The neuronal transporter gene SLC6A15 confers risk to major depression.

Martin A Kohli, Susanne Lucae, Philipp G Saemann, Mathias V Schmidt, Ayse Demirkan, Karin Hek, Darina Czamara, Michael Alexander, Daria Salyakina, Stephan Ripke, David Hoehn, Michael Specht, Andreas Menke, Johannes Hennings, Angela Heck, Christiane Wolf, Marcus Ising, Stefan Schreiber, Michael Czisch, Marianne B Müller, Manfred Uhr, Thomas Bettecken, Albert Becker, Johannes Schramm, Marcella Rietschel, Wolfgang Maier, Bekh Bradley, Kerry J Ressler, Markus M Nöthen, Sven Cichon, Ian W Craig, Gerome Breen, Cathryn M Lewis, Albert Hofman, Henning Tiemeier, Cornelia M van Duijn, Florian Holsboer, Bertram Müller-Myhsok, Elisabeth B Binder
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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.