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Major depression (MD) is one of the most prevalent psychiatric disorders and a leading cause of loss in work productivity. A combination of genetic and environmental risk factors probably contributes to MD. We present data from a genome-wide association study revealing a neuron-specific neutral amino acid transporter (SLC6A15) as a susceptibility gene for MD. Risk allele carrier status in humans and chronic stress in mice were associated with a downregulation of the expression of this gene in the hippocampus, a brain region implicated in the pathophysiology of MD. The same polymorphisms also showed associations with alterations in hippocampal volume and neuronal integrity. Thus, decreased SLC6A15 expression, due to genetic or environmental factors, might alter neuronal circuits related to the susceptibility for MD. Our convergent data from human genetics, expression studies, brain imaging, and animal models suggest a pathophysiological mechanism for MD that may be accessible to drug targeting.

Original publication

DOI

10.1016/j.neuron.2011.04.005

Type

Journal article

Journal

Neuron

Publication Date

28/04/2011

Volume

70

Pages

252 - 265

Keywords

Adult, Amino Acid Transport Systems, Neutral, Analysis of Variance, Animals, Aspartic Acid, Chromosomes, Human, Pair 12, Depressive Disorder, Major, Disease Models, Animal, Female, Gene Expression Regulation, Gene Frequency, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Germany, Hippocampus, Humans, Linkage Disequilibrium, Magnetic Resonance Imaging, Magnetic Resonance Spectroscopy, Male, Meta-Analysis as Topic, Mice, Middle Aged, Nerve Tissue Proteins, Polymorphism, Single Nucleotide, RNA, Messenger, Risk Factors, Stress, Psychological, Tritium, United Kingdom