Could a Gut Hormone Hold Clues to ADHD?

A 2022 study in Scientific Reports uncovers a potential link between an ADHD-associated gene, a blood sugar hormone, and brain development — and it may change how we think about the biological roots of ADHD.

Here's something that might surprise you: the same hormone your gut releases to trigger insulin after a meal may also play a role in how the ADHD brain develops before birth.

That's the implication of a 2022 study published in Scientific Reports by researchers at Universidad del Norte and Universidad de Antioquia in Colombia. The paper takes a deep dive into the genetics of ADHD — specifically, a gene called ADGRL3 — and arrives at an unexpected finding: certain ADHD-linked genetic variants may disrupt how this gene interacts with a gut hormone called GIP, with potential consequences for brain development.

This is early-stage, computational research. No clinical recommendations come out of it yet. But the doors it opens are genuinely fascinating — and they shed new light on something many people with ADHD have quietly suspected: that ADHD isn't just about dopamine and focus. There may be a whole metabolic dimension to the story.

ADHD Is Genetic, But the Genetics Are Complicated

We know ADHD runs in families. Studies estimate it's about 74% heritable — meaning the majority of the reason ADHD develops comes down to genetics. That's a higher heritability than many conditions people commonly think of as "genetic."

And yet, when scientists have scanned the entire genome looking for risk genes using large population studies (called genome-wide association studies, or GWAS), those studies only explain about 21% of ADHD's heritability. There's a significant gap between what we know genes contribute and what we've actually been able to find and measure. Researchers call this the "missing heritability" problem, and it's one of the driving questions in ADHD genetics right now.

One of the genes that does show up consistently in ADHD research — across multiple countries, ethnicities, and study designs — is ADGRL3. You may have seen it listed by its older name, LPHN3, or latrophilin 3. This gene has been linked to ADHD susceptibility in populations from Colombia, the United States, Canada, Spain, Korea, and beyond. Variants in this gene have been associated not just with ADHD itself, but with how severe it is, whether it co-occurs with conduct disorder or substance use disorder, and how well patients respond to stimulant medication. It's one of the best-established genetic players in ADHD research.

But — and this is key — why it matters, and exactly how it affects the brain, has remained largely mysterious.

What Does ADGRL3 Actually Do?

Think of ADGRL3 as a molecular handshake specialist. It's a receptor protein that sits on the surface of neurons, helping brain cells recognize and communicate with each other. During brain development, ADGRL3 helps guide developing neurons to the right places, helps them form connections (synapses), and plays a role in maintaining the brain's wiring — especially in regions that control attention, impulse control, and executive function.

It's part of a family of receptors called G protein-coupled receptors (GPCRs) — essentially molecular switches that respond to signals from outside the cell and trigger responses inside it. The ADGRL3 protein has several distinct functional regions, called domains, each of which handles different jobs.

The Genetic Spelling Mistakes Linked to ADHD

DNA is written in a four-letter code. Most of the time, one-letter changes in that code (called single nucleotide polymorphisms, or SNPs) don't change anything meaningful — they're like changing a word's font without changing the word itself. But sometimes, a one-letter change swaps one amino acid building block for another in the resulting protein. These are called non-synonymous SNPs (nsSNPs), and they can meaningfully change how the protein folds, functions, and interacts with other molecules.

The researchers in this study focused on three specific nsSNPs in ADGRL3 that had already been reported in ADHD genetic studies across multiple populations: rs35106420, rs61747658, and rs734644.

Using six different computational tools, they assessed whether these variants were likely to be pathogenic — meaning actually harmful to protein function — rather than neutral quirks of individual genetic variation. The results were striking:

All three variants were predicted pathogenic by at least two tools. The variant rs35106420 was flagged as pathogenic by every single analytical tool used. Furthermore, the amino acid it affects (R533Q) sits at a position that has been almost perfectly conserved across species for hundreds of millions of years of evolution — meaning nature has been essentially saying "do not change this spot" for longer than mammals have existed. That kind of conservation is a strong signal that the position is critically important for function.

