Genetic architecture for hole-board behaviors across substantial time intervals in young, middle-aged and old mice.

A quantitative trait locus (QTL) analysis of behaviors across the life span was conducted in F(2) mice from a C57BL/6J x DBA/2J cross and 22 BXD recombinant inbred (RI) strains. Mice of three age groups were tested in a hole-board apparatus for 3 min on three occasions approximately 1 month apart (average age at test 150, 450 and 750 days, approximately 400 mice per group, divided equally by sex). Quantitative trait loci with small effect size were found on 11 chromosomes for hole-board activity (Hbact) and hole-board rearing (Hbrear). Analysis of 22 RI strains tested at 150 and 450 days of age found only suggestive linkage, with four QTL for Hbact overlapping with those from the F(2) analysis. There was a significant phenotypic correlation between Hbact and Hbrear (approximately 0.55-0.69) and substantial commonality among QTL for the two behaviors. QTL analyses of head-pokes (HP) and fecal boli (FB) only identified QTL at the suggestive level of significance. Age accounted for approximately 15% of the phenotypic variance (sex approximately 3%), and there were genotype by age interactions at approximately 25% of the Hbact and Hbrear QTL. Quantitative trait loci for Hbrear were relatively stable across the three measurement occasions (those for Hbact somewhat less so), although mean levels of each index declined markedly comparing the first to subsequent trials. Considered as a whole, the polygenic system influencing exploratory behaviors accounts for approximately the same amount of phenotypic variance as age (within the range studied), is stable across substantial periods of time, and acts, for the most part, independently of age and sex.

Genetic determinants of weight of fast- and slow-twitch skeletal muscle in 500-day-old mice of the C57BL/6J and DBA/2J lineage.

C57BL/6J (B6) and DBA/2J (D2) strains and two derivative populations, BXD recombinant inbred strains (BXD RIs) and B6D2F2, were used to explore genetic basis for variation in muscle weight at 500 days of age. In parallel with findings in 200-day-old mice (Lionikas A, Blizard DA, Vandenbergh DJ, Glover MG, Stout JT, Vogler GP, McClearn GE, and Larsson L. Physiol Genomics 16: 141-152, 2003), weight of slow-twitch soleus, mixed gastrocnemius, and fast-twitch tibialis anterior (TA) and extensor digitorum longus (EDL) muscles was 13-22% greater (P < 0.001) in B6 than in D2. Distribution of BXD RI strain means indicated that genetic influence on muscle weight (strain effect P < 0.001, all muscles) was of polygenic origin, and effect of genetic factors differed between males and females (strain-by-sex interaction: P < 0.01 for soleus, EDL; P < 0.05 for TA, gastrocnemius). Linkage analyses in B6D2F2 population identified QTL affecting muscle weight on Chr 1, 2, 6, and 9. Pleiotropic influences were observed for QTL on Chr 1 (soleus, TA), 2 (TA, EDL, gastrocnemius), and 9 (soleus, TA, EDL) and were not related to muscle type (fast/slow-twitch) or function (flexor/extensor). Effect of QTL on Chr 9 on soleus muscle was male specific. QTL on Chr 2 and 6 were previously observed at 200 days of age, whereas QTL on Chr 1 and 9 are novel muscle weight QTL. In summary, muscle weight in B6/D2 lineage is affected by a polygenic system that has variable influences at different ages, between males and females, and across muscles in a manner independent of muscle type.

Genetic architecture of fast- and slow-twitch skeletal muscle weight in 200-day-old mice of the C57BL/6J and DBA/2J lineage.

