The Neuronal Transporter Gene SLC6A15 Confers Risk to Major Depression

Max Planck Institute of Psychiatry, D-80804 Munich, Germany.
Neuron (Impact Factor: 15.05). 04/2011; 70(2):252-65. DOI: 10.1016/j.neuron.2011.04.005
Source: PubMed


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.

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Available from: Henning Tiemeier
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    • "This is an Open Access article, distributed under the terms of the Creative Commons Attribution licence (http://creativecommons .org/licenses/by/3.0/), which permits unrestricted re-use, distribution, and reproduction in any medium, provided the original work is properly cited. 2011; Shyn et al. 2011; Wray et al. 2012), with only one locus of genome-wide significance (Kohli et al. 2011). A recently published mega-analysis of GWAS studies in MDD by the Psychiatric Genomics Consortium (PGC) failed to identify any genome-wide significant findings (PGC, 2013). "
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    • "The DMR of ZBTB20 we identified is hypermethylated in subjects with MDD and occurs within an identified splice region, which may have the effect of creating distinct isoforms based upon the specific methylation profile. ZBTB20 is also functionally related to the only SNP so far associated with MDD to a genome-wide significance in a genome-wide association study (common SNP rs1545843 (minor allele frequency = 0.41)) [36] occurring within the gene SLC6A15, which like ZTBT20 is associated with hippocampal structure. Down-regulation of SLC6A15 causes a reduced hippocampal volume (an effect that was replicated in stress-susceptible mice) and lower SLC6A15 expression in hippocampus reduces neural integrity and excitatory neurotransmission in the brain. "
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    • "In the general population, it is thought that between 33% and 77% of major depression can be attributed to genetic susceptibility [15, 16]. Several genome-wide association studies have been conducted [17–24] with some evidence for genetic susceptibility variants. Some studies described an association between perinatal depression and a family history of depression or perinatal depression [25–27]; however, only few studies have investigated specific genetic risk factors for perinatal depression. "
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