Evaluation of the Genetic Association Between Adult Obesity and Neuropsychiatric Disease

Diabetes. 2019 Dec;68(12):2235-2246. doi: 10.2337/db18-1254. Epub 2019 Sep 10.


Extreme obesity (EO) (BMI >50 kg/m2) is frequently associated with neuropsychiatric disease (NPD). As both EO and NPD are heritable central nervous system disorders, we assessed the prevalence of protein-truncating variants (PTVs) and copy number variants (CNVs) in genes/regions previously implicated in NPD in adults with EO (n = 149) referred for weight loss/bariatric surgery. We also assessed the prevalence of CNVs in patients referred to University College London Hospital (UCLH) with EO (n = 218) and obesity (O) (BMI 35-50 kg/m2; n = 374) and a Swedish cohort of participants from the community with predominantly O (n = 161). The prevalence of variants was compared with control subjects in the Exome Aggregation Consortium/Genome Aggregation Database. In the discovery cohort (high NPD prevalence: 77%), the cumulative PTV/CNV allele frequency (AF) was 7.7% vs. 2.6% in control subjects (odds ratio [OR] 3.1 [95% CI 2-4.1]; P < 0.0001). In the UCLH EO cohort (intermediate NPD prevalence: 47%), CNV AF (1.8% vs. 0.9% in control subjects; OR 1.95 [95% CI 0.96-3.93]; P = 0.06) was lower than the discovery cohort. CNV AF was not increased in the UCLH O cohort (0.8%). No CNVs were identified in the Swedish cohort with no NPD. These findings suggest that PTV/CNVs, in genes/regions previously associated with NPD, may contribute to NPD in patients with EO.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Comorbidity
  • DNA Copy Number Variations*
  • Female
  • Gene Frequency
  • Genetic Association Studies
  • Genetic Predisposition to Disease*
  • Humans
  • Male
  • Mental Disorders / epidemiology
  • Mental Disorders / genetics*
  • Middle Aged
  • Obesity / epidemiology
  • Obesity / genetics*
  • Polymorphism, Single Nucleotide
  • Sweden
  • Whole Exome Sequencing