Population analysis of ~459,000 UK Biobank participants shows that carriers of neurodevelopmental CNVs (ND-CNVs) have higher odds of co-occurring internalizing (depression, anxiety, somatic) and cardiometabolic conditions (hypertension, dyslipidemia, obesity, T2D, CKD). Effects are stronger for deletions than duplications, greater in females, and linked to the number of haploinsufficient genes within deletions.
0:00Welcome to Base by Base, the papercast that brings genomics to you wherever you are. Thanks for listening, and don't forget to follow and rate us in your podcast app. Imagine a patient walks into a clinic at say, age 55.
0:13Okay, pretty standard age for some health issues to pop up. Right. But they get diagnosed with severe depression and type 2 diabetes on the exact same day. Oh, wow. That is a rough day. Yeah, it really is.
0:25And under our current medical system, their doctors will likely send them to 2 entirely different specialists, you know, like located in 2 completely different buildings. Yeah, treating them as 2 totally unrelated misfortunes.
0:37Exactly. But what if the doctors are missing the underlying story? Like, what if both of those life-altering diseases were triggered by the exact same microscopic missing piece of DNA? A piece that just vanished from their genome before they were even born.
0:51Right, because we have known for years that certain rare genetic variants cause early childhood conditions, uh, like autism or EDHD. Yeah, those early neurodevelopmental impacts. But the real mystery here is what really happens when these rare genetic variants shape not just our neurodevelopment, but our physical and mental health as we age.
1:10Today, we celebrate the work of Iowana K Ketsuru, Marianne Van Den Brie, the LINC consortium, and their colleagues at Cardiff University and Partner Institutions who have advanced our understanding of how rare genomic variations impact multimorbidity risk.
1:26It is such an important study. It really is. The research is titled, Neurodevelopmental copy number variants, increase risk of internalizing and cardio metabolic multimorbidity. Findings from the UK bio bank.
1:38It was published in the American Journal of Human Genetics on June 4, 2026. And for those keeping track, the DOI is 10.101 Sane, J...ajhg.2026.021. And the reason we're doing a deep dive into this today is because this team essentially mapped out a hidden biological bridge, right?
1:58Yes, exactly. They finally connected those childhood genetic diagnoses to adult chronic diseases. It fundamentally challenges the whole timeline of how we view human health. It really does. So let's just strip away the clinical terminology for a 2nd because the scale of the problem they are addressing is just staggering.
2:16Staggering is the right word for it. They focus on this thing called ICMMM, which stands for internalizing and cardiomatabolic multimorbidity. It's quite a mouthful. Yeah, it is. But in practical terms, It just means someone is battling a mental health disorder, like depression, anxiety or a somatic symptom disorder, while simultaneously fighting a physical metabolic condition.
2:37Right, like hypertension or obesity, or type 2 diabetes, or even chronic kidney disease. And the thing is, this happening at the same time isn't just some rare statistical anomaly. Oh, far from it. I mean, multimorbidity is a global public health crisis.
2:53Current estimates show that at least 50000000 people are affected in the European Union alone. Wow, 50 million. Yeah. And in high income countries, you're looking at roughly a quarter of the adult population living with 2 or more chronic conditions.
3:04That is wild. But the combination of an internalizing condition, with a cardio metabolic one that is uniquely destructive, because of how these systems interact biologically. Right, because they feed off each other in this kind of physiological loop.
3:19Exactly. It's a vicious cycle. Because it's not just about the psychological burden of managing a chronic illness, even though that alone is huge. There is a systemic biological mechanism going on. Right, like systemic inflammation.
3:32Yes. Poor metabolic health, like severe obesity or insulin resistance, actually triggers systemic inflammation, and that inflammation can cross the blood brain barrier. Which is wild to think about. It physically alters neurotransmitter function and drives depressive symptoms.
3:48Exactly. And then on the flip side, severe anxiety or depression chronically elevates stress hormones. Like cortisol. Right, cortisol. Which then directly tells the body to store visceral fat and resist insulin.
3:59So it's literally a biological downward spiral. And that biodirectional loop just ruins a person's quality of life. It slashes life expectancy, and frankly, places an unsustainable burden on healthcare infrastructure.
