This K08 Mentored Clinical Scientist Development Award proposes to provide advanced research training in the genetics of fear and anxiety disorders for Dr. John M. Hettema, M.D., Ph.D. Dr. Kenneth S. Kendler, M.D., a world renowned researcher in psychiatric genetics, will serve as Dr. Hettema's primary sponsor. The training will take place at the Virginia Institute for Psychiatric and Behavioral Genetics of Virginia Commonwealth University, which provides a rich, stimulating environment for the conduct of training and research. Dr. Hettema proposes to receive training in epidemiology, statistical and molecular genetics, and experimental methods for measuring anxiety-related traits, including psychophysiology and neuroimaging. Specific research objectives include i) examining the stability, reliability, and heritability of self-report measures in anxiety disorders using a longitudinal design; ii) determine the extent to which the high comorbidity observed between the anxiety disorders is determined by genetic and environmental factors shared between them, including specific individual risk factors such as gender, early enviroment, stressful life events, etc.; iii) determine the genetic correlations between neuroticism and the anxiety disorders and the causal relations between them; iv) elucidate the genetic and environmental factors underlying the increased risk for major depression caused by pre-existing anxiety disorders and what effects gender has on this relationship; v) understand the genetic structure of fear conditioning in humans and to what extent this is shared with phobias. In addition, Dr. Hettema intends to apply knowledge gained in training to design pilot studies that incorporate experimentally derived anxiety-related measures from a genetically informative sample of twins from the Virginia Twin Registry, combining this data with the existing database of self-report anxiety measures. This research training plan will allow Dr. Hettema to emerge at the end of the proposal period as an independent researcher in the genetics of anxiety disorders, seeking to extend this work further by combining self-report and experimentally derived anxiety-related measures with linkage and association studies to identify genetic loci and brain mechanisms involved in the anxiety disorders.
| Hettema, John M; An, Seon-Sook; van den Oord, Edwin J C G et al. (2013) Genetic association between RGS1 and internalizing disorders. Psychiatr Genet 23:56-60 |
| Hettema, John M; Kettenmann, Birgit; Ahluwalia, Vishwadeep et al. (2012) Pilot multimodal twin imaging study of generalized anxiety disorder. Depress Anxiety 29:202-9 |
| Middeldorp, Christel M; Vink, Jacqueline M; Hettema, John M et al. (2010) An association between Epac-1 gene variants and anxiety and depression in two independent samples. Am J Med Genet B Neuropsychiatr Genet 153B:214-9 |
| Pham, Xuan; Sun, Cuie; Chen, Xiangning et al. (2009) Association study between GABA receptor genes and anxiety spectrum disorders. Depress Anxiety 26:998-1003 |
| Hettema, John M; An, Seon-Sook; van den Oord, Edwin J C G et al. (2009) Association study of CREB1 with Major Depressive Disorder and related phenotypes. Am J Med Genet B Neuropsychiatr Genet 150B:1128-32 |
| Hettema, J M; An, S S; van den Oord, E J C G et al. (2008) Association study between the serotonin 1A receptor (HTR1A) gene and neuroticism, major depression, and anxiety disorders. Am J Med Genet B Neuropsychiatr Genet 147B:661-6 |
| Hettema, John M; An, Seon-Sook; Bukszar, Jozsef et al. (2008) Catechol-O-methyltransferase contributes to genetic susceptibility shared among anxiety spectrum phenotypes. Biol Psychiatry 64:302-10 |
| Hettema, John M; Annas, Peter; Neale, Michael C et al. (2008) The genetic covariation between fear conditioning and self-report fears. Biol Psychiatry 63:587-93 |
| Hettema, John M; An, Seon-Sook; Neale, Michael C et al. (2008) Lack of association between the amiloride-sensitive cation channel 2 (ACCN2) gene and anxiety spectrum disorders. Psychiatr Genet 18:73-9 |
| Bienvenu, O Joseph; Hettema, John M; Neale, Michael C et al. (2007) Low extraversion and high neuroticism as indices of genetic and environmental risk for social phobia, agoraphobia, and animal phobia. Am J Psychiatry 164:1714-21 |
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