Anxiety Disorders: Flint J

Flint J, Shifman S. · Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK. · Curr Opin Genet Dev. · Pubmed #18657615 No free full text.

Abstract: Animal models of psychiatric diseases are useful tools for screening new drugs and for investigating the mechanisms of those disorders. Despite the difficulties inherent in modelling human psychiatric phenotypes in animals, there has been recent success identifying mutations in mice that give rise to some of the characteristic features of anxiety, depression, schizophrenia, autism, obsessive-compulsive disorder and bipolar disorder. In some cases these models have the additional strength that drugs used to treat the human condition alleviate the symptoms in mice. Robust genetic evidence of the involvement of multiple susceptibility genes in psychiatric disease will enable future studies to move from single-gene models to models with multiple modified loci, with the promise of better representing the complexity of the human diseases.

Flint J. · Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK. · Semin Cell Dev Biol. · Pubmed #12524005 No free full text.

Abstract: Genetic approaches to psychiatric illness need appropriate animal models both for investigating how genetic variants give rise to behavioural disorder and for identifying genes that may be important in human conditions. Yet the relevance of many animal models to psychiatric illness is often not clear. Here I discuss how genetic approaches can be used to validate animal models of anxiety, an approach which is applicable to other animal models. One drawback of genetic validation is the difficulty inherent in identifying the molecular variants that influence the phenotype. I review genetic approaches that have the potential to overcome this problem.

Flint J. · Wellcome Trust Centre for Human Genetics, Roosevelt Drive, Oxford OX3 7BN, United Kingdom. · J Neurobiol. · Pubmed #12486698 No free full text.

Abstract: Behavioral differences between inbred strains of mice and rats have a genetic basis that can now be dissected using quantitative trait locus (QTL) analysis. Over the last 10 years, a large number of genetic loci that influence behavior have been mapped. In this article I review what that information has revealed about the genetic architecture of behavior. I show that most behaviors are influenced by QTL of small effect, each contributing to less than 10% of the variance of a behavioral trait. The small effect of each QTL on behavioral variation suggests that the mutational spectrum is different from that which results in Mendelian disorders. Regions of DNA should be appropriately prioritized to find the molecular variants, for instance by looking at sequences that control the level of gene expression rather than variants in coding regions. While the number of allelic loci that can contribute to a trait is large, this is not necessarily the case: the analysis of selected strains shows that a remarkably small number of QTL can explain the bulk of the genetic variation in behavior. I conclude by arguing that genetic mapping has more to offer than a starting point for positional cloning projects. With advances in multivariate analyses, mapping can also test hypotheses about the psychological processes that give rise to behavioral variation.

Flint J. · Wellcome Trust Centre for Human Genetics, University of Oxford, OX3 7BN, UK. · Curr Biol. · Pubmed #11719235 No free full text.

Abstract: A duplication of part of chromosome 15q, apparently inherited in a non-Mendelian fashion, has been found to be strongly associated with phobic disorders. This unusual genetic mechanism may partly explain the heritability of phobias and other complex traits.

Cotton CH, Flint J, Campbell TG. · Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK. · Nature. · Pubmed #19340021 No free full text.

Abstract: Psychiatric genetics has been hampered by the fact that initially exciting findings from underpowered studies are so often not replicated in larger, more powerful, data sets. Here we show that the claims of Zhou et al. that neuropeptide Y (NPY) diplotype-predicted expression is correlated with trait anxiety (neuroticism) is not replicated in a data set consisting of phenotypically extreme individuals drawn from a large (n = 88,142) non-clinical population. We found no association between NPY diplotype or diplotype-predicted expression and neuroticism. Our reply to Zhou and colleagues forms part of a larger debate (see, for example, http://www.nature.com/news/2008/080709/full/454154a.html) about the efficacy and replicability of candidate driven versus genome wide approaches to psychiatric genetics.

Fullerton JM, Willis-Owen SA, Yalcin B, Shifman S, Copley RR, Miller SR, Bhomra A, Davidson S, Oliver PL, Mott R, Flint J. · Wellcome Trust Centre for Human Genetics, Headington, Oxford, United Kingdom. · Biol Psychiatry. · Pubmed #18083140 No free full text.

