Biomedical subjects

I B Borecki

Publications and source records attributed to I B Borecki.

At least 19 recordsLinked to original sources

PubMed2001

Familial and genetic determinants of systemic markers of inflammation: the NHLBI family heart study.

Inflammation is thought to play a central role in the etiology and outcome of atherosclerosis. Animal studies as well as in vitro and in vivo human studies suggest that host factors modulate the magnitude and extent of inflammatory responses. We investigated familial aggregation of three systemic markers of inflammation (C-reactive protein (CRP), white blood cell count (WBC), and albumin) in a large, cross-sectional study conducted in four US communities. We found evidence of substantial heritability (35-40%) for CRP levels as well as for WBC and albumin levels. Negligible spouse correlations suggested little influence of shared household environment on these traits. The combination of sociodemographic factors (age, center, education), behavioral and lifestyle factors (cigarette smoking, alcohol intake, hormone replacement therapy), obesity and fat patterning, and prevalent diabetes explained 13-30% the interindividual variability of these traits. There was no evidence that these inflammation phenotypes were linked to a microsatellite marker in the interleukin-1 gene cluster on chromosome 2q, a region that includes several candidate genes for chronic inflammatory diseases. Our findings suggest that CRP levels, albumin levels, and WBC are determined at least partially by genetic factors. Further efforts to identify gene loci affecting these traits are warranted.

Adult↗

PubMed2001

Familial resemblance and heritability.

Familial resemblance, which arises when members within families are more similar than are unrelated pairs of individuals, may be estimated in terms of correlations (or covariances) among family members. The magnitudes of such correlations generally reflect both the extent of environmental sharing and the degree of biological relationship between the relatives. Heritability, or more appropriately multifactorial heritability or generalized heritability, quantifies the strength of the familial resemblance and represents the percentage of variance ina trait that is due to all additive familial effects including additive genetic effects and those of the familial environment. However, the traditional concept of heritability, which may be more appropriately called the genetic heritability, represents only the percentage of phenotypic variance due to additive genetic effects. Resolving the sources of familial resemblance entails other issues. For example, there may be major gene effects that may be largely or entirely nonadditive, temporal or developmental trends, and gene-gene (epistasis) and gene-environment interactions. The design of a family study determines which of these sources are resolvable. For example, in intact nuclear families consisting of parents and offspring, the genetic and familial environmental effects are not resolvable because these relatives share both genes and environments. However, extended pedigrees and twin and adoption study designs allow separation of the heritable effects and, possibly, more complex etiologies, including interactions. Various factors affect the estimation and interpretability of heritability, for example, assumptions regarding linearity and additivity of the effects, assortative mating, and the underlying distribution of the data. Nonnormality of the data can lead to errors in hypothesis testing, although it yields reasonably unbiased estimates. Fortunately, these and other complications can be directly modeled in many of the sophisticated software packages available today in genetic epidemiology.

Adoption↗

PubMed2001

Linkage and association: basic concepts.

Many investigators are turning their efforts to dissecting the etiology of complex traits. The primary tools for gene discovery, localization, and functional analysis are linkage and association studies. While the conceptual underpinnings of these approaches have long been known, advances in recent decades in molecular genetics, in the development of efficient computational algorithms, and in computing power have enabled the large-scale application of these methods. Here, we review the biological basis of linkage and association among loci and the common methods used to assess these relationships with respect to observed phenotypes. We further consider the two most common approaches--genome scans and candidate gene studies--especially their respective strengths, weaknesses, and resource requirements. Finally, we highlight some of the major challenges that arise from these investigative approaches and those that are inherent in the nature of complex traits. The chapters that follow elaborate on many of these topics.

Chromosome Mapping↗

PubMed2001

Genomic scan for genes affecting body composition before and after training in Caucasians from HERITAGE.

