The findings, published in Nature Communications, suggest that MASLD can develop through several different biological pathways. Some subtypes are closely linked to obesity and diabetes, while others appear to be influenced by genetic differences.

One of the most important discoveries involves the genetic form of the disease. These subtypes may be more likely to progress to advanced liver damage, even in people who do not have the metabolic risk factors commonly associated with fatty liver disease.

Identifying these differences could eventually help doctors recognize vulnerable patients sooner, improve screening, and select treatments based on the biological processes driving each person’s disease.

“When clinical and genomic data are analyzed together at this scale, we begin to see patterns of disease progression that would normally remain hidden,” said co-senior author Dr. Shulan Tian, a bioinformatician at Mayo Clinic. “Separating these subtypes allows us to match treatments to the biology that is actually causing the disease.”

Why fatty liver disease can become dangerous

MASLD, formerly known as non-alcoholic fatty liver disease, occurs when excess fat accumulates in the liver. Many people have no noticeable symptoms, allowing the condition to remain undetected for years.

Fatty liver disease does not always cause serious complications, but it can progress to inflammation, scarring, and permanent liver damage. In severe cases, it can lead to cirrhosis, a condition in which extensive scarring prevents the liver from functioning properly.

MASLD is the leading cause of cirrhosis, liver cancer, and liver transplantation worldwide. Understanding why some patients develop severe complications while others do not has therefore become an important research goal.

Genetic analysis reveals five MASLD subtypes

To investigate differences among patients, the research team analyzed genetic sequencing results alongside extensive medical information from more than 4,600 people diagnosed with MASLD.

The analysis included liver enzyme measurements, body mass index, blood lipid levels, and other indicators of metabolic health. Researchers also considered additional conditions, including diabetes, depression, and sleep apnea.

Using advanced computer models, the researchers searched for patterns linking patients with similar genetic characteristics and clinical findings. This approach revealed five distinct groups, each with its own underlying biological characteristics.

The results suggest that people with the same diagnosis of fatty liver disease may actually have substantially different forms of the condition, along with different risks of developing serious complications.

“What we’re seeing here is a way to systematically identify meaningful subgroups within a complex disease,” said co-senior author Eric Klee, Ph.D., the Everett J. and Jane M. Hauck Midwest Research and Innovation Associate Director. “It will help us map complex diseases with great precision, allowing us to predict their course and intervene before the most serious damage occurs.”

How large-scale DNA research made the discovery possible

The researchers used Mayo Clinic’s Research Data Atlas, a system designed to connect patients’ genetic information with detailed medical records. Combining these large datasets can reveal relationships that may be difficult to identify when studying individual patients.

Dr. Klee helped develop the platform, which leverages resources such as Tapestry Research.

The project created Mayo Clinic’s largest exome data collection, including more than 100,000 participants. The exome is the part of a person’s DNA that contains instructions for making proteins involved in many essential body functions. Studying exome data can reveal genetic differences that influence how diseases begin and progress.

Combining genetic information with medical history allows researchers to examine diseases in greater detail and potentially identify differences that traditional diagnostic methods cannot detect.

“This is exactly the kind of insight that large-scale genomic studies are built to provide,” said Dr. Konstantinos Lazaridis, executive director of the Carlson & Nelson Center for Individualized Medicine. Dr. Lazaridis led the Tapestry study and co-authored the research. “By combining genetic data with detailed clinical information across large populations, we can begin to redefine disease in ways that directly impact patient care.”

Links between MASLD, depression, sleep apnea, and migraines

The findings also suggest that differences among MASLD subtypes extend beyond the liver.

Researchers identified associations between specific MASLD subtypes and conditions or symptoms such as depression, sleep apnea, and migraines.

These associations suggest that the biological processes underlying certain forms of fatty liver disease may be connected to health problems affecting multiple parts of the body.

However, the study does not prove that fatty liver disease directly causes depression, sleep apnea, or migraines. Instead, the findings highlight the potential connections between liver health and other biological systems.

Could personalized treatment improve fatty liver disease care?

The discovery could eventually change how doctors assess and treat MASLD. Rather than treating all patients as though they have the same disease, clinicians could use genetic and clinical information to identify specific subtypes and determine which complications are most likely to occur.

This approach could be especially valuable for identifying patients with genetic forms of MASLD associated with severe liver damage, including people who have relatively few traditional metabolic risk factors.

The research team plans to evaluate the findings in a larger, more diverse patient population. Scientists also want to determine whether the subtypes respond differently to available treatments, including GLP-1 receptor agonists, a type of drug used to treat conditions such as type 2 diabetes and obesity.

If future studies confirm these differences, the findings could help move fatty liver disease care toward more accurate screening, earlier intervention, and treatments tailored to each patient’s underlying biology.