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PLoS Genet. 2020 Jan 24;16(1):e1008544. doi: 10.1371/journal.pgen.1008544. eCollection 2020 Jan.

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 information

1
Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
2
The Bioinformatics Centre, Department of Biology, University of Copenhagen, Copenhagen, Denmark.
3
Department of Epidemiology Research, Statens Serum Institut, Copenhagen, Denmark.
4
PEPperPRINT GmbH, Heidelberg, Germany.
5
National Institute of Public Health, University of Southern Denmark, Copenhagen, Denmark.
6
Greenland Centre for Health Research, University of Greenland, Nuuk, Greenland.
7
Department of Biostatistics, School of Public Health, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.
8
Department of Infectious Diseases, Rigshospitalet University Hospital, Copenhagen, Denmark.
9
Department of Epidemiology, School of Public Health, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.
10
Department of Obstetrics and Gynecology, Center for Developmental Health, Knight Cardiovascular Institute, Oregon Health & Science University, Portland, Oregon, United States of America.
11
Center for Alaska Native Health Research, University of Alaska Fairbanks, Fairbanks, Alaska, United States of America.
12
Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
13
Department of Medicine, Stanford University School of Medicine, Stanford, California, United States of America.
14
Steno Diabetes Center Copenhagen, Gentofte, Denmark.
15
Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark.

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.

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