Substance abuse genetics: in search for shared and substance-specific variants


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Background

Substance use disorders (SUDs), including drug, alcohol use disorders, and smoking, are global physical and psychical health threats. They are leading to millions of deaths annually and severe health consequences.

Virginia Adult Twin Study of Psychiatric and Substance Use Disorders that included 5000 participants showed that the effects of genetic factors gradually increased with increasing age (fig.1). Heritability estimates for different SUDs varied from 0.39 – 0.72, and overall concordance ratios for monozygotic and dizygotic twins suggested a polygenic genetic architecture of these disorders with multiple additive genetic effects, modifiable by environmental factors.

Fig. 1 Additive genetic effects contribute to alcohol and nicotine consumption. Their effect increases with age, whereas effect of familial environmental factors decreases, and individual environmental factors contribute evenly throughout the lifespan (adapted from Goldman et al., 2013, doi:/10.1016/B978-0-12-383834-6.00119-1)

Genome-wide and candidate gene studies identified a number of loci, associated with predominantly either smoking or alcoholism in big cohorts (fig. 2). However, fewer loci have been associated with drug abuse, and few studies focused on genetic overlap between disorders. Therefore, genetic risk factors, common and specific for liability to different substances, are still not completely uncovered.

We perform a candidate gene study of several loci related to substance metabolism or neurobiologic response, with liability to one or more of SUDs in Ukrainian population. The loci have been selected considering their reported associations with a substance use disorder in GWASs or candidate gene studies.  Besides, we use the psychometric study to measure personality traits and dispositions of several cognitive-behavioral processes, such as executive functions, impulsivity, risk-taking, anxiety sensitivity, and decision-making

Figure 2. Loci associated with SUDs in GWASs and candidate gene studies. The left panel: GWAS signals mapped on chromosomes. The upper right panel: variations in the loci involved in substance metabolism (on the example of alcohol) are associated with liability to dependence. The lower right panel: variations affecting neurobiologic pathways, such as reward system, may be also associated with substance abuse or dependence. The presented loci have been replicated in ≥ studies.

Our Goals

Our goal is to elucidate, which genetic polymorphic loci are associated with specific substance use disorders (e.g., specifically with amphetamine or nicotine dependence), and which loci are associated with certain comorbidities (e.g., alcohol + nicotine, or opiate + alcohol co-dependencies). We have some preliminary findings and we want to be more confident in them, and also to find some new associations if they exist, by testing more loci in a bigger dataset.

In case we get a sufficient number of men and women in each group, we will search for possible gender-specific associations with each of the disorders.

Why is this project Important?

According to WHO’s data, about 35 million people are suffering from drug use disorders and almost 271 million people (or 5.5% of global population aged 15-64) worldwide had used psychoactive drugs at least once in previous years. Alcohol abuse results in 3 million deaths annually, accounting for 5.3% of all deaths. Direct tobacco use results in more than 7 million of those deaths. Nowadays around 1.1 billion smokers live in low-and middle-income countries, which comprise 80% of all smokers around the world.

Ukraine, along with other countries of Eastern Europe, has high prevalence and specific spectrum of illicit drugs use (i.e., opium, modified opiates, amphetamine, methamphetamine and some custom-made drugs, along with more traditional heroin and cocaine). According to the estimation of the Ministry of Health of Ukraine in 2018, there were 346,000 people who injected drugs in Ukraine. Alcohol consumption levels and smoking prevalence are also in general higher than in western countries. So, across Eastern Europe (Russia, Ukraine, Belarus and Lithuania), the proportion of deaths attributed to alcohol consumption comprises nearly one-third of them. Our results could be useful for other countries as well, and data on genetic associations with drug types would shed light on involvement of novel, traditionally overlooked pathways in dependence formation, and give some guidance to rehab specialists that want to use personalized medicine in treatment of their patients.

Potential Outcomes

The findings can indicate specific pathways, dysregulation of which contributes in distinct substance use disorders` development, and, in case of sufficient number of participants of different genders in all groups might reveal some gender-specific genetic effects. The availability of several psychological questionnaires data can shed light on some psychological patterns associated with the disorders. Our data on genetic variants associated with comorbid disorders can help rehab centres in patients` management, e.g. if they see a patient with one dependence and highly imbalanced psychological profiles and an increased number of risk alleles for another substance abuse, they can pay an increased attention to them and attempt to prevent their interest in another substance. However, we realize that in any case our findings will need to be replicated in independent and larger datasets, and are focused on understanding mechanisms rather than on prognosis.

Your budget

The following estimates for 300 individuals are approximate, since we intend to buy the reagents from different suppliers and in different currencies. Also, local companies in Ukraine can add to these values the cost of shipping and customs clearance. We estimate that buccal swabs will cost around 150 GBP, DNA extraction kits around 760 GBP, PCR reagents – 450 GBP (25 reagent mixes for 200 reactions each); primers, probes, and restriction endonucleases for genotyping – around 1250-1300 GBP. Hopefully, we will have enough agarose for DNA electrophoresis in our laboratory not to buy it for the loci genotyped using allele-specific and restriction fragment length polymorphism techniques. If we do not approach the target sum, we will likely take less participants or exclude some loci from further genotyping plan. Also, due to current pandemic situation, we may be unable to get the cheaper alternatives of some of the reagents, in such case we would either require a significantly bigger budget, or could allow a significantly shrinked cohort size.

