Effect of metabotropic glutamate receptor 3 genotype on N-acetylaspartate levels and neurocognition in non-smoking, active alcoholics.
BACKGROUND
We studied the effects of single nucleotide polymorphisms (SNPs) in the metabotropic glutamate receptor 3 (GRM3) gene on brain N-acetylaspartate (NAA) concentrations and executive function (EF) skills in non-smoking, active alcoholics, and evaluated associations between these variables.


METHODS
SNPs (rs6465084, rs1468412, and rs2299225) in GRM3 were genotyped in 49 male, non-smoking, alcohol-dependent patients and 45 healthy control subjects using ligase detection reactions. NAA/creatine (Cr) ratios in left prefrontal gray matter (GM) and white matter (WM), left parietal GM, left parietal WM, and cerebellar vermis regions were measured by Proton 1 H Magnetic resonance spectroscopy (MRS). EF was measured by the Wisconsin Card Sorting Test (WCST).


RESULTS
Compared to controls, alcoholics had lower NAA/Cr ratios in prefrontal GM and WM regions and performed more poorly on all EF tests (P < 0.001). Alcoholics with the A/A genotype for SNP rs6465084 had lower NAA/Cr ratios in prefrontal GM and WM regions and had poorer EF skills than alcoholics who were G-carriers for this SNP (P < 0.01). Non-alcoholics with the A/A genotype for rs6465084 also had lower NAA/Cr levels in prefrontal GM and made more random errors in the WCST than G-carriers (P < 0.01). The A/A genotype group for SNP rs6465084 was significantly different from the G carriers for the variables of NAA/Cr ratios and WCST scores in both alcoholics and controls (P < 0.05). Alcoholics who were T-carriers for rs1468412 had lower NAA/Cr ratios in prefrontal GM and showed poorer EF skills (P < 0.05). No effects of rs2299225 genotype on NAA/Cr or executive skills were observed. NAA/Cr in left prefrontal regions correlated with certain parameters of EF testing in both alcoholics and controls (P < 0.05), but the significance of this correlation among alcoholics disappeared after adjustment for the effects of genotype.


CONCLUSIONS
Our results provide evidence that glutamate system dysfunction may play a role in the prefrontal functional abnormalities seen in alcohol dependence. It is possible that certain GRM3 SNP genotypes (the A/A genotype of rs6465084 and the T allele of rs1468412) may further lower NAA/Cr levels and EF skills in addition to the effect of alcohol.
Mental Health Institute, Mental Health Centre, 1st Affiliated Hospital of Harbin Medical University, 23 Youzheng Street, Harbin, Heilongjiang Province 150001, PR China.
Yan
Y
Xia
Dongying
D
Ma
Jian
J
Hu
Chunling
C
Tang
Zheng
Z
Wu
Lei
L
Liu
Feng
F
Xin
D000328:Adult; D000437:Alcoholism / Q000235:genetics* / Q000378:metabolism / Q000523:psychology; D001224:Aspartic Acid / Q000031:analogs & derivatives* / Q000378:metabolism; D003071:Cognition / Q000502:physiology; D056344:Executive Function / Q000502:physiology*; D005838:Genotype; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D008875:Middle Aged; D009483:Neuropsychological Tests; D020641:Polymorphism, Single Nucleotide; D017397:Prefrontal Cortex / Q000378:metabolism*; D018094:Receptors, Metabotropic Glutamate / Q000235:genetics*; D012907:Smoking
D018094:Receptors, Metabotropic Glutamate; C102718:metabotropic glutamate receptor 3; D001224:Aspartic Acid; C000179:N-acetylaspartate