To test these hypotheses in an independent cohort, we interrogated very rare variants (MAF < 0.025%) in TAOK2, DCHS1, and FAT4 in approximately 50,000 exomes from UK Biobank (Methods) using a case–control approach for severe obesity (n = 925 cases, BMI > 40 kg/m2; n = 46,673 controls, BMI ≤ 40 kg/m2). Here, TAOK2 is linked to obesity due to melanocortin 4 receptor deficiency.