An autosomal genomewide search for genes related to body composition and its changes after a 20-wk endurance-exercise training program has been completed in the HERITAGE Family Study. Phenotypes included body mass index (BMI), sum of eight skinfold thicknesses, fat mass (FM), fat-free mass, percent body fat (%Fat), and plasma leptin levels. A maximum of 364 sib-pairs from 99 Caucasian families was studied with the use of 344 markers with single-point and multipoint linkage analyses. Evidence of significant linkage was observed for changes in fat-free mass with the S100A and the insulin-like growth factor I genes (P = 0.0001). Suggestive evidence (2.0 < or = Lod < 3.0; 0.0001 < P < or = 0.001) was also observed for the changes in FM and %Fat at 1q31 and 18q21-q23, in %Fat with the uncoupling protein 2 and 3 genes, and in BMI at 5q14-q21. At baseline, suggestive evidence was observed for BMI at 8q23-q24, 10p15, and 14q11; for FM at 14q11; and for plasma leptin levels with the low-density lipoprotein receptor gene. This is the first genomic scan on genes involved in exercise-training-induced changes in body composition that could provide information on the determinants of weight loss.

Adipose Tissue↗

PubMed2000

Genome-wide linkage analysis of systolic and diastolic blood pressure: the Québec Family Study.

BACKGROUND: Blood pressure (BP), an important risk factor for coronary heart disease, is a complex trait with multiple genetic etiologies. While some loci affecting BP variation are known (eg, angiotensinogen), there are likely to be novel signals that can be detected with a genome scan approach. METHODS AND RESULTS: A genome-wide scan was performed in 125 random and 81 obese families participating in the Québec Family Study. A multipoint variance-components linkage analysis of 420 markers (353 microsatellites and 67 restriction fragment length polymorphisms) revealed several signals (P:<0.0023) for systolic BP on 1p (D1S551, ATP1A1), 2p (D2S1790, D2S2972), 5p (D5S1986), 7q (D7S530), 8q (CRH), and 19p (D19S247). Suggestive evidence (0.0023<P:<0.01) was found on 3q, 10p, 12p, 14q, and 22q. The results were encouraging for HSD3B1 (P:<0.03), AGT (P:<0.03), ACE (P:<0.02), and adipsin (P:<0.005) but null with regard to other candidates (eg, renin, and glucocorticoid and adrenergic receptors). CONCLUSIONS: Multiple linkage regions support the notion that risk for hypertension is due to multiple (ie, oligogenic) susceptibility loci. Comparisons across the complete, random, and obese samples suggest that some regions are specific to BP and others may involve obesity (eg, pleiotropy, epistasis, or gene-environment interaction). Some of these areas harbor known candidates. Others involve novel regions, some of which replicate previous reports and provide a focus for future studies to identify novel genes that influence interindividual variation in BP.

Age Distribution↗

PubMed2000

Genome-wide search for genes related to the fat-free body mass in the Québec family study.

Fat-free mass (FFM) consists mostly of skeletal muscle and bone tissues, and identification of the genes and molecular mechanisms involved in the control of FFM would have implications for the understanding of sarcopenia and potentially osteoporesis associated with aging, as well as the response to starvation, refeeding, anorexia, and any other conditions in which lean body mass is important. A genome-wide search for genes related to body leanness has been completed in the Quebec Family Study (QFS). Microsatellite markers (N = 292) from the 22 autosomal chromosomes were typed. The mean spacing of the markers was 11.9 centimorgans (cM) (range, <0.1 to 41). FFM was calculated from percent body fat, derived from underwater weighing, and body weight and was adjusted by regression for age and sex effects before analysis. A maximum of 336 sib pairs or 609 pairs of extended relatives were analyzed using single-point Haseman-Elston regression (SIBPAL and RELPAL) and multipoint variance component (SEGPATH) linkage analyses. Significant linkages were observed on chromosomes 15q25-q26 for a CA repeat within the insulin-like growth factor 1 receptor (IGF1R) gene (Lod score = 3.56) and at 18q12 with D18S877 (Lod score = 3.53) and D18S535 (Lod score = 3.58), 2 markers located 10 cM apart. A moderately significant linkage was also observed on chromosome 7p15.3 with the marker D7S1808 (Lod score = 2.72). The most obvious candidate genes within the regions identified by these linkages include the IGF1R on 15q and neuropeptide Y (NPY) and growth hormone-releasing hormone (GHRH) receptor on 7p. On 18q, the melanocortin receptor 4 (MC4R) is not likely the candidate gene for the observed linkage. This study represents the first genome-wide search for genes that may be involved in the regulation of the lean component of body mass in humans.

