A commonly carried allele of the obesity-related FTO gene is associated with reduced brain volume in the healthy elderly

Abstract

A recently identified variant within the fat mass and obesity-associated (FTO) gene is carried by 46% of Western Europeans and is associated with an approximately 1.2 kg higher weight, on average, in adults and an approximately 1 cm greater waist circumference. With >1 billion overweight and 300 million obese persons worldwide, it is crucial to understand the implications of carrying this very common allele for the health of our aging population. FTO is highly expressed in the brain and elevated body mass index (BMI) is associated with brain atrophy, but it is unknown how the obesity-associated risk allele affects human brain structure. We therefore generated 3D maps of regional brain volume differences in 206 healthy elderly subjects scanned with MRI and genotyped as part of the Alzheimer's Disease Neuroimaging Initiative. We found a pattern of systematic brain volume deficits in carriers of the obesity-associated risk allele versus noncarriers. Relative to structure volumes in the mean template, FTO risk allele carriers versus noncarriers had an average brain volume difference of approximately 8% in the frontal lobes and 12% in the occipital lobes-these regions also showed significant volume deficits in subjects with higher BMI. These brain differences were not attributable to differences in cholesterol levels, hypertension, or the volume of white matter hyperintensities; which were not detectably higher in FTO risk allele carriers versus noncarriers. These brain maps reveal that a commonly carried susceptibility allele for obesity is associated with structural brain atrophy, with implications for the health of the elderly.

Fig. 1.

(Upper) 3D maps show areas where regional brain tissue volumes were significantly associated with carrying the risk allele at the obesity-associated tagging SNP, rs3751812, in healthy elderly subjects (n = 206). (Lower) In the significant areas, the regression coefficients (unstandardized beta values) are shown at each voxel. These values represent the estimated degree of tissue excess or deficit at each voxel (in cubic millimeters relative to the template) that is associated with the presence of the risk allele, after statistically controlling for effects of age and sex on brain structure. Images are in radiological convention (left side of the brain shown on the right) and are displayed over the MDT.

Fig. 2.

(Upper) 3D maps show areas where regional brain volumes were significantly associated with BMI in healthy elderly subjects (n = 206). (Lower) In the significant areas, the regression coefficients (unstandardized beta values or “slopes”) are shown at each voxel. These represent the estimated degree of tissue excess or deficit at each voxel (in cubic millimeters relative to the template) for each unit gain in body mass index, after statistically controlling for effects of age and sex, on brain structure. Images are displayed in radiological convention (left side of the brain shown on the right) and are displayed over the MDT.

Fig. 3.

3D maps show regions of significant brain volume differences from both presence of the FTO risk allele and higher BMI using a conjunction analysis displayed over a study-specific template. Images are displayed in radiological convention (left side of the brain shown on the right). Images are corrected for multiple comparisons on the basis of FDR (FDR q-level = 0.05, critical uncorrected P = 5.007 × 10⁻⁴). The same slices as in Fig. 1 are shown.