Effects of a Polymorphism of the Neuronal Amino Acid Transporter SLC6A15 Gene on Structural Integrity of White Matter Tracts in Major Depressive Disorder
October
Effects of a Polymorphism of the Neuronal Amino Acid Transporter SLC6A15 Gene on Structural Integrity of White Matter Tracts in Major Depressive Disorder
Sunyoung Choi 1 2 3
Kyu-Man Han 0 1 3
June Kang 1 3
Eunsoo Won 0 1 3
Hun Soo Chang 1 3
Woo Suk Tae 1 3
Kyu Ri Son 1 3
Su-Jin Kim 1 3
Min-Soo Lee 0 1 3
Byung-Joo Ham 0 1 3
0 Department of Psychiatry, Korea University College of Medicine, Seoul, Republic of Korea, 3 Department of Biomedical Sciences, Korea University College of Medicine , Seoul , South Korea , 4 Department of Medical Bioscience, Graduate school, Soonchunhyang University , Bucheon , South Korea , 5 Brain Convergence Research Center, Korea University Anam Hospital , Seoul , South Korea , 6 Department of Radiology, Anam Hospital, Korea University College of Medicine, Seoul, Republic of Korea, 7 Department of Emergency Medicine, College of Medicine, Korea University , Seoul , Republic of Korea
1 Health Technology R&D Project, Ministry of Health & Welfare, Republic of Korea , A120004
2 Department of Brain and Cognitive Engineering, Korea University , Seoul , Republic of Korea
3 Editor: Xiang Yang Zhang, University of Texas Health Science Center at San Antonio Cancer Therapy and Research Center at Houston , UNITED STATES
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OPEN ACCESS
Data Availability Statement: All relevant data are
within the paper and its Supporting Information
files.
Competing Interests: There is no conflict of
interest to declare.
Background
The SLC6A15 gene has been identified as a novel candidate gene for major depressive dis
order (MDD). It is presumed to be involved in the pathophysiology of MDD through
regulation of glutamate transmission in the brain. However, the involvement of this gene in
microstructural changes in white matter (WM) tracts remains unclear. We aimed to
investigate the influence of a polymorphism of this gene (rs1545853) on the structural integrity of
WM tracts in the cortico-limbic network.
Methods
Eighty-six patients with MDD and 64 healthy controls underwent T1-weighted structural
magnetic resonance imaging, including diffusion tensor imaging (DTI), and genotype
analysis. We selected the genu of the corpus callosum, the uncinate fasciculus, cingulum, and
fornix as regions of interest, and extracted fractional anisotropy (FA) values using the
FMRIB Diffusion Toolbox software.
Results
FA values for the left parahippocampal cingulum (PHC) was significantly reduced in the
patients with MDD compared to healthy control participants (p = 0.004). We also found that
MDD patients with the A allele showed reduced FA values for the left PHC than did healthy controls with the A allele (p = 0.012). There was no significant difference in the FA value of left PHC for the comparison between the G homozygotes of MDD and healthy control group.
Conclusions
We observed an association between the risk allele of the SLC6A15 gene rs1545843 and the WM integrity of the PHC in MDD patients, which is known to play an important role in the neural circuit involved in emotion processing.
Introduction
Major depressive disorder (MDD) is one of the leading causes of disability and poses a great
socioeconomic burden worldwide [
1, 2
]. Characterization of neurobiological mechanisms
underlying MDD is a fundamental aim and goal of biological psychiatry and related fields of
neuroscience research. In recent decades, numerous studies have suggested that the interaction
of susceptible genotype and environmental factors, such as childhood adversity or stressful life
events, play an important role in the pathophysiology of MDD [
3, 4
]. The
gene-by-environment interaction is known to lead to biochemical disturbance, dysfunctional neural networks,
and structural alteration of the brain in MDD patients [
5
]. Recent developments in techniques
of neuroimaging analysis have encouraged novel methodological approaches using structural
changes in the brain as an endophenotype in genetic studies of MDD [
6
]. Numerous studies
have found that several candidate genetic polymorphisms, including serotonin
transporterlined polymorphic region (5-HTTLPR), brain-derived neurotrophic factor (BDNF) Val66Met,
tryptophan hydroxylase-2 (TPH-2), catechol-o-methyltransferase (COMT) Val158Met,
serotonin receptor 1A gene (HTR1A), and monoamine oxidase A gene (MAOA) modulate
morphologic brain changes in MDD patients [
6, 7
].
The SLC6A15 gene, which belongs to the solute carrier 6 (SLC6) family, was recently
identified by a genome-wide association study (GWAS) as a candidate gene for MDD [
8
]. This gene
encodes a sodium-dependent branched-chain amino acid transporter, which is highly
expressed in neurons in several brain regions [
9
]. Because proline has a high affinity for
SLC6A15 and is a precursor of glutamate synthesis, the SLC6A15 gene is thought to be involved
in the pathophysiology of the regulation of glutamate transmission in the brain in MDD [
8
]. In
a very recent animal study, a SLC6A15-knockout mouse sho (...truncated)