OBJECTIVE

While variations in the first intron of the (, rs9939609 T/A variant) have long been identified as a major contributor to polygenic obesity, the mechanisms underlying weight gain in risk allele carriers still remain elusive. On a behavioral level, variants have been robustly linked to trait impulsivity. The regulation of dopaminergic signaling in the meso-striatal neurocircuitry by these variants might represent one mechanism for this behavioral alteration. Notably, recent evidence indicates that variants of also modulate several genes involved in cell proliferation and neuronal development. Hence, FTO polymorphisms might establish a predisposition to heightened trait impulsivity during neurodevelopment by altering structural meso-striatal connectivity. We here explored whether the greater impulsivity of variant carriers was mediated by structural differences in the connectivity between the dopaminergic midbrain and the ventral striatum.

METHODS

Eighty-seven healthy normal-weight volunteers participated in the study; 42 FTO risk allele carriers (rs9939609 T/A variant, group: AT, AA) and 39 non-carriers ( group: TT) were matched for age, sex and body mass index (BMI). Trait impulsivity was assessed via the Barratt Impulsiveness Scale (BIS-11) and structural connectivity between the ventral tegmental area/substantia nigra (VTA/SN) and the nucleus accumbens (NAc) was measured via diffusion weighted MRI and probabilistic tractography.

RESULTS

We found that risk allele carriers compared to non-carriers, demonstrated greater motor impulsivity ( = 0.04) and increased structural connectivity between VTA/SN and the NAc (p< 0.05). Increased connectivity partially mediated the effect of FTO genetic status on motor impulsivity.

CONCLUSION

We report altered structural connectivity as one mechanism by which variants contribute to increased impulsivity, indicating that variants may exert their effect on obesity-promoting behavioral traits at least partially through neuroplastic alterations in humans.