Abstract: BACKGROUND: Exploiting synteny between mouse and human disease loci has been proposed as a cost-effective method for the identification of human susceptibility genes. Here we explore its utility in an analysis of a human personality trait, neuroticism, which can be modeled in mice by tests of emotionality. We investigated a mouse emotionality locus on chromosome 1 that contains no annotated genes but abuts four regulators of G protein signaling, one of which (rgs2) has been previously identified as a quantitative trait gene for emotionality. This locus is syntenic with a human region that has been consistently implicated in the genetic aetiology of neuroticism. METHODS: The functional candidacy of 29 murine sequence variants was tested by a combination of gel shift and transient transfection assays. Murine sequences that contained functional variants and exhibited significant cross-species conservation were prioritized for investigation in humans. Genetic association with neuroticism was tested in 1869 high and 2032 low unrelated individuals scored for neuroticism, selected from the extremes of 88,141 people from southwest England. RESULTS: Fifteen sequence variants contributed to variation in the expression of rgs18, the gene lying at the edge of the quantitative trait loci (QTL) interval. There was no evidence of association between neuroticism and single nucleotide polymorphisms (SNPs) lying in the human regions homologous to those of mouse functional variants. One SNP, rs6428058, in a region of sequence conservation 644 kb upstream of RGS18, showed significant association (p = .000631). CONCLUSIONS: It is unlikely that a single variant is responsible for the mouse emotionality locus on chromosome 1. This level of underlying genetic complexity means that although cross-species QTL concordance may be invaluable for the identification of human disease loci, it is unlikely to be as informative in the identification of human disease-causing variants.

Shifman S, Bhomra A, Smiley S, Wray NR, James MR, Martin NG, Hettema JM, An SS, Neale MC, van den Oord EJ, Kendler KS, Chen X, Boomsma DI, Middeldorp CM, Hottenga JJ, Slagboom PE, Flint J. · Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK. · Mol Psychiatry. · Pubmed #17667963 No free full text.

Abstract: We describe a multistage approach to identify single nucleotide polymorphisms (SNPs) associated with neuroticism, a personality trait that shares genetic determinants with major depression and anxiety disorders. Whole genome association with 452 574 SNPs was performed on DNA pools from approximately 2000 individuals selected on extremes of neuroticism scores from a cohort of 88 142 people from southwest England. The most significant SNPs were then genotyped on independent samples to replicate findings. We were able to replicate association of one SNP within the PDE4D gene in a second sample collected by our laboratory and in a family-based test in an independent sample; however, the SNP was not significantly associated with neuroticism in two other independent samples. We also observed an enrichment of low P-values in known regions of copy number variations. Simulation indicates that our study had approximately 80% power to identify neuroticism loci in the genome with odds ratio (OR)>2, and approximately 50% power to identify small effects (OR=1.5). Since we failed to find any loci accounting for more than 1% of the variance, the heritability of neuroticism probably arises from many loci each explaining much less than 1%. Our findings argue the need for much larger samples than anticipated in genetic association studies and that the biological basis of emotional disorders is extremely complex.

Goldacre MJ, Wotton CJ, Yeates D, Seagroatt V, Flint J. · Unit of Health-Care Epidemiology, Dept. of Public Health, University of Oxford, Old Road Campus, Old Road, Oxford, OX3 7LF, UK. · Soc Psychiatry Psychiatr Epidemiol. · Pubmed #17530150 No free full text.

Abstract: BACKGROUND: It has been suggested that the risk of cancer may be higher in people with psychological disorders, like depression and anxiety, than in the general population. AIMS: To determine cancer risk in cohorts of people with depression or anxiety, compared with that in a control cohort. METHOD: Analysis of linked statistical records of hospital admission and mortality. RESULTS: Lung cancer was more common in those with depression (risk ratio 1.36, 95% confidence intervals 1.19-1.54) or anxiety (1.29, 1.12-1.48) than in others. Excluding lung cancer, the risk ratio for all other cancers combined was 0.98 (0.92-1.04) in the depression cohort and 1.01 (0.95-1.07) in the anxiety cohort. There was a significant association, in the short-term only, between depression, anxiety and the subsequent diagnosis of brain tumours. CONCLUSIONS: With the exception of lung and brain tumours, cancer risk was not increased in people with depression or anxiety.

