Human genetic evidence challenges NCOA1 as a monogenic obesity gene

Obesity is a heterogeneous disease with a substantial genetic component. Rare pathogenic variants in genes of the leptin-melanocortin pathway can cause monogenic obesity and support targeted therapies such as setmelanotide, a melanocortin 4 receptor agonist. Pathogenic variants in NCOA1, encoding the nuclear receptor co-activator SRC-1, have recently been proposed as a cause of monogenic obesity through impaired leptin-induced POMC activation, leading to the inclusion of NCOA1 variant carriers in the EMANATE setmelanotide trial. However, despite biological rationale, the contribution of NCOA1 variants to human obesity remains elusive. Here, we assess NCOA1 variants with case-control analyses in adults and children from the RaDiO study, combined with in vitro assays and replication in the UK Biobank. We find no association between pathogenic NCOA1 variants and obesity or body mass index.