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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

04/2011

Volume

70

Pages

252 - 265

Addresses

Max Planck Institute of Psychiatry, D-80804 Munich, Germany.

Keywords

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