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 MelbyeBert B. Boyer, Marit E. Jørgensen, Anders Albrechtsen, Torben Hansen

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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.

Original languageEnglish (US)
Article numbere1008544
JournalPLoS genetics
Volume16
Issue number1
DOIs
StatePublished - Jan 1 2020

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ASJC Scopus subject areas

  • Ecology, Evolution, Behavior and Systematics
  • Molecular Biology
  • Genetics
  • Genetics(clinical)
  • Cancer Research

Cite this

Andersen, M. K., Jørsboe, E., Skotte, L., Hanghøj, K., Sandholt, C. H., Moltke, I., Grarup, N., Kern, T., Mahendran, Y., Søborg, B., Bjerregaard, P., Larsen, C. V. L., Dahl-Petersen, I. K., Tiwari, H. K., Feenstra, B., Koch, A., Wiener, H. W., Hopkins, S. E., Pedersen, O., ... Hansen, T. (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, 16(1), [e1008544]. https://doi.org/10.1371/journal.pgen.1008544