FTO genotype is associated with phenotypic variability of body mass index

Abstract

There is evidence across several species for genetic control of phenotypic variation of complex traits1–4, such that the variance among phenotypes is genotype dependent. Understanding genetic control of variability is important in evolutionary biology, agricultural selection programmes and human medicine, yet for complex traits, no individual genetic variants associated with variance, as opposed to the mean, have been identified. Here we perform a meta-analysis of genome-wide association studies of phenotypic variation using 170,000 samples on height and body mass index (BMI) in human populations. We report evidence that the single nucleotide polymorphism (SNP) rs7202116 at the FTO gene locus, which is known to be associated with obesity (as measured by mean BMI for each rs7202116 genotype)5–7, is also associated with phenotypic variability. We show that the results are not due to scale effects or other artefacts, and find no other experiment-wise significant evidence for effects on variability, either at loci other than FTO for BMI or at any locus for height. The difference in variance for BMI among individuals with opposite homozygous genotypes at the FTO locus is approximately 7%, corresponding to a difference of 0.5 kilograms in the standard deviation of weight. Our results indicate that genetic variants can be discovered that are associated with variability, and that between-person variability in obesity can partly be explained by the genotype at the FTO locus. The results are consistent with reported FTO by environment interactions for BMI8, possibly mediated by DNA methylation9,10. Our BMI results for other SNPs and our height results for all SNPs suggest that most genetic variants, including those that influence mean height or mean BMI, are not associated with phenotypic variance, or that their effects on variability are too small to detect even with samples sizes greater than 100,000.

Behavioral idiosyncrasy reveals genetic control of phenotypic variability

“…Under this model, intragenotypic variability is assumed to be attributable to nongenetic environmental perturbations (1). There is, however, growing evidence for the importance of genetic control of variance (2)(3)(4) and that variance itself is a quantitative trait. Although studies of morphology (5-7) and animal breeding (8,9) have long noted the heterogeneity of variance among genotypes, this axis of variation has received little attention compared with the effect of genetic variation on trait means.…”

“…As a result, the mechanisms by which variable phenotypes arise from a uniform genetic background are still poorly understood, particularly in the context of behavior, where variability may be a critical determinant of phenotypic differences (10,11). Most recently, with the advent of genome-wide association studies, several groups (3,4,12,13) have mapped quantitative trait loci affecting variance (vQTLs) by comparing phenotypic variances among individuals that share alleles. These studies examine the average effect of QTL alleles across genetic backgrounds and heterogeneous environments across individuals (14), in the process losing any specific effects intrinsic to each individual.…”

Meta-analysis of SNPs involved in variance heterogeneity using Levene’s test for equal variances

“…gene, which is known to be associated with BMI 16 and severe obesity in a pediatric cohort, 5 was in weak LD (r 2 ¼ 0.325; D' ¼ 0.888; Distance ¼ 231.44 kb) with rs12132044 and also nominally significant for variance heterogeneity (P ¼ 0.0076). None of the other top hits for log(BMI) or log(height) were correlated with variants associated with other traits or diseases in their neighboring regions (Supplementary Table S2).…”

“…Indeed, a recent report has associated an FTO variant (rs7202116) with the phenotypic variability of body mass index (BMI) (P ¼ 2.4E-10; N ¼ 131 233) in a meta-analysis using the squared residual as the response variable. 5 In addition to finding genetic variants influencing phenotypic variance, a meta-analysis of variance heterogeneity can also be used to prioritize potentially interacting variants to test for gene-environment and gene-gene interactions. The high-dimensional nature of genomewide data inevitably poses computational and statistical challenges, such as multiple testing burden.…”

Behavioral individuality reveals genetic control of phenotypic variability

“…As a result, the mechanisms by which variable phenotypes arise from a uniform genetic background are still poorly understood, particularly in the context of behavior, where variability may be a critical determinant 14,15 . Most recently with the advent of genome-wide association studies, several groups 7,8,16,17 have mapped quantitative traits loci affecting variance (vQTLs) by comparing phenotypic variances among individuals that share genotypes. These studies examine the average effect of QTL alleles across genetic backgrounds and heterogeneous environmental across individuals 18 , in the process losing any specific effects intrinsic to each individual.…”