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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\n                    <jats:italic>GPR151<\/jats:italic>\n                    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\n                    <jats:italic>in vitro<\/jats:italic>\n                    as loss-of-function. We test if\n                    <jats:italic>GPR151<\/jats:italic>\n                    plof is associated with BMI, T2D, or other metabolic traits and find that\n                    <jats:italic>GPR151<\/jats:italic>\n                    deficiency in complete human knockouts is not associated with clinically significant differences in these traits. Relative to\n                    <jats:italic>Gpr151<\/jats:italic>\n                    <jats:sup>\n                      <jats:italic>+\/+<\/jats:italic>\n                    <\/jats:sup>\n                    mice,\n                    <jats:italic>Gpr151<\/jats:italic>\n                    <jats:sup>\n                      <jats:italic>-\/-<\/jats:italic>\n                    <\/jats:sup>\n                    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.\n                  <\/jats:p>","DOI":"10.1371\/journal.pgen.1010093","type":"journal-article","created":{"date-parts":[[2022,4,5]],"date-time":"2022-04-05T13:53:16Z","timestamp":1649166796000},"page":"e1010093","update-policy":"https:\/\/doi.org\/10.1371\/journal.pgen.corrections_policy","source":"Crossref","is-referenced-by-count":4,"title":["Analyzing human knockouts to validate GPR151 as a therapeutic target for reduction of body mass 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