4:12Yeah, totally unsustainable. Yeah. But historically, when science looked for the genetic architecture behind these adult diseases like diabetes or anxiety, they mostly looked at common genetic variants.
4:23Right. Right. The tiny single nucleotide changes, just a single letter difference in the genetic code that is super widespread across the general population. But this deep dive shifts the focus entirely.
4:35We're talking about structural variants known as copy number variants, or CNVs. Yes, CNVs are a whole different beast. I want to make sure the mechanics of a CNV are crystal clear for everyone. Let's think of the human genome not as a book, but as a massive city power grid.
4:51Oh I like that analogy. So a common genetic variant is sort of like a flickering street limp. If you have enough flickering street lamps across town, The lighting is poor. That represents a gradual accumulation of risk.
5:03Annoying, but the city keeps running. Right, but a copy number variant is entirely different. It is not a street lamp. It is a blown substation. Boom. Exactly. A huge section of the grid is either completely missing, or maybe an extra substation was built where it shouldn't be, causing these massive power surges.
5:22That is an incredibly apt biological framing. And in this study specifically, the researchers targeted NDCNVs, neurodevelopmental copy number variants. Right, because for decades, the medical field only paid attention to these blown substations when they caused profound immediate disruptions in early childhood.
5:41Yeah, we're talking about severe intellectual disabilities or early onset schizophrenia. But the fundamental question here. The whole reason for this study was what happens to the people who carry these rare structural variants into later adulthood.
5:55Do these massive missing chunks of the genome serve as the hidden biological mechanism driving that devastating mind body loop we just talked about? And to find that answer, they needed just a mountain of longitudinal data.
6:07Which is where the UK bio bank comes in. Exactly. It's this massive perspective cohort study. They tracked over 500,000 participants who were recruited between the ages of 40 and 69. It's an absolute gold mine for this kind of epidemiology.
6:21It is. So they filtered for high quality genetic profiles, which left them with roughly 459,000 individuals. Okay, so nearly half a 1000000 people. Right. And within that group, they found 7,549 people, which is about one.
6:3662% who carried a rare NDCMV. Okay, so a small percentage, but a very significant absolute number. Definitely. They then mapped those specific genetic profiles against decades of electronic healthcare records.
6:50They pulled data from primary care visits, hospital admissions, all of it, just to track the onset of those physical and mental conditions. Which is brilliant, but I have to stop you here because I think a lot of people will have the same question.
7:02Okay, hit me. How do you even separate the effect of this one rare missing piece of DNA from all the other common genetic risk as a person has accumulated? I mean, what if they just have a heavy family history of diabetes?
7:14How do you know the rare variant is actually the culprit? That is the critical question, right? It addresses the central challenge in modern genetic epidemiology. Because everyone has a baseline level of genetic risk built from 1000s of those common flickering street lamps.
7:28Exactly. So to solve this, the researchers used polygenic risk scores or PRSs. A PRS is basically a mathematical summary of all the common genetic variants a person carries that influence a specific trait.
7:41Like blood pressure or body mass index. So wait, they calculated a personalized background risk for every single participant. They did for almost half a 1000000 people. That is wild computing power. It is.
7:54And to make sure those scores were accurate. They used a highly advanced Besian algorithm called PRS CS. Okay, PRSCS. How does that work? Simply put. Think of the algorithm, like a really sophisticated sound engineer, trying to isolate a single vocal track in a recording of a full symphony orchestra.
8:11Oh, I see. The algorithm applies something called a continuous shrinkage prior. In plain English, it systematically shrinks or mutes the volume of all that complex background genetic noise. That makes perfect sense.
8:24So by mathematically controlling for every participant's common polygenic risk for obesity or depression, the researchers could isolate the true standalone biological signal coming from the rare variant.
8:37Exactly. They turned down the orchestra so they could hear the soloist. And that level of statistical isolation is super necessary, because structural variants don't all behave the same way. Right. They categorize the affected genes based on something called dosage sensitivity.
8:52Yeah, they mapped out whether the genes inside these variants were haply insufficient or triple sensitive. Let's break down the biology of that for a second. Yeah please do. If a gene is happily insufficient.