The aim of the study was to explore the genetic architecture influencing weight of fast- and slow-twitch skeletal muscles. The weights of the slow-twitch soleus, the mixed gastrocnemius, the fast-twitch tibialis anterior (TA), and extensor digitorum longus (EDL) muscles were 11-34% greater (P < 0.001) in 200-day-old C57BL/6J (B6) than in DBA/2J (D2) mice. Male muscles were 13-28% larger than female (P < 1 x 10(-5), no strain by sex interaction). The sex-related difference in muscle weight, however, varied significantly among the 23 derivative BXD recombinant inbred (RI) strains (strain by sex interaction for soleus, P < 0.01; TA, P < 1 x 10(-4); EDL, not significant; and gastrocnemius, P < 0.001). Quantitative trait loci (QTL) affecting muscle weight were mapped in an F2 intercross of B6 and D2 mice (B6D2F2) and BXD RIs. A total of 10 autosomal, muscle-specific, but not muscle-type-specific, QTL, explaining a total of 5.4, 7.7, 22.9, and 8.6% of phenotypic variance for soleus, TA, EDL, and gastrocnemius muscles, respectively, were found across chromosomes 1 (Chr 1), 2, 3 (female-specific), 5 (two), 6, 7, 8, and 9 in B6D2F2 mice. The QTL on Chr 8 for EDL and the female-specific QTL on Chr 3 for gastrocnemius muscles were statistically significant, but the remaining QTL were at the suggestive level of statistical significance. Ten QTL on Chr 1, 2, 4, 5, 7, 8, 14, 17 (two), and 19 were identified in BXD RIs. Half of the QTL in BXD RIs had pleiotropic effects and were at the suggestive level of significance (except for the significant QTL for gastrocnemius muscle on Chr 17). The B6D2F2 nominated QTL on Chr 8 for EDL weight was validated in BXD RIs (P < 0.03). Support intervals for the QTL on Chr 1 and 5 overlapped between B6D2F2 and BXD RIs. An epistatic interaction between markers on Chr 1 and 17 affected gastrocnemius weight in BXD RIs. The interaction was not, however, validated in the B6D2F2 population. Our results indicate that the differences in muscle weight in the B6 and D2 segregating populations were the outcome of a polygenic system, with each factor contributing a small amount to the phenotypic variance and the genetic architecture affecting muscle weight was muscle specific, but not muscle-type specific, and in some instances sex specific.

A powerful and rapid approach to human genome scanning using small quantities of genomic DNA.

Dense maps of short-tandem-repeat polymorphisms (STRPs) have allowed genome-wide searches for genes involved in a great variety of diseases with genetic influences, including common complex diseases. Generally for this purpose, marker sets with a 10 cM spacing are genotyped in hundreds of individuals. We have performed power simulations to estimate the maximum possible intermarker distance that still allows for sufficient power. In this paper we further report on modifications of previously published protocols, resulting in a powerful screening set containing 229 STRPs with an average spacing of 18.3 cM. A complete genome scan using our protocol requires only 80 multiplex PCR reactions which are all carried out using one set of conditions and which do not contain overlapping marker allele sizes. The multiplex PCR reactions are grouped by sets of chromosomes, which enables on-line statistical analysis of a set of chromosomes, as sets of chromosomes are being genotyped. A genome scan following this modified protocol can be performed using a maximum amount of 2.5 micrograms of genomic DNA per individual, isolated from either blood or from mouth swabs.

Genetic and state variables of neurocognitive dysfunction in schizophrenia: a twin study.

To characterize the familiality of cognitive dysfunction in schizophrenia, we studied performance on three tasks (visuospatial attention; visuolinguistic conflict, arrow-word; and Wisconsin Card Sorting Test [WCST]) by monozygotic (MZ) and dizygotic (DZ) twin pairs discordant for schizophrenia. The subject sample consisted of six MZ twin pairs, nine DZ twin pairs, and one MZ and one DZ nonschizophrenia cotwin of a patient with schizophrenia. There were two sources of cognitive dysfunction: a nonheritable, state component and a heritable, trait component. Deficits surfaced during the WCST in nonschizophrenia MZ cotwins; this impairment resolved following training in nonschizophrenia MZ cotwins, but not in the probands with schizophrenia, who performed abnormally in all tasks. The results suggest that nonheritable protective factors modulate the specific, plastic, and sometimes subtle neurocognitive deficits related to the schizophrenia genotype.

Genetic and environmental influences on body fat distribution, fasting insulin levels and CVD: are the influences shared?

