Genetic analysis of extreme obesity

Abstract

Obesity is an increasing health problem worldwide as a result of the changing environment, with calorie-dense food and a sedentary lifestyle. However, numerous twin studies indicate that genetics plays a significant role in determining which individuals become obese or stay lean while sharing the same ‘obesogenic’ environment. Genetic research in obesity has two major goals: the first being to elucidate the pathophysiological basis of obesity, and the second is to provide an evidential foundation for personalised medicine. An obesity cohort was established, consisting of over a thousand severely-obese individuals (mean BMI 48.1 kg/m2 [± 8.67 SD]) undergoing bariatric surgery, as the basis for genetic and phenotypic analysis of the severely obese. The relatively high proportion of metabolically-healthy, but severely-obese individuals in this cohort illustrated some of the many unknown pathophysiological mechanisms, while a consistent increase of public distress among the more severely obese confirmed the ongoing stigmatisation of the obese in UK society. Screening for the most common form of Mendelian obesity, MC4R deficiency identified a lower than anticipated prevalence (0.77%) in the bariatric cohort, but analysis of treatment outcomes indicated that bariatric surgery both (RYGB and VSG) is effective for the individuals affected. Lifestyle intervention for children with MC4R deficiency, on the other hand, appeared to have less beneficial outcomes long term. Using whole exome sequencing on 40 super-obese bariatric participants, a higher than anticipated prevalence of putative Mendelian obesity (20.5%) was found, including several novel disruptive variants in known obesity genes. Finally, a novel Mendelian obesity and diabetes syndrome was detected, in a consanguineous family with a complex obesity phenotype, caused by a homozygous truncating mutation of the CPE gene (c.76_98del; p.Glu26ArgfsX68).