9:04It means the human body absolutely requires 2 working copies of it to function normally. Like a vital backup system. Exactly. So if a deletion removes one copy, that single remaining copy just cannot produce enough protein to maintain biological stability.
9:17The system crashes. Okay, and what about triple sensitive? That's the reverse. The body cannot tolerate an extra copy. Producing too much of a certain protein throws off the delicate balance within the cell, and that leads to dysfunction.
9:31This categorization is so cool because it moves the research beyond just noticing that a piece of DNA is altered. It actually begins to ask how that specific alteration mechanically breaks the cell. Right.
9:44It gets to the Y and the how. So if the Bayesian algorithm successfully muted the background genetic noise, what was the actual signal from these rare variants? What were the key findings? The numbers here are pretty striking.
9:57The data showed that carrying an NDCMV increases the likelihood of suffering from both mental and metabolic conditions by roughly 25%. 25% increase. Just from that one missing or duplicated piece. Right.
10:09In raw numbers, 14.2% of people with an NDC and V had this multimorbidity compared to 11.5% of people without one. Which might not sound like a massive gap initially, but when applied to a population of millions, that percentage jump translates to a huge number of patients requiring intense complex care.
10:26The human impact is profound. And it's worth noting that the risk increase wasn't uniform across all 8 conditions they looked at. Right. There were specific combinations that spiked. Exactly. The odds spiked highest for combinations like internalizing conditions, paired with obesity, or type 2 diabetes, or chronic kidney disease.
10:46This clustering is super informative. Because it suggests that the genes disrupted by these rare variants operate on shared biological pathways. Yes, pleotropic pathways. Pleotropy. He is a concept we don't talk about enough.
10:59It's this idea that a single gene can influence multiple, completely, seemingly unrelated traits. Right, it's doing double duty. Exactly. A gene that helps build a receptor in your brain's dopamine reward circuit might also be critical for building the filtration tubules in your kidneys.
11:16So if that gene gets deleted, you don't just get an isolated symptom. You get cascading failures across totally different organ systems. It makes so much sense when you look at it that way. And the researchers also uncovered some really interesting demographic nuances, specifically regarding biological sex.
11:32Yeah, the female participants who carried these rare variants face a noticeably higher risk for developing both type 2 diabetes and internalizing conditions compared to the males with the exact same variants.
11:43Which is fascinating. It points to a really complex interaction between structural variants and sex hormones, like estrogen. Estrogen plays a huge role in both metabolic regulation and neuroprotection.
11:56There is clearly still so much to uncover there. But going back to the mutations themselves. The data presented a really clear distinction between deletions and duplications. Right, losing genetic material proved to be far more dangerous here than gaining it.
12:09Missing those happily insufficient genes, the ones where you absolutely need 2 copies, directly drove the risk for severe obesity and depression. Well, having extra copies didn't show the same consistent driving effect.
12:20Right. And they actually pinpointed the geography of where these missing pieces cause the most damage. Deletions on the short arm of chromosome 16 were major culprits. Specifically, the region known as 16 P 11.2.
12:32Yes, 16 P 11.2. That chromosomal neighborhood must be incredibly important for that mind body connection we keep talking about. It is highly pleotropic. We already knew that missing this section is strongly associated with early onset severe obesity and various neurodevelopmental challenges.
12:50But the researchers were careful, right? They anticipated that this one specific famous variant might be skewing their overall results. Exactly. To test the robustness of their findings, they ran a sensitivity analysis where they just completely removed all the individuals carrying the 16 P 11.2 deletion from the data set.
13:09Oh, wow. So did the connection to multimorbidity disappear without it? Nope. The association remain highly significant, which means the elevated risk is widespread across multiple different rare variants distributed throughout the genome?
13:21It's not just one infamous deletion. It's a fundamental consequence of broad structural genetic disruption. Precisely. That actually brings me back to the polygenic risk scores, because the interaction, or rather, the lack of interaction between the common risk and the rare variant, was the absolute aha moment for me in this deep dive.
13:39Yeah, this part is brilliant. They ran the analysis to see if a high background risk amplified the rare variant, or if a low background risk offered some sort of protection. And what did they find? Absolutely no interaction.
13:52Wait, none. None. Statistically and biologically, it demonstrates high penetrance. The rare NDCNV operates on an entirely independent track from common genetic risks. So let me get this straight. A patient might have phenomenal genetic luck regarding their common variants.
