Nature and nurture in neuropsychiatric genetics: Where do we stand?

Department of Psychiatry, Virginia Institute of Psychiatric and Behavioral Genetics, Richmond 23298, USA.
Dialogues in clinical neuroscience 03/2010; 12(1):7-23.
Source: PubMed


Both genetic and nongenetic risk factors, as well as interactions and correlations between them, are thought to contribute to the etiology of psychiatric and behavioral phenotypes. Genetic epidemiology consistently supports the involvement of genes in liability. Molecular genetic studies have been less successful in identifying liability genes, but recent progress suggests that a number of specific genes contributing to risk have been identified. Collectively, the results are complex and inconsistent, with a single common DNA variant in any gene influencing risk across human populations. Few specific genetic variants influencing risk have been unambiguously identified, Contemporary approaches, however hold great promise to further elucidate liability genes and variants, as well as their potential inter-relationships with each other and with the environment. We will review the fields of genetic epidemiology and molecular genetics, providing examples from the literature to illustrate the key concepts emerging from this work.

Download full-text


Available from: Brien Patrick Riley, Oct 04, 2015
28 Reads
  • Source
    • "Etiology of complex mental disorders of aberrant neurodevelopment such as schizophrenia and autism remains poorly understood. Familial aggregation and high levels of heritability of these disorders suggests important contribution of genetic factors 1,2. At the same time epidemiological studies provide substantial evidence that pre and/or perinatal environmental risk factors, possibly in conjunction with genetic vulnerability, contribute significantly in triggering the developmental cascade of these disorders [3], [4]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Epidemiological evidence supports that maternal infection during gestation are notable risk factors for developmental mental illnesses including schizophrenia and autism. In prenatal lipopolysaccharide (LPS) model of immune activation in rats, the offspring exhibit significant impairments in behaviors mediated by central dopamine (DA) system. This study aimed to examine the temporal and regional pattern of postnatal DA development in the male offspring of pregnant Sprague-Dawley rats administered with 100 µg/kg LPS or saline at gestational days 15/16. Using ligand autoradiography, D1 and D2 dopamine receptors (D1R, D2R) and dopamine transporter (DAT) binding levels were measured in the prefrontal cortex (PFC) and sub cortical regions (dorsal striatum and nucleus accumbens core and shell) at pre pubertal (P35) and post pubertal ages (P60). We found a significant decrease in D2R ligand [(3)H] YM-90151-2 binding in the medial PFC (mPFC) in prenatal LPS-treated animals at P35 and P60 compared to respective saline groups. The decrease in D2R levels was not observed in the striatum or accumbens of maternal LPS-treated animals. No significant changes were observed in [(3)H] SCH23390 binding to D1R. However, the level of [(125)I] RTI-121 binding to DAT was selectively reduced in the nucleus accumbens core and shell at P35 in the prenatal LPS group. Immunohistochemical analysis showed that number of D2R immunopositive cells in infralimbic/prelimbic (IL/PL) part of mPFC was significantly reduced in the LPS group at P60. Prenatal LPS treatment did not significantly affect either the total number of mature neurons or parvalbumin (PV)-immunopositive interneurons in this region. However the number of PV and D2R co-labeled neurons was significantly reduced in the IL/PL subregion of PFC of LPS treated animals. Our data suggests D2R deficit in the PFC and PV interneurons may be relevant to understanding mechanisms of cortical dysfunctions described in prenatal infection animal models as well as schizophrenia.
    PLoS ONE 01/2013; 8(1):e54439. DOI:10.1371/journal.pone.0054439 · 3.23 Impact Factor
  • Source
    • "Its cost to society in terms of health care demands and lost productivity is well documented (Rice 2009), as are the personal stories of lifelong anguish and suffering among SZ patients and their families. While both genetic and epigenetic factors are associated with a risk for developing this disorder (Dick et al. 2010), the etiology and pathophysiology of SZ remain incompletely understood. More than 50 years after the introduction of drugs that target its symptoms, the standard medications for SZ are at best modestly effective. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Current antipsychotic medications do little to improve real-life function in most schizophrenia patients. A dispassionate view of the dispersed and variable neuropathology of schizophrenia strongly suggests that it is not currently, and may never be, correctable with drugs. In contrast, several forms of cognitive therapy have been demonstrated to have modest but lasting positive effects on cognition, symptoms, and functional outcomes in schizophrenia patients. To date, attempts to improve clinical outcomes in schizophrenia by adding pro-cognitive drugs to antipsychotic regimens have had limited success, but we propose that a more promising strategy would be to pair drugs that enhance specific neurocognitive functions with cognitive therapies that challenge and reinforce those functions. By using medications that engage spared neural resources in the service of cognitive interventions, it might be possible to significantly enhance the efficacy of cognitive therapies. We review and suggest several laboratory measures that might detect potential pro-neurocognitive effects of drugs in individual patients, using a "test dose" design, aided by specific biomarkers predicting an individual's drug sensitivity. Lastly, we argue that drug classes viewed as "counter-intuitive" based on existing models for the pathophysiology of schizophrenia-including pro-catecholaminergic and NMDA-antagonistic drugs-might be important candidate "pro-cognitive therapy" drugs.
    Handbook of experimental pharmacology 10/2012; 213(213):81-111. DOI:10.1007/978-3-642-25758-2_4
  • Source
    • "The number of recent claims by social scientists to have discovered a statistically significant association between a particular common gene variant—either on its own or in conjunction with a particular environment—and complex, politically relevant behaviors warrants careful evaluation. This evaluation is particularly needed because the search for genes that could predict prevalent and devastating behavioral phenotypes such as schizophrenia and autism, not to mention global killers such as diabetes and hypertension, has to date been unsuccessful (Dick, Riley, and Kendler 2010; Franke, Neale, and Faraone 2009; Plomin and Davis 2009; Talmud et al. 2010). The purpose of this article is to undertake such an evaluation. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Political scientists are making increasing use of the methodologies of behavior genetics in an attempt to uncover whether or not political behavior is heritable, as well as the specific genotypes that might act as predisposing factors for—or predictors of—political “phenotypes.” Noteworthy among the latter are a series of candidate gene association studies in which researchers claim to have discovered one or two common genetic variants that predict such behaviors as voting and political orientation. We critically examine the candidate gene association study methodology by considering, as a representative example, the recent study by Fowler and Dawes according to which “two genes predict voter turnout.” In addition to demonstrating, on the basis of the data set employed by Fowler and Dawes, that two genes do not predict voter turnout, we consider a number of difficulties, both methodological and genetic, that beset the use of gene association studies, both candidate and genome-wide, in the social and behavioral sciences.
    American Political Science Review 02/2012; 106(01). DOI:10.1017/S0003055411000554 · 3.93 Impact Factor
Show more