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By Michelle Yang

For genetic disorders such as sickle cell anemia or Huntington’s disease, doctors have often focused on how effectively patients’ symptoms can be managed. Recently, scientists have discovered how to address them at their root cause. 

But what happens when we try to treat genetic mutations that don’t necessarily qualify as disorders? Even as we’re researching them, scientists still aren’t quite sure. 

In Feb. 2025, researchers from Mie University in Japan developed a method for removing the third copy of chromosome 21, the structure responsible for causing Down syndrome, through the gene editing tool Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR). CRISPR allows scientists to pinpoint targets in DNA that may contain a mutation and remove them using an enzyme called Cas-9. 

The use of CRISPR-based gene editing, which biochemist Dr. Jennifer Doudna pioneered in 2012, is “probably one of the top ten discoveries in human history, from a biomedical field,” according to Dr. Danith Ly, a professor of chemistry at Carnegie Mellon. 

Down syndrome is the most common chromosomal form of intellectual and physical disability, resulting in large deficits in cognitive and motor development. If CRISPR can be applied in clinical use to treat Down syndrome, it could impact one in 691 people born. 

Using CRISPR-based therapies to treat conditions such as Down syndrome, however, comes with a host of financial, ethical, and accessibility concerns. 

For one, they are expensive. Casgevy, the only FDA-approved CRISPR therapy to treat sickle cell anemia, costs $2.2 million per patient. Lenmeldy, another gene therapy, is the most expensive drug in the United States, costing $4.25 million per patient. 

The reason for these high costs, Dr. Ly explained, is due to the amount of funding required to go through clinical testing and use. Performing clinical trials may “cost anywhere from half a billion to a couple billion dollars” and take anywhere from five to 10 years on top of how long it takes for therapies to get approved for use. 

The currently approved gene therapies work “ex vivo”, meaning they are given to blood cells outside of a person’s body that then circulate throughout their system. These genetic changes last as long as the blood cells are alive, making them impermanent. 

However, the proposed therapy for Down syndrome takes place at the embryonic level, which means parents have to go through IVF for the procedure to take place. “And you come back to, ‘Who can afford this?’” says Dr. Stephanie Wong-Noonan, a professor of biology at Carnegie Mellon. “It’s going to be inaccessible unless there’s some way to support that, either through making it easier to produce the product, or providing some kind of government funding so that it doesn’t cost people so much.”

Embryonic changes also affect the genome itself — meaning that its revisions will affect all future generations. That means a mistake in the editing, “even a 0.1 percent difference, will not only change you in your lifetime, but your children down the road,” Dr. Ly said. 

There’s also the question of the extent to which CRISPR-based treatments should be used. While not many therapies are approved now, Dr. Ly acknowledges that this “technology will eventually be perfected, and I think the more options we have, the better off we will be. The scientific community really embraces the idea, but we just don’t know.”

“If you can correct one thing, you can correct everything. And the question is always where you draw the line,” Dr. Wong-Noonan said. “What things will we correct? Or should we correct? There are lots of morally gray areas when it comes to these types of technologies.” 

And maybe there’s not meant to be a clear answer. “CRISPR is never 100 percent, right, and understandably so. In evolution, there’s always a blurry line,” Dr. Ly said. “And maybe that’s a part of evolution. It’s designed to generate diversity as we progress through life.”

New genetic evidence suggests that targeting GIPR and GLP1R could reduce harmful drinking patterns while improving liver and metabolic health, opening the door to repurposing existing metabolic drugs for alcohol use disorders.

Study: Genetically modeled GLP1R and GIPR agonism reduce binge drinking and alcohol-associated phenotypes: a multi-ancestry drug-target Mendelian randomization study. Image Credit: Voyagerix / Shutterstock

A recent study published in the journal Molecular Psychiatry investigated whether genetically proxied agonism of glucagon-like peptide 1 receptor (GLP1R) and glucose-dependent insulinotropic polypeptide receptor (GIPR) influences alcohol use disorder (AUD) and problematic alcohol use (PAU) behaviors.