Keays DA, Tian G, Poirier K, Huang GJ, Siebold C, Cleak J, Oliver PL, Fray M, Harvey RJ, Molnár Z, Piñon MC, Dear N, Valdar W, Brown SD, Davies KE, Rawlins JN, Cowan NJ, Nolan P, Chelly J, Flint J. · Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, OX3 7BN, UK. · Cell. · Pubmed #17218254 links to  free full text

Abstract: The development of the mammalian brain is dependent on extensive neuronal migration. Mutations in mice and humans that affect neuronal migration result in abnormal lamination of brain structures with associated behavioral deficits. Here, we report the identification of a hyperactive N-ethyl-N-nitrosourea (ENU)-induced mouse mutant with abnormalities in the laminar architecture of the hippocampus and cortex, accompanied by impaired neuronal migration. We show that the causative mutation lies in the guanosine triphosphate (GTP) binding pocket of alpha-1 tubulin (Tuba1) and affects tubulin heterodimer formation. Phenotypic similarity with existing mouse models of lissencephaly led us to screen a cohort of patients with developmental brain anomalies. We identified two patients with de novo mutations in TUBA3, the human homolog of Tuba1. This study demonstrates the utility of ENU mutagenesis in the mouse as a means to discover the basis of human neurodevelopmental disorders.

Leygraf A, Hohoff C, Freitag C, Willis-Owen SA, Krakowitzky P, Fritze J, Franke P, Bandelow B, Fimmers R, Flint J, Deckert J. · Laboratory of Molecular Psychiatry, Department of Psychiatry, University of Münster, Münster, Germany. · J Neural Transm. · Pubmed #16736243 No free full text.

Abstract: Rgs2 (regulator of G-protein signalling 2) gene recently was reported as a quantitative trait gene for anxious behaviour in mice and male Rgs2 knockout mice have been shown to be more anxious than wildtype mice. Therefore we investigated four non-coding single nucleotide polymorphisms in a sample of 173 patients with panic disorder and 173 matched controls of German descent. At the genotype level all four SNPs were associated with panic disorder (p = 0.02-0.05). At the haplotype level the strongest association was observed for a haplotype containing SNP3 and SNP 4 (subgroup men and men with agoraphobia: p = 0.01 and 0.03). This points towards a functional polymorphism at the 3' end of the gene. Our results support the hypothesis that variations of the Rgs2 gene play a role also for the development of anxiety in humans.

Surtees PG, Wainwright NW, Willis-Owen SA, Sandhu MS, Luben R, Day NE, Flint J. · Strangeways Research Laboratory and University of Cambridge, Department of Public Health and Primary Care, Worts Causeway, Cambridge CB1 8RN, UK. · J Psychiatr Res. · Pubmed #16497333 No free full text.

Abstract: Recent research has suggested that brain-derived neurotrophic factor (BDNF) may be implicated in the aetiology of mood-related phenotypes. Here we report an investigation of the association between a BDNF coding variant (Val66Met, rs6265) and mood status in a large non-clinical sample of men and women. We genotyped 7389 adult men and women, aged 41-80 years, selected from participants in the European Prospective Investigation into Cancer and Nutrition in Norfolk (EPIC-Norfolk, United Kingdom). Evidence of past year prevalent, lifetime and recurrent episodic major depressive disorder (MDD) and of past year prevalent and lifetime generalised anxiety disorder (GAD), defined by DSM-IV diagnostic criteria, was assessed through questionnaire together with a five-item version of the Mental Health Inventory (MHI-5). A total of 1214 (16.4%) participants reported lifetime MDD and 355 (4.8%) reported lifetime GAD. In this population based study we found no evidence to support an association between the BDNF gene Val66Met polymorphism and mood status.

Surtees PG, Wainwright NW, Willis-Owen SA, Sandhu MS, Luben R, Day NE, Flint J. · No affiliation provided · J Psychiatr Res. · Pubmed #16872631 No free full text.

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