The researchers also found that all of these variants destabilize the ADGRL3 protein — they reduce its structural integrity, similar to removing a key support beam from a building. The protein doesn't fold quite right, which affects how it does its job.

The Unexpected Discovery: A Gut Hormone Connection

Part of the ADGRL3 protein is a region called the Hormone Receptor Domain (HRM). Despite its name, this particular domain of ADGRL3 had never been studied before in the context of ADHD. The researchers decided to take a close computational look at what molecules this domain naturally interacts with.

Using a technique called protein-protein docking — essentially a sophisticated 3D molecular puzzle where you figure out which molecules fit together — they tested the HRM domain against a range of candidate molecules. They used five different docking tools independently to make sure results were reproducible.

What they found was that the HRM domain appears to interact with GIP — the Glucose-dependent Insulinotropic Polypeptide, also known as the Gastric Inhibitory Polypeptide. This molecule consistently showed up as the best-fit binding partner for ADGRL3's hormone domain, across multiple computational approaches.

GIP is most famous for its role in blood sugar regulation. After you eat, your gut releases GIP, which tells the pancreas to secrete insulin. It's part of a system called the incretin response — the mechanism by which food-triggered gut hormones amplify the insulin response. GIP is, along with GLP-1, one of the most potent incretin hormones in the body. (This same system is targeted by some of the most widely discussed medications of recent years.)

But GIP doesn't only act in the gut and pancreas. It is also produced and active in the brain — specifically in the hippocampus, the cerebral cortex, and the cerebellum. And this is where the ADHD connection comes in.

GIP and the Developing Brain

Research in animal models has revealed that GIP plays a significant role in neurogenesis — the birth of new neurons and the growth of brain cells. In rats, GIP promotes the proliferation of progenitor cells in the hippocampal dentate gyrus, a region critical for memory, learning, and emotional regulation. When scientists removed the GIP receptor from mice entirely, hippocampal neurogenesis dropped significantly. Animals without functioning GIP receptor signaling showed impairments in learning, synaptic plasticity, and neurogenesis.

Consider those three words together: the hippocampus, synaptic plasticity, and neurogenesis. These are exactly the processes that go wrong in ADHD. Imaging studies — including major meta-analyses through the ENIGMA collaboration involving thousands of participants worldwide — have consistently found that individuals with ADHD have structurally smaller brain volumes in several regions, including the hippocampus, the caudate nucleus, the putamen, and the amygdala. These are also the regions where ADGRL3 is most highly expressed.

So here's the hypothesis this study puts forward: if the ADHD-linked variants in ADGRL3 destabilize the protein and disrupt its interaction with GIP at the HRM domain, then GIP signaling in the developing brain may be impaired. And if GIP signaling is impaired during the critical windows of fetal and early childhood brain development — when neurons are proliferating, migrating, and forming connections — this could contribute to the pattern of neurological differences we see in ADHD.

In other words: the path from gene variant → ADHD brain may run, at least partly, through a metabolic hormone.

Connecting the Dots: ADHD and Metabolic Health

If you've spent time in the ADHD community, you've probably noticed patterns. Many people with ADHD report intense reactions to hunger — a kind of crashing of focus and mood regulation when blood sugar drops. There are documented associations between ADHD and obesity, between ADHD and disordered eating, between ADHD and difficulty with interoception (reading your body's hunger and fullness cues).

Researchers have noticed the population-level connections too. Studies have found that children born to parents with Type 1 diabetes have a 29% higher risk of being diagnosed with ADHD. All three types of diabetes during pregnancy — Type 1, Type 2, and gestational diabetes — have been associated with increased ADHD risk in offspring. Adults with ADHD have a higher risk of developing diabetes than adults without ADHD. And PET scan studies have found that cerebral glucose metabolism — essentially how efficiently the brain uses sugar as fuel — is about 8% lower in people with ADHD compared to healthy controls.

