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:10.1371/journal.pgen.1008544

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

Research output: Contribution to journal › Article › peer-review

2 Scopus citations

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 language	English (US)
Article number	e1008544
Journal	PLoS genetics
Volume	16
Issue number	1
DOIs	https://doi.org/10.1371/journal.pgen.1008544
State	Published - 2020
Externally published	Yes

ASJC Scopus subject areas

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

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10.1371/journal.pgen.1008544

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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

The derived allele of a novel intergenic variant at chromosome 11 associates with lower body mass index and a favorable metabolic phenotype in Greenlanders. / Andersen, Mette K.; Jørsboe, Emil; Skotte, Line; Hanghøj, Kristian; Sandholt, Camilla H.; Moltke, Ida; Grarup, Niels; Kern, Timo; Mahendran, Yuvaraj; Søborg, Bolette; Bjerregaard, Peter; Larsen, Christina V.L.; Dahl-Petersen, Inger K.; Tiwari, Hemant K.; Feenstra, Bjarke; Koch, Anders; Wiener, Howard W.; Hopkins, Scarlett E.; Pedersen, Oluf; Melbye, Mads; Boyer, Bert B.; Jørgensen, Marit E.; Albrechtsen, Anders; Hansen, Torben.

In: PLoS genetics, Vol. 16, No. 1, e1008544, 2020.

Research output: Contribution to journal › Article › peer-review

Andersen, MK, Jørsboe, E, Skotte, L, Hanghøj, K, Sandholt, CH, Moltke, I, Grarup, N, Kern, T, Mahendran, Y, Søborg, B, Bjerregaard, P, Larsen, CVL, Dahl-Petersen, IK, Tiwari, HK, Feenstra, B, Koch, A, Wiener, HW, Hopkins, SE, Pedersen, O, Melbye, M, Boyer, BB, Jørgensen, ME, Albrechtsen, A & 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, vol. 16, no. 1, e1008544. https://doi.org/10.1371/journal.pgen.1008544

Andersen, Mette K. ; Jørsboe, Emil ; Skotte, Line ; Hanghøj, Kristian ; Sandholt, Camilla H. ; Moltke, Ida ; Grarup, Niels ; Kern, Timo ; Mahendran, Yuvaraj ; Søborg, Bolette ; Bjerregaard, Peter ; Larsen, Christina V.L. ; Dahl-Petersen, Inger K. ; Tiwari, Hemant K. ; Feenstra, Bjarke ; Koch, Anders ; Wiener, Howard W. ; Hopkins, Scarlett E. ; Pedersen, Oluf ; Melbye, Mads ; Boyer, Bert B. ; Jørgensen, Marit E. ; Albrechtsen, Anders ; Hansen, Torben. / The derived allele of a novel intergenic variant at chromosome 11 associates with lower body mass index and a favorable metabolic phenotype in Greenlanders. In: PLoS genetics. 2020 ; Vol. 16, No. 1.

@article{877d2d725d1141be86532b096a502459,

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

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{\textquoteright}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{\textquoteright}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.",

author = "Andersen, {Mette K.} and Emil J{\o}rsboe and Line Skotte and Kristian Hangh{\o}j and Sandholt, {Camilla H.} and Ida Moltke and Niels Grarup and Timo Kern and Yuvaraj Mahendran and Bolette S{\o}borg and Peter Bjerregaard and Larsen, {Christina V.L.} and Dahl-Petersen, {Inger K.} and Tiwari, {Hemant K.} and Bjarke Feenstra and Anders Koch and Wiener, {Howard W.} and Hopkins, {Scarlett E.} and Oluf Pedersen and Mads Melbye and Boyer, {Bert B.} and J{\o}rgensen, {Marit E.} and Anders Albrechtsen and Torben Hansen",

note = "Funding Information: The Novo Nordisk Foundation Center for Basic Metabolic Research is an independent Research Center at the University of Copenhagen partially funded by an unrestricted donation from the Novo Nordisk Foundation (www.metabol.ku. dk). This project was also funded by the Danish Council for Independent Research (DFF-4090-00244, Sapere Aude grant DFF-11-120909 and DFF-4181-00383), the Steno Diabetes Center Copenhagen (www.steno.dk), the Lundbeck Foundation (R215-2015-4174) and the Novo Nordisk Foundation (NNF15OC0017918, NNF16OC0019986, NNF17SH0027192, NNF17OC0028136 and NNFCC0018486). The Greenlandic health surveys (IHIT and B99) were supported by Karen Elise Jensen{\textquoteright}s Foundation, the Department of Health in Greenland, NunaFonden, Medical Research Council of Denmark, Medical Research Council of Greenland, and the Commission for Scientific Research in Greenland. The CANHR studies involving Alaska Native Yup{\textquoteright}ik people were funded by the following National Institutes of Health grants: P30 GM103325, R01 DK104347, and R01DK074842. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Publisher Copyright: {\textcopyright} 2020 Andersen et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.",

year = "2020",

doi = "10.1371/journal.pgen.1008544",

language = "English (US)",

volume = "16",

journal = "PLoS Genetics",

issn = "1553-7390",

publisher = "Public Library of Science",

number = "1",

}

TY - JOUR

T1 - The derived allele of a novel intergenic variant at chromosome 11 associates with lower body mass index and a favorable metabolic phenotype in Greenlanders

AU - Andersen, Mette K.

AU - Jørsboe, Emil

AU - Skotte, Line

AU - Hanghøj, Kristian

AU - Sandholt, Camilla H.

AU - Moltke, Ida

AU - Grarup, Niels

AU - Kern, Timo

AU - Mahendran, Yuvaraj

AU - Søborg, Bolette

AU - Bjerregaard, Peter

AU - Larsen, Christina V.L.

AU - Dahl-Petersen, Inger K.

AU - Tiwari, Hemant K.

AU - Feenstra, Bjarke

AU - Koch, Anders

AU - Wiener, Howard W.

AU - Hopkins, Scarlett E.

AU - Pedersen, Oluf

AU - Melbye, Mads

AU - Boyer, Bert B.

AU - Jørgensen, Marit E.

AU - Albrechtsen, Anders

AU - Hansen, Torben

N1 - Funding Information: The Novo Nordisk Foundation Center for Basic Metabolic Research is an independent Research Center at the University of Copenhagen partially funded by an unrestricted donation from the Novo Nordisk Foundation (www.metabol.ku. dk). This project was also funded by the Danish Council for Independent Research (DFF-4090-00244, Sapere Aude grant DFF-11-120909 and DFF-4181-00383), the Steno Diabetes Center Copenhagen (www.steno.dk), the Lundbeck Foundation (R215-2015-4174) and the Novo Nordisk Foundation (NNF15OC0017918, NNF16OC0019986, NNF17SH0027192, NNF17OC0028136 and NNFCC0018486). The Greenlandic health surveys (IHIT and B99) were supported by Karen Elise Jensen’s Foundation, the Department of Health in Greenland, NunaFonden, Medical Research Council of Denmark, Medical Research Council of Greenland, and the Commission for Scientific Research in Greenland. The CANHR studies involving Alaska Native Yup’ik people were funded by the following National Institutes of Health grants: P30 GM103325, R01 DK104347, and R01DK074842. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Publisher Copyright: © 2020 Andersen et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

PY - 2020

Y1 - 2020

N2 - 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.

AB - 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.

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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

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