Segregation analyses converge in explaining the predisposition to attention-deficit/hyperactivity disorder (ADHD) as the consequence of a major gene and exclude purely environmental or cultural transmission. As a result of the ADHD phenotype restrictions, collection of extended families or design of linkage studies using families has been extremely difficult and thus currently linkage studies have been performed using only concordant or discordant sib-pairs rather than large families. On the other hand, intergenerational studies are represented by the transmission disequilibrium test (TDT) using trios. We collected pedigree data on ADHD from the Paisa community from Antioquia, Colombia, a genetic isolate. The goal of this study was to genetically map a putative gene predisposing to ADHD in a set of 27 multigenerational Paisa families. Here we present the results of a power simulation using SIMLINK to detect linkage of ADHD. ADHD was assumed to be a dichotomous trait with incomplete penetrance and a phenocopy rate of 3% in males and 0.2% in females. We simulated cosegregation of the trait and a marker locus in our pedigrees. We assumed Hardy-Weinberg and linkage equilibrium, equally frequent marker alleles and evaluated power at several recombination fractions between the trait and marker loci. Also, the ADHD trait was assumed to be genetically heterogeneous and different functions of age-dependent penetrance were simulated. We found exceptionally good power to detect linkage (expected LOD > 14 if theta is 0.1 or less), and that the presence of heterogeneity up to 50% does not affect substantially the projected LOD scores even for a theta recombination value of 0.05 (eLOD > 5.87). Having now obtained blood samples and confirmatory interviews in five families (representing 20% of the projected number of families), we performed a new analysis. The expected mean LOD in these five families reached values close to 10 and remained invariant when heterogeneity and different penetrance models were considered. We discuss the relative benefits of using extended and multigenerational families for genetic mapping studies as opposed to using nuclear families, affected sib pairs or sporadic cases which require the collection of over 1000 analytical units to get the same power exhibited by the small number of pedigrees described here.
Autism is a severe neurodevelopmental disorder defined by social and communication deficits and ritualistic-repetitive behaviors that are detectable in early childhood. The etiology of idiopathic autism is strongly genetic, and oligogenic transmission is likely. The first stage of a two-stage genomic screen for autism was carried out by the Collaborative Linkage Study of Autism on individuals affected with autism from 75 families ascertained through an affected sib-pair. The strongest multipoint results were for regions on chromosomes 13 and 7. The highest maximum multipoint heterogeneity LOD (MMLS/het) score is 3.0 at D13S800 (approximately 55 cM from the telomere) under the recessive model, with an estimated 35% of families linked to this locus. The next highest peak is an MMLS/het score of 2.3 at 19 cM, between D13S217 and D13S1229. Our third highest MMLS/het score of 2.2 is on chromosome 7 and is consistent with the International Molecular Genetic Study of Autism Consortium report of a possible susceptibility locus somewhere within 7q31-33. These regions and others will be followed up in the second stage of our study by typing additional markers in both the original and a second set of identically ascertained autism families, which are currently being collected. By comparing results across a number of studies, we expect to be able to narrow our search for autism susceptibility genes to a small number of genomic regions. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 88:609-615, 1999.
Four experiments were conducted to determine whether fluctuations in dietary electrolyte level (milliequivalents Na+K-Cl per kilogram) or different dietary sodium chloride levels would affect performance, water intake, or excreta moisture of chickens fed semduramicin vs nonmedicated controls. In all experiments, male commercial broiler chicks were used, and all diets were fed with and without 25 mg semduramicin/kg diet. The basal diets were based on corn, soybean meal, and poultry oil. Experiments 1, 3, and 4 were conducted using male broiler chicks in battery brooders to 18 d of age. In Experiment 1, six electrolyte levels were fed [basal (0.2% Na, 0.33% Cl, 1.10% K); basal plus 0.1% Na (from sodium chloride); basal plus 0.1% K (from potassium chloride); basal plus 0.2% Na (from sodium carbonate); basal plus 0.34% K (from potassium chloride); basal plus 0.15% Cl (from ammonium chloride)]. There were no significant changes in BW gain, feed consumption, or feed conversion ratio caused by any dietary treatment. Water consumption was not affected by the inclusion of Na, Cl, K, or electrolyte levels, but excreta moisture was affected. The highest and lowest excreta moisture levels came from chicks fed the lowest chloride levels. There were no significant dietary effects on serum Na, Cl, or K by dietary electrolytes or semduramicin. Experiment 2 was conducted with triplicate floor pens of 33 male broilers each for 42 d with four electrolyte levels [basal (0.2% Na, 0.34% Cl, 1.03% K); basal plus 0.1% Na (from sodium carbonate); basal plus 0.1% Cl (from ammonium chloride); basal plus 0.18% K (from potassium carbonate)]. Increasing electrolyte level had a significant effect on BW gain at 35 d but not at 42 d [mainly because of differences in K (1.943 kg at 35 d) vs Cl (2.013 kg at 35 d)]. At 42 d, there were no differences in growth because of N, K, Cl, or semduramicin. Potassium supplementation caused a significant increase in litter moisture (P = 0.031). Semduramicin did not affect litter moisture (P = 0.892), nor were there significant semduramicin interactions with Na, K, Cl, or semduramicin. The basal diets in Experiments 3 and 4 were identical to the basal diet in Experiment 1 except there was no sodium chloride added. The diets fed in Experiment 3 contained 0, 0.1, 0.2, 0.3, or 0.4% added sodium chloride. The diets fed in Experiment 4 contained 0.1, 0.3, 0.5, 0.7, and 0.9% added sodium chloride. The results of Experiments 3 and 4 show that about 0.4% added sodium chloride is necessary to achieve maximum growth and feed conversion. It is clear that semduramicin had no significant effect upon the variation observed in any of the variables measured.
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