Analyzing human knockouts to validate GPR151 as a therapeutic target for reduction of body mass index

Novel drug targets for sustained reduction in body mass index (BMI) are needed to curb the epidemic of obesity, which affects 650 million individuals worldwide and is a causal driver of cardiovascular and metabolic disease and mortality. Previous studies reported that the Arg95Ter nonsense variant of GPR151, an orphan G protein-coupled receptor, is associated with reduced BMI and reduced risk of Type 2 Diabetes (T2D). Here, we further investigate GPR151 with the Pakistan Genome Resource (PGR), which is one of the largest exome biobanks of human homozygous loss-of-function carriers (knockouts) in the world. Among PGR participants, we identify eleven GPR151 putative loss-of-function (plof) variants, three of which are present at homozygosity (Arg95Ter, Tyr99Ter, and Phe175LeufsTer7), with a cumulative allele frequency of 2.2%. We confirm these alleles in vitro as loss-of-function. We test if GPR151 plof is associated with BMI, T2D, or other metabolic traits and find that GPR151 deficiency in complete human knockouts is not associated with clinically significant differences in these traits. Relative to Gpr151(+/+) mice, Gpr151(-/-) animals exhibit no difference in body weight on normal chow and higher body weight on a high-fat diet. Together, our findings indicate that GPR151 antagonism is not a compelling therapeutic approach to treatment of obesity. Author summaryHuman genetics studies can provide compelling targets for therapeutic intervention. While some therapeutic targets, such as PCSK9, are based on extensive genetic validation, many others are based on weaker associations with variants of unknown consequence that require further validation. Recent publications reported associations between loss of GPR151 function and low body mass index (BMI), raising the possibility of inhibiting GPR151 for the treatment of obesity and metabolic syndromes. To evaluate the relationship between GPR151 and BMI, we (1) identified and experimentally confirmed loss-of-function variants present in the Pakistan Genome Resource (PGR) biobank, one of the world's largest biobanks of human gene "knockouts", (2) analyzed these loss-of-function variants individually and in burden tests for association with BMI and other metabolic traits or diseases, and (3) verified the evolutionary conservation of our findings in mice lacking Gpr151. We observe that GPR151 loss does not affect BMI to a clinically relevant extent and conclude that inhibiting GPR151 may not be effective at treating obesity.