Meyer-Lindenberg A, Weinberger DR. Intermediate phenotypes and genetic mechanisms of psychiatric disorders. Nat Rev Neurosci 7: 818-827

Unit for Systems Neuroscience in Psychiatry, Clinical Brain Disorders Branch, National Institute for Mental Health, National Institutes of Health, 9000 Rockville Pike, Bethesda, Maryland 20892, USA.
Nature reviews Neuroscience (Impact Factor: 31.43). 11/2006; 7(10):818-27. DOI: 10.1038/nrn1993
Source: PubMed


Genes are major contributors to many psychiatric diseases, but their mechanisms of action have long seemed elusive. The intermediate phenotype concept represents a strategy for characterizing the neural systems affected by risk gene variants to elucidate quantitative, mechanistic aspects of brain function implicated in psychiatric disease. Using imaging genetics as an example, we illustrate recent advances, challenges and implications of linking genes to structural and functional variation in brain systems related to cognition and emotion.

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    • "Dopamine effects on PFC function follow an ''inverted U-shaped'' curve, where both deficient and excessive dopamine activity predicting impaired PFC function [6] [7]. Moving beyond the dopamine hypothesis, a critical role of dopamine modulation by genetic polymorphisms in PFC function and psychiatric disorders has been vigorously investigated [8]. Among these, there has been extensive interest in the effect of the catechol-O-methyltransferase (COMT) gene on neuropsychological functions and phenotypes for decades [9] [10]. "
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    ABSTRACT: Higher cognitive performance, maintenance of mental health and psychological well-being require adequate prefrontal cortex (PFC) function. “Inverted U-shaped” dopamine model indicates optimal PFC dopamine level is important to attain its function while high or low levels have adverse effects. Catechol-O-methyltransferase (COMT) and methylenetetrahydrofolate reductase (MTHFR) may be involved in this complex non-linear PFC dopamine regulation. We addressed whether genetic variation reflecting COMT and MTHFR activities can explain the inter-individual mental health differences in healthy Japanese men (n = 188). The mental health was measured by Mental Health Inventory (MHI)-5 score. The rs4633–rs4818–rs4680 haplotypes were used to represent the multilevel COMT activities, while for MTHFR, the functional single polymorphism, rs1801133 (C677T), was used. We examined the effectiveness of haplotype-based association analysis of COMT on mental health together with studying its interaction with MTHFR-C677T. As a result, the relation between activity-ranked COMT genotype and MHI-5 score showed a tendency to fit into an “inverted U-shaped” quadratic curve (P = 0.054). This curvilinear correlation was significant in the subjects with MTHFR-CC (P < 0.001), but not with MTHFR T-allele carriers (P = 0.793). Our pilot study implies a potential influence of COMT and MTHFR genotypic combination on normal variation of mental health.
    Biochemical and Biophysical Research Communications 09/2014; 451(4). DOI:10.1016/j.bbrc.2014.08.023 · 2.30 Impact Factor
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    • "Imaging genetics research provides an unprecedented opportunity for studying interactions among genes, brain and behavior in humans. For example, studies have explored associations of common genetic polymorphisms, including those related to catechol-O-methyl transferase (COMT), monoamine oxidase A (MAOA) and serotonin transporter length polymorphism (5-HTTLPR/SLC6A4), with brain structure and function [1]. Similarly, examination of rare, atypical duplications and deletions associated with disorders such as Williams-Beuren syndrome (WS) can further illuminate our understanding of gene-brain-behavior relationships [2]. "
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    ABSTRACT: In this study of eight rare atypical deletion cases with Williams-Beuren syndrome (WS; also known as 7q11.23 deletion syndrome) consisting of three different patterns of deletions, compared to typical WS and typically developing (TD) individuals, we show preliminary evidence of dissociable genetic contributions to brain structure and human cognition. Univariate and multivariate pattern classification results of morphometric brain patterns complemented by behavior implicate a possible role for the chromosomal region that includes: 1) GTF2I/GTF2IRD1 in visuo-spatial/motor integration, intraparietal as well as overall gray matter structures, 2) the region spanning ABHD11 through RFC2 including LIMK1, in social cognition, in particular approachability, as well as orbitofrontal, amygdala and fusiform anatomy, and 3) the regions including STX1A, and/or CYLN2 in overall white matter structure. This knowledge contributes to our understanding of the role of genetics on human brain structure, cognition and pathophysiology of altered cognition in WS. The current study builds on ongoing research designed to characterize the impact of multiple genes, gene-gene interactions and changes in gene expression on the human brain.
    PLoS ONE 08/2014; 9(8):e104088. DOI:10.1371/journal.pone.0104088 · 3.23 Impact Factor
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    • "They have, for example, an impact on the association between dorsolateral prefrontal cortex and hippocampus or striatum. This hypothesis is supported by the following example; COMT has been consistently associated with prefrontal regulation of dopamine, which indicates a risk of schizophrenia due to the reduced signal in the prefrontal cortex [23]. However, inconsistent results were obtained when studying the direct link between COMT and schizophrenia [23]. "
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    ABSTRACT: Background Tobacco use disorder (TUD), defined as the use of tobacco to the detriment of a person’s health or social functioning, is associated with various disorders. We hypothesized that mutual variation in genes may partly explain this link. The aims of this study were to make a non-exhaustive inventory of the disorders using (partially) the same genetic pathways as TUD, and to describe the genetic similarities between TUD and the selected disorders. Methods We developed a 3 stage approach: (i) selection of genes influencing TUD using Gene2Mesh and Ingenuity Pathway Analysis (IPA), (ii) selection of disorders associated with the selected genes using IPA and (iii) genetic similarities between disorders associated with TUD using Jaccard distance and cluster analyses. Results Fourteen disorders and thirty-two genes met our inclusion criteria. The Jaccard distance between pairs of disorders ranged from 0.00 (e.g. oesophageal cancer and malignant hypertension) to 0.45 (e.g. bladder cancer and addiction). A lower number in the Jaccard distance indicates a higher similarity between the two disorders. Two main clusters of genetically similar disorders were observed, one including coexisting disorders (e.g. addiction and alcoholism) and the other one with the side-effects of smoking (e.g. gastric cancer and malignant hypertension). Conclusions This exploratory study partly explains the potential genetic components linking TUD to other disorders. Two principle clusters of disorders were observed (i) coexisting disorders of TUD and (ii) side-effects of TUD disorders. A further deepening of this observation in a real life study should allow strengthening this hypothesis.
    BMC Medical Genetics 07/2014; 15(1):85. DOI:10.1186/1471-2350-15-85 · 2.08 Impact Factor
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