title: The cumulative effect of genetic polymorphisms on depression and brain structural integrity.
abstract: In major depressive disorder (MDD), the need to study multiple-gene effect on brain structure is emerging. Our aim was to assess the effect of accumulation of specific SERT, BDNF and COMT gene functional polymorphisms on brain structure in MDD patients. Seventy-seven MDD patients and 66 controls underwent a clinical assessment, genetic testing and MRI scan. Compared with controls, patients were more BDNF-Val homozygotes, COMT-Met carriers and SERT-L' carriers. Thus, subjects were split into three groups: 1. High-frequency susceptibility polymorphism group (hfSP, subjects with all three SPs); 2. Intermediate-frequency SP group (ifSP, two SPs); and 3. Low-frequency SP group (lfSP, one/none SP). Cortical thickness, volumetry of hippocampus, amygdala and subcortical structures, and white matter (WM) tract integrity were assessed. Compared to controls, hfSP patients showed thinning of the middle frontal cortex bilaterally, left frontal pole, and right lateral occipital cortex, and smaller hippocampal volume bilaterally; and both hfSP and lfSP patient groups showed thinning of the left inferior parietal cortex and reduced WM integrity of the corpus callosum. Compared to patients, hfSP controls showed greater integrity of the fronto-occipital cortices and corpus callosum. We showed that cortical prefrontal and occipital damage of MDD patients is modulated by the SP accumulation, while damage to the parietal cortex and corpus callosum seem to be independent of genetic accumulation. HfSP controls may experience protective mechanisms leading to a preserved integrity of critical cortical and WM regions. Investigating the effect of multiple genes is promising to understand the pathological mechanisms underlying MDD. Hum Brain Mapp 37:2173-2184, 2016. © 2016 Wiley Periodicals, Inc.
authors.affiliation: Institute of Mental Health, Belgrade, Serbia.
authors.forename: Milutin
authors.initials: M
authors.lastname: Kostic
authors.affiliation: Neuroimaging Research Unit, Institute of Experimental Neurology, Division of Neuroscience, San Raffaele Scientific Institute and Vita-Salute San Raffaele University, Milan, Italy.
authors.forename: Elisa
authors.initials: E
authors.lastname: Canu
authors.affiliation: Neuroimaging Research Unit, Institute of Experimental Neurology, Division of Neuroscience, San Raffaele Scientific Institute and Vita-Salute San Raffaele University, Milan, Italy.
authors.forename: Federica
authors.initials: F
authors.lastname: Agosta
authors.affiliation: Institute of Mental Health, Belgrade, Serbia.
authors.forename: Ana
authors.initials: A
authors.lastname: Munjiza
authors.affiliation: Neurology Clinic, Clinical Center of Serbia, Belgrade, Serbia.|School of Medicine, University of Belgrade, Belgrade, Serbia.
authors.forename: Ivana
authors.initials: I
authors.lastname: Novakovic
authors.affiliation: Neurology Clinic, Clinical Center of Serbia, Belgrade, Serbia.
authors.forename: Valerija
authors.initials: V
authors.lastname: Dobricic
authors.affiliation: Neuroimaging Research Unit, Institute of Experimental Neurology, Division of Neuroscience, San Raffaele Scientific Institute and Vita-Salute San Raffaele University, Milan, Italy.
authors.forename: Pilar
authors.initials: P
authors.lastname: Maria Ferraro
authors.affiliation: School of Electrical Engineering, University of Belgrade, Belgrade, Serbia.
authors.forename: Vera
authors.initials: V
authors.lastname: Miler Jerkovic
authors.affiliation: School of Medicine, University of Belgrade, Belgrade, Serbia.
authors.forename: Tatjana
authors.initials: T
authors.lastname: Pekmezovic
authors.affiliation: Institute of Mental Health, Belgrade, Serbia.|School of Medicine, University of Belgrade, Belgrade, Serbia.
authors.forename: Dusica
authors.initials: D
authors.lastname: Lecic Tosevski
authors.affiliation: Neuroimaging Research Unit, Institute of Experimental Neurology, Division of Neuroscience, San Raffaele Scientific Institute and Vita-Salute San Raffaele University, Milan, Italy.|Department of Neurology, Institute of Experimental Neurology, Division of Neuroscience, San Raffaele Scientific Institute and Vita-Salute San Raffaele University, Milan, Italy.
authors.forename: Massimo
authors.initials: M
authors.lastname: Filippi
mesh_terms: D000328:Adult; D001921:Brain / Q000000981:diagnostic imaging*; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics*; D002394:Catechol O-Methyltransferase / Q000235:genetics*; D003865:Major Depressive Disorder / Q000000981:diagnostic imaging* / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing; D066128:Gray Matter / Q000000981:diagnostic imaging; D006801:Humans; D007406:Interview, Psychological; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D020412:Multifactorial Inheritance; D009929:Organ Size; D020641:Polymorphism, Single Nucleotide; D011569:Psychiatric Status Rating Scales; D050486:Serotonin Plasma Membrane Transport Proteins / Q000235:genetics*; D066127:White Matter / Q000000981:diagnostic imaging; D055815:Young Adult
chemical_list: D019208:Brain-Derived Neurotrophic Factor; C493230:SLC6A4 protein, human; D050486:Serotonin Plasma Membrane Transport Proteins; C579455:BDNF protein, human; C588010:COMT protein, human; D002394:Catechol O-Methyltransferase
keywords: accumulation model; cortical thickness; functional polymorphisms; major depression disorder; tractography