Adult↗

PubMed2000

Complex segregation analysis of blood pressure and heart rate measured before and after a 20-week endurance exercise training program: the HERITAGE Family Study.

Complex segregation analysis of baseline resting blood pressure (BP) and heart rate (HR) and their responses to training (post-training minus baseline) were performed in a sample of 482 individuals from 99 white families who participated in the HERITAGE Family Study. Resting BP and HR were measured at baseline and after a 20-week training program. Baseline resting BP and HR were age-adjusted and age-BMI-adjusted, and the responses to training were age-adjusted and age-baseline-adjusted, within four gender-by-generation groups. This study also analyzed the responses to training in two subsets of families: (1) the so-called "high" subsample, 45 families (216 individuals) with at least one member whose baseline resting BP is in the high end of the normal BP range (the upper 95th percentile: systolic BP [SBP] > or = 135 or diastolic BP [DBP] > or = 80 mm Hg); and (2) the so-called "nonhigh" subsample, the 54 remaining families (266 individuals). Baseline resting SBP was influenced by a multifactorial component (23%), which was independent of body mass index (BMI). Baseline resting DBP was influenced by a putative recessive locus, which accounted for 31% of the variance. In addition to the major gene effect, which may impact BMI as well, baseline resting DBP was also influenced by a multifactorial component (29%). Baseline resting HR was influenced by a putative dominant locus independent of BMI, which accounted for 31% of the variance. For the responses to training, no familiality was found in the whole sample or in the nonhigh subsample. However, in the high subsample, resting SBP response to training was influenced by a putative recessive locus, which accounted for 44% of the variance. No familiality was found for resting DBP response to training. Resting HR response to training was influenced by a major effect (accounting for 35% of the variance), with an ambiguous transmission from parents to offspring.

Adolescent↗

PubMed2000

Lack of association between the angiotensin-converting enzyme insertion/deletion polymorphism and plasminogen activator inhibitor-1 antigen levels in the National Heart, Lung, and Blood Institute Family Heart Study.

Experimental and clinical research supports a direct link between activation of the renin-angiotensin system and production of plasminogen activator inhibitor-1 (PAI-1), the primary physiologic inhibitor of tissue plasminogen activator. Several studies have reported higher PAI-1 levels in individuals carrying the deletion (D) allele of the angiotensin-converting enzyme (ACE) gene. We investigated the association between ACE genotypes and plasma PAI-1 levels in a family study of 577 women and 428 men from four US communities. Participants were between 25 and 84 years of age without evidence of coronary heart disease (CHD). Mean geometric plasma PAI-1 levels adjusted for ethnicity were 17.4, 17.9, and 18.1 ng/ml in participants with the DD, insertion-deletion (ID), and II genotypes, respectively (P = 0.89 for difference). We found no associations between ACE I/D genotypes and plasma PAI-1 antigen concentrations in a subset of participants without major CHD risk factors (hypertension, hypercholesterolemia, overweight, smoking, diabetes) or in a small sample of African-Americans. Our findings suggest that the ACE insertion/deletion polymorphism has relatively little, if any, influence on circulating PAI-1 levels in the population at large.

Adult↗

PubMed2000

Replication of linkage of familial combined hyperlipidemia to chromosome 1q with additional heterogeneous effect of apolipoprotein A-I/C-III/A-IV locus. The NHLBI Family Heart Study.

