On May 15, 2025, researchers at the Translational Genomics Research Institute (TGen), part of City of Hope, announced they have identified several genetic variants related to the accumulation of liver fat in normal-weight individuals, a population often overlooked in studies of metabolic liver disease.

Their findings, published in JHEP Reports, provide a glimpse into possible genetic determinants of metabolic dysfunction-associated steatotic liver disease or MASLD.

MASLD and its severe progressive form, metabolic dysfunction-associated steatohepatitis (MASH), are typically associated with obesity, but the new study emphasizes that the underlying biology of the disease is much more complex than its relationship with body mass index (BMI).

“Our findings reveal genetic factors for MASLD that exist regardless of weight,” said Johanna K. DiStefano, Ph.D., a professor in TGen’s Early Detection and Prevention Division, head of its Metabolic Disease Research Unit, and senior author of the paper. “This challenges the common belief that thin individuals are inherently healthier.”

Formerly known as non-alcoholic fatty liver disease, MASLD affects about 30% of the global population, a number that is expected to nearly double by 2040. People with MASH have a greater risk of deadly and disabling conditions such as fibrosis, cirrhosis, and hepatocellular carcinoma.

The researchers analyzed data from 10,918 normal weight people (with a BMI less than 25) in the UK Biobank in a genome-wide association study, looking for variants related to excess fat in liver cells. DiStefano and her colleagues performed further fine genome mapping and gene expression studies to help them focus on the specific variants that could potentially cause liver fat accumulation.

Future studies should look for these variants and others in a more diverse population, he noted, since the UK Biobank participants are predominantly of European ancestry. But there are few existing databanks that include both detailed genetic data and liver fat measurements for a large number of non-European individuals with a normal BMI.