicated by genotype x environment interactions and, possibly, by the action of other loci. Further, the data also are consistent with the hypothesis that modifying factors may include the adoption of a more prudent life-style by individuals genetically predisposed to heaviness and a secular increase in the incidence, prevalence, and potency of environmentally based triggers leading to a higher penetrance of the "heavy" genotype in the young.     

Inheritance of dermatoglyphic asymmetry in 500 Indian pedigrees: complex segregation analysis

The major aim of this study is to determine the mode of inheritance of asymmetry of quantitative dermatoglyphic traits based on principal factors through the application of complex segregation (genetic model fitting) analyses on a large ethnically homogeneous sample of 500 Indian pedigrees (2435 individuals) of two generations. By segregation analysis of the traits- PC1_FA both Mendelian and Environmental models were rejected (< 0.001) with the General model, i.e. that despite presence of significant inheritance (rejection of Environmental model), the nature of inheritance is more complex, than Mendelian one. Although a little genetic effect was observed due to familial correlations on asymmetry traits, no evidence was found of major gene contribution to be involved, but this does not contradict the notion postulated by several earlier authors that asymmetry (fluctuating) provides a measure of developmental instability in human.     

A family study of dermatoglyphic traits in India: segregation analysis of accessory palmar triradii and the atd angle

Accessory triradii and the atd angle were examined via complex segregation analysis in order to evaluate possible genetic effects on these dermatoglyphic traits, measured in an endogamous Brahmin caste of peninsular India. The phenotypes considered included: presence of accessory palmar triradii a' and d', associated with the interdigital areas II and IV, respectively; presence of an accessory axial triradius tt' associated with the proximal margin of the palm; and an arctanh-transformation of the atd angle measurement. For all accessory triradii considered in the present investigation familial resemblance was evident. The most parsimonious model which could account for the observed resemblance was a multifactorial model that includes polygenic effects as well as transmissible environmental effects that are inherited in the same pattern as polygenes. Evidence of familial resemblance was also found for the arctanh-transformed atd angle, which could be attributed, initially, to both a major effect and a multifactorial component. Tests of transmission of a putative major gene were performed which yielded results consistent with Mendelian transmission, although an alternative test of no transmission of the major effect also fit the data. In light of these contrasting results we are precluded from accepting with confidence the notion of a major gene influence on the atd angle. We have concluded that the accessory triradii a', d', and tt', and the atd angle are influenced by multifactorial effects, including additive polygenes and possible environmental factors, such as intrauterine effects.     

Segregation analysis of serum uric acid in the NHLBI Family Heart Study

Segregation analysis was performed on the serum uric acid measurements from 523 randomly ascertained Caucasian families from the NHLBI Family Heart Study. Gender-specific standardized residuals were used as the phenotypic variable in both familial correlation and segregation analysis. Uric acid residuals were adjusted for age, age2, age3, body mass index (kg/m2), creatinine level, aspirin use (yes/no), total drinks (per week), HOMA insulin resistance index [(glucose * insulin)/22.5], diuretic use (yes/no), and triglyceride level. Sibling correlations (r=0.193) and parent-offspring correlations (r=0.217) were significantly different from zero, but these two familial correlations were not significantly different from one another. After adjustment for covariates, the heritability estimate for serum uric acid was 0.399. Segregation analysis rejected the "no major gene" model but was unable to discriminate between an "environmental" and a "Mendelian major gene" model. These results support the hypothesis that uric acid is a multifactorial trait possibly influenced by more than one major gene, modifying genes, and environmental factors.     

Racial differences in correlates of misreporting of energy intake in adolescent females

Objective: To determine the extent of misreporting of energy intake (EI) and its anthropometric, demographic, and psychosocial correlates in a bi‐racial cohort of young women. Research Methods and Procedures: This was a cross‐sectional study of 60 black and 60 white young women, 18 to 21 years old, enrolled in a longitudinal study. Total energy expenditure was assessed using doubly labeled water. Self‐reported EI was obtained from 3‐day food records. BMI was computed from height and weight. Fat mass was assessed by DXA. Multivariate analyses examined racial differences on the extent of misreporting and its effect on other potential correlates of misreporting. Race‐specific step‐wise linear regression analysis was performed to examine the effect of BMI, parental education, and drive for thinness on misreporting of EI. Results: More white women tended to under‐report EI than black women (22% vs. 13%, p = 0.07). In black women, under‐reporting was significantly (p = 0.01) associated with drive for thinness score but was only marginally (p = 0.1) associated with BMI. Each point increase in drive for thinness score was associated with under‐reporting by 40 kcal/d. In white women, under‐reporting was significantly (p = 0.03) associated with higher parental education by 440 kcal/d and also only marginally (p = 0.09) with BMI. Discussion: This tendency for under‐reporting of EI limits the use of self‐reported EI in studying energy balance in free‐living subjects. Most black and almost all white women in their late teens significantly under‐reported their EI, whereas under‐reporting was not as evident among lean young black women.     

Familial resemblance for immunoglobulin levels

The familial resemblance for immunoglobulin A, D, E, G, and M levels was investigated with family data collected in Canada and the U.S., entertaining both multifactorial and single gene hypotheses. Significant familial effects were found for each of the immunoglobulins, and there was significant support for a major gene hypothesis for IgA and IgD levels. Whereas there have been several reports suggesting a major gene determinant for IgE levels, including that from our own Canadian study, analysis of the U.S. sample suggested that a multifactorial component parsimoniously explained the observed familial resemblance.