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Diabetes. 2017 Aug;66(8):2284-2295. doi: 10.2337/db16-1565. Epub 2017 May 5.

A Genome-Wide Association Study Using a Custom Genotyping Array Identifies Variants in GPR158 Associated With Reduced Energy Expenditure in American Indians.

Author information

1
Phoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Phoenix, AZ paolo.piaggi@gmail.com paolo.piaggi@nih.gov.
2
Obesity Research Center, Endocrinology Unit, University Hospital of Pisa, Pisa, Italy.
3
Phoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Phoenix, AZ.
4
Laboratory of Diabetes and Metabolic Disorders, Institute of Experimental Endocrinology, Biomedical Research Center, Slovak Academy of Sciences, Bratislava, Slovakia.
5
Diabetes Unit and Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA.
6
Programs in Metabolism and Medical and Population Genetics, Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA.

Abstract

Pima Indians living in Arizona have a high prevalence of obesity, and we have previously shown that a relatively lower energy expenditure (EE) predicts weight and fat mass gain in this population. EE is a familial trait (heritability = 0.52); therefore, in the current study, we aimed to identify genetic variants that affect EE and thereby influence BMI and body fatness in Pima Indians. Genotypic data from 491,265 variants were analyzed for association with resting metabolic rate (RMR) and 24-h EE assessed in a whole-room calorimeter in 507 and 419 Pima Indians, respectively. Variants associated with both measures of EE were analyzed for association with maximum BMI and percent body fat (PFAT) in 5,870 and 912 Pima Indians, respectively. rs11014566 nominally associated with both measures of EE and both measures of adiposity in Pima Indians, where the G allele (frequency: Pima Indians = 0.60, Europeans <0.01) associated with lower 24-h EE (β = -33 kcal/day per copy), lower RMR (β = -31 kcal/day), higher BMI (β = +0.6 kg/m2), and higher PFAT (β = +0.9%). However, the association of rs11014566 with BMI did not directionally replicate when assessed in other ethnic groups. rs11014566 tags rs144895904, which affected promoter function in an in vitro luciferase assay. These variants map to GPR158, which is highly expressed in the brain and interacts with two other genes (RGS7 and CACNA1B) known to affect obesity in knockout mice. Our results suggest that common ethnic-specific variation in GPR158 may influence EE; however, its role in weight gain remains controversial, as it either had no association with BMI or associated with BMI but in the opposite direction in other ethnic groups.

TRIAL REGISTRATION:

ClinicalTrials.gov NCT00340132.

PMID:
28476931
PMCID:
PMC5521859
DOI:
10.2337/db16-1565
[Indexed for MEDLINE]
Free PMC Article

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