Central body fat distribution has been shown to be related to hyperinsulinemia, insulin resistance, hypertriglyceridemia, and atherosclerosis to a greater degree than general obesity. There are known to be both genetic and environmental effects on all components of this clustering. Whether these genetic effects are due to one set of genes in common to the components or whether genetic influences on insulin resistance and/or general/abdominal fatness 'turn on' other genes that affect other components of the syndrome is not clear. We analyzed data from the Swedish Adoption/Twin Study of Aging (60% female; monozygotic = 116, dizygotic = 202; average age 65 years) to determine whether there were genetic and/or environmental factors shared among general body fat distribution, abdominal body fat distribution, fasting insulin levels and cardiovascular disease. We found additive genetic effects in males to be significantly different from those in females with genetic effects accounting for variance in waist-hip ratio (males = 28%; females = 49%), body mass index (males = 58%; females = 73%), fasting insulin levels (FI) (males = 27%; females = 49%), and cardiovascular disease (CVD) (males = 18%; females = 37%). There were also shared genetic and environmental effects among all the variables except CVD, but a majority of the genetic variance for these measures was trait specific.

Epistatic quantitative trait loci for alcohol preference in mice.

Alcohol consumption is a complex trait, responding to the influence of various genes and environmental influences acting in a quantitative fashion. Various studies in alcohol consumption processes have identified quantitative trait locus (QTL) regions across the mouse genome that appear to contribute to this phenotype. The purpose of this study was to examine the influence of interactions between alleles at different loci, a phenomenon known as epistasis, on previously identified QTLs for alcohol consumption in mice. A multiple regression model was developed and applied to test for the significance of the interaction between two QTLs and to quantify this interaction. Our results indicate the presence of epistasis between loci on mouse chromosomes 2 and 3 accounting for 7-8% of the variation in alcohol preference, respectively.

Sex-exclusive quantitative trait loci influences in alcohol-related phenotypes.

During the past half century, researchers have identified and examined sex differences in alcohol-related phenotypes, focusing more recently on understanding of the mechanisms underlying these differences. In general, the genetic contributions influencing these differences are not consistent with an interpretation of sex linkage and must, therefore, reflect some form of sex limitation in which allelic differences at particular autosomal loci have different consequences in males and females. Significant sex differences in measures of alcohol consumption in mice have been demonstrated in previous work in our laboratory. To investigate these differences further, we explore the limiting case of sex-exclusive effects using data from (BXD) recombinant inbred (RI) strains of mice and from an intercross derived from the same progenitors, C57BL/6J (B) and DBA/2J (D). By the use of two statistical approaches (examination of residual scores as a sex-exclusive phenotypic value for the RI strains and multivariate regression on sex and genotype in the F(2)) we have identified and confirmed female-exclusive markers for alcohol acceptance on chromosomes 9 and 12 and one marker for alcohol preference on chromosome 2. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 88:647-652, 1999.

Implications of body fat distribution in an older twin population.

BACKGROUND: As people age, fat becomes preferentially deposited in the abdominal region over the periphery, and such changes are thought to be associated with adverse metabolic outcomes. We were interested in whether body mass index (BMI) and waist-hip ratio (WHR) are differentially associated with fasting insulin levels, triglycerides, and blood pressure (systolic and diastolic) in an older population. We were also interested in whether these associations change after controlling for genetic influences. METHODS: Data were obtained as part of the Swedish Adoption/Twin Study of Aging. All blood samples and anthropometric measures were assessed from 1989-1991 except insulin, which was assessed from 1986-1988. The sample contains 263 twin pairs (97 monozygotic and 166 dizygotic), 56% women, average age 65 years. RESULTS: In men and women, WHR and BMI were significantly associated with all the metabolic variables except for diastolic blood pressure. When BMI's association with the metabolic variables was assessed independent of WHR, it remained significantly associated with all metabolic variables except diastolic blood pressure in men and triglycerides in women. When WHR's association with the metabolic variables was assessed independent of BMI, it did not remain significantly associated with any of the metabolic variables in men and remained significantly associated with insulin and diastolic pressure in women. After controlling for genetic effects, the relationship between WHR and the metabolic variables became nonsignificant. However, BMI remained significantly associated with systolic blood pressure and triglycerides in men, independent of WHR. CONCLUSION: The results suggest that overall body fat is important to consider in relation to these metabolic parameters in older individuals. The results also suggest that BMI may share associations with blood pressure and triglycerides beyond those that can be attributed to familial influences.

Genetic and environmental influences on waist-to-hip ratio and waist circumference in an older Swedish twin population.

