Biomedical Science and Research Journals | The Genetic Revolution: The Challenges of Genetic Sequencing in Substance-Use Disorders
The Genetic Revolution: The Challenges of Genetic Sequencing in Substance-Use Disorders
Introduction
Substance Use Disorders present a global public-health issue
and are responsible for approximately 12.4% of deaths worldwide
as well as injury or illness in over 40 million individuals every year
[1]. Substance Use Disorders are associated with loss of productivity,
higher levels of domestic violence, and increased propensity for
criminal behavior and incarceration [2]. Due to the high numbers
of people affected by this disorder and the large burden it places
on society as a whole, developing effective treatment protocols to
combat substance Use Disorders is necessary. The brain-disease
model can reduce the stigma around addiction as it suggests that
the likelihood of substance abuse is influenced by factors such as
genetics and neural pathways rather than any moral shortcomings
or poor decision-making skills [2]. Next-generation sequencing
(NGS) and Genome-Wide Association Studies (GWAS) allow
scientists to investigate genes associated with substance-use on a
much deeper level [3].
Genes and Substance Abuse
Current models for Genetic Architecture of Human Dependence
The general consensus for the genetic basis of human dependence
on drugs is that it is affected approximately 50% by polygenic
influences which each contribute a small amount to the likelihood
of abuse [1]. The first major GWAS study for alcohol abuse was
published in 2008 and analyzed genetic samples from 1,024
German males compared to a control sample of 1,358 subjects from
separate population-based studies (487 from PopGen, 488 from
KORA-gen, and 383 from the Heinz Nixdorf Risk Factors, Evaluation
of Coronary Calcium, and Lifestyle (RECALL)) [3]. All patients
were diagnosed with alcohol dependence by two independent
psychiatrists using the DSM-IV criteria and were separated by
sex, ethnicity, age at onset and recruitment procedures; results
were compared with a study in rats [3]. Through this method, the
researchers found two strong markers: rs7590720 and rs1344694
on chromosome region 2q35 which were previously linked to
alcohol dependence. The gene most associated with these Single
Nucleotide Polymorphisms (SNPs) was PECR which is an enzyme
involved in fatty acid metabolism [3]. This study provides promising
data that this variant may be involved with alcohol-use disorders by
affecting the metabolic pathway in alcohol consumption.
Several studies have suggested that the endogenous opioid
system is involved in the neurobiological pathway of alcohol
addiction [4]. The A118G polymorphism of the OPRM1 gene causes
a functional difference in the opioid receptors which cause the
receptor to bind endorphin three times more strongly than other
variants. One study showed that individuals with the G allele had
stronger feelings of intoxication, sedation, and happiness across all
trials compared to the control, and were three times more likely to
report a history of familial alcohol abuse [4].
Studies that examine the genes involved in the nicotine pathway
and addiction have revealed several markers in the chromosome 15
gene cluster which encode for nicotine acetylcholine receptors such
as the 3,5, and 4receptors and differ significantly between heavy
and light smokers [5]. Identifying these types of genetic markers could help further understanding of the mechanisms involved with
substance use as well as inform the way patients think about their
substance use. Researchers have already begun to investigate the
emotional impact of receiving genetic predisposition information
for nicotine addicts. One such study surveyed 269 British adult
smokers—both men and women with a mean age of 41.5 years—
who smoked at least 1 cigarette a day. The study investigated the
individual’s perceived control over stopping smoking as well as
preferred cessation methods given their genetic results (i.e. “using
my own willpower,” “taking Zyban, a drug that reduces cravings for
nicotine by increasing dopamine levels,” “using nicotine replacement
therapy such as gum or patches,” “asking my family doctor for
advice” etc.). This study did suggest that learning about a genetic
predisposition to nicotine may increase the desire for effective
cessation methods, increasing the likelihood of reaching out to get
help [5].
While most genetic studies of addiction focus on specific
Substance Use Disorders and particular genetic pathways, one
study attempted to find potential addiction variants by converging
genome scanning data from multiple studies [6]. The study analyzed
more than 104 markers that have previously been found to have
a positive correlation with addiction based on previous linkage
studies. They then used the criteria of ‘5 Mb’ which follows that
positive markers linked to substance abuse vulnerability in at least
two different samples lie within 5 Mb of each other and found that
34 of the 104 markers fell into 15 5-Mb chromosome regions. They
found that 6 different human chromosome areas contained positive
markers for addiction [6]. Further studies based on this analysis
should be done to understand the molecular genetic pathway of
those identified chromosome regions.
Conclusion
NSG and GWAS studies represent powerful tools for
investigating possible genetic factors involved in Substance Use
Disorders. The research in this area is still in its early stages and
more work is needed to identify genes linked to different types of
Substance Use Disorders and to uncover the mechanisms by which
these genes act. Improving the understanding of genes involved in
Substance Use Disorders could allow for more precise and effective
treatment options as well as shift perceptions around Substance
Use Disorders. Providing robust and informative genetic counseling
be an essential part of the future genetic research and precision
medicine for people with Substance Use Disorders to ensure that
patients understand the complexity, limitations, and significance of
their results.
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