In the unlikely case if we fit into a lower budget than we manage to collect, we will think whether we have ability to collect DNA samples from more individuals and apply for a grant that would cover GWAS, or to start sample collection for another project in psychiatric -omics, which is currently being planned by a part of the team (the latter option requires significantly more money, and the project will engage several cities in Ukraine and internationally. We are currently searching for grants that we could apply for, but we expect the issue to be a bit more achievable if we will at least work through the collection process and sample treatment).

Our team 

Vitalina Bashynska

Vitalina Bashynska (Bashinskaya) defended her PhD thesis in molecular biology at Pirogov Russian National Research Medical University, Moscow, Russia (12.2016). Currently works as researcher at Diagen genetic laboratory and as junior researcher at Laboratory of Epigenetics, Institute of Gerontology NAMS, Kyiv, Ukraine. Her main scientific interests lie in the area of complex disorders genomics, with focus on neuropsychiatric and autoimmune genetics. Apart from research on multiple sclerosis and substance use disorders genetics, Vitalina participates in a number of other research and industry projects, and coordinates setup of NGS platforms for clinical investigations in oncology and other biomedical applications in Diagen lab.

“It is a great honor to be a member of this research group and make a contribution to the development of Ukrainian science”

Oksana Zahorodnia

Oksana Zahorodnia is a senior year student of Bachelor programme in Biology at Taras Shevchenko National University of Kyiv, Ukraine. For today, Oksana reconciles her active undergraduate study and working at both Diagen molecular genetic laboratory and Geron epigenetic one, Kyiv, Ukraine. She is full of motivation and enthusiasm to investigate mental and neurodegenerative diseases, namely psychoactive substance dependencies, Alzheimer’s, Parkinson’s and Huntington’s disorders. In view of this, Oksana is excited to take active part in substance use disorder project and have a chance to broaden knowledge delving into such disciplines as Genetics and Neurobiology.

Yuliia Borysovych

Yuliia Borysovych is a senior year student of Bachelor programme in Biology at Taras Shevchenko National University of Kyiv. Yuliia successfully combines her undergraduate studies and work in Diagen molecular genetic laboratory, Kyiv, Ukraine. Furthermore, she is a Mitacs Globalink Research internship alumnus. Her main research interest is a complex influence of genetics in human disease formation, such as cancer and neurodegenerative diseases. For this reason, Yuliia is motivated and inspired to improve her knowledge of Genetic discipline by actively participating in a substance use disorder project.

Alexander Koliada

DIAGEN Laboratory Co-founder, Head of R&D department (since 03/2017), Longevity School Educational program Founder (since 01/2018). MSc in Genetics (2008). Has a number of research papers and reviews in areas of human and animal model genetics, epigenetics, ageing.

Daria Osichanskaya

Psychologist. Addictologist. Hypnologist. Transactional Analyst. Polarity Therapy Specialist.
The main activity profile is work with addicts. 6 years of practice.
Works in the Medlux clinic and in the departments of psychological assistance Medluxrehab

Nariman Darvishov

Clinical psychologist.
-Graduated from Taras Shevchenko National University of Kyiv with a master’s degree in clinical psychology.
– Studying client-centered psychotherapy in Ukrainian psychotherapy university.
-Ph.D. student in the department of clinical psychology and psychodiagnostics, Taras Shevchenko National University of Kyiv
-awardee of ITC 2018 (International test commission) scholarship
-Topics of scientific interests: cognitive neuroscience, personality psychology, decision-making process.
– Writing Ph.D. thesis on the topic “Psychological structure of substance addict’s decision-making “.

These are the core participants of the project as for today. The full list of authors will additionally include other researchers and physicians that contribute to some part of experimental work, provide access to rehab patients, or give consulting on statistical approaches that fit better to this study design.

References
https://wdr.unodc.org/wdr2019/en/exsum.html World Drug Report 2019
https://www.who.int/news-room/fact-sheets/detail/alcohol
WHO, “Report on the global tobacco epidemic, 2017: Monitoring tobacco use and prevention policies Geneva World Health,” Organization, 2017.
https://www.niaaa.nih.gov/publications/brochures-and-fact-sheets/women-and-alcohol
Ducci F, Goldman D. The genetic basis of addictive disorders. Psychiatr Clin North Am. 2012;35(2):495-519. doi: 10.1016/j.psc.2012.03.010.
Kora‐Mareen Bühler Elena Giné Victor Echeverry‐Alzate Javier Calleja‐Conde Fernando Rodriguez de Fonseca Jose Antonio López‐Moreno. Common single nucleotide variants underlying drug addiction: more than a decade of research. Addiction Biology, 2015; 20: 845– 871. doi: 10.1111/adb.12204.
Bashynska V, Koliada A, Murlanova K, Zahorodnia O, Borysovych Yu, Moseiko V, Lushchak O, Vaiserman A. Genetic risk factors for nicotine dependence in Ukraine: a population genetic study. Genetics Research International, 2019, Article ID 2483270. doi: 10.1155/2019/2483270
https://bioinfo.uth.edu/ancogenedb/

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