OBJECTIVE: To investigate the genetic and environmental influences on waist-to-hip ratio (WHR) and waist circumference (WC) measurements in males and females. DESIGN: Measurements taken from 1989-1991 as part of The Swedish Adoption/Twin Study of Aging (SATSA) were used for analysis. The SATSA sample contains both twins reared together as well as twins reared apart. SUBJECTS: 322 pairs of twins (50 identical, 82 fraternal male pairs and 67 identical, 123 fraternal female pairs); age range: 45-85y (average age, 65y). MEASUREMENTS: Waist-to-hip ratio (WHR), waist circumference (WC) and body mass index (BMI). RESULTS: In males, additive genetic effects were found to account for 28% of the variance in WHR and 46% of the variance in WC. In females, additive genetic effects were found to account for 48% of the variance in WHR and 66% of the variance in WC. The remaining variance in males was attributed to unique environmental effects (WHR, 72%; WC, 54%) and in females the remaining variance was attributed to unique environmental effects (WHR, 46%; WC, 34%) and age (WHR, 6%). When BMI was added into these models it accounted for a portion of the genetic and environmental variance in WHR, and over half of the genetic and environmental variance in WC. CONCLUSION: There are both genetic and environmental influences on WHR and WC, independent of BMI in both males and females, and the differences between the sexes are significantly different.

Dose-dependent cortisol-induced increases in plasma leptin concentration in healthy humans.

BACKGROUND: Leptin is a hormone that regulates fat metabolism and appetite. The secretion of leptin is regulated by adiposity and, in the rodent, by factors such as insulin, beta-adrenergic agonists, and glucocorticoids (GCs). Increased secretion of the endogenous human GC, cortisol, occurs during stress and in disorders such as major depression. Pharmacological GCs can robustly increase plasma leptin concentrations in humans, leading us to hypothesize that cortisol may serve as a physiological regulator of human leptin secretion. METHODS: A randomized double-blind placebo-controlled comparison of 2 fixed oral dosages of cortisol (40 mg/d and 160 mg/d), given for 4 days to matched groups of healthy subjects (n=47). Low-dose treatment approximated GC output during mild stress, while high-dose treatment approximated GC output during maximal stress, spanning a range of GC secretion relevant to physiological stress. RESULTS: Cortisol produced dose-dependent and time-dependent increases in plasma leptin concentrations (time x treatment condition x body mass index; F6,123=10.73; P<.001). Initial treatment-induced increases in plasma leptin concentration returned toward baseline values during 4 treatment days, suggesting tolerance to this GC effect in these healthy subjects. CONCLUSIONS: The results indicate an important role for GCs in the short-term regulation of human leptin secretion. Glucocorticoid-induced increases in leptin secretion suggest a mechanism that may contribute to anorexia and weight loss during stress and disease states such as major depression, if these conditions are associated with sustained increases in plasma leptin concentrations.

A genetic basis for neuroendocrine-immune interactions.

Psychoneuroimmunology is an exciting, complex field that elucidates interactions among the nervous, endocrine, and immune systems. The contribution of psychosocial factors and behavioral processes to these interactions has been the focus of numerous studies designed to investigate the intricate pathways that are involved in the "mind-body connection." In addition, the effects of this connection on the development and progression of various disease conditions are of considerable interest. Although efforts have been made to identify the cellular and molecular mechanisms underlying these relationships, the impact of genetic makeup on the communication among these systems has yet to be fully realized. The development of sophisticated genetic analytical methods and gene mapping techniques now provide the "tools" to determine the influence of genetics on behavior-neuroendocrine-immune interactions--an area of study that may represent the next frontier in psychoneuroimmunology.

Testing causal hypotheses in multivariate linkage analysis of quantitative traits: general formulation and application to sibpair data.

We provide a general framework for the development of model-free methods for the linkage analysis of multivariate phenotypic data. It is possible within this framework to test both for linkage of a set of phenotypes to one or more markers and for the presence of structural relations among the phenotypes themselves. This report presents the general model, paying special attention to the assumptions that enter its formulation, and outlines the estimation procedures that may be used.

Filter ventilation and nicotine content of tobacco in cigarettes from Canada, the United Kingdom, and the United States.

