On the association of common and rare genetic variation influencing body mass index: a combined SNP and CNV analysis

BMC Genomics

Bradley T Webb¹  Danielle M Dick²  Howard J Edenberg⁷  John I Nurnberger⁴  Lance O Bauer³  Victor M Hesselbrock³  John R Kramer⁹  Peng Lin⁵  Hermine H Maes⁶  Roseann E Peterson⁸ 

[1] Virginia Institute for Psychiatric and Behavioral Genetics, Department of Psychiatry, School of Medicine, Virginia Commonwealth University, Richmond, VA 23298, USA;Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, VA 23298, USA;Department of Psychiatry, School of Medicine, University of Connecticut, Farmington, CT 06030, USA;Institute of Psychiatric Research, Department of Psychiatry, School of Medicine, Indiana University, Indianapolis, IN 46226, USA;Department of Psychiatry, Washington University, St. Louis, MO 63105, USA;Virginia Institute for Psychiatric and Behavioral Genetics, Department of Human and Molecular Genetics, Massey Cancer Center, School of Medicine, Virginia Commonwealth University, Richmond, VA 23298, USA;Department of Biochemistry and Molecular Biology, School of Medicine, Indiana University, Indianapolis, IN 46226, USA;Virginia Institute for Psychiatric and Behavioral Genetics, Department of Human and Molecular Genetics, School of Medicine, Virginia Commonwealth University, Biotech I, 800 E. Leigh Street, Richmond, VA 23298-0126, USA;Department of Psychiatry, University of Iowa, Iowa City, IA 52240, USA

关键词: MC4R;    FTO;    Polygenic score;    Risk prediction;    Copy number variation;    Genome-wide association;    Obesity;    Body mass index;   

Others  :  1217233
DOI  :  10.1186/1471-2164-15-368

 received in 2013-06-12, accepted in 2014-04-27,  发布年份 2014

【 摘 要 】

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.

【 授权许可】

   
2014 Peterson et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

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