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A genome‐wide identified risk variant for PTSD is a methylation quantitative trait locus and confers decreased cortical activation to fearful faces
Author(s) -
Almli Lynn M.,
Stevens Jennifer S.,
Smith Alicia K.,
Kilaru Varun,
Meng Qian,
Flory Janine,
AbuAmara Duna,
Hammamieh Rasha,
Yang Ruoting,
Mercer Kristina B.,
Binder Elizabeth B.,
Bradley Bekh,
Hamilton Steven,
Jett Marti,
Yehuda Rachel,
Marmar Charles R.,
Ressler Kerry J.
Publication year - 2015
Publication title -
american journal of medical genetics part b: neuropsychiatric genetics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.393
H-Index - 126
eISSN - 1552-485X
pISSN - 1552-4841
DOI - 10.1002/ajmg.b.32315
Subject(s) - genome wide association study , epigenetics , single nucleotide polymorphism , snp , genetics , dna methylation , quantitative trait locus , locus (genetics) , allele , psychology , biology , gene , clinical psychology , genotype , gene expression
Genetic factors appear to be highly relevant to predicting differential risk for the development of post‐traumatic stress disorder (PTSD). In a discovery sample, we conducted a genome‐wide association study (GWAS) for PTSD using a small military cohort (Systems Biology PTSD Biomarkers Consortium; SBPBC, N = 147) that was designed as a case‐controlled sample of highly exposed, recently returning veterans with and without combat‐related PTSD. A genome‐wide significant single nucleotide polymorphism (SNP), rs717947, at chromosome 4p15 (N = 147, β = 31.34, P = 1.28 × 10 −8 ) was found to associate with the gold‐standard diagnostic measure for PTSD (the Clinician Administered PTSD Scale). We conducted replication and follow‐up studies in an external sample, a larger urban community cohort (Grady Trauma Project, GTP, N = 2006), to determine the robustness and putative functionality of this risk variant. In the GTP replication sample, SNP rs717947 associated with PTSD diagnosis in females (N = 2006, P = 0.005), but not males. SNP rs717947 was also found to be a methylation quantitative trait locus (meQTL) in the GTP replication sample (N = 157, P = 0.002). Further, the risk allele of rs717947 was associated with decreased medial and dorsolateral cortical activation to fearful faces (N = 53, P < 0.05) in the GTP replication sample. These data identify a genome‐wide significant polymorphism conferring risk for PTSD, which was associated with differential epigenetic regulation and with differential cortical responses to fear in a replication sample. These results may provide new insight into understanding genetic and epigenetic regulation of PTSD and intermediate phenotypes that contribute to this disorder. © 2015 Wiley Periodicals, Inc.