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Higher BMI, but not obesity-related genetic polymorphisms, correlates with reduced structural connectivity of the reward network

By Frauke Beyer, Rui Zhang, Markus Scholz, Kerstin Wirkner, Markus Loeffler, Michael Stumvoll, Arno Villringer, A. Veronica Witte

Posted 10 May 2020
medRxiv DOI: 10.1101/2020.05.06.20087577

Background: Obesity is of complex origin, involving genetic and neurobehavioral factors. Most consistently, polymorphisms in the fat-and-obesity associated gene (FTO) may increase the risk for developing obesity by modulating dopaminergic signaling in the brain. Dopamine-dependent behaviors, such as reward processing, are crucial for eating behavior and are altered in obesity. Yet, few studies have investigated the association of obesity, related genetic variants and structural connectivity of the dopaminergic reward network. Methods: We analyzed 378 participants (age range: 20 - 59 years, BMI range: 17 - 38 kg/m2) of the LIFE-Adult Study. Genotyping for the single nucleotid polymorphisms rs1558902 (FTO) and rs1800497 (near dopamine D2 receptor) was performed on a micro-array. Structural connectivity of the reward network was derived from diffusion-weighted magnetic resonance imaging at 3 Tesla using deterministic tractography of Freesurfer-derived regions of interest. Using graph metrics, we extracted summary measures of clustering coefficient and connectivity strength between frontal and striatal brain regions, normalized for global connectivity. We applied linear regression models to test the association of BMI, risk alleles of both variants and reward network connectivity. Results: Higher BMI was significantly associated with reduced connectivity strength for fractional anisotropy ({beta}= -0.0011, 95%-C.I. [-0.0019, -0.0003], p= 0.0062) and number of streamlines ({beta} = -0.0026, 95%-C.I.:[-0.004,-0.0009], p= 0.0024), but not clustering coefficient. Strongest associations were found for right accumbens, right lateral orbitofrontal cortex and left putamen. As expected, the polymorphism rs1558902 in FTO was associated with higher BMI (F=7.9, p<0.001). None of the genetic variants was associated with reward network structural connectivity. Conclusions: Here, we provide evidence that higher BMI correlates with reduced reward network structural connectivity. This result is in line with previous findings of obesity-related decline in white matter microstructure. We did not find any association of variants in FTO or near DRD2 receptor and reward network structural connectivity, indicating that the genetic influence of these variants is small or non-existent. Future research should investigate the behavioral implications of structural connectivity differences in the fronto-striatal network and incorporate larger sample sizes with longitudinal designs in order to gain further insight into the genetic determinants of obesity in the brain.

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