Calcium absorption in adult mono and dizygotic twins will be examinedfrom inheritance from the comparison of the variance of absorption in the2 populations. The same will be done on measurements of plasmacalcitriol, calcidiol, vitamin D binding protein, PTH and calcitonin andplasma and urine calcium and phosphate.The primary aim of this project is to carry out family studies to searchfor single genes and to test the hypothesis that there are detectablesingle gene effects on bone mass.A genetic-epidemiological study of adults, who had a parent with HD willbe done to determine familial HD age of onset. This study will test thehypothesis that HD is a factor of central nervous system aging. It willprovide insight into the maternal influence that delays the symptoms ofneuronal death and measure the effects of neuronal death on biomarkersof aging.The self-administration of alcohol is influenced by environmental and bygenetic factors. The heritable differences in the reinforcing oraversive actions of ethanol, the development of tolerance and ethanolmetabolism will be estimated through comparison studies of monozygoticand dizygotic twins and subjects from families with multiple individualssuffering from alcoholism.This study will measure bone mass in juvenile twins of known placentaltype to test whether bone mass is influenced by the prenatal environmentas measured by placentation. Cortical and trabecular bone mass will bemeasured in female twins aged 40-70 to test whether there are differentgenetic and environmental influences on these two types of bone and ifan important genetic influence is the presence or absence of intestinallactase activity.The primary objective of this project is to search for genes associatedwith peak bone density as a risk factor for osteoporotic fractures. Primary osteoporosis is characterized by increased susceptibility tofractures. A potentially modifiable risk factorfor osteoporotic fracturesis low bone density. Preliminary studies have indicated that the majorityof variation in peak bone density is determined by genetic factors andthere are significant genetic factors influencing skeletal architecturewhich are alsorelated to the risk for osteoporotic fractures. Thesestudies will therefore concentrate upon the search for genetic factorswhich determine peak bone density and skeletal architecture. Past studieshave concentrated on twins to estimate heritability and search forevidence of the modes of inheritance of these osteoporosis risk factors. We have recently begun a study of sibling pairs sibpairs to begin agenome wide search for genetic markers linked to bone density, skeletalarchitecture and intermediate phenotypes related to bone metabolism. Positive findings will map loci which are in close proximity to or withingenes which influence these quantitative traits. We plan to extend studiesof approximately 200 Caucasian, adult, female sibpairs begun in the 09 and10 years of the present granting period with the addition of 300 moreCaucasian sibpairs and 250 African American sibpairs during years 11through 15 of the project. The genetic markers being used are the highlyinformative dC-dAn.dC-dTn microsatellites.In the original application of the Indiana Alcohol Research Center ARCthis core resource was included because of the increasing body ofevidence that alcoholism and alcohol abuse have a strong geneticbackground. Originally this component contained ongoingalcoholchallenge studies which are now part of the Human Genetics ResearchComponent. The Human Genetics Core Resource will continue with the primary missionof providing coordination, experimental design, data storage and dataanalysis for human genetic ARC studies of the effects of alcoholingestion. This model is designed to provide databases and resourcesthat will become increasingly valuable as the years progress. Currentdatabases collected as a result of research within the ARC includemultivariate alcohol challenge data on 150 pairs of adult twins, pedigrees of 120 alcoholic probands who have multiple affected familymembers and DNA samples from individuals with documented responses toalcohol. A secondary mission of this core resource is to collaborate with othertwin studies to further understand genetic epidemiological influences onthe chronic effects of alcohol. To carry out this mission, collaborativeresearch has been initiated with and data obtained for analysis from theNational Academy of Sciences - National Research Council Twin Panel, theNational Heart Lung and Blood Institute Twin Panel and the DukeUniversity Twin Study of Memory in Aging. These resources will providedata on Caucasian male twins born between 1917 and 1927 who have hadalcohol consumption data collected over the past two decades.This research component had its origins as part of the Human GeneticsCore Resource in the original application for the Indiana AlcoholResearch Center ARC. It is now a separate component which consolidatesand supports alcohol challenge studies in twins and families whilecontinuing to rely on the Human Genetics and Database Core Resource forstatistical support and zygosity confirmation. During the first years of the ARC, multiple physiological andbiobehavioral variables were studied and many were found to have evidencefor significant genetic effects. The strongest evidence for geneticcontrol of the acute effects of alcohol was found forelectroencephalographic EEG changes after alcohol. Variability withindizygotic DZ twin-pairs increased markedly after alcohol while thevariability within monozygotic MZ pairs generally decreased indicatingthe presence of genetic influences. The relative changes in the within- pair variability for the two zygosities was so great that multipleadditive heritability estimates ofthe fraction of total variance dueto genetic variance values were found greater than the theoretical upperlimit of 10 This suggested an upward bias of heritability due to geneinteractions. The post-alcohol heritability values were the largest inthe alpha-slow 76 - 100 Hertz and beta-slow 126 - 200 Hertzfrequency bands and over the frontal lobes. The Human Genetics Research Component will continue twin studies of theacute effects of alcohol, development of acute tolerance to alcohol andplacebo effects on EEG changes and related biobehavioral variables. These twin studies will be carried out both in a clinical researchhospital ward in Indianapolis and in the Department of Psychology inBloomington. Studies comparing family history positive and familyhistorynegative young adult males will also be carried out inBloomington. The results of these studies will be used to develop aprotocol designed to detect segregation of single genes in families oftwins with extreme responses to alcohol.
Quantitative genetics of aging; alcoholism; cardiovascular disease risk factors; twin studies; clinical genetics
,, -, African American, Age Difference, Aging, Alcoholic Beverage Consumption, Alcoholism Alcohol Abuse, Alcoholism Alcohol Abuse Information System, Behavioral Genetics, Behavioral Habituation Sensitization, Beta Galactosidase, Binding Protein, Biomarker, Biomedical Facility, Blood Chemistry, Blood Test, Bone Density, Bone Development, Bone Metabolism, Brain Electrical Activity, Breath Test, Calcitonin;, Caucasian American, Cell Death, Child Physical Development, Clinical Chemistry, Computer Data Analysis, Computer Program Software, Developmental Genetics, Dietary Calcium, Dihydroxycholecalciferol;, Disease Proneness Risk, Dizygotic Twin, Dosage, Drug Metabolism, Drug Tolerance, Electroencephalography, Enzyme Activity, Ethanol, Evoked Potential, Expectancy, Eye Movement, Family Genetics, Fatigue, Female, Gastrointestinal Nutrient Absorption, Genetic Marker, Genetic Polymorphism, Genetic Registry Referral Center, Genotype, Hormone Regulation Control Mechanism, Human Genetic Material Tag, Human Subject, Huntington's Chorea, Linkage Mapping, Monozygotic Twin, Nervous System Disorder Epidemiology, Neuron, Neuropsychological Test, Nutrition Related Tag, Osteoporosis, Parathyroid Hormone, Patient Disease Registry, Personality Test, Phenotype, Photon Absorptiometry, Placebo, Polymerase Chain Reaction, Pregnancy, Psychophysiology, Racial Ethnic Difference, Reinforcer, Self Medication, Sibling, Skeletal Visualization, Speech, Statistics Biometry, Twin Multiplet, Young Adult Human
