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Genome Wide Sequencing Compared to Candidate Gene Association Studies for Predisposition to Substance Abuse a Subset of Reward Deficiency Syndrome (RDS): Are we throwing the Baby Out with the Bathwater?

Kenneth Blum, Eric R. Braverman, Florian Kreuk, Kristina Dushaj, Mona Li, Debmayla Barh, and Marlene Oscar-Berman

In 1990 Blum, Noble and associates utilized a candidate approach to associate the first genetic polymorphic association with severe alcoholism that was published in JAMA. This experiment was based on a “blue print” of the reward circuitry proposed as the “brain Reward Cascade”. Impairment of this system leads to aberrant substance seeking behavior. Over the last five years newer and more sophisticated techniques have been developed, including whole genome sequencing, as well as exome sequencing. While there are different schools of thought regarding appropriate approaches to dissecting a very complex disorder known as Reward Deficiency Syndrome (RDS) as an umbrella term for all addictions, future approaches may combine both genome sequencing with gene candidates. Importantly, GWAS/WES generally provides the most value for highly penetrant, rare alleles and as such may not currently be as informative as the candidate gene approach. However, since there is convergence of GWAS and neurotransmitter clusters including specific genes (e.g. DRD1, DRD2, DAt1, etc.) albeit small contributions for each gene, thousands of studies have elucidated risk alleles to RDS behaviors. Thus, we are proposing herein that we should not hasten to “throw out the baby with the bathwater”, because genetic addiction risk stratification depends upon the current candidate gene analysis.