Familial combined hyperlipidemia (FCHL), the most common familial dyslipidemia, is implicated in up to 20% of cases of premature coronary heart disease. Although underlying mutations for FCHL have yet to be identified, several candidate genes/regions have been identified. A positive linkage to chromosome 1q markers has been reported, with the highest lod score of 5.93 occurring at a location between D1S104 and D1S1677. Using the same diagnostic criteria, the Family Heart Study (FHS) has defined 71 FCHL families, comprising 170 cases, for a total of 137 possible affected sibling pairs. The FCHL criteria require elevation in serum low density lipoprotein cholesterol and triglyceride levels within the family, with at least 2 affected first-degree relatives. Markers D1S104 and D1S1677 were typed, and significant allele sharing was found in FCHL sibships (multipoint lod score with use of the model from the Finnish study was 2.52, and multipoint nonparametric score was 2.48; P=0.007), replicating linkage in this chromosome 1 region. In addition, previously reported linkage of FCHL to apolipoprotein A-I/C-III/A-IV has been investigated in FHS families. FHS results revealed positive but nonsignificant allele sharing among FCHL sibships with apolipoprotein A-I/C-III/A-IV by use of marker D11S4127 (nonparametric linkage score 1.11, P=0.13). Two-locus analyses of D1S104 and D11S4127 suggested possible heterogeneity rather than epistasis, with a maximum 2-locus lod score of 3.05. A nonparametric 2-locus analysis revealed significant improvement in the 2-locus versus single-locus scores. Finally, no linkage was found with markers near the lipoprotein lipase gene region.

Alleles↗

PubMed2000

Segregation analysis of apolipoproteins A-1 and B-100 measured before and after an exercise training program: the HERITAGE Family Study.

Complex segregation analyses of apolipoproteins (apo) A-1 and B-100 were performed in a sample of 520 individuals from 99 white families who participated in the HERITAGE Family Study. In these sedentary families, plasma apo A-1 and B-100 concentrations were measured before and after a 20-week endurance exercise training program. Baseline apo A-1 and B-100 were adjusted for the effects of age (age-adjusted baseline apo A-1 and B-100) and for the effects of age and BMI (age-BMI-adjusted baseline apo A-1 and B-100). The change in response to training was computed as a simple Delta (posttraining minus baseline) and was adjusted for age and the baseline (age-baseline-adjusted apo A-1 and B-100 responses to training). In the present study, a major gene could not be inferred for baseline apo A-1. Rather, we found a major effect along with a multifactorial effect accounting for 8% to 9% and 51% to 56% of the variance, respectively. In addition, no clear evidence supported a major-gene effect for its response to training, whereas the transmission of a major effect from parents to offspring was ambiguous, ie, genetic in nature or familial environmental in origin. The major effect accounted for 15% of the variance, with an additional 21% and 58% of the variance being accounted for by a multifactorial effect in parents and offspring, respectively. It is interesting to have obtained evidence of a putative recessive major locus for baseline apo B-100, which accounted for 50% to 56% of the variance, with an additional 25% to 29% of the variance due to a multifactorial effect. In contrast, no major effect for its response to training was identified, although a multifactorial effect was found that accounted for 27% of the variance. The novel findings arising from the present study are summarized as follows. Baseline apo A-1 and its response to training were influenced by a major effect and a multifactorial effect. Baseline apo B-100 was influenced by a putative major recessive gene with a multifactorial component, but its response to training was influenced solely by a multifactorial component in these sedentary families.

Adolescent↗

PubMed2000

Associations between the leptin receptor gene and adiposity in middle-aged Caucasian males from the HERITAGE family study.

Linkage and association studies between three exonic polymorphisms in the leptin receptor gene and body composition variables in the HERITAGE Family Study were undertaken. Polymorphisms K109R, Q223R, and K656N have been analyzed with body mass index (BMI), sum of height skinfolds (SF8), fat mass (FM), percent body fat (%FAT), fat free mass, and plasma leptin level. Single-point linkage analysis and covariance analysis across genotypes were performed, by race, on phenotypes adjusted for age and sex. Blacks (88 parents; 231 adult offspring) from 115 nuclear families (72-119 sibpairs) and Caucasians (192 parents; 330 adult offspring) from 99 nuclear families (319-364 sibpairs) were used for these analyses. In Caucasians, BMI and FM showed suggestive linkages with K109R (P = 0.02 and P = 0.05, respectively) and associations with Q223R (P = 0.005 and P = 0.03, respectively). In blacks, no statistically significant linkage or association was observed. In Caucasians, associations with Q223R were observed in parents, but not in offspring, for BMI, FM, and %FAT (0.04< or =P< or =0.0001). Males, not females, showed differences across genotypes for the same phenotypes plus SF8 and leptin (0.03< or = P< or =0.0002). Carriers of the R223 allele showed higher values than noncarriers for BMI (+4 U, P = 0.0001), SF8 (+30 mm, P = 0.01), FM (+7 kg, P = 0.0004), %FAT (+5%, P = 0.0002), and leptin (+4 ng/mL, P = 0.0006). These results indicate a significant effect of leptin receptor on adiposity in middle-aged Caucasian males.

