GRIN2B Gene and Associated Brain Cortical White Matter Changes in Bipolar Disorder: A Preliminary Combined Platform Investigation

Abstract

Abnormalities in glutamate signaling and glutamate toxicity are thought to be important in the pathophysiology of bipolar disorder (BD). Whilst previous studies have found brain white matter changes in BD, there is paucity of data about how glutamatergic genes affect brain white matter integrity in BD. Based on extant neuroimaging data, we hypothesized that GRIN2B risk allele is associated with reductions of brain white matter integrity in the frontal, parietal, temporal, and occipital regions and cingulate gyrus in BD. Fourteen patients with BD and 22 healthy controls matched in terms of age, gender and handedness were genotyped using blood samples and underwent diffusion tensor imaging. Compared to G allele, brain FA values were significantly lower in BD patients with risk T allele in left frontal region (P = 0.001), right frontal region (P = 0.002), left parietal region (P = 0.001), left occipital region (P = 0.001), right occipital region (P < 0.001), and left cingulate gyrus (P = 0.001). Further elucidation of the interactions between different glutamate genes and their relationships with such structural, functional brain substrates will enhance our understanding of the link between dysregulated glutamatergic neurotransmission and neuroimaging endophenotypes in BD.

The relationship between genetic risk variants with brain structure and function in bipolar disorder: A systematic review of genetic-neuroimaging studies

“…Two studies found that distinct variations of the ANK3 gene were associated with DTI findings (reduced FA) compatible with widespread white matter deficits in several brain regions, such as the forceps minor, the uncinate fasciculus, the anterior cingulate gyrus, the dorsolateral frontal cortex, the left temporoparietal WM, and in posterior dorsomedial WM (Lippard et al, 2016;Ota et al, 2016). Finally, compared to the G allele of the GRIN2 B gene, brain FA values were significantly lower in BD patients with risk T allele in left and right frontal regions, left parietal region, left and right occipital regions and the left cingulate gyrus (Kuswanto et al, 2013).…”

Genetic Studies on the Tripartite Glutamate Synapse in the Pathophysiology and Therapeutics of Mood Disorders

“…In MDD, GRM1 was associated with brain hippocampal glutamate levels (Menke et al, 2012). In BD patients, GRIN2B was associated with white matter integrity (Kuswanto et al, 2013), and SLC1A2 was found to modulate gray matter volume (Poletti et al, 2014). However, the results reported across studies have also obtained inconsistent results, which might be due to the high prevalence, relatively moderate heritability, and phenotypic heterogeneity of mood disorders.…”

Genetic variation withinGRIN2Bin adolescents with alcohol use disorder may be associated with larger left posterior cingulate cortex volume

“…Genetic polymorphisms within GRIN2B have previously been associated with variation in brain structure. In particular, the GRIN2B SNP rs890 was shown to have an association with reduced fractional anisotropy (FA) in several brain areas, including the bilateral frontal region and left cingulate gyrus, in individuals with bipolar disorder (25). Our findings support previous research implicating the GRIN2B gene in AUD, and linking it to the posterior cingulate, although in adults the volume is smaller not larger (16).…”