Discovery of gene deletions and duplications associated with severe obesity
Final Report Abstract
The growing obesity epidemic represents one of the biggest challenges mankind is facing in the 21st century increasing the risk of severe health problems like cardiovascular disease or cancer. Family, twin, and adoption studies have consistently demonstrated that 40%– 70% of the variation in body weight between people living in a given environment can be explained by genetic factors. Finding the genes, whose disruption causes obesity, can not only provide a diagnosis for patients but also informs future precision medicine therapy approaches. In this project, we investigated the contribution of deletions (loss of a certain part of a chromosome and hence the genes on this part of the chromosome) to the development of obesity and associated metabolic impairments. This project built on previous work, where Professor Farooqi and her team demonstrated that the deletion of a certain area of chromosome 16 (specifically chromosome 16p11.2 breakpoint (BP) 2 to BP 3) was associated with severe early-onset obesity and severe insulin resistance, which is an early stage in the development of type 2 diabetes mellitus, in children. Interrogating deletions in Professor Farooqi’s discovery set of ~700 UK Caucasian patients from the Genetics of Obesity Study (GOOS) cohort, we recovered this deletion as one of the most frequent deletions in this earlyonset obesity cohort. We further detected a surprisingly high number of carriers of this deletion in further clinical children cohorts. The clinical consequences of this deletion in adulthood remained, however, unclear. Of the nine genes involved the 16p11.2 BP2-3 deletion, SH2B1 is suggested to cause the observed early-onset obesity. SH2B1 (Sarcoma homology 2 (SH2) B adaptor protein 1) is an adaptor molecule relevant for insulin, leptin, and Brain–Derived Neurotrophic Factor (BDNF) signaling and its loss in mice causes obesity, high blood sugar values and fatty liver disease. We have identified 79 carriers of this SH2B1 encompassing deletion on chromosome 16 in the population-based cohorts UK Biobank and Estonian biobank. Compared to non-carriers, deletion carriers had a higher rate early-onset obesity and early-onset type 2 diabetes, which was difficult to treat. Deletion carriers also had more diabetes-associated co-morbidities. Due to the role of SH2B1 in Epo-signialing, which is important for blood cell formation, deletion carriers had higher rates of anaemia. There was also evidence of lower cognitive function and social isolation in deletion carriers, which can be explained by the relevance of SH2B1 in BDNF-Signaling in the brain. Collectively, our results are of direct clinical consequence: Current clinical guidelines suggest that people with severe obesity of early-onset (before the age of 5 years) should be offered genetic testing. These testing methods should include the testing for deletions on chromosome 16. Chromosomal deletions may be identified by a range of physicians, who organize genetic testing. As people with SH2B1 deficiency have an accelerated form of metabolic disease, it is important that people with this disorder are referred to and managed by Paediatric Endocrinologists or Endocrinologists so that insulin sensitizers and other glucose lowering agents can be started at a young age to limit the impact of poor glycemic control on subsequent complications.
Publications
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Chromosomal deletions on 16p11.2 encompassing SH2B1 are associated with accelerated metabolic disease. Cell Reports Medicine, 4(8), 101155.
Hanssen, Ruth; Auwerx, Chiara; Jõeloo, Maarja; Sadler, Marie C.; Henning, Elana; Keogh, Julia; Bounds, Rebecca; Smith, Miriam; Firth, Helen V.; Kutalik, Zoltán; Farooqi, I. Sadaf; Reymond, Alexandre & Lawler, Katherine
