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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    • "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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    ABSTRACT: Strategies to dissect phenotypic and genetic heterogeneity of major depressive disorder (MDD) have mainly relied on subphenotypes, such as age at onset (AAO) and recurrence/episodicity. Yet, evidence on whether these subphenotypes are familial or heritable is scarce. The aims of this study are to investigate the familiality of AAO and episode frequency in MDD and to assess the proportion of their variance explained by common single nucleotide polymorphisms (SNP heritability). For investigating familiality, we used 691 families with 2-5 full siblings with recurrent MDD from the DeNt study. We fitted (square root) AAO and episode count in a linear and a negative binomial mixed model, respectively, with family as random effect and adjusting for sex, age and center. The strength of familiality was assessed with intraclass correlation coefficients (ICC). For estimating SNP heritabilities, we used 3468 unrelated MDD cases from the RADIANT and GSK Munich studies. After similarly adjusting for covariates, derived residuals were used with the GREML method in GCTA (genome-wide complex trait analysis) software. Significant familial clustering was found for both AAO (ICC = 0.28) and episodicity (ICC = 0.07). We calculated from respective ICC estimates the maximal additive heritability of AAO (0.56) and episodicity (0.15). SNP heritability of AAO was 0.17 (p = 0.04); analysis was underpowered for calculating SNP heritability of episodicity. AAO and episodicity aggregate in families to a moderate and small degree, respectively. AAO is under stronger additive genetic control than episodicity. Larger samples are needed to calculate the SNP heritability of episodicity. The described statistical framework could be useful in future analyses.
    Psychological Medicine 02/2015; 45(10):1-11. DOI:10.1017/S0033291715000215 · 5.94 Impact Factor
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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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    ABSTRACT: Although genetic variation is believe to contribute to an individual's susceptibility to major depressive disorder, genome-wide association studies have not yet identified associations that could explain the full etiology of the disease. Epigenetics is increasingly believed to play a major role in the development of common clinical phenotypes, including major depressive disorder. Genome-wide MeDIP-Sequencing was carried out on a total of 50 monozygotic twin pairs from the UK and Australia that are discordant for depression. We show that major depressive disorder is associated with significant hypermethylation within the coding region of ZBTB20, and is replicated in an independent cohort of 356 unrelated case-control individuals. The twins with major depressive disorder also show increased global variation in methylation in comparison with their unaffected co-twins. ZBTB20 plays an essential role in the specification of the Cornu Ammonis-1 field identity in the developing hippocampus, a region previously implicated in the development of major depressive disorder. Our results suggest that aberrant methylation profiles affecting the hippocampus are associated with major depressive disorder and show the potential of the epigenetic twin model in neuro-psychiatric disease.
    Genome biology 04/2014; 15(4):R56. DOI:10.1186/gb-2014-15-4-r56 · 10.81 Impact Factor
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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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    ABSTRACT: Purpose: The aim of this study was to investigate whether single nucleotide polymorphisms (SNPs) in genes of the stress hormone signaling pathway, specifically FKBP5, NR3C1, and CRHR1, are associated with depressive symptoms during and after pregnancy. Methods: The Franconian Maternal Health Evaluation Study (FRAMES) recruited healthy pregnant women prospectively for the assessment of maternal and fetal health including the assessment of depressiveness. The German version of the 10-item Edinburgh Postnatal Depression Scale (EPDS) was completed at three time points in this prospective cohort study. Visit 1 was at study entry in the third trimester of the pregnancy, visit 2 was shortly after birth, and visit 3 was 6-8 months after birth. Germline DNA was collected from 361 pregnant women. Nine SNPs in the above mentioned genes were genotyped. After construction of haplotypes for each gene, a multifactorial linear mixed model was performed to analyse the depression values over time. Results: EPDS values were within expected ranges and comparable to previously published studies. Neither did the depression scores differ for comparisons among haplotypes at fixed time points nor did the change over time differ among haplotypes for the examined genes. No haplotype showed significant associations with depressive symptoms severity during pregnancy or the postpartum period. Conclusion: The analysed candidate haplotypes in FKBP5, NR3C1, and CRHR1 did not show an association with depression scores as assessed by EPDS in this cohort of healthy unselected pregnant women.
    03/2014; 2014:469278. DOI:10.1155/2014/469278
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