Obesity is highly prevalent and disabling, especially in individuals with severe mental illness including bipolar disorders (BD). The brain is a target organ for both obesity and BD. Yet, we do not understand how cortical brain alterations in BD and obesity interact.

We obtained body mass index (BMI) and MRI-derived regional cortical thickness, surface area from 1231 BD and 1601 control individuals from 13 countries within the ENIGMA-BD Working Group. We jointly modeled the statistical effects of BD and BMI on brain structure using mixed effects and tested for interaction and mediation. We also investigated the impact of medications on the BMI-related associations.

BMI and BD additively impacted the structure of many of the same brain regions. Both BMI and BD were negatively associated with cortical thickness, but not surface area. In most regions the number of jointly used psychiatric medication classes remained associated with lower cortical thickness when controlling for BMI. In a single region, fusiform gyrus, about a third of the negative association between number of jointly used psychiatric medications and cortical thickness was mediated by association between the number of medications and higher BMI.

We confirmed consistent associations between higher BMI and lower cortical thickness, but not surface area, across the cerebral mantle, in regions which were also associated with BD. Higher BMI in people with BD indicated more pronounced brain alterations. BMI is important for understanding the neuroanatomical changes in BD and the effects of psychiatric medications on the brain.

To date, besides genome-wide association studies, a variety of other genetic analyses (e.g. polygenic risk scores, whole-exome sequencing and whole-genome sequencing) have been conducted, and a large amount of data has been gathered for investigating the involvement of common, rare and very rare types of DNA sequence variants in bipolar disorder. Also, non-invasive neuroimaging methods can be used to quantify changes in brain structure and function in patients with bipolar disorder.

To provide a comprehensive assessment of genetic findings associated with bipolar disorder, based on the evaluation of different genomic approaches and neuroimaging studies.

We conducted a PubMed search of all relevant literatures from the beginning to the present, by querying related search strings.

ANK3, CACNA1C, SYNE1, ODZ4 and TRANK1 are five genes that have been replicated as key gene candidates in bipolar disorder pathophysiology, through the investigated studies. The percentage of phenotypic variance explained by the identified variants is small (approximately 4.7%). Bipolar disorder polygenic risk scores are associated with other psychiatric phenotypes. The ENIGMA-BD studies show a replicable pattern of lower cortical thickness, altered white matter integrity and smaller subcortical volumes in bipolar disorder.

The low amount of explained phenotypic variance highlights the need for further large-scale investigations, especially among non-European populations, to achieve a more complete understanding of the genetic architecture of bipolar disorder and the missing heritability. Combining neuroimaging data with genetic data in large-scale studies might help researchers acquire a better knowledge of the engaged brain regions in bipolar disorder.