Objective. Rare variants in DYRK1B have been described in some patients with central obesity, type 2 diabetes and early-onset coronary disease. Due to the limited number of conducted studies, the broader impact of DYRK1B variants on a larger scale has yet to be investigated. Research Design and Methods. DYRK1B was sequenced in 9,353 participants from a case-control study for obesity and type 2 diabetes. Each DYRK1B variant was functionally assessed in vitro. Variant pathogenicity was determined using criteria from the American College of Medical Genetics and Genomics (ACMG). The effect of pathogenic or likely pathogenic (P/LP) variants on metabolic traits was assessed using adjusted mixed-effects score tests. Results. 65 rare, heterozygous DYRK1B variants were identified and were not associated with obesity or type 2 diabetes. Following functional analyses, 20 P/LP variants were pinpointed, including six variants that exhibited a fully inhibitory effect (P/LP-null) on DYRK1B activity. P/LP and P/LP-null DYRK1B variants were associated with increased body mass index and obesity risk; however, the impact was notably more pronounced for the P/LP-null variants (effect of 8.0±3.2 and odds ratio of 7.9 [1.2-155]). Furthermore, P/LP-null variants were associated with higher fasting glucose and type 2 diabetes risk (effect of 2.9±1.0 and odds ratio of 4.8 [0.85-37]), while P/LP variants had no effect on glucose homeostasis. Conclusions. P/LP, total loss-of-function DYRK1B variants cause monogenic obesity associated with type 2 diabetes. This study underscores the significance of conducting functional assessments in order to accurately ascertain the tangible effects of P/LP DYRK1B variants.
