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Genetic Signature for Drug Addiction Revealed in New Analysis of More Than A Million Genomes

Drug addiction is prevalent and deadly. In the US in 2021, more than 46 million people aged 12 or older had addiction to at least one substance, yet only 6.3% received treatment, according to the National Institute on Drug Abuse (NIDA).

A complex mix of gene variants and environmental factors lies behind the compulsion to repeatedly take a drug and increase the dose, despite knowing the dangers. Environmental influences are well known. Now a report in Nature Mental Health from an international team led by researchers at Washington University in St. Louis fills in the genetics side of the picture. They have identified shared points of variability among more than a million human genomes that track with substance use disorders.

Centered on Receptors

People have ingested mind-altering substances from nature for millennia. Modern understanding of why we do so began in the 1970s with descriptions of the receptor proteins on cells to which the substances bind. That event triggers a response – a cascade of enzyme activity, opening surface channels for ions underlying an electrical response – that prompts the cell to release the pleasure-associated neurotransmitter dopamine.

A trio of papers from 1973 reported discovery of opiate receptors, hypothesized to exist in 1954. Poppies make opium, people make opioid drugs, and a human body makes endorphins, which are peptides (short proteins) that bind the opiate receptors. Narcan (naloxone) works by plugging opiate receptors.

The first receptor identified was the nicotinic acetylcholine receptor, in 1959. In 1988 came discovery of the cannabinoid receptor.

Genes encode the proteins that serve as receptors, many of which snake through a cell membrane in seven characteristic loops. Genes also encode proteins that control the metabolism of synthesizing and breaking down receptor parts as well as dismantling drug molecules. So scrutinizing genomes for genes that control drug dependency could inspire treatments. That’s the goal of the new report.

Gene Mapping’s Awful Abbreviations: From RFLPs to SNPs to GWAS to PRS

Geneticists are known for inventing terribly non-memorable and non-pronounceable names for gene mapping. “Restriction fragment length polymorphism” was one of the first, and one of the worst. But it led to today’s ways of tracking variability at the genome level.

“RFLPs” are sites in a DNA sequence where a bacterial enzyme, called a restriction enzyme, cuts. Different enzymes cut at different short sequences. For a time, RFLP mapping overlapped the pieces, revealing gene orders. In 1987, the approach enabled construction of the first human genome map, which laid the groundwork for one method of sequencing an entire genome.

The 1990s saw the race to sequence “the” human genome. Of course, there’s no such thing as “a” human genome – we vary quite a bit. (See The Age of the Pangenome Dawns, here at DNA Science from a few months ago.)

As the first genomes were being sequenced, researchers began identifying the sites where the 4 DNA bases vary among individuals. That lead to another unpronounceable term, single nucleotide polymorphisms, aka SNPs. This is a single-base site in a genome that varies – an adenine (A) in one person, perhaps a guanine (G), cytosine (C), or thymine (T) in another. Genomes are riddled with them.

As researchers assembled and tracked sets of SNPs, a new way of interrogating a genome emerged: the genome-wide association study, or GWAS.

A GWAS generates an avalanche of data, but the idea is straightforward: it identifies patterns of SNPs among the 23 chromosome pairs that are found statistically significantly more often among individuals with a particular trait (or illness) than among individuals who do not have it. A GWAS can encompass millions of SNPs – a human genome has more than 10 million. The first SNP map was published in 2001 and the first GWAS in 2005. SNP patterns can trace a “signature” of tendency to become dependent on a substance.

Because GWAS data are so complex, yet another term and abbreviation arose, the polygenic risk score, in 2007. A PRS summarizes the input of many SNPs and GWAS.

The New Findings

The researchers’ meta-analysis of GWAS represents 1,025,550 people of European descent and 92,630 individuals with African ancestry. They identified 19 genome regions that harbor genes associated with general risk of addiction, as well as 9 for alcohol, 32 for tobacco, 5 for cannabis, and 1 for opioids. Such genes might encode receptors or proteins involved in drug metabolism. A highly significant gene is PDE4B, which regulates dopamine. The finding confirms the role of the neurotransmitter in addiction and highlights a potential drug target.

Lead author Alexander Hatoum described the significance of the findings. “Using genomics, we can create a data-driven pipeline to prioritize existing medications for further study and improve chances of discovering new treatments. To do this accurately, it’s critical that the genetic evidence we gather includes globally representative populations and that we have members of communities historically underrepresented in biomedical research leading and contributing to these kinds of studies.”

But the African ancestry part of the study revealed only one SNP associated with general addiction risk and one substance-specific SNP for risk of alcohol use disorder. The African sample may not have represented the genetic diversity of people with African ancestry, which is considerably greater than that of white Europeans who have traditionally been the subject of most genetic studies. Genetically speaking, past emphasis on the restricted genomes of white people makes little sense.

The new study also reveals genetic patterns that predict addiction to two or more substances, as well as elevated risk of mental and physical illnesses, including psychiatric disorders, suicidal behavior, respiratory disease, heart disease, and chronic pain conditions. “The shared genetic mechanisms between substance use and mental disorders revealed in this study underscore the importance of thinking about these disorders in tandem,” said National Institute of Mental Health director Joshua A. Gordon.

Added Nora Volkow, director of NIDA, which funded the study with other NIH centers, the investigation could “illuminate factors that may protect or predispose a person to substance use disorders, knowledge that can be used to expand preventative services and empower individuals to make informed decisions about drug use. A better understanding of genetics also brings us one step closer to developing personalized interventions that are tailored to an individual’s unique biology, environment, and lived experience in order to provide the most benefits.”

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