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

Ruth Hanssen; Chiara Auwerx; Maarja Jõeloo; Marie C Sadler; Estonian Biobank Research Team; Elana Henning; Julia Keogh; Rebecca Bounds; Miriam Smith; Helen V Firth; Zoltán Kutalik; I Sadaf Farooqi; Alexandre Reymond; Katherine Lawler

doi:10.1016/j.xcrm.2023.101155

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

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

Authors

Affiliations

¹ University of Cambridge Metabolic Research Laboratories, Wellcome-MRC Institute of Metabolic Science and NIHR Cambridge Biomedical Research Centre, Addenbrooke's Hospital, Cambridge CB2 0QQ, UK.
² Center for Integrative Genomics, University of Lausanne, 1015 Lausanne, Switzerland; Department of Computational Biology, University of Lausanne, 1015 Lausanne, Switzerland; Swiss Institute of Bioinformatics, 1015 Lausanne, Switzerland; University Center for Primary Care and Public Health, 1010 Lausanne, Switzerland.
³ Institute of Molecular and Cell Biology, University of Tartu, 51010 Tartu, Estonia; Estonian Genome Centre, Institute of Genomics, University of Tartu, 51010 Tartu, Estonia.
⁴ Department of Computational Biology, University of Lausanne, 1015 Lausanne, Switzerland; Swiss Institute of Bioinformatics, 1015 Lausanne, Switzerland; University Center for Primary Care and Public Health, 1010 Lausanne, Switzerland.
⁵ Estonian Genome Centre, Institute of Genomics, University of Tartu, 51010 Tartu, Estonia.
⁶ Department of Clinical Genetics, Cambridge University Hospitals NHS Foundation Trust & Wellcome Sanger Institute, Cambridge, UK.
⁷ University of Cambridge Metabolic Research Laboratories, Wellcome-MRC Institute of Metabolic Science and NIHR Cambridge Biomedical Research Centre, Addenbrooke's Hospital, Cambridge CB2 0QQ, UK. Electronic address: isf20@cam.ac.uk.
⁸ Center for Integrative Genomics, University of Lausanne, 1015 Lausanne, Switzerland. Electronic address: alexandre.reymond@unil.ch.
⁹ University of Cambridge Metabolic Research Laboratories, Wellcome-MRC Institute of Metabolic Science and NIHR Cambridge Biomedical Research Centre, Addenbrooke's Hospital, Cambridge CB2 0QQ, UK. Electronic address: kl229@cam.ac.uk.

Abstract

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.

Keywords: 16p11.2; CNVs; SH2B1; UK Biobank; obesity; precision medicine; type 2 diabetes.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adaptor Proteins, Signal Transducing
Diabetes Mellitus, Type 2* / genetics
Humans
Insulins*
Leptin
Metabolic Diseases*
Obesity / genetics

Substances

Leptin
Insulins
SH2B1 protein, human
Adaptor Proteins, Signal Transducing