The Psychiatric Genomics Consortium Posttraumatic Stress Disorder Workgroup: Posttraumatic Stress Disorder Enters the Age of Large-Scale Genomic Collaboration

Abstract

The development of posttraumatic stress disorder (PTSD) is influenced by genetic factors. Although there have been some replicated candidates, the identification of risk variants for PTSD has lagged behind genetic research of other psychiatric disorders such as schizophrenia, autism, and bipolar disorder. Psychiatric genetics has moved beyond examination of specific candidate genes in favor of the genome-wide association study (GWAS) strategy of very large numbers of samples, which allows for the discovery of previously unsuspected genes and molecular pathways. The successes of genetic studies of schizophrenia and bipolar disorder have been aided by the formation of a large-scale GWAS consortium: the Psychiatric Genomics Consortium (PGC). In contrast, only a handful of GWAS of PTSD have appeared in the literature to date. Here we describe the formation of a group dedicated to large-scale study of PTSD genetics: the PGC-PTSD. The PGC-PTSD faces challenges related to the contingency on trauma exposure and the large degree of ancestral genetic diversity within and across participating studies. Using the PGC analysis pipeline supplemented by analyses tailored to address these challenges, we anticipate that our first large-scale GWAS of PTSD will comprise over 10 000 cases and 30 000 trauma-exposed controls. Following in the footsteps of our PGC forerunners, this collaboration-of a scope that is unprecedented in the field of traumatic stress-will lead the search for replicable genetic associations and new insights into the biological underpinnings of PTSD.

Figure 1

A comparison of ancestral diversity in (a) representative Psychiatric Genomics Consortium (PGC) samples of primarily European ancestry and (b) representative PGC–PTSD samples. Key: mrsa, mrsb—subsets (a and b) of the Marine Resilience Study (Nievergelt); gtpx—Grady Trauma Project (Ressler); gsdx—Genetics of Substance Dependence (Gelernter); fscd—Family Studies of Cocaine Dependence (Bierut); dnhs—Detroit Neighborhood Health Study (Aiello); cogb, coga—subsets (a and b) of the COGEND study (Bierut); Note that African American refers to subjects from the USA who typically have a mix of African and European ancestry, whereas African Ancestry refers to subjects from Africa without admixed ancestry. PTSD, posttraumatic stress disorder.

Figure 2

Effect size necessary to have 80% power for case-control and quantitative-trait association analyses demonstrating the relation between increasing sample size and ability to detect loci of smaller effect sizes. Key: calculated assuming PTSD prevalence of 15%, additive model, a type I error rate of 5 × 10⁻⁸, and perfect LD between marker and trait allele for MAF>5%). Calculations were based on a 1 : 3 PTSD case-control ratio or quantitative traits such as PTSD symptoms. PTSD, posttraumatic stress disorder.