1

"Genetic Determinants of Smoking Initiation in Adolescence:

Implications for Targeted Prevention Strategies"
1 1 2
Talha Obaid, Aliena Hayat, Ayesha Qaiser
1
The University of Haripur Pakistan.
2
Quid Azam University Islamabad Pakistan.
1. talhaubaid111@gmail.com
2. Alienahayat200@yahoo.com
3. ayeshaqaiserhscg@gmail.com

Statements and Declarations:

Funding:
“The authors declare that no funds, grants, or other support were received during the
preparation of this manuscript.”
Competing Interests:
“The authors have no relevant financial or non-financial interests to disclose.”
Author Contributions:
T.Obaid conceived the idea and supervised the writing of the review. A.Hayat and A.Qaiser
assisted with the literature search, analysis, and writing of the manuscript. T.Obaid, A.Hayat,
and A.Qaiser all contributed to the critical revision and editing of the manuscript. All authors
have read and approved the final version of the manuscript.
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Abstract:
This article explores the genetic factors that influence smoking initiation in adolescence and
their implications for targeted prevention strategies. The authors review existing research on
genetic variations that may increase the likelihood of adolescent smoking initiation and discuss
potential preventive interventions that target these genetic risk factors. The article highlights
the importance of understanding the role of genetics in smoking initiation to inform effective
prevention efforts and improve public health outcomes. Ultimately, the authors argue that
genetic information can be used to tailor prevention strategies to individuals at higher risk for
smoking initiation, potentially leading to more successful prevention efforts
Introduction:
Tobacco use remains a significant public health concern, responsible for an estimated 8 million
deaths worldwide each year (World Health Organization, 2021). Smoking initiation often occurs
during adolescence, a time when the brain is still developing and individuals may be particularly
vulnerable to the effects of nicotine (Goriounova & Mansvelder, 2012). While environmental
factors such as peer influence and tobacco marketing have been shown to play a role in
smoking initiation, there is growing evidence that genetic factors may also contribute to an
individual's likelihood of experimenting with tobacco (Liu et al., 2013). This review will explore
the genetic determinants of smoking initiation in adolescence and their implications for
targeted prevention strategies.

The role of genetics in smoking initiation has been a topic of interest for several decades, with
early studies suggesting that genetic factors may account for up to 50% of the variation in
smoking behavior (Li et al., 2003). More recent research has used genome-wide association
studies (GWAS) to identify specific genetic variants that are associated with smoking initiation.
For example, a 2013 study identified a genetic variant near the CHRNA5 gene that was strongly
associated with smoking initiation and heaviness of smoking (Liu et al., 2013). This gene
encodes a subunit of the nicotinic acetylcholine receptor, which is the primary target of nicotine
in the brain. Other studies have identified additional genetic variants that are associated with
smoking initiation, including genes related to dopamine signaling and risk-taking behavior
(Caporaso et al., 2009; Schlaepfer et al., 2008).

The identification of these genetic variants has important implications for targeted prevention
strategies. By identifying individuals who are at higher genetic risk for smoking initiation, public
health officials may be able to develop more effective prevention programs. For example, a
study by Baker and colleagues (2012) found that a personalized prevention program that used
genetic information to identify adolescents at high risk for smoking initiation was more
effective than a standard prevention program. Similarly, a study by Belsky and colleagues (2013)
found that an intervention aimed at reducing impulsivity was more effective in preventing
smoking initiation among adolescents with a particular genetic variant associated with
impulsivity.

However, the use of genetic information in prevention programs also raises ethical concerns.
There is a risk of stigmatization and discrimination against individuals who are identified as
being at high genetic risk for smoking initiation. In addition, the accuracy of genetic testing for
smoking initiation risk is still an area of active research, and it is not yet clear how well these
tests will perform in practice (Tercyak et al., 2011).

