Psychiatric genetics: Progress amid controversy. Nature Reviews Genetics, 9, 527-540

Molecular and Behavioral Neuroscience Institute, University of Michigan, 5061 BSRB, 109 Zina Pitcher Place, Ann Arbor, Michigan 48109-2200, USA.
Nature Reviews Genetics (Impact Factor: 36.98). 08/2008; 9(7):527-40. DOI: 10.1038/nrg2381
Source: PubMed


Several psychiatric disorders--such as bipolar disorder, schizophrenia and autism--are highly heritable, yet identifying their genetic basis has been challenging, with most discoveries failing to be replicated. However, inroads have been made by the incorporation of intermediate traits (endophenotypes) and of environmental factors into genetic analyses, and through the identification of rare inherited variants and novel structural mutations. Current efforts aim to increase sample sizes by gathering larger samples for case-control studies or through meta-analyses of such studies. More attention on unique families, rare variants, and on incorporating environment and the emerging knowledge of biological function and pathways into genetic analysis is warranted.

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Available from: Melvin Mcinnis, Mar 27, 2014
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    • "The same sample size weakness is noted in terms of ADH1B genotype. Although there exists controversy about sample size requirements in behavioral genetics (Burmeister et al., 2008), there is a robust literature on these functional polymorphisms in alcohol-metabolizing genes, including their biobehavioral mechanism of action. As a result, ALDH2 and ADH are among the most widely studied and supported polymorphisms in alcoholism genetics (for review, see Eng et al., 2007; Wall, 2005), thus justifying their evaluation in this sample. "
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    ABSTRACT: Objective: Among Asian American young adults, variations in alcohol-metabolizing genes (i.e., aldehyde dehydrogenase [ALDH2] and alcohol dehydrogenase [ADH1B]) are protective, whereas Korean ethnicity, family history of alcohol problems (FH), and acculturation represent risk factors for alcohol misuse. This study aims to integrate these genetic and environmental factors in a sample of Asian Americans expressing a wide range of alcohol use behaviors and problems. Method: Participants were 97 Asian American young adults (42% female) recruited as heavy and light drinkers (n = 49 and 48, respectively). Participants completed the Alcohol Use Disorders Identification Test, Timeline Followback, Vancouver Acculturation Index, and Family Tree Questionnaire. All participants provided buccal cell samples for DNA analysis. Results: Family history-positive (FH+) subjects reported greater alcohol use than family history-negative (FH-) subjects. A FH × ALDH2 interaction was observed such that FH- subjects demonstrated no ALDH2 effect, yet in FH+ subjects, the ALDH2*2 genotype was associated with increased alcohol use. A significant main effect of acculturation was also moderated by FH such that the positive association between acculturation and alcohol use was greater among FH+ subjects and, in particular, among FH+ men. Conclusions: Although preliminary, these results suggest that the potential protective effects conferred by ALDH2 and ADH1B are moderated by FH, such that a positive FH appeared to abolish the protective effect of these genes. Further, acculturation was associated with greater alcohol use in FH+ subjects only. If replicated in larger samples, these data suggest that alcohol-metabolism genes may not be protective in the context of high environmental risk.
    Journal of studies on alcohol and drugs 09/2015; 76(5):690-699. DOI:10.15288/jsad.2015.76.690 · 2.76 Impact Factor
    • "Furthermore, unlike in ASD, traits associated with the BAP are often domain-specific and do not necessarily co-occur. Individuals commonly only exhibit a single BAP trait (Sasson et al., 2013b), reduced social motivation, pragmatic language abnormalities, or rigid personality, suggesting that conceptualizing autism-related characteristics as " fractionable " rather than as the unitary concept required for diagnosis may help address the genetic heterogeneity of ASD (Burmeister et al., 2008; Happé and Ronald, 2008). For example, in the general population, social BAP traits, but not rigid personality, are associated with reduced social cognitive performance and interpersonal skill (Sasson et al., 2013c), indicating that the social difficulties characterizing ASD may extend to a lesser degree to those with social BAP traits. "