The therapeutic potential of GLP1R agonists and dual GIPR/GLP1R agonists (henceforth, GIPR/GLP1R) extends beyond metabolic diseases, such as obesity and diabetes. Growing evidence suggests that these therapies may also address AUD and substance use disorders (SUDs). GLP1R agonists have been promising in decreasing drug and alcohol intake.

Preclinical evidence indicates GIPR agonism influences weight regulation and glucose metabolism. Further, genetic variants in GIPR are linked to alcohol dependence, highlighting its relevance in addiction biology. Moreover, GIPR/GLP1R agonists exhibit superior metabolic efficacy than GLP1R agonists alone, underscoring the potential synergistic effects of targeting both.

About the study

The present study assessed whether genetically proxied GLP1R and GIPR agonism influences AUD and PAU behaviors using drug-target Mendelian randomization (MR). GIPR and GLP1R were instrumented using body mass index (BMI) and glycated hemoglobin (HbA1c) data, as these traits capture the core effects of their agonists.

Single-nucleotide polymorphisms (SNPs) located within 500 kilobases of the GLP1R locus and associated with HbA1c levels in European ancestry participants of the United Kingdom Biobank (UKB) were used to investigate GLP1R agonism. GLP1R and GIPR instruments were separately developed using BMI genome-wide association study (GWAS) data.

BMI and HbA1c instruments for GIPR and GLP1R were aggregated into single instruments capturing both loci to model the effects of GIPR/GLP1R agonists. To validate instruments, their associations with obesity and type 2 diabetes (T2D) were examined for each exposure. Further, the proportion of individuals carrying at least one activation allele at GLP1R and GIPR loci was estimated in European, African, and East Asian populations. Findings were replicated in independent datasets, supported by colocalization analyses, and tested with multiple sensitivity instruments to strengthen causal inference.

A comprehensive set of alcohol-related outcomes was curated to assess the therapeutic potential of GIPR and GLP1R agonism. The primary analysis focused on PAU; in addition, distinct alcohol intake behaviors were examined.

Drinks-per-week results were largely null in European ancestry participants, suggesting effects may concentrate on binge/heavy patterns. Moreover, alcohol misuse classes identified through latent class analysis of over 410,000 UKB participants were incorporated to explore in-depth how GIPR and GLP1R activity may differentially affect drinking behaviors.

Relationships with other SUDs, including cannabis (CUD), opioid (OUD), and tobacco (TUD) use disorders, and food liking behaviors were also investigated. Further, six liver-related outcomes were analyzed; these were alcohol-related liver disease (ALD), non-alcoholic fatty liver disease (NAFLD), and liver enzymes: alkaline phosphatase, gamma-glutamyl transferase (GGT), and alanine aminotransferase (ALT), and aspartate aminotransferase.

This study used summary-level GWAS data relating to glycated hemoglobin (HbA1c) and body mass index (BMI) to construct genetic instruments modeling GLP1R and GIPR agonism. We constructed three instrument types: one that proxies GLP1R agonism, one that proxies GIPR agonism, and one combined instrument that proxies dual GLP1R and GIPR agonism. Each instrument type included multiple exposure sources mimicking the expected physiological responses to pharmacological modulation of the targets (lowered glycated hemoglobin [HbA1c], reduced body mass index [BMI], and GLP1R or GIPR gene expression in the cortex). Instrument sets for each BMI and HbA1c exposure were constructed in two independent GWAS summary statistics (UK Biobank [plus GIANT for BMI] and the Million Veterans Program [MVP]). After instrumentation and validation with the primary clinical indications for GLP1R and GIPR agonism (type 2 diabetes and obesity), and assessing their impact on liver health, we obtained a selection of outcomes related to alcohol use disorder (AUD) and alcohol consumption behavior to assess the impact of GLP1R and GIPR agonism. We contextualized the alcohol-related analyses by analyzing other substance use disorders and investigating outcomes related to self-reported food liking. Because of the availability of large sample sizes and the most relevant endpoints, we used data from European ancestry as the main analysis set, but we also performed analyses using East Asian and African ancestry data sources. Finally, for all drug-target MR estimates demonstrating evidence of a relationship (main drug-target MR method P < 0.05), we performed colocalization analyses to assess evidence of shared causal variants between the biomarker exposures and outcomes in the GLP1R and GIPR genomic loci. MR Mendelian Randomization, GLP1R Glucagon-like peptide-1 receptor, GIPR glucose-dependent insulinotropic polypeptide receptor, NAFLD Non-alcoholic fatty liver disease, ALD Alcohol-related liver disease, SNP Single nucleotide polymorphism, BMI Body mass index.

