Biotechnical development of genetic addiction risk score (GARS) and selective evidence for inclusion of polymorphic allelic risk in substance use disorder (SUD)

Abstract

Research into the neurogenetic basis of addiction identified and characterized by Reward Deficiency Syndrome (RDS) includes all drug and non-drug addictive, obsessive and compulsive behaviors. We are proposing herein that a new model for the prevention and treatment of Substance Use Disorder (SUD) a subset of RDS behaviors, based on objective biologic evidence, should be given serious consideration in the face of a drug epidemic. The development of the Genetic Addiction Risk Score (GARS) followed seminal research in 1990, whereby, Blum's group identified the first genetic association with severe alcoholism published in JAMA. While it is true that no one to date has provided adequate RDS free controls there have been many studies using case -controls whereby SUD has been eliminated. We argue that this deficiency needs to be addressed in the field and if adopted appropriately many spurious results would be eliminated reducing confusion regarding the role of genetics in addiction. However, an estimation, based on these previous literature results provided herein, while not representative of all association studies known to date, this sampling of case- control studies displays significant associations between alcohol and drug risk. In fact, we present a total of 110,241 cases and 122,525 controls derived from the current literature. We strongly suggest that while we may take argument concerning many of these so-called controls (e.g. blood donors) it is quite remarkable that there are a plethora of case -control studies indicating selective association of these risk alleles ( measured in GARS) for the most part indicating a hypodopaminergia. The paper presents the detailed methodology of the GARS. Data collection procedures, instrumentation, and the analytical approach used to obtain GARS and subsequent research objectives are described. Can we combat SUD through early genetic risk screening in the addiction field enabling early intervention by the induction of dopamine homeostasis? It is envisaged that GARS type of screening will provide a novel opportunity to help identify causal pathways and associated mechanisms of genetic factors, psychological characteristics, and addictions awaiting additional scientific evidence including a future meta- analysis of all available data -a work in progress.

Keywords: dopamine. brain reward circuitry; genetic addiction risk score (gars®); precision addiction management (pam®); reward deficiency syndrome (rds); substance use disorder (sud).

Figure 1.

The brain reward cascade (BRC). Figure1 illustrates the interaction of at least six principal neurotransmitter pathways involved in the Brain Reward Cascade (BRC). In the hypothalamus, environmental stimulation causes the release of serotonin, which in turn via, for example, 5HT-2a receptors activate (green, equal sign) the subsequent release of opioid peptides also in the hypothalamus. Then, in turn, the opioid peptides having two distinct effects possibly via two different opioid receptors: A) inhibits (red hash sign) through the mu-opioid receptor (possibly via enkephalin) and projects to the Substania Nigra to GABA_A neurons B) stimulates (green equal sign) Cannabinoid neurons (e.g., Anandamide and 2-archydonoglcerol) through Beta –Endorphin linked delta receptors, which in turn inhibits GABA_A neurons at the substania nigra. Cannabinoids primarily 2-archydonoglcerol, when activated, can also indirectly disinhibit (red hash sign) GABA_A neurons in the Substania Nigra through activation of G1/0 coupled to CB1 receptors. Similarly, Glutamate neurons located in the Dorsal Raphe Nuclei (DRN) can indirectly disinhibit GABA_A neurons in the Substania Nigra through activation of GLU M₃ receptors (red hash sign). GABA_A neurons, when stimulated, will, in turn, powerfully (red hash signs) inhibit VTA glutaminergic drive via GABAB ₃ neurons. Finally, Glutamate neurons in the VTA will project to dopamine neurons through NMDA receptors (green, equal sign) to preferentially release dopamine at the Nucleus Accumbens (ACH)shown as a bullseye indicating euphoria (a wanting response)

Figure 2.

Pipelines for meta-analyses, functional SNP annotations and interaction analyses (with permission)

Figure 3.

GARS panel

Figure 4A.

Single nucleotide polymorphisms (SNPs)

Figure 4B.

Simple sequence repeats (Variable number tandem repeats and insertion/deletions)

Figure 4C.

Dinucleotide repeats

Figure 5.

GARS single nucleotide polymorphism assays information

Figure 6.

GARS repeats primer details

Figure 7.

Provides a simple schematic portraying our proposal