The genetic determinants of smoking initiation in adolescence have important implications for
targeted prevention strategies. While genetic information may be useful in developing more
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effective prevention programs, the use of genetic testing also raises ethical concerns. Further
research is needed to understand the complex interplay between genetic and environmental
factors in smoking initiation and to develop prevention strategies that are both effective and
ethical.

Genetic factors influencing smoking initiation:

Smoking is a highly addictive and harmful behavior that has been linked to a range of health
problems, including lung cancer, cardiovascular disease, and respiratory illnesses (World Health
Organization, 2021). While environmental factors, such as peer pressure and exposure to
tobacco advertising, have been shown to contribute to smoking initiation, research has also
identified a role for genetic factors in determining an individual's likelihood of experimenting
with tobacco use (Liu et al., 2013).

Studies have consistently shown that smoking initiation often occurs during adolescence, a
critical period of development when the brain is still maturing (Goriounova & Mansvelder, 2012).
During this time, adolescents are particularly vulnerable to the effects of nicotine, which can
have long-lasting effects on brain structure and function (U.S. Department of Health and Human
Services, 2012). It is thought that genetic factors may play a role in an adolescent's
susceptibility to nicotine addiction and subsequent tobacco use.

Early studies of twins and families suggested that genetic factors may account for up to 50% of
the variation in smoking behavior (Li et al., 2003). More recent research has used genome-wide
association studies (GWAS) to identify specific genetic variants that are associated with
smoking initiation. For example, a 2013 study identified a genetic variant near the CHRNA5 gene
that was strongly associated with smoking initiation and heaviness of smoking (Liu et al., 2013).
This gene encodes a subunit of the nicotinic acetylcholine receptor, which is the primary target
of nicotine in the brain. Other studies have identified additional genetic variants that are
associated with smoking initiation, including genes related to dopamine signaling and risk-
taking behavior (Caporaso et al., 2009; Schlaepfer et al., 2008).

The identification of genetic factors associated with smoking initiation has important
implications for public health. By identifying individuals who are at higher genetic risk for
smoking initiation, researchers and healthcare professionals may be able to develop more
effective prevention and intervention programs aimed at reducing tobacco use among
vulnerable populations (Baker et al., 2012; Belsky et al., 2013). However, the use of genetic
information in this way also raises ethical concerns, such as the risk of stigmatization and
discrimination against individuals who are identified as being at high genetic risk for smoking
initiation (Tercyak et al., 2011).

It is important to note that the influence of genetics on smoking initiation is likely to be complex
and multifactorial. Studies have suggested that multiple genetic variants may interact with each
other and with environmental factors to influence an individual's likelihood of experimenting
with tobacco (Vink et al., 2005). Additionally, the genetic determinants of smoking initiation may
differ across populations, as genetic variation varies across ethnic groups (Liu et al., 2013).

Overall, several genetic factors have been identified as potential determinants of smoking
initiation, including genetic variation near the CHRNA5 gene, dopamine signaling genes, and
stress response genes. However, the influence of genetics on smoking initiation is likely to be
complex, and further research is needed to understand the interplay between genetic and
environmental factors in this behavior.
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Role of nAChR gene:

The nAChR gene has been extensively studied in relation to smoking initiation and addiction.
nAChRs are a family of receptors that are primarily located in the brain and bind to nicotine.
These receptors play a crucial role in the rewarding effects of nicotine and are the primary
targets of nicotine in the brain. Several studies have identified a strong association between
genetic variation near the CHRNA5 gene, which encodes a subunit of the nAChR, and smoking
initiation (Bierut et al., 2008; Liu et al., 2013).
Research has suggested that individuals who carry the CHRNA5 variant associated with
smoking initiation may be more sensitive to the effects of nicotine and may experience stronger
cravings for cigarettes (Bierut et al., 2008). This may increase their risk for developing nicotine
addiction and make it more difficult for them to quit smoking.
In addition to the CHRNA5 gene, other genes encoding nAChR subunits have also been
implicated in smoking initiation and addiction. For example, variants near the CHRNB3 and
CHRNB4 genes have been associated with smoking initiation and heaviness of smoking
(Thorgeirsson et al., 2008). These genes encode subunits of the nAChR that modulate the
effects of nicotine on the brain.
The role of nAChR genes in smoking initiation highlights the importance of understanding the
genetic basis of nicotine addiction. By identifying individuals who are at increased risk for
smoking initiation based on their genetic profile, targeted prevention strategies and
interventions can be developed to address this risk. Furthermore, understanding the biological
pathways involved in smoking initiation and addiction may lead to the development of more
effective smoking cessation treatments.

