This collaborative R01 involves three sites: New York State Psychiatric Institute/Research Foundation for Mental Hygiene, Inc., in New York City, USA (Mann), McGill University in Montreal, Canada (Turecki) and University of Munich, Germany (Rujescu) to examine the complex genetic basis of suicidal behavior. We have contributed to the original observations showing that suicide and nonfatal suicide attempts have biologic changes that are distinct from those of major psychiatric disorders that underlie suicide such as major depressive disorder or bipolar disorder. We have reported candidate gene associations that are independently associated with mood disorders or with suicide attempts. We believe the field is ready for a major effort to survey the genome to seek genes associated with suicidal behavior that are independent of the major psychiatric illnesses. We have developed and tested a potential predictive stress-diathesis model of suicidal behavior derived from a comprehensive assessment of risk factors. Depressed individuals with prominent (1) pessimism and (2) severity of life-time aggression/impulsivity are at greater risk for suicidal behavior and the effects are additive. These clinical phenotypic components can be measured in the field in patients and suicides. We now propose to use genome-wide screens to identify candidate genes and conserved haplotype blocks within those genes 4000 cases that span the higher severity range of suicidal behavior, namely completed suicide and attempted suicide compared to both psychiatrically matched controls and to healthy volunteers. We have data on Axis I and Axis II diagnoses and data on lifetime aggression scores and current severity of depression to permit assessment of these potential etiological factors and potential behavioral endophenotypes. We have data on childhood reported histories of physical or sexual abuse which will be a focus for an exploratory gene-early environment interaction analysis. Causal SNPs will be further identified by sequencing the most promising gene segments.
The predisposition to suicidal behavior is substantially determined by genetic factors independent of those associated with major psychiatric disorders. This study will screen the genome in the largest collection of samples ever assembled for such a study of suicidal behavior in order to identify the responsible genes.
|Yin, Honglei; Galfalvy, Hanga; Pantazatos, Spiro P et al. (2016) GLUCOCORTICOID RECEPTOR-RELATED GENES: GENOTYPE AND BRAIN GENE EXPRESSION RELATIONSHIPS TO SUICIDE AND MAJOR DEPRESSIVE DISORDER. Depress Anxiety 33:531-540|
|Yin, Honglei; Pantazatos, Spiro P; Galfalvy, Hanga et al. (2016) A pilot integrative genomics study of GABA and glutamate neurotransmitter systems in suicide, suicidal behavior, and major depressive disorder. Am J Med Genet B Neuropsychiatr Genet 171B:414-426|
|Pantazatos, Spiro P; Andrews, Stuart J; Dunning-Broadbent, Jane et al. (2015) Isoform-level brain expression profiling of the spermidine/spermine N1-Acetyltransferase1 (SAT1) gene in major depression and suicide. Neurobiol Dis 79:123-34|
|Haghighi, Fatemeh; Xin, Yurong; Chanrion, Benjamin et al. (2014) Increased DNA methylation in the suicide brain. Dialogues Clin Neurosci 16:430-8|
|Mann, J John (2013) The serotonergic system in mood disorders and suicidal behaviour. Philos Trans R Soc Lond B Biol Sci 368:20120537|
|Galfalvy, Hanga; Zalsman, Gil; Huang, Yung-Yu et al. (2013) A pilot genome wide association and gene expression array study of suicide with and without major depression. World J Biol Psychiatry 14:574-82|
|Mann, J J; Currier, D M (2010) Stress, genetics and epigenetic effects on the neurobiology of suicidal behavior and depression. Eur Psychiatry 25:268-71|