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

Author

Listed:
  • 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

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

Suggested Citation

  • 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 L, 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," PLOS Genetics, Public Library of Science, vol. 16(1), pages 1-17, January.
    • Handle: RePEc:plo:pgen00:1008544
    DOI: 10.1371/journal.pgen.1008544
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    1. Ida Moltke & Niels Grarup & Marit E. Jørgensen & Peter Bjerregaard & Jonas T. Treebak & Matteo Fumagalli & Thorfinn S. Korneliussen & Marianne A. Andersen & Thomas S. Nielsen & Nikolaj T. Krarup & Ane, 2014. "A common Greenlandic TBC1D4 variant confers muscle insulin resistance and type 2 diabetes," Nature, Nature, vol. 512(7513), pages 190-193, August.
    2. Bryan N Howie & Peter Donnelly & Jonathan Marchini, 2009. "A Flexible and Accurate Genotype Imputation Method for the Next Generation of Genome-Wide Association Studies," PLOS Genetics, Public Library of Science, vol. 5(6), pages 1-15, June.
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