PTSD-Genetics Study

This is a longitudinal study of patients who are being followed at The Johns Hopkins Burn Center after sustaining severe burns. It will add genetic and neuroendocrine testing to a battery of psychometric, demographic and medical measurements that are currently being collected in patients following severe burn trauma. Genetic methods will include microarray methodology with a 1,536 SNP array that contains all of the SNPs that have been previously evaluated in PTSD, as well as more than 1,000 SNPs associated with genes that have been implicated in stress, substance abuse, and depression. In addition to SNP analyses, we will genotype patients for three candidate genes that have been implicated in PTSD or stress: 5HTTLPR, FKBP5, and NPY. The dexamethasone suppression test at the time of discharge from the burn unit will be employed to evaluate function of the glucocorticoid system  and its relationship to subsequent PTSD or genetic polymorphisms. We will explore the potential role and/or relationships between personality features, childhood trauma, alcohol and substance abuse, comorbid psychiatric diagnoses and PTSD. It is hypothesized that one or several of the SNPs included on the microarray and/or candidate genes that are evaluated will interact with psychosocial and environmental variables and will be associated with increased risk for PTSD.

Safety, Meaning, Activation, and Relaxation Training (SMART)

Burns are painful, life-threatening and disfiguring. Severe psychological distress, pain and sleep disturbance are among the most common, enduring, and disabling of secondary complications, but no evidence-based treatments exist for these complex problems in the acute burn-care setting. The current study is a randomized, controlled effectiveness trial comparing a focused cognitive-behavioral therapy program (SMART) to supportive counseling.

Family and Genetic Studies of OCD

Principal Investigator: Gerald Nestadt, M.D., M.P.H.
The goal of this research program is to elucidate the causes and pathophysiology of obsessive-compulsive disorder (OCD).  The program was initiated in the 1990’s to investigate the genetic etiology of OCD. 

In the OCD Family Study (1996-2001), we evaluated over 800 individuals in 153 families. We found the occurrence of OCD to be six times greater in relatives of OCD cases than in relatives of the control group. Other anxiety disorders, especially agoraphobia and generalized anxiety disorder, also were more prevalent in case families. Segregation analysis provided evidence that genes of major effect are involved in OCD. 

In the OCD Collaborative Genetics Study (2001-2007), we directed a genetics study of OCD in collaboration with five other academic centers in the United States. The collaboration diagnostically evaluated and collected DNA samples from over 200 affected sibling pairs, and completed the first large genome-wide genetic linkage scan of OCD. We found evidence of genetic linkage of OCD to regions on chromosomes 1, 3, 6, 7, and 15. We also found intrafamilial correlation of factor dimensions, especially hoarding behavior, in OCD families.  In addition, we found significant linkage of compulsive hoarding behavior to a region on chromosome 14. We have been following up these findings with fine mapping of these regions and family-based association studies of functional candidate genes.  This research has been funded by grants from the National Institutes of Health, the OCD Foundation, and the James E. Marshall OCD Foundation.

In the OCD Collaborative Genetics Association Study (2007-2012), we and our collaborators at five other academic centers interviewed, and collected DNA samples from, 2000 individuals with OCD and their parents.  We conducted a genome-wide association study to identify even smaller chromosomal regions associated with OCD.  Our most significant finding was for a genetic marker on chromosome 9, near the protein tyrosine phosphatase receptor type D gene (PTPRD). This gene is involved in the differentiation of glutamatergic synapses (Molecular Psychiatry, 2015).

Currently, in collaboration with Dr. David Goldstein’s laboratory at Columbia University, we are conducting exome sequencing on OCD-affected individuals and their unaffected parents, in order to identify rare (de novo) genetic variants associated with OCD.  Our groups also are conducting whole genome sequencing of families with multiple-affected relatives, in order to identify rare genetic variants strongly predisposing to some types of OCD.

In addition, we are using questionnaires and a computer-based task to explore uncertainty and decision-making in OCD and other disorders.

Our research continues to be funded by the National Institute of Mental Health (NIMH), and the James E. Marshall OCD Foundation.