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Background As the architecture of complex traits incorporates a widening spectrum of genetic variation, analyses integrating common and rare variation are needed. Body mass index (BMI) represents a model trait, since common variation shows robust association but accounts for a fraction of the heritability. A combined analysis of single nucleotide polymorphisms (SNP) and copy number variation (CNV) was performed using 1850 European and 498 African-Americans from the Study of Addiction: Genetics and Environment. Genetic risk sum scores (GRSS) were constructed using 32 BMI-validated SNPs and aggregate-risk methods were compared: count versus weighted and proxy versus imputation.
Results The weighted SNP-GRSS constructed from imputed probabilities of risk alleles performed best and was highly associated with BMI (p = 4.3×10−16) accounting for 3% of the phenotypic variance. In addition to BMI-validated SNPs, common and rare BMI/obesity-associated CNVs were identified from the literature. Of the 84 CNVs previously reported, only 21-kilobase deletions on 16p12.3 showed evidence for association with BMI (p = 0.003, frequency = 16.9%), with two CNVs nominally associated with class II obesity, 1p36.1 duplications (OR = 3.1, p = 0.009, frequency 1.2%) and 5q13.2 deletions (OR = 1.5, p = 0.048, frequency 7.7%). All other CNVs, individually and in aggregate, were not associated with BMI or obesity. The combined model, including covariates, SNP-GRSS, and 16p12.3 deletion accounted for 11.5% of phenotypic variance in BMI (3.2% from genetic effects). Models significantly predicted obesity classification with maximum discriminative ability for morbid-obesity (p = 3.15×10−18).
Conclusion Results show that incorporating validated effect sizes and allelic probabilities improve prediction algorithms. Although rare-CNVs did not account for significant phenotypic variation, results provide a framework for integrated analyses.
© 2014 Peterson et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited.
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VCU Psychiatry Publications
Association results of 32 BMI SNPs.
1471-2164-15-368-s2.xlsx (27 kB)
CNVs catalogued from the literature and frequency in the SAGE sub-sample.
1471-2164-15-368-s3.xlsx (38 kB)
Comparison of the association of GRSSs with BMI constructed by count and weighted methods by self-reported ancestry.
1471-2164-15-368-s4.xlsx (14 kB)
Common and rare CNV-GRSS.
1471-2164-15-368-s5.docx (103 kB)
Linear models predicting BMI by ancestry.
1471-2164-15-368-s6.docx (106 kB)
Discriminative accuracy of covariates, SNP-GRSS and CNV predicting BMI category by self-reported ancestry.