Article open access publication

Gene-based meta-analysis of genome-wide association studies implicates new loci involved in obesity

Human Molecular Genetics, Oxford University Press (OUP), ISSN 1460-2083

Volume 24, 23, 2015

DOI:10.1093/hmg/ddv379, Dimensions: pub.1059645671, PMC: PMC4643645, PMID: 26376864,


Hägg, Sara (1) (2)
Ganna, Andrea (3) (4)
Esko, Tonu (4) (6) (7) (8)
Pers, Tune H. (4) (7) (8) (9) (10)
Kahali, Bratati (14) (15)
North, Kari E (13) (17)
Loos, Ruth J F (18) (19) (20) (21)
Hirschhorn, Joel N (4) (7) (8)
Ingelsson, Erik (2) (22) (23)



  1. (1) Karolinska Institute, grid.4714.6
  2. (2) Uppsala University, grid.8993.b
  3. (3) Massachusetts General Hospital, grid.32224.35
  4. (4) Broad Institute, grid.66859.34
  5. (5) University Medical Center Utrecht, grid.7692.a
  6. (6) University of Tartu, grid.10939.32
  7. (7) Boston Children's Hospital, grid.2515.3
  8. (8) Harvard University, grid.38142.3c
  9. (9) State Serum Institute, grid.6203.7
  10. (10) University of Copenhagen, grid.5254.6, KU
  11. (11) Center for Statistical Genetics, Department of Biostatistics,
  12. (12) National Institutes of Health, grid.94365.3d
  13. (13) Department of Epidemiology,
  14. (14) Department of Internal Medicine, Division of Gastroenterology,
  15. (15) University of Michigan, grid.214458.e
  16. (16) St George's, University of London, grid.264200.2
  17. (17) University of North Carolina at Chapel Hill, grid.10698.36
  18. (18) Icahn School of Medicine at Mount Sinai, grid.59734.3c
  19. (19) Institute of Metabolic Science, grid.470900.a
  20. (20) The Genetics of Obesity and Related Metabolic Traits Program,
  21. (21) The Mindich Child Health and Development Institute,
  22. (22) Stanford University, grid.168010.e
  23. (23) Wellcome Centre for Human Genetics, grid.270683.8


To date, genome-wide association studies (GWASs) have identified >100 loci with single variants associated with body mass index (BMI). This approach may miss loci with high allelic heterogeneity; therefore, the aim of the present study was to use gene-based meta-analysis to identify regions with high allelic heterogeneity to discover additional obesity susceptibility loci. We included GWAS data from 123 865 individuals of European descent from 46 cohorts in Stage 1 and Metabochip data from additional 103 046 individuals from 43 cohorts in Stage 2, all within the Genetic Investigation of ANthropometric Traits (GIANT) consortium. Each cohort was tested for association between ∼2.4 million (Stage 1) or ∼200 000 (Stage 2) imputed or genotyped single variants and BMI, and summary statistics were subsequently meta-analyzed in 17 941 genes. We used the 'VErsatile Gene-based Association Study' (VEGAS) approach to assign variants to genes and to calculate gene-based P-values based on simulations. The VEGAS method was applied to each cohort separately before a gene-based meta-analysis was performed. In Stage 1, two known (FTO and TMEM18) and six novel (PEX2, MTFR2, SSFA2, IARS2, CEP295 and TXNDC12) loci were associated with BMI (P < 2.8 × 10(-6) for 17 941 gene tests). We confirmed all loci, and six of them were gene-wide significant in Stage 2 alone. We provide biological support for the loci by pathway, expression and methylation analyses. Our results indicate that gene-based meta-analysis of GWAS provides a useful strategy to find loci of interest that were not identified in standard single-marker analyses due to high allelic heterogeneity.


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Relative Citation ratio (RCR): 1.97

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