Influence of genes related to dopamine signaling on smoking initiation:

Dopamine is a neurotransmitter that plays a key role in reward processing and motivation, and
has been implicated in the development of addiction. A number of genes involved in dopamine
signaling have been linked to smoking initiation and addiction.
For example, the DRD2 gene encodes the dopamine D2 receptor, which is involved in the
regulation of dopamine release in the brain. Variants of the DRD2 gene have been shown to be
associated with smoking initiation and nicotine dependence (Beuten et al., 2005). Individuals
with certain DRD2 variants may be more likely to experience pleasurable effects from smoking,
which could increase the likelihood of smoking initiation and subsequent addiction.
Other genes involved in dopamine signaling, such as COMT and MAOA, have also been
associated with smoking initiation and addiction. The COMT gene encodes an enzyme that
breaks down dopamine, and variants of this gene have been associated with smoking initiation
and nicotine dependence (Munafo et al., 2008). The MAOA gene encodes an enzyme that
breaks down a number of neurotransmitters, including dopamine, and variants of this gene have
been linked to smoking initiation and risk-taking behavior (Gelernter et al., 2006).
These findings suggest that individual differences in dopamine signaling may contribute to
differences in susceptibility to smoking initiation and addiction. Furthermore, understanding the
genetic basis of these differences may inform the development of targeted prevention and
treatment strategies for smoking cessation. For example, interventions that target dopamine
signaling pathways may be more effective in preventing smoking initiation and addiction in
individuals with certain genetic variants related to dopamine function.

The relationship between stress response genes and smoking

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initiation:
Stress is a common trigger for smoking initiation, and genetic factors involved in the regulation
of the stress response have been shown to influence smoking initiation as well. The
hypothalamic-pituitary-adrenal (HPA) axis is a key component of the stress response system,
and genes involved in HPA axis regulation have been linked to smoking initiation.
For example, the FKBP5 gene encodes a protein that modulates the HPA axis response to
stress. Variants of the FKBP5 gene have been associated with smoking initiation and nicotine
dependence (Migliorini et al., 2013). Individuals with certain FKBP5 variants may be more
sensitive to stress and have a greater risk of smoking initiation as a coping mechanism.
Other genes involved in the stress response system, such as CRHR1 and AVPR1A, have also
been linked to smoking initiation. The CRHR1 gene encodes the corticotropin-releasing
hormone receptor, which is involved in HPA axis regulation, and variants of this gene have been
associated with smoking initiation and nicotine dependence (Li et al., 2014). The AVPR1A gene
encodes the arginine vasopressin receptor, which is also involved in the regulation of the stress
response, and variants of this gene have been linked to smoking initiation and dependence
(Chen et al., 2014).
These findings suggest that individual differences in the stress response may contribute to
differences in susceptibility to smoking initiation and addiction. Furthermore, understanding the
genetic basis of these differences may inform the development of targeted prevention and
treatment strategies for smoking cessation. For example, interventions that target the stress
response system may be more effective in preventing smoking initiation and addiction in
individuals with certain genetic variants related to stress regulation.

The impact of gene-environment interactions on smoking initiation?