These connections have long been observed without a clear mechanistic explanation. The ADGRL3-GIP hypothesis provides a possible molecular bridge: a gene critical to brain development that also, through its interaction with an incretin hormone, connects ADHD to the glucose regulation system.

The researchers also note a link to the Wnt/β-catenin signaling pathway, a fundamental pathway in brain development that has been separately implicated in ADHD. Wnt signaling has been shown to stimulate GIP production, and disruptions in Wnt-regulated pathways during neurodevelopment have been proposed as contributors to the ADHD phenotype. This suggests GIP may sit at an intersection of multiple developmental pathways relevant to ADHD.

What This Means — and What It Doesn't

It's important to be clear about what kind of study this is. All of the findings here are in silico — meaning they were generated through computational modeling and bioinformatics tools, not laboratory experiments or clinical trials. The researchers explicitly call for in vitro validation (actual lab experiments) as the essential next step.

Computational docking predicts that two molecules could interact in a biologically meaningful way. It doesn't prove they do so in living tissue, or that disrupting this interaction produces ADHD symptoms, or that addressing GIP signaling would treat ADHD. There is a long road between a computational prediction and a clinical application.

That said, computational studies like this one are valuable precisely because they do the molecular groundwork that makes experimental research tractable. By identifying which specific genetic variants matter, which protein domains are affected, and which molecular interactions are disrupted, this work gives laboratory researchers a focused and well-justified set of hypotheses to test.

Why This Matters for ADHD Understanding

This study contributes something important to the ADHD picture in several ways.

It deepens the genetic story. By showing that these known ADHD-linked variants in ADGRL3 are not just correlated with the disorder but are likely to be functionally damaging to the protein, it helps explain how — not just whether — this gene contributes to ADHD risk.

It opens a new mechanistic window. The HRM domain of ADGRL3 had never been studied in the context of ADHD. Identifying it as potentially relevant — and specifically relevant through a GIP interaction — introduces an entirely new mechanistic category to consider: metabolic signaling in neurodevelopment.

It offers a framework for the ADHD-metabolic comorbidity. The well-observed but poorly explained clustering of ADHD with diabetes, obesity, and glucose dysregulation now has a candidate molecular explanation that could be tested and built upon.

It suggests new therapeutic angles. If GIP signaling in the brain is genuinely disrupted in some forms of ADHD, GIP receptor pathways become a new category of potential therapeutic targets to explore — separate from the dopamine pathways that current medications address. This doesn't mean existing diabetes drugs treat ADHD; it means there are new questions worth asking.

The Bigger Picture

ADHD research is entering an exciting era. For decades, the story was primarily told in terms of dopamine and attention. What's emerging is a much more complex picture — one where genetics, metabolism, hormones, brain development, sex differences, and environmental factors are all woven together.

The ADGRL3-GIP connection is one thread in that emerging tapestry. It reminds us that the developing brain doesn't form in isolation from the body's metabolic systems — that the hormones regulating blood sugar and digestion also participate in the building of the brain. And it suggests that the "missing heritability" of ADHD may be hiding in exactly these kinds of unexpected intersections between systems we tend to think of as separate.

There's still a great deal we don't know. But that's precisely why research like this matters.

A Note on the Study

"ADGRL3 genomic variation implicated in neurogenesis and ADHD links functional effects to the incretin polypeptide GIP" was published in Scientific Reports in 2022 (Vol. 12, Article 15922) by Oscar M. Vidal, Jorge I. Vélez, and Mauricio Arcos-Burgos at Universidad del Norte and Universidad de Antioquia, Colombia. It is open access under the Creative Commons Attribution 4.0 License. No competing interests were declared.

At ADHD Awearness, we believe understanding the biology behind ADHD — however complex — leads to better empathy, better treatment, and better lives. If this post raised questions, brought something into focus for you, or just made you think, share it with someone who might need it.