Evaluation of the Genetic Association Between Adult Obesity and Neuropsychiatric Disease

• Published in: Diabetes (New York, N.Y.) Vol. 68; no. 12; pp. 2235 - 2246
• Main Authors: Stahel, Priska, Nahmias, Avital, Sud, Shawn K., Lee, So Jeong, Pucci, Andrea, Yousseif, Ahmed, Youseff, Alaa, Jackson, Timothy, Urbach, David R., Okrainec, Allan, Allard, Johane P., Sockalingam, Sanjeev, Yao, Tony, Barua, Moumita, Jiao, Hong, Magi, Reedik, Bassett, Anne S., Paterson, Andrew D., Dahlman, Ingrid, Batterham, Rachel L., Dash, Satya
• Format: Journal Article
• Language: English
• Published: United States American Diabetes Association 01.12.2019
• Subjects: Adult; Body weight loss; Central nervous system; Comorbidity; Copy number; DNA Copy Number Variations; Exome Sequencing; Female; Gastrointestinal surgery; Gene Frequency; Genetic Association Studies; Genetic Predisposition to Disease; Genomes; Humans; Male; Mental disorders; Mental Disorders - epidemiology; Mental Disorders - genetics; Middle Aged; Obesity; Obesity - epidemiology; Obesity - genetics; Patients; Polymorphism, Single Nucleotide; Surgery; Sweden; Weight control; Sweden
• ISSN: 0012-1797; 1939-327X; 1939-327X
• DOI: 10.2337/db18-1254

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.