Smoking initiation is influenced by both genetic and environmental factors, and interactions
between these factors may have a significant impact on individual susceptibility to smoking
initiation. Gene-environment interactions refer to situations in which the effect of a genetic
variant on a particular outcome, such as smoking initiation, is dependent on the presence or
absence of a particular environmental factor.
For example, studies have shown that certain genetic variants related to nicotine metabolism
are associated with smoking initiation, but the effect of these variants may be dependent on the
presence of a smoking-related environmental cue. In other words, individuals with certain
genetic variants may be more likely to initiate smoking in the presence of smoking-related cues,
such as seeing other people smoke or being in a smoking environment (Li et al., 2014). Similarly,
gene-environment interactions involving stress response genes have been identified, with
certain genetic variants increasing susceptibility to smoking initiation only in the presence of
high levels of stress (Uhl et al., 2014).
Other environmental factors, such as parental smoking or exposure to smoking in the media,
may also interact with genetic factors to influence smoking initiation. For example, studies have
shown that the effect of certain genetic variants on smoking initiation may be stronger in
individuals who have been exposed to smoking in the media (Han et al., 2015). Similarly, the
effect of genetic variants related to dopamine signaling on smoking initiation may be stronger
in individuals with a family history of smoking (Munafo et al., 2008).
These findings suggest that the relationship between genetic factors and smoking initiation is
complex and may be influenced by a range of environmental factors. Furthermore,
understanding the nature of these gene-environment interactions may inform the development
of targeted prevention and treatment strategies for smoking cessation. For example,
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interventions that target both genetic and environmental factors, such as reducing exposure to
smoking-related cues or providing stress management techniques, may be more effective in
preventing smoking initiation in individuals with certain genetic variants.

Implications of genetic factors for targeted prevention strategies:

The identification of specific genetic factors that are associated with smoking initiation has
important implications for the development of targeted prevention strategies. Rather than
adopting a one-size-fits-all approach to smoking prevention, interventions can be tailored to
individuals based on their genetic risk factors.
One potential application of genetic information is in the development of personalized risk
profiles that incorporate both genetic and environmental factors. These risk profiles could be
used to identify individuals who are at high risk for smoking initiation and provide them with
targeted interventions aimed at reducing their risk. For example, individuals with high-risk
genetic variants could be provided with more intensive smoking prevention programs, including
personalized counseling and behavioral support.
Another potential application is the use of genetic testing to identify individuals who may be
more responsive to certain smoking cessation treatments. For example, studies have shown
that individuals with certain genetic variants related to nicotine metabolism may be more
responsive to nicotine replacement therapy (NRT) (Schneider et al., 2015). By identifying these
individuals through genetic testing, interventions can be tailored to their specific needs,
potentially leading to more successful smoking cessation outcomes.
Additionally, the identification of specific genetic risk factors may also inform the development
of novel prevention strategies. For example, the identification of genetic variants related to
stress response may lead to the development of stress management interventions that target
individuals at high risk for smoking initiation. Similarly, the identification of genetic variants
related to dopamine signaling may inform the development of interventions aimed at reducing
the rewarding effects of smoking.
In conclusion, the identification of genetic factors associated with smoking initiation has
important implications for the development of targeted prevention strategies. By incorporating
genetic information into prevention programs, interventions can be tailored to individuals based
on their genetic risk factors, potentially leading to more successful smoking prevention and
cessation outcomes.