OBJECTIVES: The purpose was to determine filter ventilation and the nicotine content of tobacco and their contribution to machine-smoked yields of cigarettes from the United States, Canada, and the United Kingdom. METHODS: Ninety-two brands of cigarettes (32 American, 23 Canadian, and 37 British brands) were purchased at retail outlets in State College, Pennsylvania, United States, Toronto, Canada, and London, United Kingdom. A FIDUS FDT filter ventilation tester measured the percentage air-dilution from filter vents. High-pressure, liquid chromatography was used to measure the nicotine content of tobacco. Regression techniques were used to examine the contributions of tobacco nicotine content and filter ventilation to machine-smoked yields of tar, nicotine, and carbon monoxide (CO). RESULTS: Ninety-four per cent of the American brands, 91% of the Canadian brands, and 79% of British brands were ventilated. The total nicotine content of tobacco and percent nicotine (by weight of tobacco) averaged 10.2 mg (standard error of the mean (SEM) 0.25, range: 7.2 to 13.4) and 1.5% (SEM 0.03, range 1.2 to 2) in the United States, 13.5 mg (SEM 0.49, range: 8.0 to 18.3) and 1.8% (SEM 0.06, range: 1.0 to 2.4) in Canada, 12.5 mg (SEM 0.33, range: 9 to 17.5) and 1.7% (SEM 0.04, range: 1.3 to 2.4) in the United Kingdom. Multiple regression analyses showed that ventilation was by far the largest factor influencing machine-smoked yields of tar, nicotine, and CO. CONCLUSION: Filter ventilation appears to be the predominant method for reducing machine-smoked yields of tar, nicotine, and CO in three countries. However, some brands contain about twice as much nicotine (total content or percent nicotine) as do others, indicating that tobacco types or blends and tobacco castings can be used to manipulate nicotine content and nicotine delivery of cigarettes.

Genetics and behavioral medicine: risk factors for cardiovascular disease.

This is the second in a series of three articles addressing the intersection of interests in behavioral genetics and behavioral medicine. In this article, we use risk factors for cardiovascular disease as a prototypical trait for which behavioral genetic approaches provide powerful tools for understanding how risk factors, behavior, and health outcomes are related. The approach synthesizes a number of methods and areas of interest in an attempt to arrive at a comprehensive, whole-organism understanding of health-related risk factors and their response to behavioral interventions.

A multivariate model for the analysis of sibship covariance structure using marker information and multiple quantitative traits.

A model was developed to detect effects of quantitative trait loci (QTLs) in sibships from simulated nuclear family data using the full covariance structure of the data and analyzing all five quantitative traits simultaneously in a multivariate model. Evidence of the presence of loci was detected on chromosomes 4, 8, 9, and 10. The method provided stable results and is worth further exploration for its performance and optimal sample size requirements under realistic conditions.

Genetics and behavioral medicine.

Genetics has substantial relevance to behavioral medicine. A rapidly growing body of evidence indicates the influence of genetics on health and disease and on the behavioral factors related to them. The model of quantitative genetics provides a general interpretational scheme for this burgeoning field. The model focuses on variability, and a major research objective is the decomposition of observed individual differences into portions attributable to various types of genetic and environmental sources of variability. This approach emphasizes the coaction of genes and environments and stands in sharp contrast to the archaic view that places nature and nurture in opposition. Some relevant examples are given in this first article to illustrate the general analytic process. A detailed application to cardiovascular health and disease is provided in the second article, and some policy implications are briefly considered in the third article.

Predictors of ability to walk after selective dorsal rhizotomy in children with cerebral palsy.

Serial evaluations were completed after selective dorsal rhizotomy on 90 children with spastic cerebral palsy to analyze whether age, the preoperative gait score, voluntary dorsiflexion at the ankle, the diagnosis (quadriplegia or diplegia), or the length of follow-up correlated with the ability to walk after rhizotomy. The preoperative gait score (P < 0.0001), the diagnosis (diplegia versus quadriplegia, P < 0.0001), unilateral dorsiflexion (P = 0.0029), and bilateral dorsiflexion (P < 0.0001) were significant predictors of the maximal postoperative gait score in the univariate regression analysis, but only the preoperative gait score (P < 0.0001) and the diagnosis (P = 0.0015) retained significant predictive power in the multivariate analysis. These data suggest that the preoperative gait score and the diagnosis are the strongest predictors of ability to walk after selective dorsal rhizotomy. Dorsiflexion demonstrated predictive power only in the univariate model, suggesting that it might have some prognostic value but less than the preoperative gait score or the diagnosis.