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    ABSTRACT: Background: Milder but qualitatively similar subclinical traits of autism known as the “broad autism phenotype” (BAP) have been associated with difficulties forming and maintaining quality relationships (Wainer et al., 2013). However, the process by which the BAP influences relationship outcomes remains unclear. Objectives: The current study examined how BAP traits in previously unfamiliar college roommates were associated with their interpersonal behaviors during relationship development and their relationship quality after several months of cohabitation. Social BAP traits (i.e., aloofness and pragmatic language abnormalities), but not nonsocial BAP traits (i.e., rigidity), were hypothesized to be associated with decreased relationship satisfaction and commitment to the relationship by the end of the study. Drawing upon Interpersonal Theory (Horowitz et al., 2006), the behaviors of warmth and dominance were hypothesized to mediate the effects of social BAP traits on relationship outcomes. Methods: Newly formed same-sex roommate dyads with limited to no previous familiarity (N = 160 individuals) were assessed every two weeks for 10 weeks. Participants initially completed the Broad Autism Phenotype Questionnaire (BAPQ), and subsequently reported on the warm and dominant behaviors exchanged within the dyad, as well as their overall relationship satisfaction and commitment at the end of the study. Results: We used Actor-Partner Interdependence Models (APIMs) to evaluate our hypotheses. An interaction of roommates’ aloof traits predicted relationship satisfaction, and simple slopes analyses revealed that low aloof participants were less satisfied with high aloof roommates (b = -.34 [95% CI: -.62, -.07], SE = .14, p = .016). Aloof traits were associated with both warmth (b = -.32, 95% CI [-.53, -.15], SE = .09, p < .001) and dominance (b = -.35, 95% CI [-.53, -.18] SE = .09, p < .001), with warmth mediating the effects of aloofness on relationship outcomes measured through indirect effects (i.e, ab). Participants’ aloofness predicted their own expressions of warmth, which subsequently predicted relationship satisfaction (ab = -.08, 95% CI [-.15, -.02], κ2 = .17). Also, high aloof participants evoked less warm behaviors from roommates, which led participants to feel less satisfied (ab = -.16, 95% CI [-.26, -.07], κ2 = .10) and less committed (ab = -.29, 95% CI [-.51, -.11], κ2 = .07). Neither pragmatic language abnormalities nor rigidity were associated with mediators or outcomes. Conclusions: Aloof traits in unfamiliar roommates were associated with relationship quality after 10 weeks of cohabitation, with behaviors of warmth mediating some of these effects. Roommates more similar on aloof traits, including those both high on aloofness, were more satisfied, suggesting that compatibility on this BAP feature may be particularly relevant to relationship satisfaction. Despite constituting an additional social BAP trait, pragmatic language abnormalities were not associated with relationship satisfaction. This suggests that not all social BAP traits are equally predictive of relationship outcomes, with social motivation (aloofness) more predictive than social competence (pragmatic language abnormalities).
    The International Meeting for Autism Research; 05/2015
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    • "Recently, the NIMH Research Criteria Project suggested that cognition should be one of five core research domains in the field of psychiatric diseases (Morris and Cuthbert, 2012). SCZ and BD are highly heritable disorders (Lichtenstein et al., 2009) with complex genetic and environmental interactions involved (Burmeister et al., 2008). Several lines of research indicate that the immune system may be involved in these interactions (Kinney et al., 2010) and it has been suggested that mononuclear phagocyte cells including microglial cells may play a key role in their pathogenesis. "
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    ABSTRACT: The mechanisms underlying cognitive impairment in schizophrenia and bipolar disorders are largely unknown. Immune abnormalities have been found in both disorders, and inflammatory mediators may play roles in cognitive function. We investigated if inflammatory markers are associated with general cognitive abilities. Participants with schizophrenia spectrum (N=121) and bipolar spectrum (N=111) disorders and healthy controls (N=241) were included. General intellectual abilities were assessed using the Wechsler Abbreviated Scale of Intelligence (WASI). Serum concentrations of the following immune markers were measured: Soluble tumor necrosis factor receptor 1 (sTNF-R1), interleukin 1 receptor antagonist (IL-1Ra), osteoprotegerin, von Willebrand factor, C-reactive protein, interleukin-6 and CD40 ligand. After adjusting for age, sex and diagnostic group, significant negative associations with general cognitive function were found for sTNF-R1 (p=2×10(-5)), IL-1Ra (p=0.002) and sCD40 ligand (p=0.003). Among patients, the associations remained significant (p=0.006, p=0.005 and p=0.02) after adjusting for possible confounders including education, smoking, psychotic and affective symptoms, body mass index, cortisol, medication and time of blood sampling. Subgroup analysis, showed that general cognitive abilities were significantly associated with IL-1Ra and sTNF-R1 in schizophrenia patients, with sCD40L and IL-1Ra in bipolar disorder patients and with sTNF-R1 in healthy controls. The study shows significant negative associations between inflammatory markers and general cognitive abilities after adjusting for possible confounders. The findings strongly support a role for inflammation in the neurophysiology of cognitive impairment. Copyright © 2015. Published by Elsevier B.V.
    Schizophrenia Research 05/2015; 165(2-3). DOI:10.1016/j.schres.2015.04.004 · 3.92 Impact Factor
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