Exome Sequencing Identifies A Nonsense Variant in DAO Associated With Reduced Energy Expenditure in American Indians

• Published in: The journal of clinical endocrinology and metabolism Vol. 105; no. 11; pp. e3989 - e4000
• Main Authors: Piaggi, Paolo, Köroğlu, Çiğdem, Nair, Anup K, Sutherland, Jeff, Muller, Yunhua L, Kumar, Pankaj, Hsueh, Wen-Chi, Kobes, Sayuko, Shuldiner, Alan R, Kim, Hye In, Gosalia, Nehal, Van Hout, Cristopher V, Jones, Marcus, Knowler, William C, Krakoff, Jonathan, Hanson, Robert L, Bogardus, Clifton, Baier, Leslie J
• Format: Journal Article
• Language: English
• Published: US Oxford University Press 01.11.2020
• Subjects: Adolescent; Adult; Alleles; American Indians or Alaska Natives - genetics; Amino acid oxidase; Analysis; Clinical s; Codon; Codon, Nonsense; D-Amino-acid oxidase; D-Amino-Acid Oxidase - genetics; Dopamine; Energy balance; Energy expenditure; Energy metabolism; Energy Metabolism - genetics; Ethylenediaminetetraacetic acid; Exome; Female; Gene Frequency; Genetic analysis; Genetic diversity; Glucose Tolerance Test; Humans; Male; Middle Aged; Minority & ethnic groups; Native Americans; Native North Americans; Nonsense mutation; Obesity; Obesity - genetics; Oxidases; Proteolysis; Stop codon; Type 2 diabetes; Whole Exome Sequencing; Young Adult; India; respiratory quotient; energy expenditure; thrifty metabolic phenotype; whole-exome sequencing; energy metabolism
• ISSN: 0021-972X; 1945-7197; 1945-7197
• DOI: 10.1210/clinem/dgaa548

Abstract Background Obesity and energy expenditure (EE) are heritable and genetic variants influencing EE may contribute to the development of obesity. We sought to identify genetic variants that affect EE in American Indians, an ethnic group with high prevalence of obesity. Methods Whole-exome sequencing was performed in 373 healthy Pima Indians informative for 24-hour EE during energy balance. Genetic association analyses of all high-quality exonic variants (≥5 carriers) was performed, and those predicted to be damaging were prioritized. Results Rs752074397 introduces a premature stop codon (Cys264Ter) in DAO and demonstrated the strongest association for 24-hour EE, where the Ter allele associated with substantially lower 24-hour EE (mean lower by 268 kcal/d) and sleeping EE (by 135 kcal/d). The Ter allele has a frequency = 0.5% in Pima Indians, whereas is extremely rare in most other ethnic groups (frequency < 0.01%). In vitro functional analysis showed reduced protein levels for the truncated form of DAO consistent with increased protein degradation. DAO encodes D-amino acid oxidase, which is involved in dopamine synthesis which might explain its role in modulating EE. Conclusion Our results indicate that a nonsense mutation in DAO may influence EE in American Indians. Identification of variants that influence energy metabolism may lead to new pathways to treat human obesity. Clinical Trial Registration Number NCT00340132.