Genetic Variation in the Mitochondrial Glycerol‐3‐Phosphate Acyltransferase Is Associated With Liver Injury

Background and Aims Most of the genetic basis of chronic liver disease remains undiscovered. Approach and Results To identify genetic loci that modulate the risk of liver injury, we performed genome‐wide association studies on circulating levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), and total bilirubin across 312,671 White British participants in the UK Biobank. We focused on variants associated with elevations in all four liver biochemistries at genome‐wide significance ( P < 5 × 10 −8 ) and that replicated using Mass General Brigham Biobank in 19,323 European ancestry individuals. We identified a genetic locus in mitochondrial glycerol‐3‐phosphate acyltransferase ( GPAM rs10787429) associated with increased levels of ALT ( P = 1.4 × 10 −30 ), AST ( P = 3.6 × 10 −10 ), ALP ( P = 9.5 × 10 −30 ), and total bilirubin ( P = 2.9 × 10 −12 ). This common genetic variant was also associated with an allele dose‐dependent risk of alcohol‐associated liver disease (odd ratio OR = 1.34, P = 2.6 × 10 −5 ) and fatty liver disease (OR = 1.18, P = 5.8 × 10 −4 ) by International Classification of Diseases, 10th Revision codes. We identified significant interactions between GPAM rs10787429 and elevated body mass index in association with ALT and AST ( P = 7.1 × 10 −9 and 3.95 × 10 −8 , respectively), as well as between GPAM rs10787429 and weekly alcohol consumption in association with ALT, AST, and alcohol‐associated liver disease ( P = 4.0 × 10 −2 , 1.6 × 10 −2 , and 1.3 × 10 −2 , respectively). Unlike previously described genetic variants that are associated with an increased risk of liver injury but confer a protective effect on circulating lipids, GPAM rs10787429 was associated with an increase in total cholesterol ( P = 2.0 × 10 −17 ), LDL cholesterol ( P = 2.0 × 10 −10 ), and HDL cholesterol ( P = 6.6 × 10 −37 ). Single‐cell RNA‐sequencing data demonstrated hepatocyte‐predominant expression of GPAM in cells that co‐express genes related to VLDL production ( P = 9.4 × 10 −103 ). Conclusions Genetic variation in GPAM is associated with susceptibility to liver injury. GPAM may represent a therapeutic target in chronic liver disease.