Cell Rep Med.: auth.: group Reymond

Cell Rep Med. 2023 Aug 15;4(8):101155.
doi: 10.1016/j.xcrm.2023.101155.

Chromosomal deletions on 16p11.2 encompassing SH2B1 are associated with accelerated metabolic disease

Ruth Hanssen 1Chiara Auwerx 2Maarja Jõeloo 3Marie C Sadler 4Estonian Biobank Research Team 5Elana Henning 1Julia Keogh 1Rebecca Bounds 1Miriam Smith 1Helen V Firth 6Zoltán Kutalik 4I Sadaf Farooqi 7Alexandre Reymond 8Katherine Lawler 9


New approaches are needed to treat people whose obesity and type 2 diabetes (T2D) are driven by specific mechanisms. We investigate a deletion on chromosome 16p11.2 (breakpoint 2-3 [BP2-3]) encompassing SH2B1, a mediator of leptin and insulin signaling. Phenome-wide association scans in the UK (N = 502,399) and Estonian (N = 208,360) biobanks show that deletion carriers have increased body mass index (BMI; p = 1.3 × 10-10) and increased rates of T2D. Compared with BMI-matched controls, deletion carriers have an earlier onset of T2D, with poorer glycemic control despite higher medication usage. Cystatin C, a biomarker of kidney function, is significantly elevated in deletion carriers, suggesting increased risk of renal impairment. In a Mendelian randomization study, decreased SH2B1 expression increases T2D risk (p = 8.1 × 10-6). We conclude that people with 16p11.2 BP2-3 deletions have early, complex obesity and T2D and may benefit from therapies that enhance leptin and insulin signaling.