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H Coon

Publications and source records attributed to H Coon.

At least 55 records · Page 3Linked to original sources
PubMed1994

Search for mutations in the beta 1 GABAA receptor subunit gene in patients with schizophrenia.

As alterations in GABAergic neurotransmission have been indirectly implicated in the pathogenetics of schizophrenia, GABAA receptor subunit genes are plausible candidate genes for the illness. We undertook a search for sequence variations in the coding region of beta 1 subunit gene by designing intron-based primers to amplify its 9 exons. Using single strand conformation polymorphism (SSCP) analysis, we found an exon 9 variant present in 3 of 86 unrelated schizophrenic cases derived from families having at least 2 first-degree relatives with schizophrenia. Direct sequencing of the SSCP variant revealed a C-->G nucleotide transversion at codon 396 predicting a histidine to glutamine substitution in the beta 1 peptide. The predicted amino acid substitution occurs at a highly conserved site, 9 residues from a cAMP-dependent serine phosphorylation consensus sequence. All known GABAA beta 1 subunit genes including human, bovine, and rat, code for histidine at position 396. Although the variant cosegregated with disease in a family with 2 affected sibs, it was only transmitted to 2 of 3 affected sibs in a multiplex family. The variant was not found in an additional sample comprising 155 unrelated schizophrenics and the sequence variant was present at a low frequency (approximately 1.1%) in control groups. Although these results indicate that the sequence variant is likely to be a natural polymorphism, it is possible that the variant may be a predisposing allele in rare instances. It is also possible that the variant may change the function or regulation of the GABAA receptor complex and it may be of pharmacogenetic relevance.

Adolescent↗
PubMed1994

Genomic scan for genes predisposing to schizophrenia.

We initiated a genome-wide search for genes predisposing to schizophrenia by ascertaining 9 families, each containing three to five cases of schizophrenia. The 9 pedigrees were initially genotyped with 329 polymorphic DNA loci distributed throughout the genome. Assuming either autosomal dominant or recessive inheritance, 254 DNA loci yielded lod scores less than -2.0 at theta = 0.0, 101 DNA markers gave lod scores less than -2.0 at theta = 0.05, while 5 DNA loci produced maximum lod scores greater than 1: D4S35, D14S17, D15S1, D22S84, and D22S55. Of the DNA markers yielding lod scores greater than 1, D4S35 and D22S55 also were suggestive of linkage when the Affected-Pedigree-Member method was used. The families were then genotyped with four highly polymorphic simple sequence repeat markers; possible linkage diminished with DNA markers mapping nearby D4S35, while suggestive evidence of linkage remained with loci in the region of D22S55. Although follow-up investigation of these chromosomal regions may be warranted, our linkage results should be viewed as preliminary observations, as 35 unaffected persons are not past the age of risk.

Adolescent↗
PubMed1994

Analysis of chromosome 22 markers in nine schizophrenia pedigrees.

Previous results of a genome-wide survey for schizophrenia susceptibility genes in nine multiplex families indicated a possible region of linkage on chromosome 22. We therefore tested for linkage using ten highly polymorphic chromosome 22 DNA markers. Lod score analyses were suggestive of linkage for several markers on the distal end of the chromosome; however, no lod score exceeded 3 assuming either autosomal dominant or autosomal recessive transmission. The highest lod score was 2.09 (theta = 0.10) for marker D22S276 under autosomal recessive inheritance. Based on simulation analyses, this result is unlikely to represent a false positive. Analyses using information from affected individuals only resulted in reduced lod scores, with a maximum of 1.40 (theta = 0.05) for D22S276 assuming autosomal recessive inheritance. Two nonparametric methods, sib pair analysis and the Affected-Pedigree-Member method, also yielded suggestive but inconclusive findings; results were positive, but strict thresholds of significance were not met. Additionally, we tested one candidate gene, the Arylsulfatase A gene, located in the region of 22q13.31-qter. Results were again inconclusive, though the DNA marker available for this gene was a 2-allele RFLP with heterozygosity of 0.5, and therefore not maximally informative. Further investigation of this chromosomal region and this and other candidate genes may be warranted.

Adolescent↗
PubMed1994

Schizophrenia and glutamate receptor genes.

Nine multiplex schizophrenia families were genotyped with polymorphisms for the GLUR5 and NMDAR1 glutamate receptor subunit genes. Using the lod score technique, evidence of linkage was not found assuming either dominant or recessive transmission. Similarly, the non-parametric sib pair test did not yield significant evidence of linkage.

Genetic Linkage↗
PubMed1994

Analysis of GABAA receptor subunit genes in multiplex pedigrees with manic depression.

