title: A novel locus in the oxidative stress-related gene ALOX12 moderates the association between PTSD and thickness of the prefrontal cortex.
abstract: Oxidative stress has been implicated in many common age-related diseases and is hypothesized to play a role in posttraumatic stress disorder (PTSD)-related neurodegeneration (Miller and Sadeh, 2014). This study examined the influence of the oxidative stress-related genes ALOX 12 and ALOX 15 on the association between PTSD and cortical thickness. Factor analyses were used to identify and compare alternative models of the structure of cortical thickness in a sample of 218 veterans. The best-fitting model was then used for a genetic association analysis in White non-Hispanic participants (n=146) that examined relationships between 33 single nucleotide polymorphisms (SNPs) spanning the two genes, 8 cortical thickness factors, and each SNP×PTSD interaction. Results identified a novel ALOX12 locus (indicated by two SNPs in perfect linkage disequilibrium: rs1042357 and rs10852889) that moderated the association between PTSD and reduced thickness of the right prefrontal cortex. A whole-cortex vertex-wise analysis showed this effect to be localized to clusters spanning the rostral middle frontal gyrus, superior frontal gyrus, rostral anterior cingulate cortex, and medial orbitofrontal cortex. These findings illustrate a novel factor-analytic approach to neuroimaging-genetic analyses and provide new evidence for the possible involvement of oxidative stress in PTSD-related neurodegeneration.
authors.affiliation: National Center for PTSD, Behavioral Science Division, VA Boston Healthcare System, Boston, MA, USA; Department of Psychiatry, Boston University School of Medicine, Boston, MA, USA.
authors.forename: Mark W
authors.initials: MW
authors.lastname: Miller
authors.affiliation: National Center for PTSD, Behavioral Science Division, VA Boston Healthcare System, Boston, MA, USA; Department of Psychiatry, Boston University School of Medicine, Boston, MA, USA.
authors.forename: Erika J
authors.initials: EJ
authors.lastname: Wolf
authors.affiliation: National Center for PTSD, Behavioral Science Division, VA Boston Healthcare System, Boston, MA, USA; Department of Psychiatry, Boston University School of Medicine, Boston, MA, USA.
authors.forename: Naomi
authors.initials: N
authors.lastname: Sadeh
authors.affiliation: Research Service, VA Boston Healthcare System, Boston, MA, USA; Biomedical Genetics, Boston University School of Medicine, Boston, MA, USA; Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Logue
authors.affiliation: Department of Psychiatry, Boston University School of Medicine, Boston, MA, USA; Neuroimaging Research for Veterans Center, VA Boston Healthcare System, Boston, MA, USA.
authors.forename: Jeffrey M
authors.initials: JM
authors.lastname: Spielberg
authors.affiliation: National Center for PTSD, Behavioral Science Division, VA Boston Healthcare System, Boston, MA, USA; Department of Psychiatry, Boston University School of Medicine, Boston, MA, USA.
authors.forename: Jasmeet P
authors.initials: JP
authors.lastname: Hayes
authors.affiliation: Department of Psychiatry, Boston University School of Medicine, Boston, MA, USA.
authors.forename: Emily
authors.initials: E
authors.lastname: Sperbeck
authors.affiliation: Pharmacogenomics Analysis Laboratory, Research Service, Central Arkansas Veterans Healthcare System, Little Rock, AR, USA.
authors.forename: Steven A
authors.initials: SA
authors.lastname: Schichman
authors.affiliation: Pharmacogenomics Analysis Laboratory, Research Service, Central Arkansas Veterans Healthcare System, Little Rock, AR, USA.
authors.forename: Angie
authors.initials: A
authors.lastname: Stone
authors.affiliation: Pharmacogenomics Analysis Laboratory, Research Service, Central Arkansas Veterans Healthcare System, Little Rock, AR, USA.
authors.forename: Weleetka C
authors.initials: WC
authors.lastname: Carter
authors.affiliation: Massachusetts Veterans Epidemiology Research and Information Center, VA Boston Healthcare System, Boston, MA, USA.
authors.forename: Donald E
authors.initials: DE
authors.lastname: Humphries
authors.affiliation: Geriatric Research Educational and Clinical Center and Translational Research Center for TBI and Stress Disorders, VA Boston Healthcare System, Boston, MA, USA; Department of Psychiatry, Harvard Medical School, Boston, MA, USA.
authors.forename: William
authors.initials: W
authors.lastname: Milberg
authors.affiliation: Geriatric Research Educational and Clinical Center and Translational Research Center for TBI and Stress Disorders, VA Boston Healthcare System, Boston, MA, USA; Department of Psychiatry, Harvard Medical School, Boston, MA, USA.
authors.forename: Regina
authors.initials: R
authors.lastname: McGlinchey
mesh_terms: D000328:Adult; D001092:Arachidonate 12-Lipoxygenase / Q000235:genetics*; D001093:Arachidonate 15-Lipoxygenase / Q000235:genetics; D005260:Female; D056726:Genetic Association Studies; D006801:Humans; D008297:Male; D008875:Middle Aged; D018384:Oxidative Stress / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D017397:Prefrontal Cortex / Q000473:pathology*; D013313:Stress Disorders, Post-Traumatic / Q000235:genetics* / Q000473:pathology*; D014728:Veterans; D055815:Young Adult
chemical_list: D001092:Arachidonate 12-Lipoxygenase; C476558:ALOX12 protein, human; C515716:ALOX15 protein, human; D001093:Arachidonate 15-Lipoxygenase
keywords: ALOX12; Cortical thickness; Factor analysis; Genetic association analysis; Oxidative stress; Posttraumatic stress disorder