A genome-wide association study of post-traumatic stress disorder identifies the retinoid-related orphan receptor alpha (RORA) gene as a significant risk locus

Abstract

We describe the results of the first genome-wide association study of PTSD performed using trauma-exposed white non-Hispanic participants from a cohort of veterans and their intimate partners (295 cases and 196 controls). Several SNPs yielded evidence of association. One SNP (rs8042149), located in the retinoid-related orphan receptor alpha gene (RORA), reached genome-wide significance. Nominally significant associations were observed for other RORA SNPs in two African American replication samples—one from the veteran cohort (43 cases and 41 controls) and another independent cohort (100 cases and 421 controls). However, only the associated SNP from the veteran African American replication sample survived gene-level multiple testing correction. RORA has been implicated in prior GWAS studies of psychiatric disorders and is known to play an important role in neuroprotection and other behaviorally-relevant processes. This study represents an important step towards identifying the genetic underpinnings of PTSD.

Genomic predictors of combat stress vulnerability and resilience in U.S. Marines: A genome-wide association study across multiple ancestries implicates PRTFDC1 as a potential PTSD gene

“…This finding was supported by a smaller, independent VA cohort including 491 EA veterans and their intimate partners with 313 lifetime-PTSD cases (Logue et al, 2013a). PRTFDC1 is a ∼100 kb long gene located on chromosome 10p12.…”

“…In regards to our inability to replicate previous findings from GWASs, which met the stringent genome-wide significant thresholds, power calculations indicated that MRS was sufficiently powered for a replication of rs8042149 in RORA (Logue et al, 2013a) for EA's (OR 2.1 in original study and 1.22 in MRS; data not shown). However, the association of rs6812849 in TLL1 (Xie et al, 2013) was originally detected in a larger study, and rs10170218 in LINC01090 (Guffanti et al, 2013) was originally found in an all-female AA cohort, which was also larger than the all-male MRS AA cohort, and MRS findings for these genes remain inconclusive.…”

“…Sample ascertainment, characterization, genotyping, and data cleaning methods used have been described elsewhere in detail (Logue et al, 2013a). Briefly, the sample is a subset of a cohort of military veterans and their intimate partners ascertained from two studies performed at U.S. Department of Veterans Affairs (VA) medical centers.…”

“…Most of the genes were identified in candidate gene studies, but LINC01090 (Guffanti et al, 2013), RORA (Logue et al, 2013a), and TLL1 (Xie et al, 2013) came from recent GWASs, thus meeting the stricter level for genome-wide significance in the original studies. We first investigated the specific SNP reported in the literature and found that none of the reported SNPs were nominally significant in the MRS EA or AA subgroups.…”

“…The first study on European American (EA) military veterans and their intimate partners identified the retinoid-related orphan receptor alpha (RORA) as a potential PTSD gene (Logue et al, 2013a). The second study, including EAs recruited for substance abuse, identified the Tolloid-Like 1 gene (TLL1) (Xie et al, 2013), and the third, a study in primarily African American women, implicated a lincRNA (LINC01090, alias AC068718.1) as a risk factor for PTSD (Guffanti et al, 2013).…”