The gamma-aminobutyric acid (GABA) neurotransmitter system has been implicated in the pathogenesis of manic depression. Tests of this hypothesis can now be carried out due to the recent characterization of simple sequence repeat polymorphisms for the GABAA receptor alpha 1, alpha 2, alpha 4, alpha 5, alpha 6, beta 1, beta 3 and gamma 2 subunit genes. Using both parametric and non-parametric methods, we tested for linkage between manic depression and these polymorphisms in six multi-generational pedigrees. No evidence of linkage was found.

Adolescent↗
PubMed1994

Linkage analysis between schizophrenia and a microsatellite polymorphism for the D5 dopamine receptor gene.

Using 23 multiplex pedigrees we tested for linkage between schizophrenia and a microsatellite polymorphism for the D5 dopamine receptor gene (DRD5). Assuming autosomal dominant inheritance and a maximum penetrance of 0.6, an overall lod score of -4.54 was derived at 0% recombination. For recessive transmission the summary lod score was -8.37 at 0% recombination. These data suggest that mutations of the D5 dopamine receptor gene are unlikely to be of major etiological importance in the pathogeneses of schizophrenia in the families studied. However, our study does not exclude the D5 dopamine receptor gene as a candidate gene for schizophrenia because some of our families were not informative for linkage and because of the likelihood of genetic heterogeneity.

Adolescent↗
PubMed1993

Use of a neurophysiological trait in linkage analysis of schizophrenia.

Traditional diagnostic techniques may not provide all the information necessary to reveal the genetic causes of schizophrenia through linkage analysis. Use of neurophysiological indicator variables that are associated with the disease may increase the probability of detecting linkage. Such variables not only produce simpler phenotypes for analysis, but they also may be more proximal to the gene products involved in neurological dysfunctions underlying schizophrenia. We have used a previously characterized neurophysiological variable, the P50 evoked-auditory response, to search for chromosomal regions that may be of interest in the study of schizophrenia. Although our scan of over 300 markers did not show strong evidence for linkage to P50 in nine families, this exploratory analysis has revealed several chromosomal regions that may deserve further study.

Adolescent↗
PubMed1993

C to T nucleotide substitution in codon 713 of amyloid precursor protein gene not found in 86 unrelated schizophrenics from multiplex families.

Jones et al. Nature Genet 1:306-309, [1992] recently detected a C to T nucleotide transition (codon 713) in a highly conserved region of the beta-amyloid precursor gene in a single case of schizophrenia. Although the sequence variant may be a natural polymorphism, it is crucial to determine whether the mutation might be present in a small subset of schizophrenics. We isolated DNA from 86 unrelated chronic schizophrenics who had a first degree relative with chronic schizophrenia or chronic schizoaffective disorder. After PCR amplification of exon 17, we were unable to detect the presence of the codon 713 variant in these schizophrenic cases, as well as in 156 controls. Unless additional cases are found with the codon 713 mutation, it is unlikely that the sequence variant is pathogenic for schizophrenia.

Amyloid beta-Protein Precursor↗
PubMed1993

Linkage analysis of schizophrenia with five dopamine receptor genes in nine pedigrees.

Alterations in dopamine neurotransmission have been strongly implicated in the pathogenesis of schizophrenia for nearly 2 decades. Recently, the genes for five dopamine receptors have been cloned and characterized, and genetic and physical map information has become available. Using these five loci as candidate genes, we have tested for genetic linkage to schizophrenia in nine multigenerational families which include multiple affected individuals. In addition to testing conservative disease models, we have used a neurophysiological indicator variable, the P50 auditory evoked response. Deficits in gating of the P50 response have been shown to segregate with schizophrenia in this sample and may identify carriers of gene(s) predisposing for schizophrenia. Linkage results were consistently negative, indicating that a defect at any of the actual receptor sites is unlikely to be a major contributor to schizophrenia in the nine families studied.

Adolescent↗
PubMed1993

A genome-wide search for genes predisposing to manic-depression, assuming autosomal dominant inheritance.

Manic-depressive illness (MDI), also known as "bipolar affective disorder," is a common and devastating neuropsychiatric illness. Although pivotal biochemical alterations underlying the disease are unknown, results of family, twin, and adoption studies consistently implicate genetic transmission in the pathogenesis of MDI. In order to carry out linkage analysis, we ascertained eight moderately sized pedigrees containing multiple cases of the disease. For a four-allele marker mapping 5 cM from the disease gene, the pedigree sample has > 97% power to detect a dominant allele under genetic homogeneity and has > 73% power under 20% heterogeneity. To date, the eight pedigrees have been genotyped with 328 polymorphic DNA loci throughout the genome. When autosomal dominant inheritance was assumed, 273 DNA markers gave lod scores < -2.0 at recombination fraction (theta) = .0, 174 DNA loci produced lod scores < -2.0 at theta = .05, and 4 DNA marker loci yielded lod scores > 1 (chromosome 5--D5S39, D5S43, and D5S62; chromosome 11--D11S85). Of the markers giving lod scores > 1, only D5S62 continued to show evidence for linkage when the affected-pedigree-member method was used. The D5S62 locus maps to distal 5q, a region containing neurotransmitter-receptor genes for dopamine, norepinephrine, glutamate, and gamma-aminobutyric acid. Although additional work in this region may be warranted, our linkage results should be interpreted as preliminary data, as 68 unaffected individuals are not past the age of risk.