Adipose Tissue↗

PubMed1999

Exploring genetic analysis of complex traits through the paradigm of alcohol dependence: summary of GAW11 contributions.

We discuss the Genetic Analysis Workshop 11 analyses of data from the Collaborative Study on the Genetics of Alcoholism from a methodological perspective, concentrating on approaches and issues relevant to linkage and association studies of complex human phenotypes. Genome screening by parametric linkage, nonparametric linkage, association, and combined linkage/association methods are discussed. Issues particular to complex disease include etiologic heterogeneity, multivariate phenotype modeling, and parent-of-origin effects. Other methodological topics discussed are new and enhanced methods, ascertainment, weighting of nonindependent sib pairs, and data cleaning and validation.

Alcoholism↗

PubMed1999

The impact of marker allele frequency misspecification in variance components quantitative trait locus analysis using sibship data.

In cases where sibship data are collected for a quantitative trait locus (QTL) linkage study without access to parental genotypes, the proportion of genes shared identical by descent must be estimated using the marker allele frequencies. No systematic study has been conducted to date to evaluate the effect of misspecification of these frequencies on a test of quantitative trait linkage. Analysis of both simulated and actual data on quantitative traits was carried out under various sets of allele frequency estimates. While correctly specifying the allele frequency distribution led to a slightly more powerful test and higher lod scores, the differences were small and would not likely alter the conclusion of a study. These results suggest that, at least for QTL analysis, there is a great deal of tolerance for misspecifying marker allele frequencies with little, if any, appreciable effect on the linkage test. However, the observed variations may be sufficiently large to alter the priority on might give to a positive finding for follow up.

Alcoholism↗

PubMed1999

Familial aggregation of resting blood pressure and heart rate in a sedentary population: the HERITAGE Family Study. Health, Risk Factors, Exercise Training, and Genetics.

The familial aggregation of resting systolic blood pressure (SBP), diastolic blood pressure (DBP), and heart rate (HR) was assessed in 98 white families, who participated in the HERITAGE Family Study, and were selected to be sedentary, and primarily nonobese and normotensive. In the present study, 522 family members were sedentary at baseline examination, and resting SBP, DBP, and HR measured during this examination were investigated. If physical activity level is a potent environmental factor, then we expected that the relative contribution of environmental factors to the familial aggregation of blood pressure (BP) would be somewhat reduced, because activity was controlled for in this study. Using a familial correlation model, maximal heritabilities were estimated to be 54%, 41%, and 32% for resting SBP, DBP, and HR, respectively, in these families; and they were 51%, 42%, and 34% for resting SBP, DBP, and HR, respectively, when the data were adjusted for body mass index. The estimates are somewhat higher for BP but similar for HR to those reported in previous family studies, suggesting that the distribution of the underlying etiologic factors in these sedentary families may be similar to those in the general population. There was substantial spouse resemblance in this study, which may be explained by a higher concordance for correlated lifestyle factors including diet, similar activity levels, or by assortative mating for relative weight or dietary preferences.

Adolescent↗

PubMed1998

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.

Body Mass Index↗

PubMed1998

Angiotensinogen and angiotensin converting enzyme genotypes and carotid atherosclerosis: the atherosclerosis risk in communities and the NHLBI family heart studies.

