Chromosomal deletions on 16p11.2 encompassing SH2B1 are associated with accelerated metabolic disease
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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.
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2666-3791
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Wellcome Trust (207462/Z/17/Z)
Cambridge University Hospitals NHS Foundation Trust (CUH) (146281)
Department of Health (via National Institute for Health Research (NIHR)) (NF-SI-0616-10065)