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Irving I Gottesman

Publications and source records attributed to Irving I Gottesman.

24 records · Page 2Linked to original sources
PubMed2003

Monozygotic twins exhibit numerous epigenetic differences: clues to twin discordance?

The goal of this pilot study was to explore the putative molecular mechanisms underlying the phenotypic discordance of monozygotic (MZ) twins. Thus, patterns of epigenetic DNA modification were investigated in the 5'-regulatory region of the dopamine D2 receptor gene (DRD2) in two pairs of monozygotic twins, one concordant and one discordant for schizophrenia. The bisulfite DNA modification-based approach was used to fine-map methylated cytosines in DRD2 in genomic DNA extracted from lymphocytes. Numerous DNA methylation differences were identified in the analyzed region both within and between the pairs of MZ twins. "Epigenetic distances" between MZ twins were calculated and used for the comparison of twin DRD2 methylation profiles. It was detected that the affected twin from the pair discordant for schizophrenia was epigenetically "closer" to the affected concordant twins than to his unaffected MZ co-twin. Although the epigenetic analysis was conducted for only several hundred base pairs of DRD2, the fact that numerous studies identified nonuniform methylation patterns across the clones of bisulfite-modified DNA from the same individual, as well as nonuniform patterns across different individuals, argues for the universality of intra- and interindividual epigenetic variation. Epigenetic studies should provide insight into the molecular causes of differential susceptibility to a disease in genetically identical organisms that may generalize to singletons.

Adolescent↗
PubMed2003

The endophenotype concept in psychiatry: etymology and strategic intentions.

Endophenotypes, measurable components unseen by the unaided eye along the pathway between disease and distal genotype, have emerged as an important concept in the study of complex neuropsychiatric diseases. An endophenotype may be neurophysiological, biochemical, endocrinological, neuroanatomical, cognitive, or neuropsychological (including configured self-report data) in nature. Endophenotypes represent simpler clues to genetic underpinnings than the disease syndrome itself, promoting the view that psychiatric diagnoses can be decomposed or deconstructed, which can result in more straightforward-and successful-genetic analysis. However, to be most useful, endophenotypes for psychiatric disorders must meet certain criteria, including association with a candidate gene or gene region, heritability that is inferred from relative risk for the disorder in relatives, and disease association parameters. In addition to furthering genetic analysis, endophenotypes can clarify classification and diagnosis and foster the development of animal models. The authors discuss the etymology and strategy behind the use of endophenotypes in neuropsychiatric research and, more generally, in research on other diseases with complex genetics.

Disease Models, Animal↗
PubMed2003

Changes in adolescent response patterns on the MMPI/MMPI--a across four decades.

The purpose of this study was to explore changes in adolescent self-presentation on the Minnesota Multiphasic Personality Inventory (MMPI; Hathaway & McKinley, 1940) and MMPI-A (Butcher et al., 1992) over a 40-year period. The primary samples used for comparison in this study include 1,235 adolescents, age 14 through 16, derived from the MMPI-A normative sample (Butcher et al., 1992) collected in 1989 and 10,514 adolescents, age 14 through 16, collected in 1948 and 1954 from Hathaway and Monachesi's (1963) study of adolescent personality and behavior. MMPI basic scale and item-level data were also included for 817 adolescents, age 14 through 16, collected by Colligan and Offord (1992) in 1985 as a further comparison. Between-sample analyses at the profile level revealed that adolescents from the MMPI-A normative sample scored significantly higher across basic clinical scales and lower on validity scales L and K than adolescents from the Hathaway and Monachesi (1963) sample, with mean data from the Colligan and Offord (1992) sample typically falling at a midpoint value. Analyses of Harris-Lingoes (Harris & Lingoes, 1955) subscale and item-level data were conducted to provide refined definitions of the contents of scale-level changes. Results were interpreted as reflecting moderate to large changes in response frequencies between eras of data collection, and emphasis was placed on the relatively high frequency of item endorsements by contemporary adolescents in the clinical direction in the MMPI-A normative sample. A series of cautions and limitations are also offered in interpreting these patterns.

Adolescent↗
PubMed2002

The glial growth factors deficiency and synaptic destabilization hypothesis of schizophrenia.

BACKGROUND: A systems approach to understanding the etiology of schizophrenia requires a theory which is able to integrate genetic as well as neurodevelopmental factors. PRESENTATION OF THE HYPOTHESIS: Based on a co-localization of loci approach and a large amount of circumstantial evidence, we here propose that a functional deficiency of glial growth factors and of growth factors produced by glial cells are among the distal causes in the genotype-to-phenotype chain leading to the development of schizophrenia. These factors include neuregulin, insulin-like growth factor I, insulin, epidermal growth factor, neurotrophic growth factors, erbB receptors, phosphatidylinositol-3 kinase, growth arrest specific genes, neuritin, tumor necrosis factor alpha, glutamate, NMDA and cholinergic receptors. A genetically and epigenetically determined low baseline of glial growth factor signaling and synaptic strength is expected to increase the vulnerability for additional reductions (e.g., by viruses such as HHV-6 and JC virus infecting glial cells). This should lead to a weakening of the positive feedback loop between the presynaptic neuron and its targets, and below a certain threshold to synaptic destabilization and schizophrenia. TESTING THE HYPOTHESIS: Supported by informed conjectures and empirical facts, the hypothesis makes an attractive case for a large number of further investigations. IMPLICATIONS OF THE HYPOTHESIS: The hypothesis suggests glial cells as the locus of the genes-environment interactions in schizophrenia, with glial asthenia as an important factor for the genetic liability to the disorder, and an increase of prolactin and/or insulin as possible working mechanisms of traditional and atypical neuroleptic treatments.

Adolescent↗
PubMed2002

Normal and abnormal personality traits: evidence for genetic and environmental relationships in the Minnesota Study of Twins Reared Apart.

Recent studies have demonstrated substantial correlations between normal and abnormal personality traits. Yet little is known about how these correlations are mediated genetically and environmentally: Do normal and abnormal personality traits stem from the same underlying genes and environments? We addressed this question using data from 128 monozygotic and dizygotic twin pairs in the Minnesota Study of Twins Reared Apart (MISTRA). Additive genetic and nonshared environmental correlations between scales of the Minnesota Multiphasic Personality Inventory (MMPI)--an index of abnormal personality--and the Multidimensional Personality Questionnaire (MPQ)--an index of normal personality--were estimated. Results indicated that phenotypic correlations between normal and abnormal personality were mediated by genetic as well as environmental factors, although the magnitude of genetic mediation tended to be larger overall. Moreover, the patterns of phenotypic, genetic, and environmental relationships among the scales were similar, suggesting that influences on normal and abnormal personality act through systems common to both. It is suggested that future research focus on the neurogenetic substrates of these shared systems and how dysfunction in these systems influences development of disordered personality.

Adult↗