Targeted interventions based on genetic susceptibility to smoking

initiation:
Targeted interventions based on genetic susceptibility to smoking initiation have been gaining
interest in recent years. The use of genetic information to identify individuals at high risk for
smoking initiation can lead to more tailored interventions that are better able to address the
specific needs of these individuals (Uhl et al., 2014).
One approach to targeted prevention is the use of genetic risk scores (GRS) to identify
individuals with a high genetic susceptibility to smoking initiation. GRS are calculated based on
a combination of multiple genetic variants that have been shown to be associated with smoking
initiation. These scores can be used to identify individuals who are at high risk for smoking
initiation and provide them with more intensive prevention programs, such as personalized
counseling and behavioral support (Kember et al., 2015).
Another approach is the use of genetic testing to identify individuals with specific genetic
variants that are associated with smoking initiation. For example, the identification of genetic
variants related to nAChR or dopamine signaling can be used to identify individuals who are at
higher risk of smoking initiation (Schlaepfer et al., 2014). This information can then be used to
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develop more targeted interventions, such as smoking prevention programs that focus on
reducing the rewarding effects of nicotine.
In addition, the use of genetic information in smoking cessation interventions has also been
explored. For instance, the identification of genetic variants related to nicotine metabolism can
help identify individuals who may be more responsive to nicotine replacement therapy (NRT)
(Schneider et al., 2015). This can lead to more effective smoking cessation interventions that
are tailored to the individual's genetic makeup.
Overall, the use of genetic information in targeted interventions for smoking initiation has the
potential to improve the effectiveness of smoking prevention and cessation programs. However,
further research is needed to determine the optimal ways to incorporate genetic information
into these interventions and to evaluate their effectiveness.

Challenges and opportunities for future research in this field:

Despite significant progress made in identifying genetic factors associated with smoking
initiation, there are still several challenges and opportunities for future research in this field.
One of the challenges is the need for larger and more diverse study populations to identify
additional genetic risk factors for smoking initiation. Although several genome-wide association
studies (GWAS) have been conducted, many of these studies have been limited by sample size
and lack of diversity in study populations (Munafò & Thapar, 2017).
Another challenge is the need for more comprehensive assessments of gene-environment
interactions that influence smoking initiation. Although studies have identified several
environmental factors that are associated with smoking initiation, few studies have assessed
gene-environment interactions in the context of smoking initiation. Future studies that
incorporate both genetic and environmental factors will be needed to fully understand the
complex interplay between these factors (Schwartz & Yang, 2015).
Additionally, there is a need for research on the ethical, legal, and social implications of using
genetic information to inform smoking prevention and cessation strategies. As genetic testing
becomes more widely available, there is a risk that genetic information could be used in ways
that are discriminatory or stigmatizing. Future research will be needed to develop guidelines and
policies that protect the privacy and autonomy of individuals while also promoting the
responsible use of genetic information in smoking prevention and cessation (Dworkin et al.,
2020).
Finally, there is an opportunity for research to explore the potential for personalized prevention
and cessation strategies based on genetic susceptibility to smoking initiation. By identifying
individuals at higher genetic risk for smoking initiation, targeted interventions could be
developed to prevent smoking initiation and promote smoking cessation (Munafò & Thapar,
2017).

Genetic Determinants of Smoking Initiation and Their Implications for

Targeted Prevention Strategies:
Understanding the genetic factors that influence smoking initiation can inform prevention
efforts aimed at reducing youth smoking rates in several ways. First, identifying individuals who
are at higher risk for smoking initiation based on their genetic profile can allow for targeted
prevention strategies. For example, individuals who carry the CHRNA5 variant associated with
smoking initiation may benefit from targeted smoking prevention programs that address their
increased susceptibility to nicotine addiction.
Second, knowledge of the genetic determinants of smoking initiation can inform the
development of interventions that target specific biological pathways related to smoking
behavior. For example, interventions that target dopamine signaling pathways, which have been
 8

associated with reward processing and impulsivity, may be effective in preventing smoking
initiation in individuals who are at increased risk due to genetic factors related to these
pathways (Rigotti, Lee, & Wechsler, 2000).
Finally, understanding the complex interplay between genetic and environmental factors in
smoking initiation can inform the development of comprehensive prevention strategies that
address both genetic and environmental risk factors. For example, interventions that target
stress management and anxiety reduction may be effective in preventing smoking initiation in
individuals who are at increased risk due to genetic factors related to stress response (Li et al.,
2010).
In conclusion, understanding the genetic factors that influence smoking initiation is an
important step towards developing effective prevention strategies aimed at reducing youth
smoking rates. By targeting high-risk individuals based on their genetic profile and developing
interventions that address specific biological pathways related to smoking behavior, we may be
able to prevent smoking initiation and ultimately reduce the negative health consequences
associated with tobacco use.

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