Adult↗
PubMed1992

Continuous culture of neuronal cells from adult human olfactory epithelium.

Cells from the olfactory epithelium of adult human cadavers have been propagated in primary culture and subsequently cloned. These cells exhibit neuronal properties including: neuron-specific enolase, olfactory marker protein, neurofilaments, and growth-associated protein 43. Simultaneously, the cells exhibit nonneuronal properties such as glial fibrillary acidic protein and keratin, the latter suggesting properties of neuroblasts or stem cells. These clonal cultures contain 5-10% of cells sufficiently differentiated to show odorant-dependent cyclic adenosine 3',5'-monophosphate (cAMP) or calcium-release responses when challenged with submicromolar concentrations of odorants. The potential of culturing neuronal cells from patients with neuropsychiatric disorders, such as Alzheimer's disease or schizophrenia, could enable the study of the pathophysiology of these neurons in the culture dish and allow new approaches to the study of mental illness.

Adult↗
PubMed1992

Identifying children in the Colorado Adoption Project at risk for conduct disorder.

Clustering techniques were used to identify a subsample of young adopted and nonadopted children in the Colorado Adoption Project at risk for conduct disorder. Although data from both boys and girls were analyzed, a cluster of girls large enough for subsequent statistical analysis could not be identified; therefore, results are reported for boys only. Identifying measures were selected based on the DSM-III-R diagnostic criteria. Cluster analyses confirmed the existence of a small group of boys who appeared to be significantly at risk. Subsequent parental and teacher ratings of these children verified the stability over time of the classification. The poor conduct group was significantly associated with difficult temperament in infancy, with poor conduct on the part of parents when they were youths, and with high achievement orientation in the home environment.

Adoption↗
PubMed1991

Parent-offspring and sibling adoption analyses of parental ratings of temperament in infancy and childhood.

A first step toward understanding the etiology of personality is to investigate the relative impact of genetic and environmental factors using twin and adoption designs. Twin studies of infants and young children indicate substantial genetic influence for parental ratings of temperament in the preschool years. Adoption studies, however, have not previously been reported during the early years of life. We present parent-offspring comparisons for temperament (emotionality, activity, sociability, and impulsivity) for adopted and nonadopted children yearly from 1 to 7 years of age and their biological, adoptive, and nonadoptive parents. Also presented are correlations for adoptive and nonadoptive siblings when each child was 1, 2, 3, and 4 years of age. In contrast with twin results, little evidence is found for genetic influence. The average correlation between biological parents and their adopted-away children for data averaged over the 7 years is only .03. Similarly, the average parent-offspring correlation in nonadoptive families (.08) is no greater than in adoptive families (.12). Results for nonadoptive and adoptive siblings also indicate little genetic influence. The difference between the twin and adoption results may be due to environmental effects or to nonadditive genetic variance.

Adoption↗
PubMed1990

A simple method of model fitting for adoption data.

Traditional models used with adoption data often make strong assumptions concerning the nature of genetic transmission and assortative mating. A simple model is presented which avoids these assumptions. The model is linearized and, thus, has the further advantage that it can be used with standard statistical packages such as LISREL or EQS. The model allows tests of the internal consistency of the data, in addition to tests of the relative strength of genetic and environmental transmission parameters. To illustrate the model, measures of general cognitive ability in parents and their 7-year-old children from the Colorado Adoption Project (CAP) were fit to the model using the LISREL program. This relatively simple model may be expanded to incorporate more complex designs involving multiple measures or siblings. Although the model will not always allow constraints on the parameter estimates in more complex models, it offers a quick, flexible method for initial exploration of adoption data.

Adoption↗
PubMed1989

Genetic and environmental determinants of musical ability in twins.

Analyses of musical ability data from the Loehlin and Nichols National Merit Scholarship study are presented. Musical ability is indexed by four measures: interest in a profession in music, performance in school, performance outside of school, and receiving honors in music. These variables pose a challenge for behavior genetic analysis since they do not conform to the assumptions of traditional linear models. For example, there is a dependent relationship between the honors and the performance variables; one cannot obtain honors without performance. Several methods were employed to deal with these relationships, and the following conclusions appeared regardless of the method used. First, twin correlations were always high, ranging from 0.44 to 0.90 in monozygotic (MZ) twins and from 0.34 to 0.83 in dizygotic (DZ) twins. Second, although there was evidence for heritable variation, the effects of common environment were almost always larger than the effects of heredity. Third, marital assortment was not of sufficient magnitude to account for these common environment effects. In the young adults in this sample, musical ability is influenced more by shared family environment than by shared genes.

Adolescent↗