GABAergic Neuron Deficit As An Idiopathic Generalized Epilepsy Mechanism: The Role Of BRD2 Haploinsufficiency In Juvenile Myoclonic Epilepsy

Idiopathic generalized epilepsy (IGE) syndromes represent about 30% of all epilepsies. They have strong, but elusive, genetic components and sex-specific seizure expression. Multiple linkage and population association studies have connected the bromodomain-containing gene BRD2 to forms of IGE. In mice, a null mutation at the homologous Brd2 locus results in embryonic lethality while heterozygous Brd2+/− mice are viable and overtly normal. However, using the flurothyl model, we now show, that compared to the Brd2+/+ littermates, Brd2+/− males have a decreased clonic, and females a decreased tonic-clonic, seizure threshold. Additionally, long-term EEG/video recordings captured spontaneous seizures in three out of five recorded Brd2+/− female mice. Anatomical analysis of specific regions of the brain further revealed significant differences in Brd2+/− vs +/+ mice. Specifically, there were decreases in the numbers of GABAergic (parvalbumin- or GAD67-immunopositive) neurons along the basal ganglia pathway, i.e., in the neocortex and striatum of Brd2+/− mice, compared to Brd2+/+ mice. There were also fewer GABAergic neurons in the substantia nigra reticulata (SNR), yet there was a minor, possibly compensatory increase in the GABA producing enzyme GAD67 in these SNR cells. Further, GAD67 expression in the superior colliculus and ventral medial thalamic nucleus, the main SNR outputs, was significantly decreased in Brd2+/− mice, further supporting GABA downregulation. Our data show that the non-channel-encoding, developmentally critical Brd2 gene is associated with i) sex-specific increases in seizure susceptibility, ii) the development of spontaneous seizures, and iii) seizure-related anatomical changes in the GABA system, supporting BRD2's involvement in human IGE

Serotonin transporter gene polymorphisms and brain function during emotional distraction from cognitive processing in posttraumatic stress disorder

BACKGROUND: Serotonergic system dysfunction has been implicated in posttraumatic stress disorder (PTSD). Genetic polymorphisms associated with serotonin signaling may predict differences in brain circuitry involved in emotion processing and deficits associated with PTSD. In healthy individuals, common functional polymorphisms in the serotonin transporter gene (SLC6A4) have been shown to modulate amygdala and prefrontal cortex (PFC) activity in response to salient emotional stimuli. Similar patterns of differential neural responses to emotional stimuli have been demonstrated in PTSD but genetic factors influencing these activations have yet to be examined. METHODS: We investigated whether SLC6A4 promoter polymorphisms (5-HTTLPR, rs25531) and several downstream single nucleotide polymorphisms (SNPs) modulated activity of brain regions involved in the cognitive control of emotion in post-9/11 veterans with PTSD. We used functional MRI to examine neural activity in a PTSD group (n = 22) and a trauma-exposed control group (n = 20) in response to trauma-related images presented as task-irrelevant distractors during the active maintenance period of a delayed-response working memory task. Regions of interest were derived by contrasting activation for the most distracting and least distracting conditions across participants. RESULTS: In patients with PTSD, when compared to trauma-exposed controls, rs16965628 (associated with serotonin transporter gene expression) modulated task-related ventrolateral PFC activation and 5-HTTLPR tended to modulate left amygdala activation. Subsequent to combat-related trauma, these SLC6A4 polymorphisms may bias serotonin signaling and the neural circuitry mediating cognitive control of emotion in patients with PTSD. CONCLUSIONS: The SLC6A4 SNP rs16965628 and 5-HTTLPR are associated with a bias in neural responses to traumatic reminders and cognitive control of emotions in patients with PTSD. Functional MRI may help identify intermediate phenotypes and dimensions of PTSD that clarify the functional link between genes and disease phenotype, and also highlight features of PTSD that show more proximal influence of susceptibility genes compared to current clinical categorizations

A pure likelihood approach to the analysis of genetic association data: an alternative to Bayesian and frequentist analysis

Investigators performing genetic association studies grapple with how to measure strength of association evidence, choose sample size, and adjust for multiple testing. We apply the evidential paradigm (EP) to genetic association studies, highlighting its strengths. The EP uses likelihood ratios (LRs), as opposed to P-values or Bayes' factors, to measure strength of association evidence. We derive EP methodology to estimate sample size, adjust for multiple testing, and provide informative graphics for drawing inferences, as illustrated with a Rolandic Epilepsy (RE) fine-mapping study. We focus on controlling the probability of observing weak evidence for or against association (W) rather than type I errors (M). For example, for LR⩾32 representing strong evidence, at one locus with n=200 cases, n=200 controls, W=0.134, whereas M=0.005. For n=300 cases and controls, W=0.039 and M=0.004. These calculations are based on detecting an OR=1.5. Despite the common misconception, one is not tied to this planning value for analysis; rather one calculates the likelihood at all possible values to assess evidence for association. We provide methodology to adjust for multiple tests across m loci, which adjusts M and W for m. We do so for (a) single-stage designs, (b) two-stage designs, and (c) simultaneously controlling family-wise error rate (FWER) and W. Method (c) chooses larger sample sizes than (a) or (b), whereas (b) has smaller bounds on the FWER than (a). The EP, using our innovative graphical display, identifies important SNPs in elongator protein complex 4 (ELP4) associated with RE that may not have been identified using standard approaches