14:09Like their background polygetic risk score for type 2 diabetes could be in the lowest possible percentile. But if they happen to inherit or spontaneously develop one of these rare neurodevelopmental deletions.
14:22That low background risk is totally irrelevant. The structural variant bypasses the normal polygenic pathways and forces the biological system toward multimorbidity all on its own. It singlehandedly punches a hole right through their health defense.
14:34So if a rare variant can do that. If it can force lifelong physical and mental illness, regardless of your background risk, how can our medical infrastructure continue to operate the way it does? It really can't, not effectively.
14:47The current system relies heavily on clinical silos. Right, you see a psychiatrist for your anxiety. And an endocrinologist for your diabetes. And they almost never communicate. They treat the symptoms as completely separate entities rather than downstream effects of the exact same blown genetic substation.
15:05The clinical implications of this deep dive demand a total restructuring of care. This research proves that we need proactive, multidisciplinary medicine. What does that look like in practice? Consider the timeline.
15:17Today, because of better genetic screening, a child might be diagnosed with an NDC and V because they present with developmental delays or autism. In the past, the medical intervention would focus exclusively on the pediatric neuro development.
15:31But this study dictates that the care cannot stop there. They need a holistic approach. Exactly. Doctors cannot just treat the neurodevelopmental symptoms that child's pediatrician and eventually their adult GP must implement lifelong monitoring for blood pressure anomalies, kidney function, and glucose regulation.
15:50Because the genetic fuse for adult multimorbidity is already lit. Yes. It gives physicians a decades long head start for preventative care. It functions as an early warning system. And because these variants can be inherited, the implications extend way beyond just the individual patient, it affects their whole family.
16:09That is a crucial point. Some individuals carry an NDCNV, but experience reduced penetrance during childhood. Meaning the genetic trait doesn't fully manifest into severe developmental symptoms when they're young.
16:22Right. So they might go their whole lives unaware they carry the variant, only to be struck by severe depression and metabolic disease in their 50s. So identifying a pro band, you know, the 1st affected person in a family could initiate was called cascade screening.
16:37Exactly. Offering proactive cardiovascular and metabolic care to seemingly unaffected relatives who might silently carry the variant. That level of proactive screening is definitely the ideal outcome here, but I think any robust scientific discussion has to acknowledge the limitations of the data.
16:54For sure. And the researchers were very transparent about this. They highlight a critical concept known as survival bias. which is just inherent in massive cohorts like the UK Biobank. Right, because volunteering for a long-term health study requires a certain baseline of health and stability to begin with.
17:11Yeah, the participants naturally skew older, wealthier, and healthier than the general population. So, if having a severe structural variant combined with early onset multimorbidity, drastically reduces your life expectancy.
17:25The patient suffering the absolute worst effects of these mutations likely didn't survive into their 60s to volunteer for the study. Right. The most severe outcomes are just entirely missing from the data set.
17:36Exactly. The healthy volunteer effect masks the true mortality of the condition. So that 25% increased risk of multimorbidity they documented. That should really be interpreted as a conservative lower bound estimate.
17:49Wow. Yeah. In the broader real world population, the physiological toll of these rare variants is undoubtedly much, much higher. That is sobering, but the biological reality is undeniable, even when we were only measuring the healthiest survivors.
18:03Absolutely. So to try and synthesize the main takeaways from this deep dive for you all. Rare genetic structural variations, which were long categorized solely as drivers of childhood brain development issues, actually possess a profound lifelong reach.
18:19Yes they do. By disrupting shared biological pathways. These missing or duplicated pieces of DNA significantly increase a person's vulnerability to suffering from simultaneous, overlapping physical and mental, chronic illnesses decades later.
18:34It bridges the gap. Understanding this genetic bridge is the necessary 1st step toward treating the entirety of a patient's biology over their lifespan, rather than just reacting to isolated symptoms. The mechanistic link is no longer a mystery.
18:47We possess the genetic data and the statistical tools to identify the risk long before the chronic conditions manifest. So what does this mean for how we design our healthcare systems to treat the whole patient, rather than just treating isolated symptoms in separate rooms?
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