Human Genetics

, Volume 129, Issue 2, pp 221–230

Genetic risk sum score comprised of common polygenic variation is associated with body mass index

  • Roseann E. Peterson
  • Hermine H. Maes
  • Peter Holmans
  • Alan R. Sanders
  • Douglas F. Levinson
  • Jianxin Shi
  • Kenneth S. Kendler
  • Pablo V. Gejman
  • Bradley T. Webb
Original Investigation

DOI: 10.1007/s00439-010-0917-1

Cite this article as:
Peterson, R.E., Maes, H.H., Holmans, P. et al. Hum Genet (2011) 129: 221. doi:10.1007/s00439-010-0917-1

Abstract

Genome-wide association studies (GWAS) of body mass index (BMI) using large samples have yielded approximately a dozen robustly associated variants and implicated additional loci. Individually these variants have small effects and in aggregate explain a small proportion of the variance. As a result, replication attempts have limited power to achieve genome-wide significance, even with several thousand subjects. Since there is strong prior evidence for genetic influence on BMI for specific variants, alternative approaches to replication can be applied. Instead of testing individual loci sequentially, a genetic risk sum score (GRSS) summarizing the total number of risk alleles can be tested. In the current study, GRSS comprising 56 top variants catalogued from two large meta-analyses was tested for association with BMI in the Molecular Genetics of Schizophrenia controls (2,653 European-Americans, 973 African-Americans). After accounting for covariates known to influence BMI (ancestry, sex, age), GRSS was highly associated with BMI (p value = 3.19E−06) although explained a limited amount of the variance (0.66%). However, area under receiver operator criteria curve (AUC) estimates indicated that the GRSS and covariates significantly predicted overweight and obesity classification with maximum discriminative ability for predicting class III obesity (AUC = 0.697). The relative contributions of the individual loci to GRSS were examined post hoc and the results were not due to a few highly significant variants, but rather the result of numerous variants of small effect. This study provides evidence of the utility of a GRSS as an alternative approach to replication of common polygenic variation in complex traits.

Abbreviations

GWAS

Genome-wide association study

BMI

Body mass index

GRSS

Genetic risk sum score

AUC

Area under the curve

FTO

Fat mass and obesity-associated gene

MC4R

Melanocortin 4 receptor

kg

Kilogram

m

Meter

MGS-C

Molecular Genetics of Schizophrenia control sample

PC

Principal component

ROC

Receiver operator criteria

SNP

Single nucleotide polymorphism

CNV

Copy number variation

AA

African-American

EA

European-American

Supplementary material

439_2010_917_MOESM1_ESM.jpeg (36 kb)
Supplemental Figure 1 (JPEG 36.2 kb)
439_2010_917_MOESM2_ESM.jpeg (49 kb)
Supplemental Figure 2 (JPEG 49.0 kb)
439_2010_917_MOESM3_ESM.xls (58 kb)
Supplemental Table 1 Displays the 78 SNPs catalogued, alleles, frequencies, proxy and association information (XLS 58 kb)
439_2010_917_MOESM4_ESM.doc (48 kb)
Supplemental Table 2 Linear model predicting BMI including GRSS interactions with covariates (DOC 48 kb)

Copyright information

© Springer-Verlag 2010

Authors and Affiliations

  • Roseann E. Peterson
    • 1
    • 4
  • Hermine H. Maes
    • 1
    • 3
    • 4
    • 2
  • Peter Holmans
    • 6
  • Alan R. Sanders
    • 5
  • Douglas F. Levinson
    • 7
  • Jianxin Shi
    • 8
  • Kenneth S. Kendler
    • 1
    • 3
    • 4
  • Pablo V. Gejman
    • 5
  • Bradley T. Webb
    • 1
    • 3
  1. 1.Virginia Institute for Psychiatric and Behavioral GeneticsVirginia Commonwealth University School of MedicineRichmondUSA
  2. 2.Massey Cancer CenterVirginia Commonwealth University School of MedicineRichmondUSA
  3. 3.Department of PsychiatryVirginia Commonwealth University School of MedicineRichmondUSA
  4. 4.Department of Human and Molecular GeneticsVirginia Commonwealth University School of MedicineRichmondUSA
  5. 5.Department of Psychiatry and Behavioral Sciences, Center for Psychiatric GeneticsNorthShore University HealthSystemEvanstonUSA
  6. 6.Department of Psychological Medicine and Neurology, MRC Centre for Neuropsychiatric Genetics and Genomics, School of MedicineCardiff UniversityCardiffUK
  7. 7.Department of Psychiatry and Behavioral SciencesStanford UniversityStanfordUSA
  8. 8.Division of Cancer Epidemiology and GeneticsNational Cancer InstituteBethesdaUSA