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Extreme obesity (EO) (BMI >50 kg/m 2 ) 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/m 2 ; 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., (© 2019 by the American Diabetes Association.)