title: Genetic risk mechanisms of posttraumatic stress disorder in the human brain.
abstract: Posttraumatic stress disorder (PTSD) follows exposure to a traumatic event in susceptible individuals. Recently, genome-wide association studies have identified a number of genetic sequence variants that are associated with the risk of developing PTSD. To follow up on identifying the molecular mechanisms of these risk variants, we performed genotype to RNA sequencing-derived quantitative expression (whole gene, exon, and exon junction levels) analysis in the dorsolateral prefrontal cortex (DLPFC) of normal postmortem human brains. We further investigated genotype-gene expression associations within the amygdala in a smaller independent RNA sequencing (Genotype-Tissue Expression [GTEx]) dataset. Our DLPFC analyses identified significant expression quantitative trait loci (eQTL) associations for a "candidate" PTSD risk SNP rs363276 and the expression of two genes: SLC18A2 and PDZD8, where the PTSD risk/minor allele T was associated with significantly lower levels of gene expression for both genes, in the DLPFC. These eQTL associations were independently confirmed in the amygdala from the GTEx database. Rs363276 "T" carriers also showed significantly increased activity in the amygdala during an emotional face-matching task in healthy volunteers. Taken together, our preliminary findings in normal human brains represent a tractable approach to identify mechanisms by which genetic variants potentially increase an individual's risk for developing PTSD. © 2016 Wiley Periodicals, Inc.
authors: Lieber Institute for Brain Development, Baltimore, Maryland.
authors: Rahul A
authors: RA
authors: Bharadwaj
authors: Lieber Institute for Brain Development, Baltimore, Maryland.|Department of Mental Health, Johns Hopkins University Bloomberg School of Public Health, Baltimore, Maryland.|Department of Biostatistics, Johns Hopkins University Bloomberg School of Public Health, Baltimore, Maryland.
authors: Andrew E
authors: AE
authors: Jaffe
authors: Lieber Institute for Brain Development, Baltimore, Maryland.
authors: Qiang
authors: Q
authors: Chen
authors: Lieber Institute for Brain Development, Baltimore, Maryland.
authors: Amy
authors: A
authors: Deep-Soboslay
authors: Lieber Institute for Brain Development, Baltimore, Maryland.
authors: Aaron L
authors: AL
authors: Goldman
authors: Lieber Institute for Brain Development, Baltimore, Maryland.
authors: Michelle I
authors: MI
authors: Mighdoll
authors: Lieber Institute for Brain Development, Baltimore, Maryland.
authors: John A
authors: JA
authors: Cotoia
authors: Lieber Institute for Brain Development, Baltimore, Maryland.
authors: Anna C
authors: AC
authors: Brandtjen
authors: Lieber Institute for Brain Development, Baltimore, Maryland.
authors: JooHeon
authors: J
authors: Shin
authors: Lieber Institute for Brain Development, Baltimore, Maryland.|Department of Neurology, Johns Hopkins School of Medicine, Baltimore, Maryland.|Department of Psychiatry, Johns Hopkins School of Medicine, Baltimore, Maryland.
authors: Thomas M
authors: TM
authors: Hyde
authors: Lieber Institute for Brain Development, Baltimore, Maryland.|Departments of Neurology and Radiology, Johns Hopkins School of Medicine, Baltimore, Maryland.
authors: Venkata S
authors: VS
authors: Mattay
authors: Lieber Institute for Brain Development, Baltimore, Maryland.|Department of Psychiatry, Johns Hopkins School of Medicine, Baltimore, Maryland.|Department of Neuroscience and Institute of Genetic Medicine, Johns Hopkins School of Medicine, Baltimore, Maryland.
authors: Daniel R
authors: DR
authors: Weinberger
authors: Lieber Institute for Brain Development, Baltimore, Maryland.|Department of Psychiatry, Johns Hopkins School of Medicine, Baltimore, Maryland.
authors: Joel E
authors: JE
authors: Kleinman
mesh_terms: D000328:Adult; D000368:Aged; D001921:Brain / Q000473:pathology*; D019175:DNA Methylation / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D014644:Genetic Variation / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D040641:Quantitative Trait Loci / Q000235:genetics*; D012307:Risk Factors; D013313:Stress Disorders, Post-Traumatic / Q000235:genetics* / Q000473:pathology*; D055815:Young Adult
keywords: amygdala; dorsolateral prefrontal cortex (DLPFC); expression quantitative trait loci (eQTL); face-matching task (FMT); functional magnetic resonance imaging (fMRI); methylation quantitative trait loci (meQTL); postmortem human brain; posttraumatic stress disorder (PTSD)