Cannabis sativa L. - Botany and Biotechnology

roles that the eCB system plays in the genetic basis of marijuana use and
cannabinoid pharmacotherapeutics. The powerful influence of cannabinoid induced
retrograde signaling on GABAergic and glutamatergic systems indicates that the
main excitatory and inhibitory systems are in part under the influence of the eCB
system. Thus, the genetic basis of compulsive marijuana use may involve inter-
action ofCNRgenes with other genes and environmental factors. As with other
dependences with genetic risk factors, the risk for marijuana use is likely to be the
result ofCNRand other genes and environmental factors, each contributing a small
fraction of the overall risk (Tyndale 2003 ). Further evidence is provided by the
complexCNR1andCNR2gene structures and their associated regulatory elements.
In our current and ongoing studies many features ofCNRgene structures, single
nucleotide polymorphisms (SNPs), copy number variants (CNVs), CpG islands (i.e.
DNA sequences with high frequency of...C...phosphate...G....), microRNA
regulation and the impact ofCNRgene variants in neuropsychiatry and where
possible in rodent models are been investigated. AlthoughCNR1gene has more
CpG islands thanCNR2gene, both have CPG islands less than 300 bases, but they
may be regulated by DNA methylation. MicroRNA binding to the 3′untranlated
region of theCNR1gene with two polyadenylation sites may also potentially
regulate CB1R expression.CNR1 gene has 4 exons and there are 135 SNPs
reported in more than 1% of the population with no common SNP that changes
amino acids of CB1R currently known or reported. A CNV which is 19.5 kb found
in 4 out of 2026 people covers exons 3 and 4 and codes amino acid that could alter
the expression of CB1Rs.CNR2has 4 exons with CB2A with 3 exons and CB2B
with 2 exons; and there are about 100 SNPs found in more than 1% of the popu-
lation, which include common cSNPs that change amino acids of the CB2R,

Table 10.1 Genetic polymorphisms ofCNR2genes (CNR2 genes)a

CNR genes

polymorphism

Linkage or association References

CB2R Associated with mouse model of

impulsivity behavior

Navarrete et al. ( 2012 )

CB2,CNR2SNPs and

haplotypes

Associated with human

Osteoporosis

Karsak et al. ( 2005 )

CNR2SNPs Not associated with cardiovascular

risk factors

Reinhard et al. ( 2008 )

CNR2SNPs Associated with bone mass Yamada et al. ( 2007 )

CNR2(Q63R) SNP Risk factor for autoimmune

disorders

Sipe et al. ( 2005 )

CNR2(Q63R) but not

(H316Y)

Associated with alcoholism and

depression

Ishiguro et al. ( 2007 ),
Onaivi et al. ( 2013 )
CNR2(rs41311993) Associated with bipolar disorder Minocci et al. ( 2011 )
aThere are inconsistencies in some of the association studies of variants in elements of the eCB
system in neurological and mental diseases, as some of the association studies are not replicable
due to the heterogeneity of phenotype assessment (Ehlers et al. 2007 ), and the influence of genetic
variation on impulsivity would be contingent on environmental factors (Buchmann et al. 2014 )

238 E.S. Onaivi et al.