BACKGROUND: Polymorphisms of the renin-angiotensin system are associated with cardiovascular pathology. Therefore, the association of the insertion/deletion (I/D) polymorphism of the angiotensin converting enzyme (ACE) gene and the T235 (methionine to threonine substitution) polymorphism of the angiotensinogen (AGT) gene with intima-media thickness of the carotid artery was investigated. METHODS AND RESULTS: Subjects were randomly selected from two centers participating in both the Atherosclerosis Risk in Communities (ARIC) and NHLBI Family Heart Studies. Probands were 45-64 years of age who were free of cardiovascular disease and had B-mode ultrasound measured carotid intima-media thickness. Multiplex polymerase chain reaction amplification was used to evaluate the ACE I/D and AGT T235 polymorphisms: genotype information was available on 495 and 475 participants, respectively. The frequencies of the ACE D and AGT T alleles were 0.56 and 0.52, respectively; 30% were homozygous for the ACE D allele, and 29% were homozygous for the AGT T allele. After adjustment for systolic blood pressure, antihypertensive medication use, diabetes, age, sex and LDL cholesterol, the mean intima-media thickness was 0.729, 0.732 and 0.721 mm in the ACE DD, ID, and II genotypes, respectively (partial F test 1.53, P = 0.22), and 0.727, 0.732 and 0.724 mm in the AGT MM, MT, and TT genotypes, respectively (partial F test 0.91, P = 0.40). Combining the genotypes for ACE and AGT, there were also no differences in intima-media thickness across the eight joint genotypes. CONCLUSION: We found no evidence that the ACE I/D and AGT T235 polymorphisms of the renin-angiotensin system were associated with carotid intima-media thickness in this population-based sample of middle-aged adults with no history of cardiovascular disease. The lack of an association between these variants and intima-media thickness may indicate that early atherosclerosis is mediated by factors other than these RAS polymorphisms.

Angiotensinogen↗

PubMed1998

Lipoprotein(a) interactions with lipid and non-lipid risk factors in patients with early onset coronary artery disease: results from the NHLBI Family Heart Study.

BACKGROUND: A positive interaction between high plasma lipoprotein(a) [Lp(a)] and unfavorable plasma lipid levels has been reported to result in very high risk for premature coronary artery disease (CAD). We further examined this issue for men and women with early onset CAD. We also examined potential interactions between Lp(a) and non-lipid risk factors. METHODS AND RESULTS: In 338 men and women with early onset CAD (most with a positive family history of early CAD) and 480 general population controls, we measured Lp(a), lipids and other risk factors. In univariate analysis, relative odds for CAD was 1.7 (P = 0.002) for plasma Lp(a) >50 mg/dl. Elevated Lp(a) level was found to interact with adjusted plasma total/high density lipoprotein (HDL) cholesterol such that when Lp(a) was over 50 mg/dl and adjusted plasma total/HDL cholesterol >5.8, relative odds for CAD were 8.0-9.6 (P<0.0001) in multiple logistic regression. Non-lipid risk factors were generally found to multiply the risk associated with Lp(a) (as predicted by logistic regression) without evidence for interaction. CONCLUSIONS: We find evidence that Lp(a) does interact positively with adjusted plasma total/HDL cholesterol ratio. Aggressive risk factor intervention, especially for lipids, in those with elevated Lp(a) therefore appears indicated.

Adult↗

PubMed1998

Evidence for at least two major loci influencing human fatness.

The genetics of human fatness has been the subject of many recent studies, motivated by the increased morbidity and mortality associated with obesity, as well as the increasing prevalence of overweight and obesity. The body-mass index (BMI) and fat mass (FM), measured by underwater weighing, were assessed for 1,630 individuals from approximately 300 families from phase 1 of the Quebec Family Study. The two phenotypes are highly correlated ( approximately .8) in adults, and previous segregation analysis revealed evidence for a recessive major gene for each trait. In our study, we utilized bivariate segregation analysis to determine the source(s) of phenotypic correlation-namely, a pleiotropic major gene, shared familial factors/polygenes, or shared nontransmitted environmental factors. Analysis was performed by use of the Pedigree Analysis Package, with extensions to the bivariate case. Tests of hypotheses provided evidence for two pleiotropic recessive loci, together accounting for 64% and 47% of the variance in BMI and FM, respectively. Under the model, all sources of phenotypic correlation were significant: 73% of the covariance was attributed to the pleiotropic major loci, 8% to residual familial effects, and 19% to nontransmitted environmental factors. The high degree of genetic identity between the two traits is not surprising, since the BMI often is used as a surrogate for FM; however, simultaneous analysis of both phenotypes enabled the detection of a second major locus, which apparently does not affect extreme overweight (as does the primary major locus) but which affects variation in the "normal" range.

Adipose Tissue↗