Polygenic risk associated with post-traumatic stress disorder onset and severity

Burook Misganaw,Francis J Doyle,Kerry J Ressler,Susanne Mueller,Duna Abu-Amara,Charles R Marmar,Guia Guffanti,Rachel Yehuda,Adriana Lori,Janine D Flory,Marti Jett

doi:10.1038/s41398-019-0497-3

Abstract

Post-traumatic stress disorder (PTSD) is a psychiatric illness with a highly polygenic architecture without large effect-size common single-nucleotide polymorphisms (SNPs). Thus, to capture a substantial portion of the genetic contribution, effects from many variants need to be aggregated. We investigated various aspects of one such approach that has been successfully applied to many traits, polygenic risk score (PRS) for PTSD. Theoretical analyses indicate the potential prediction ability of PRS. We used the latest summary statistics from the largest published genome-wide association study (GWAS) conducted by Psychiatric Genomics Consortium for PTSD (PGC-PTSD). We found that the PRS constructed for a cohort comprising veterans of recent wars (n = 244) explains a considerable proportion of PTSD onset (Nagelkerke R2 = 4.68%, P = 0.003) and severity (R2 = 4.35%, P = 0.0008) variances. However, the performance on an African ancestry sub-cohort was minimal. A PRS constructed with schizophrenia GWAS also explained a significant fraction of PTSD diagnosis variance (Nagelkerke R2 = 2.96%, P = 0.0175), confirming previously reported genetic correlation between the two psychiatric ailments. Overall, these findings demonstrate the important role polygenic analyses of PTSD will play in risk prediction models as well as in elucidating the biology of the disorder.

Highlights

Post-traumatic stress disorder (PTSD) is a debilitating mental illness that can develop following a traumatic experience, such as combat, sexual assault, or natural disaster[1]
Using the heritability estimate of 30% and an estimated disease prevalence of 8%, the optimal panel trained on an infinite number of samples would have an AUC of a little over 80% (Fig. 1)
Constructing PTSD-polygenic risk score (PRS) from genome-wide association study (GWAS) summary statistics We used the two GWAS summary statistics data from the largest PTSD GWAS study published to date conducted by PGC-PTSD:[17] one performed on European ancestry cohorts and another on African ancestry

Summary

Introduction

Post-traumatic stress disorder (PTSD) is a debilitating mental illness that can develop following a traumatic experience, such as combat, sexual assault, or natural disaster[1]. It occurs in ~10% of those experiencing severe trauma, with a lifetime incidence rate of 6.8−8% in the US general public[2,3] and up to 15% among Operation Enduring Freedom and Operation Iraqi Freedom (OEF/ OIF) veterans[4,5]. Variation in patients’ willingness to self-disclose, as well as highly heterogeneous symptom presentations and severity levels of PTSD6, make accurate and timely diagnosis challenging. Despite an international effort studying military and civilian cohorts where many molecular layers and modalities were investigated[13,14,15,16], there are, as of yet, no validated blood-based PTSD biomarker panels

Methods

Results

Conclusion