Dataset Information

Exploring the genetic correlation between obesity-related traits and regional brain volumes: Evidence from UK Biobank cohort.

ABSTRACT:

Objective

To determine whether there is a correlation between obesity-related variants and regional brain volumes.

Methods

Based on a mixed linear model (MLM), we analyzed the association between 1,498 obesity-related SNPs in the GWAS Catalog and 164 regional brain volumes from 29,420 participants (discovery cohort N = 19,997, validation cohort N = 9,423) in UK Biobank. The statistically significant brain regions in association analysis were classified into 6 major neural networks (dopamine (DA) motive system, central autonomic network (CAN), cognitive emotion regulation, visual object recognition network, auditory object recognition network, and sensorimotor system). We summarized the association between obesity-related variants (metabolically healthy obesity variants, metabolically unhealthy obesity variants, and unclassified obesity-related variants) and neural networks.

Results

From association analysis, we determined that 17 obesity-related SNPs were associated with 51 regional brain volumes. Several single SNPs (e.g., rs13107325-T (SLC39A8), rs1876829-C (CRHR1), and rs1538170-T (CENPW)) were associated with multiple regional brain volumes. In addition, several single brain regions (e.g., the white matter, the grey matter in the putamen, subcallosal cortex, and insular cortex) were associated with multiple obesity-related variants. The metabolically healthy obesity variants were mainly associated with the regional brain volumes in the DA motive system, sensorimotor system and cognitive emotion regulation neural networks, while metabolically unhealthy obesity variants were mainly associated with regional brain volumes in the CAN and total tissue volumes. In addition, unclassified obesity-related variants were mainly associated with auditory object recognition network and total tissue volumes. The results of MeSH (medical subject headings) enrichment analysis showed that obesity genes associated with brain structure pointed to the functional relatedness with 5-Hydroxytryptamine receptor 4 (5-HT4), growth differentiation factor 5 (GDF5), and high mobility group protein AT-hook 2 (HMGA2 protein).

Conclusion

In summary, we found that obesity-related variants were associated with different brain volume measures. On the basis of the multiple SNPs, we found that metabolically healthy and unhealthy obesity-related SNPs were associated with different brain neural networks. Based on our enrichment analysis, modifications of the 5-HT4 pathway might be a promising therapeutic strategy for obesity.

SUBMITTER: Pan X

PROVIDER: S-EPMC8648807 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundBirth weight influences not only brain development, but also mental health outcomes, including depression, but the underlying mechanism is unclear.MethodsThe phenotypic data of 12,872-91,009 participants (59.18-63.38% women) from UK Biobank were included to test the associations between the birth weight, depression, and brain volumes through the linear and logistic regression models. As birth weight is highly heritable, the polygenic risk scores (PRSs) of birth weight were calculated from the UK Biobank cohort (154,539 participants, 56.90% women) to estimate the effect of birth weight-related genetic variation on the development of depression and brain volumes. Finally, the mediation analyses of step approach and mediation analysis were used to estimate the role of brain volumes in the association between birth weight and depression. All analyses were conducted sex stratified to assess sex-specific role in the associations.ResultWe observed associations between birth weight and depression (odds ratio [OR] = 0.968, 95% confidence interval [CI] = 0.957-0.979, p = 2.29 × 10-6). Positive associations were observed between birth weight and brain volumes, such as gray matter (B = 0.131, p = 3.51 × 10-74) and white matter (B = 0.129, p = 1.67 × 10-74). Depression was also associated with brain volume, such as left thalamus (OR = 0.891, 95% CI = 0.850-0.933, p = 4.46 × 10-5) and right thalamus (OR = 0.884, 95% CI = 0.841-0.928, p = 2.67 × 10-5). Additionally, significant mediation effects of brain volume were found for the associations between birth weight and depression through steps approach and mediation analysis, such as gray matter (B = -0.220, p = 0.020) and right thalamus (B = -0.207, p = 0.014).ConclusionsOur results showed the associations among birth weight, depression, and brain volumes, and the mediation effect of brain volumes also provide evidence for the sex-specific of associations.