Findings

For GLP1R agonism, genetically proxied reductions in BMI via GLP1R showed consistent associations with a decreased risk of obesity; lower HbA1c levels were also associated with a reduced risk of type 2 diabetes (T2D).

For GIPR agonism, genetically proxied reductions in BMI by GIPR variants were robustly associated with a lower obesity risk; lower HbA1c levels via GIPR were similarly protective against type 2 diabetes (T2D). For GIPR/GLP1R agonism, lower BMI through both receptor activation substantially reduces the risk of obesity.

Similarly, lower HbA1c levels via the GIPR/GLP1R loci were associated with a lower risk of T2D. Receptor-activating alleles at both GLP1R and GIPR loci showed high prevalence across populations. However, modest ancestry-specific variation was evident. Further, there was evidence for lower binge drinking linked to BMI lowering through GIPR/GLP1R. Consistent reductions were observed with BMI lowering through GIPR alone, but not with GLP1R.

Further, genetically lowered HbA1c via GIPR/GLP1R was associated with 38% reduced odds of broad heavy drinking with psychiatric comorbidities compared to light drinking behavior. When analyzed separately, both GLP1R and GIPR also showed protective associations with heavy-risk drinking classes. CUD, OUD, and TUD analyses provided consistent null results.

However, genetically lowered BMI via GIPR/GLP1R showed robust associations with food preferences, especially vegetarian and fatty foods. BMI lowering via GIPR/GLP1R was associated with a lower preference for fatty foods and an increased preference for vegetarian foods. These effects were primarily driven by GIPR and were stronger for BMI-linked instruments than for HbA1c. HbA1c lowering via GIPR/GLP1R also exhibited beneficial relationships with a liking for vegetarian food, albeit this impact was less consistent and generally weaker.

HbA1c lowering by GIPR/GLP1R variants was associated with lower NAFLD, and GIPR primarily drove this relationship. No association was observed for alcohol-related liver disease (ALD). Notably, GIPR or GLP1R showed no relationship with ALD. Further, HbA1c lowering via GIPR/GLP1R was consistently associated with lower ALT and GGT, which were mainly driven by GIPR. BMI lowering by GIPR variants also showed similar protective relationships with liver enzymes.

Given the robust protective associations with heavy drinking behavior and documented links between cardiovascular disease and these behaviors, the researchers used two-step MR to investigate whether alcohol intake reductions mediate the cardioprotective effects of GLP1R and GIPR agonism on coronary artery disease (CAD) risk.

This study showed that lowering BMI via GIPR/GLP1R reduces CAD risk, whereas binge drinking increases the risk, and that approximately 12.6% of the GIPR/GLP1R effect and 12.2% of the GIPR effect on CAD risk were mediated through reduced binge drinking.

Exploratory analyses in non-European cohorts were underpowered and largely directionally consistent, so firm locus-specific conclusions could not be drawn.

Conclusions

In summary, the results highlight the therapeutic potential of GIPR and GLP1R agonism, particularly in targeting GIPR/GLP1R, in improving liver health and reducing PAU behaviors. The observed benefits underscore the potential of these agents to address the burden of AUDs and metabolic comorbidities.

The authors interpret BMI-anchored associations as more consistent with behavioral or CNS-linked pathways, and HbA1c-anchored associations as more consistent with metabolic pathways, while noting that mechanistic confirmation requires clinical trials. The study also notes that genetic models cannot capture drug-specific effects, underscoring the need for future clinical trials to test translation.