A researcher uses a pipette to load DNA samples into a gel, where the DNA will separate into visible bands. Credit: Paul Henderson
Rare Fat-Gene Mutations Were More Than 3x as Common in Anorexia Patients
In A Nutshell
- Patients with anorexia were more than three times as likely as a reference group to carry a rare, likely damaging mutation in PLIN4, a gene involved in fat storage (11% vs. 3.2%).
- Mutations also traveled through families: in 4 of 6 patients with the most severe type, a relative with an eating disorder carried the same one.
- Carriers were far more likely to have high blood fats (47% vs. 12%), matching what PLIN4 is known to do in the body.
- Routine PLIN4 testing isn’t warranted yet, since the results come from one clinic and need confirmation in other patient groups.
Many people with anorexia get no lasting benefit from current therapies and medications, the paper notes, which keeps researchers hunting for new biological clues. A new genetic study found one in an unexpected place: how cells store fat. Among 154 patients at one eating disorder clinic, 11% (roughly one in nine) carried a rare mutation predicted to damage a gene called PLIN4. In a large public genetic database of people of European ancestry, that figure was 3.2%, about one in 31. Patients were more than three times as likely to carry one of these mutations, a gap too large to blame on chance.
PLIN4 isn’t known for regulating appetite or mood. It’s mostly active in fat tissue and muscle, where it helps build the tiny droplets inside cells that store fat. A fat-storage gene turning up in patients raises a question: might part of anorexia be written into body chemistry, not only brain wiring?
A related gene, BBOX1, surfaced in an earlier study from the same group. BBOX1 helps cells move stored fat to where it gets burned for energy. Between the two genes, about 15% of 183 patients carried a rare damaging mutation, though the patient groups overlap.
Family History Led Researchers to the PLIN4 Anorexia Gene
A paper in Frontiers in Psychiatry describes how the work began with one family: a patient with treatment-resistant anorexia whose mother and two sisters had been diagnosed. Researchers read the protein-making portion of the family’s DNA and found 44 rare changes shared by every affected relative. Computer scoring flagged 32 as likely harmful, and PLIN4 stood out because of its known role in fat storage.
Researchers then checked those 32 genes in 154 unrelated patients at Precision Psychiatry, a specialty eating disorder clinic in Plano, Texas. Patients were offered testing if they had strong family histories, multiple failed treatments, or unusual symptoms. Nearly all were female and of European ancestry, and anorexia typically began around age 16.
Instead of recruiting healthy volunteers, researchers compared patients with gnomAD, a public database holding genetic data from hundreds of thousands of people. Testing 32 genes at once makes false alarms likely, so a strict statistical safeguard was applied. Only PLIN4 showed a higher mutation rate than chance would predict.
PLIN4 Mutations Clustered in Families With Anorexia
Removing the original family’s patient from the count changed little: 16 of the remaining 153 patients still carried a PLIN4 mutation. Four related genes, PLIN1, PLIN2, PLIN3, and PLIN5, showed no similar excess, pointing to PLIN4 specifically.
Six patients carried the most severe type of mutation, one predicted to stop the gene from working properly. In four of those six cases, a relative with anorexia or a related eating disorder carried the identical mutation: the original family’s mother and two sisters, plus an aunt, a mother, and a daughter in three other families. A mutation that travels through a family alongside an illness is a clue geneticists look for when judging whether a gene matters. On their own, those six did not pass the strict statistical test; the signal came from all 17 carriers combined. Lab experiments have not yet confirmed how the mutations change the protein.
Patients With PLIN4 Mutations Had More High Blood Fats
Other research has found that people with a knocked-out copy of PLIN4 tend to carry less fat on the hips and thighs, more around the belly, and higher levels of triglycerides, a type of fat in the blood.
Patients in this study fit the blood-fat part of that pattern. Eight of 17 carriers (47%) had been diagnosed with high blood fats, versus about 12% of the 137 patients without a mutation. That comparison came from medical records, not standardized lab tests, and 17 carriers is a small group.
Lead author Michael Lutter and colleagues add that patients with anorexia often show an aversion to dietary fat, and that weight regained during treatment in adults tends to settle around the abdomen. They speculate that extra belly fat could intensify body image distress, a core feature of anorexia, while noting it remains uncertain whether PLIN4 affects the brain side of the illness.
Routine Anorexia Gene Testing Isn’t Warranted Yet
Researchers were explicit that routine PLIN4 testing isn’t warranted. The result needs confirmation in independent patient groups, and the added risk from a single mutation remains unknown. The study also shows an association, not that PLIN4 mutations cause anorexia. Patients came from one clinic that sees many severe, treatment-resistant cases, so they may not represent anorexia patients overall. The team has contacted the Broad Institute’s Genetics of Eating Disorders Study, which aims to recruit 10,000 patients and 10,000 comparison volunteers, about replication.
Therapy and psychiatric care remain central to anorexia treatment, and this study doesn’t change that. Still, any biological foothold is worth pursuing, since a fat-handling difference could eventually help explain why some patients respond so poorly to treatment. PLIN4 is a lead, not an answer, and only replication in other patient groups will show whether it holds up.
Disclaimer: This article is for informational purposes only and is not medical advice. The research discussed reports a statistical association in a small group of patients and does not diagnose, predict, or treat any condition. Anyone concerned about an eating disorder, for themselves or someone else, should contact a qualified health professional.
Paper Notes
Limitations
Patients came from a single specialty clinic, skewed toward treatment-resistant cases, and were almost all of non-Finnish European ancestry, so results may not apply to anorexia patients generally. Patients and the gnomAD comparison group were recruited differently, which the authors say introduces potential bias and falls short of a matched case-control design. PLIN4 was singled out after studying one family, and its p-values do not reach the threshold used in genome-wide scans; the authors argue that a correction across their 32 candidate genes is the appropriate standard, and the result passes it. The most severe mutations alone did not pass that correction. Variants other than the most severe type were flagged as damaging by computer prediction tools, a method the authors acknowledge remains debated, and lab work is still needed to show how the mutations affect the PLIN4 protein. The gene also contains a repeating DNA segment that standard sequencing cannot fully capture, so some variation may have been missed. The blood-fat, onset-age, and BMI comparisons were descriptive, with no statistical correction. The 154 patients are a subset of the 183-patient group from the earlier BBOX1 study, so the two results are not fully independent. One earlier genome-wide study linked PLIN4 to anorexia, but its result did not reach genome-wide significance.
Funding and Disclosures
According to the paper, the work was supported by internal funds of Precision Psychiatry, with no external grant supporting the analysis. Corresponding author Michael Lutter is affiliated with Precision Psychiatry, the clinic where patients were recruited. The authors declared no commercial or financial relationships that could be construed as a conflict of interest and stated that generative AI was not used in creating the manuscript. The study was approved by the International Federation of Eating Disorder Dietitians Institutional Review Board.
Publication Details
The study, titled “Increased frequency of rare damaging variants in PLIN4 in patients with anorexia nervosa,” was authored by Michael Lutter (Precision Psychiatry, Plano, Texas), Lucas G. Casten and Jacob J. Michaelson (University of Iowa), Guido K. W. Frank (University of California, San Diego), Alenka Čopič (Centre de Recherche en Biologie Cellulaire de Montpellier, CNRS, France), and Michael S. Mazei-Robison and Alfred J. Robison (Michigan State University). It was published as original research in Frontiers in Psychiatry on October 8, 2026 (Volume 17, Article 1937613), edited by Urs Heilbronner of LMU Munich University Hospital. DOI: 10.3389/fpsyt.2026.1937613.
