Evaluation of the Genetic Association Between Adult Obesity and Neuropsychiatric Disease.

Abstract

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 (<i>n</i> = 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 (<i>n</i> = 218) and obesity (O) (BMI 35-50 kg/m²; <i>n</i> = 374) and a Swedish cohort of participants from the community with predominantly O (<i>n</i> = 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]; <i>P</i> < 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]; <i>P</i> = 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.