- •Are there any risks associated with comt gene polymorphism in the presence of cannabis?
- •Abstract
- •Introduction
- •Tetrahydrocannabinol
- •Endogenous ligands
- •Gene variations of cnr1 and cnr2 in neuropsychiatric disorders
- •GxE interactions
- •Comt polymorphism is a mediator of the link between cannabis and psychosis.
- •Materials and Methods
- •Results The effect of adolescent cannabis use on adult psychosis is controlled by genetic variation in the comt gene.
- •Determination of allele frequencies by dna pooling and ld between snPs
- •Determination of genetic association with schizophrenia by employing individual genotyping
- •Association analysis at individual snPs
- •Linkage disequilibrium analysis
- •Comt rs4680 in relation to psychotic experiences
- •Discussion
- •Conclusion
- •References
Association analysis at individual snPs
A total of 748 DNA samples have been collected by phlebotomy from Spaniard patients. A group of psychiatrists have determined subjects diagnosed with one of the schizophrenia subtypes by the diagnostic and statistical manual of mental disorders (DSM-IV). All subjects, who were examined, have signed the informed consent form, and the study was approved by the national genetic committee of ministry of health. Psychiatrists have not been provided with information about COMT genotypes of the patients, when have been analysing for the history of cannabis use.
F
Table 2 Association of analyses at individual SNP of the functional COMT. Cannabis non-users showed more frequent distribution of the genotype levels for the following SNPs. Heterozygous carriers were more common in cannabis non-users. Cannabis users showed decrease in genotype distribution in comparison to cannabis non-users. Cannabis users homozygous for Met allele showed alteration in the frequencies at rs4680 (Costas 2011).
unctional haplotypes in the COMT gene, such as SNP rs4680 (Val158Met), synonymous SNP rs4633, synonymous SNP rs4818, non-coding SNP rs6269 and allelic variant rs737865 studied for an association with schizophrenia were identified by mass spectrometry using iPLEX MassArray genotyping system. Each one of the SNPs was well genotyped in more than 95% of the Spaniard samples. Genotype distributions did not show any significant differences between male and female within P values ranging from 0.37 to 0.76. Table 2 shows a strong association of each individual SNP with cannabis use in Valencia samples and consistent results of joint analysis of Santiago and Valencia samples confirmed association of cannabis use with rs4680, rs4818, rs4633 and rs6269 respectively. The effects of cannabis use in schizophrenia patients were associated with decrease in the genotype levels for each of the SNPs (Costas 2011).
SNP |
Alleles ‘a’ A1/A2 |
Genotypes ‘b’ |
|
HWE P |
Genot. P ‘d’ |
MA freq. |
|
Allelic P ‘d’ |
Allelic OR (95% CI) |
|
|
Users |
Non-users |
Case/controls ‘c’ |
|
Users |
Non-users |
|
|
rs737865 |
|
|
|
|
|
|
|
|
|
Santiago |
G/A |
10/28/27 |
41/139/137 |
0.414/0.211 |
0.867 |
0.37 |
0.35 |
0.653 |
1.09 (0.72-1.64) |
Valencia |
G/A |
3/38/45 |
31/129/104 |
0.192/0.139 |
0.025 |
0.26 |
0.36 |
0.011 |
0.61 (0.40-0.90) |
Joint |
G/A |
|
|
|
0.284 |
|
|
0.116 |
0.80 (0.61-1.06) |
|
|
|
|
|
|
|
|
|
0.81 (0.60-1.09) ‘e’ |
rs6269 |
|
|
|
|
|
|
|
|
|
Santiago |
G/A |
16/23/23 |
80/142/83 |
0.055/0.161 |
0.250 |
0.44 |
0.49 |
0.295 |
0.81 (0.54-1.22) |
Valencia |
G/A |
17/33/38 |
70/135/67 |
0.202/0.586 |
3.7e-3 |
0.38 |
0.51 |
3.4e-3 |
0.60 (0.41-0.86) |
Joint |
G/A |
|
|
|
1.8e-3 |
|
|
3.9e-3 |
0.68 (0.53-0.89) |
|
|
|
|
|
|
|
|
|
0.72 (0.54-0.95) ‘e’ |
rs4633 |
|
|
|
|
|
|
|
|
|
Santiago |
T/C |
18/28/19 |
56/133/129 |
0.013/0.144 |
0.098 |
0.49 |
0.38 |
0.023 |
155 (1.04-2.30) |
Valencia |
T/C |
30/34/25 |
46/136/90 |
0.371/0.689 |
3.2e-3 |
0.53 |
0.42 |
0.011 |
1.55 (1.09-2.21) |
Joint |
T/C |
|
|
|
7.4e-4 |
|
|
6.7e-3 |
1.54 (1.20-2.00) |
|
|
|
|
|
|
|
|
|
1.48 (1.13-1.95) ‘e’ |
rs4818 |
|
|
|
|
|
|
|
|
|
Santiago |
G/C |
16/23/26 |
81/144/92 |
0.016/0.308 |
0.186 |
0.42 |
0.48 |
0.215 |
0.79 (0.53-1.17) |
Valencia |
G/C |
18/33/39 |
70/131/73 |
0.070/0.317 |
0.012 |
0.39 |
0.49 |
9.5e-3 |
0.64 (0.44-0.91) |
Joint |
G/C |
|
|
|
3.0e-3 |
|
|
5.8e-3 |
0.70 (0.54-0.91) |
|
|
|
|
|
|
|
|
|
0.75 (0.54-0.95) ‘e’ |
rs4680 |
|
|
|
|
|
|
|
|
|
Santiago |
A/G |
17/28/20 |
55/134/128 |
0.022/0.159 |
0.173 |
0.48 |
0.38 |
0.051 |
1.46 (0.98-2.17) |
Valencia |
A/G |
29/33/28 |
46/137/92 |
0.301/0.653 |
5.1e-3 |
0.51 |
0.42 |
0.036 |
1.43 (1.01-2.04) |
Joint |
A/G |
|
|
|
2.5e-3 |
|
|
4.3e-3 |
1.45 (1.12-1.85) |
|
|
|
|
|
|
|
|
|
1.39 (1.06-1.83) ’e’ |
‘a’ - Plus standard.
‘b’ - Genotypes ordered as A1A1/A1A2/A2A2.
‘c’ - HWE in control samples was estimated to discard genotyping errors.
‘d’ - Significant values are in boldface.
‘e’ - OR adjusted for sex, age and area of recruitment by logistics regression.