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

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.

Electronic supplementary material

The online version of this article (doi:10.1186/1471-2164-15-368) contains supplementary material, which is available to authorized users.     

Association of the CHE2 locus with body mass index and butyrylcholinesterase activity

The butyrylcholinesterase (BChE; EC 3.1.1.8) activities of two electrophoretic bands of the CHE2 C5+ phenotype--C5 and C(OF) (other forms)--were quantified by densitometry in 100 individuals. The activity data suggested that, in addition to determining C5, the CHE2*C5+ allele also increases the level of other BChE forms. Since the relative activity of C5 showed the highest correlation coefficient with weight when compared with the other BChE activity variables (total, absolute C5, and absolute C(OF)), its median activity level was used for the classification of CHE2 C5+ phenotypes (faint and intense). Mean body mass index (BMI) was compared among the CHE2 locus phenotypes-controlled by sex, age, and ethnic group. It was shown that the intense CHE2 C5+ phenotype presents a significantly lower (p < 0.001) mean BMI (23.2) than the other phenotypes (faint CHE2 C5+ = 25.2; CHE2 C5- = 25.4). It seems that the relative COF activity is positively associated with fat storage, since CHE2 C5- and faint CHE2 C5+ phenotypes showed higher mean BMI than the intense CHE2 C5+ phenotype. Our hypothesis is that the presence of C5 in a relatively high proportion leads to less fat storage.     

Effect modification of body mass index on the association between ovarian cysts and endometrial cancer

BackgroundOvarian cysts represent a common condition among women. Epidemiologic studies are inconsistent in determining if women with cysts are more likely to develop endometrial cancer (EC) regardless of overweight/obesity. We investigated the combined role of cysts and body mass index (BMI) on EC risk.MethodsWe pooled data from three case-control studies conducted in Italy and Switzerland on 920 women with EC and 1700 controls. The prevalence of cysts was 5% among both cases and controls, with 63% of cases being overweight/obese. We estimated odds ratios (ORs) and 95% confidence intervals (CIs) using logistic regression models, adjusting for potential confounders. We conducted stratified analyses according to BMI, and estimated the interaction between cysts and BMI; we carried out additional analyses according to age at diagnosis of cysts.ResultsOverall, history of cysts was not associated to EC (OR=1.27, 95% CI=0.82–1.97, P = 0.29). Normal weight women reporting cysts had an increased risk of EC (OR=2.49, 95% CI=1.31–4.74), while no such effect was found among overweight/obese women (OR=0.65, 95% CI=0.36–1.18; P for interaction=0.004). The association was limited to women below 65 years of age and was stronger in those who reported cysts at age 48 or older.ConclusionsCysts appeared to be a risk factor for EC in lean women but not in overweight/obese ones; these results are consistent with an effect of cysts and obesity on EC along common pathways.     

Genetic variation at the growth hormone locus in a wild pig intercross; test of association to phenotypic traits and linkage to the blood group D locus

A polymorphism in the TATA-box of the porcine growth hormone (GH) gene was analysed in a wild pig/Large White intercross, in which 129 markers had been scored previously. Linkage analyses demonstrated that the GH locus belonged to a linkage group on chromosome 12 together with a previously unassigned marker, the erythrocyte antigen D (EAD) locus. The linear order of this linkage group is EAD-GH-S0096-S0090-S0106-arachidonate 12-lipoxygenase (ALOX12)-inhibin beta A (INHBA). The length of the linkage group was estimated at 93 cM (sex average). The effects of the GH genotype on growth and fat deposition traits were investigated using phenotypic data from the 191 F₂ animals. No significant effect of GH was detected, and we therefore conclude that this locus does not play a major role in defining the genetic differences between the wild and Large White pigs for these traits.     

Using genetic variation to disentangle the complex relationship between food intake and health outcomes

Diet is considered as one of the most important modifiable factors influencing human health, but efforts to identify foods or dietary patterns associated with health outcomes often suffer from biases, confounding, and reverse causation. Applying Mendelian randomization in this context may provide evidence to strengthen causality in nutrition research. To this end, we first identified 283 genetic markers associated with dietary intake in 445,779 UK Biobank participants. We then converted these associations into direct genetic effects on food exposures by adjusting them for effects mediated via other traits. The SNPs which did not show evidence of mediation were then used for MR, assessing the association between genetically predicted food choices and other risk factors, health outcomes. We show that using all associated SNPs without omitting those which show evidence of mediation, leads to biases in downstream analyses (genetic correlations, causal inference), similar to those present in observational studies. However, MR analyses using SNPs which have only a direct effect on the exposure on food exposures provided unequivocal evidence of causal associations between specific eating patterns and obesity, blood lipid status, and several other risk factors and health outcomes.     

Human variation and body mass index: a review of the universality of BMI cut-offs, gender and urban-rural differences, and secular changes

Use of BMI as a surrogate for body fat percentage is debatable and universal BMI cut-off points do not seem appropriate; lower cut-off points than currently recommended by WHO should be used in some populations, especially in Asia. The adult WHO BMI database indicates that, on average, women are more obese than men, while men are more likely to be pre-obese than women. Urban rates of overweight and obesity are generally higher than rural rates in both sexes. The trend in pre-obesity and obesity over time is generally upward, with very marked increases in the USA and UK in both sexes over the last 10 years.     

Nutritional influence on childhood development and genetic control of adolescent growth of Quechuas and Mestizos from the Peruvian Lowlands

The growth in height of 1,202 Quechua and Mestizo children aged 6 to 19 years of the province of Lamas in the Peruvian Eastern Lowlands was studied. As shown by evaluations of ABO, Rh systems, and skin reflectance measurements, the Quechuas are genetically different from the Mestizos. The heights of Quechuas and Mestizos were matched for nutritional status based on measurements of subcutaneous fat and body muscle. The study indicates that: (1) during childhood, Quechuas and Mestizos matched for the same nutritional status attain similar heights; (2) during adolescence (or after the age of 11 years), the Mestizos are significantly taller than the Quechuas of the same nutritional status; 3) during childhood, the relative difference in height between Quechuas and Mestizos matched for the same nutritional status is less than the difference between Quechuas (or Mestizos) of the same genetic composition characterized by good and poor nutritional status. These findings suggest that the influence of environmental factors, such as nutrition, have a greater influence in producing differences in body size during childhood than during adolescence. Conversely, the present findings support the hypothesis that the influence of genetic factors on body size are greater during adolescence than during childhood. However, comparison of adolescent samples of similar genetic composition (whether they be Quechuas or Mestizos), characterized by good and poor nutritional status, reveal large differences in height, suggesting that under conditions of malnutrition, the genetic control of growth is diminished.