The derived allele of a novel intergenic variant at chromosome 11 associates with lower body mass index and a favorable metabolic phenotype in Greenlanders.

Mette K Andersen,Howard W Wiener,Camilla H Sandholt,Line Skotte,Scarlett E Hopkins,Mads Melbye,Peter Bjerregaard,Anders Koch,Niels Grarup,Hemant K Tiwari,Bolette Søborg,Ida Moltke,Bjarke Feenstra,Bert B Boyer,Emil Jørsboe,Yuvaraj Mahendran,Torben Hansen,Anders Albrechtsen,Kristian Hanghøj,Oluf Pedersen,Timo Kern,Christina Viskum Lytken Larsen ,Marit Eika Jørgensen ,Inger Katrine Dahl-Petersen

doi:10.1371/journal.pgen.1008544

Abstract

The genetic architecture of the small and isolated Greenlandic population is advantageous for identification of novel genetic variants associated with cardio-metabolic traits. We aimed to identify genetic loci associated with body mass index (BMI), to expand the knowledge of the genetic and biological mechanisms underlying obesity. Stage 1 BMI-association analyses were performed in 4,626 Greenlanders. Stage 2 replication and meta-analysis were performed in additional cohorts comprising 1,058 Yup’ik Alaska Native people, and 1,529 Greenlanders. Obesity-related traits were assessed in the stage 1 study population. We identified a common variant on chromosome 11, rs4936356, where the derived G-allele had a frequency of 24% in the stage 1 study population. The derived allele was genome-wide significantly associated with lower BMI (beta (SE), -0.14 SD (0.03), p = 3.2x10-8), corresponding to 0.64 kg/m2 lower BMI per G allele in the stage 1 study population. We observed a similar effect in the Yup’ik cohort (-0.09 SD, p = 0.038), and a non-significant effect in the same direction in the independent Greenlandic stage 2 cohort (-0.03 SD, p = 0.514). The association remained genome-wide significant in meta-analysis of the Arctic cohorts (-0.10 SD (0.02), p = 4.7x10-8). Moreover, the variant was associated with a leaner body type (weight, -1.68 (0.37) kg; waist circumference, -1.52 (0.33) cm; hip circumference, -0.85 (0.24) cm; lean mass, -0.84 (0.19) kg; fat mass and percent, -1.66 (0.33) kg and -1.39 (0.27) %; visceral adipose tissue, -0.30 (0.07) cm; subcutaneous adipose tissue, -0.16 (0.05) cm, all p<0.0002), lower insulin resistance (HOMA-IR, -0.12 (0.04), p = 0.00021), and favorable lipid levels (triglyceride, -0.05 (0.02) mmol/l, p = 0.025; HDL-cholesterol, 0.04 (0.01) mmol/l, p = 0.0015). In conclusion, we identified a novel variant, where the derived G-allele possibly associated with lower BMI in Arctic populations, and as a consequence also leaner body type, lower insulin resistance, and a favorable lipid profile.

Highlights

Obesity is an increasing health problem worldwide
We take advantage of the genetic architecture of the Greenlandic population to identify genetic variants associated with alterations in body-mass index, as a measure of obesity
By examining more than 100,000 genetic variants in 4,626 Greenlanders we identify a specific variant, rs4936356, where the derived G-allele was associated with lower body-mass index, lower insulin resistance, and favorable lipid levels

Summary

Introduction

Obesity is an increasing health problem worldwide. The condition is caused by a combination of environmental risk factors and genetic predisposition. Compared to large outbred populations, isolated populations show extended patterns of linkage disequilibrium (LD), and a higher probability for the presence of disease-associated variants with high frequency due to genetic drift and selection [3,4] These properties are advantageous for genetic-association studies, which have recently been demonstrated in various isolated populations by the discovery of novel variants associated with cardio-metabolic traits [5,6,7,8,9,10,11,12,13], and of particular interest coding variants in CREBRF and ADCY3 have been associated with obesity in Samoans and Greenlanders, respectively [14,15]

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Conclusion