PLoS Genetics (Jan 2020)

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

DOI
https://doi.org/10.1371/journal.pgen.1008544
Journal volume & issue
Vol. 16, no. 1
p. e1008544

Abstract

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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.