ABSTRACT
Though a growing body of preclinical and translational research is illuminating a biological basis for resilience to stress, little is known about the genetic basis of psychological resilience in humans. We conducted genomewide association studies (GWAS) of self-assessed (by questionnaire) and outcome-based (incident mental disorders from pre- to post-deployment) resilience among European (EUR) ancestry soldiers in the Army Study To Assess Risk and Resilience in Servicemembers (STARRS). Self-assessed resilience (N=11,492) was found to have significant common-variant heritability (h2=0.162, se=0.050, p=5.37e-4), and to be significantly negatively genetically correlated with neuroticism (rg= −0.388, p=0.0092). GWAS results from the EUR soldiers revealed a genomewide significant locus (4 SNPs in LD; top SNP: rs4260523, p=5.654e-09) on an intergenic region on Chr 4 upstream from DCLK2 (Doublecortin-Like Kinase 2), a member of the doublecortin (DCX) family of kinases that promote survival and regeneration of injured neurons. A second gene, KLHL36 (Kelch Like Family Member 36) was detected at gene-wise genomewide significance (p=1.89e-06). A polygenic risk score derived from the self-assessed resilience GWAS was not significantly associated with outcome-based resilience. In very preliminary results, genomewide significant association with outcome-based resilience was found for one locus (top SNP: rs12580015) on Chr 12 downstream from SLC15A5 (solute carrier family 15 member 5) in the small group (N=581) of subjects exposed to the highest level of deployment stress. The further study of genetic determinants of resilience has the potential to illuminate the molecular bases of stress-related psychopathology and potentially point to new avenues for therapeutic intervention.
Acknowledgments
The Army STARRS Team consists of:
Co-Principal Investigators: Robert J. Ursano, MD (Uniformed Services University of the Health Sciences) and Murray B. Stein, MD, MPH (University of California San Diego and VA San Diego Healthcare System)
Site Principal Investigators: Steven Heeringa, PhD (University of Michigan), James Wagner, PhD (University of Michigan) and Ronald C. Kessler, PhD (Harvard Medical School) Army liaison/consultant: Kenneth Cox, MD, MPH (USAPHC (Provisional)) Other team members: Pablo A. Aliaga, MS (Uniformed Services University of the Health Sciences); COL David M. Benedek, MD (Uniformed Services University of the Health Sciences); Susan Borja, PhD (NIMH); Tianxi Cai, ScD (Harvard School of Public Health); Laura Campbell-Sills, PhD (University of California San Diego); Carol S. Fullerton, PhD (Uniformed Services University of the Health Sciences); Nancy Gebler, MA (University of Michigan); Robert K. Gifford, PhD (Uniformed Services University of the Health Sciences); Paul E. Hurwitz, MPH (Uniformed Services University of the Health Sciences); Kevin Jensen, PhD (Yale University); Kristen Jepsen, PhD (University of California San Diego); Tzu-Cheg Kao, PhD (Uniformed Services University of the Health Sciences); Lisa Lewandowski-Romps, PhD (University of Michigan); Holly Herberman Mash, PhD (Uniformed Services University of the Health Sciences); James E. McCarroll, PhD, MPH (Uniformed Services University of the Health Sciences); Colter Mitchell, PhD (University of Michigan); James A. Naifeh, PhD (Uniformed Services University of the Health Sciences); Tsz Hin Hinz Ng, MPH (Uniformed Services University of the Health Sciences); Caroline Nievergelt, PhD (University of California San Diego); Nancy A. Sampson, BA (Harvard Medical School); CDR Patcho Santiago, MD, MPH (Uniformed Services University of the Health Sciences); Ronen Segman, MD (Hadassah University Hospital, Israel); Alan M. Zaslavsky, PhD (Harvard Medical School); and Lei Zhang, MD (Uniformed Services University of the Health Sciences).