Genetic Insights into Obesity and Brain: Combine Mendelian Randomization Study and Gene Expression Analysis

Leian Chen; Shaokun Zhao; Yuye Wang; Xiaoqian Niu; Bin Zhang; Xin Li; Dantao Peng

doi:10.3390/brainsci13060892

Genetic Insights into Obesity and Brain: Combine Mendelian Randomization Study and Gene Expression Analysis

Brain Sci. 2023 May 31;13(6):892. doi: 10.3390/brainsci13060892.

Authors

Leian Chen¹, Shaokun Zhao², Yuye Wang¹, Xiaoqian Niu³, Bin Zhang¹, Xin Li², Dantao Peng^{1

3}

Affiliations

¹ Department of Neurology, China-Japan Friendship Hospital (Institute of Clinical Medical Sciences), Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100029, China.
² State Key Laboratory of Cognitive Neuroscience and Learning, Beijing Normal University, Beijing 100875, China.
³ Department of Neurology, Peking University China-Japan Friendship School of Clinical Medicine, Beijing 100029, China.

Abstract

As a major public-health concern, obesity is imposing an increasing social burden around the world. The link between obesity and brain-health problems has been reported, but controversy remains. To investigate the relationship among obesity, brain-structure changes and diseases, a two-stage analysis was performed. At first, we used the Mendelian-randomization (MR) approach to identify the causal relationship between obesity and cerebral structure. Obesity-related data were retrieved from the Genetic Investigation of ANthropometric Traits (GIANT) consortium and the UK Biobank, whereas the cortical morphological data were from the Enhancing NeuroImaging Genetics through Meta-Analysis (ENIGMA) consortium. Further, we extracted region-specific expressed genes according to the Allen Human Brian Atlas (AHBA) and carried out a series of bioinformatics analyses to find the potential mechanism of obesity and diseases. In the univariable MR, a higher body mass index (BMI) or larger visceral adipose tissue (VAT) was associated with a smaller global cortical thickness (p_BMI = 0.006, p_VAT = 1.34 × 10^-4). Regional associations were found between obesity and specific gyrus regions, mainly in the fusiform gyrus and inferior parietal gyrus. Multivariable MR results showed that a greater body fat percentage was linked to a smaller fusiform-gyrus thickness (p = 0.029) and precuneus surface area (p = 0.035). As for the gene analysis, region-related genes were enriched to several neurobiological processes, such as compound transport, neuropeptide-signaling pathway, and neuroactive ligand-receptor interaction. These genes contained a strong relationship with some neuropsychiatric diseases, such as Alzheimer's disease, epilepsy, and other disorders. Our results reveal a causal relationship between obesity and brain abnormalities and suggest a pathway from obesity to brain-structure abnormalities to neuropsychiatric diseases.

Keywords: Mendelian randomization analysis; body mass index; cerebral cortex; cognitive impairment; gene expression; obesity.

Abstract

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