Ion Channel Dysfunction and Neuroinflammation in Migraine and Depression

Migraine and major depression are debilitating disorders with high lifetime prevalence rates. Interestingly these disorders are highly comorbid and show significant heritability, suggesting shared pathophysiological mechanisms. Non-homeostatic function of ion channels and neuroinflammation may be common mechanisms underlying both disorders: The excitation-inhibition balance of microcircuits and their modulation by monoaminergic systems, which depend on the expression and function of membrane located K+, Na+, and Ca+2 channels, have been reported to be disturbed in both depression and migraine. Ion channels and energy supply to synapses not only change excitability of neurons but can also mediate the induction and maintenance of inflammatory signaling implicated in the pathophysiology of both disorders. In this respect, Pannexin-1 and P2X7 large-pore ion channel receptors can induce inflammasome formation that triggers release of pro-inflammatory mediators from the cell. Here, the role of ion channels involved in the regulation of excitation-inhibition balance, synaptic energy homeostasis as well as inflammatory signaling in migraine and depression will be reviewed.

The Factor II (FII) Expression Quantitative Trait Locus (eQTL) Prothrombin G20210A Is Pleiotropically Associated with Plasma Fibrinogen Levels and Has a Profound Effect on Obesity in Mexican Americans of South Texas

The literature on risk factors for venous thromboembolism (VTE) is replete with complex combinations of genetic and environmental determinants. Here we apply statistical genetic models to data from Mexican Americans of South Texas participating in the San Antonio Family Study (SAFS) to help disentangle some of this complexity. The SAFS has data for nearly 50 large extended pedigrees (Figure A) that are extensively phenotyped, especially for traits related to the pathophysiology of cardiovascular disease. Using a linear mixed model approach, while accounting for age, sex, and their interactions (including age-squared, age-by-sex, and age-squared-by-sex) as confounders, we found significant heritability for plasma FII (46%; N=640; p=6.9E-12) and fibrinogen (28%; N=759; p=1.6E-06) coagulant activity levels and that the Prothrombin G20210A mutation was significantly associated with both traits (FII: p=0.002; fibrinogen: p=0.037; Figure B). We also examined a dichotomous obesity variable based on the Adult Treatment Panel III criterion of sex-specific waist circumferences (>102 cm in males; >88 cm females) denoted as OBWC. Under a threshold and liability model, we found a significant heritability of the liability of OBWC (71%; N=654; p=4.4E-08) and that Prothrombin G20210A was a significant predictor (p=0.031), while still adjusting for age, sex, and their interactions. As can be seen in Figure C, the G20210A mutation profoundly impacts the liability of OBWC such that obesity prevalence, where the prevalence parameter is denoted by Kp in the figure, increases by 27% from individuals homozygous for the major G-allele (G/G) with a prevalence of 34% to heterozygous (G/A) individuals with a prevalence of 61%. To the best of our knowledge, this appears to be the largest single-allele-dose effect for obesity reported in the literature. We next performed bivariate trait analysis (each time accounting for age, sex, and their interactions as confounders) to discover potentially meaningful correlations between the three traits of interest and to see if these would influence their association with G20210A. Under a bivariate model for any two traits, denoted as trait A and B say, the parameters of the following equation are estimated: r_p(A,B) = r_g(A,B)*sqrt(h2_A)*sqrt(h2_B) + r_e(A,B)* sqrt(1-h2_A)*sqrt(1-h2_B), where r_p(A,B), r_g(A,B), and r_e(A,B) respectively denote the phenotypic, genetic, and environmental correlation coefficients of A and B, and where h2_A and h2_B denote the trait heritabilities. Moreover, we can test their significance using likelihood-based inferential statistics. For the FII and OBWC bivariate analysis, none of the correlation coefficients were significant. For the fibrinogen and OBWC bivariate analysis, we found significant phenotypic (r_p=0.24; p=2.0E-05) and genetic (r_g=0.41; p=0.024) correlations. For the FII and fibrinogen bivariate analysis, we found significant phenotypic (r_p=0.26; p=3.1E-10) and environmental (r_e=0.28; p=0.003) correlations. For all bivariate analyses, the Prothrombin G20210A mutation was always a significant predictor for both traits of any given pair. In conclusion, Prothrombin G20210A is pleiotropically associated with plasma FII and fibrinogen coagulant activity levels, and OBWC, and profoundly impacts the prevalence of obesity in our sample. The associations of the prothrombin G20210A mutation are not affected by the consideration of inter-correlations between the three traits examined and thus appears to be fairly robust. Figure 1 Figure 1. Disclosures DeFronzo: AstraZeneca: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees; Boehringer-Ingelheim: Membership on an entity's Board of Directors or advisory committees, Research Funding; Intarcia: Membership on an entity's Board of Directors or advisory committees; Merck: Research Funding.

DNA Methylation Signature in Mononuclear Cells and Proinflammatory Cytokines May Define Molecular Subtypes in Sporadic Meniere Disease

Meniere Disease (MD) is a multifactorial disorder of the inner ear characterized by vertigo attacks associated with sensorineural hearing loss and tinnitus with a significant heritability. Although MD has been associated with several genes, no epigenetic studies have been performed on MD. Here we performed whole-genome bisulfite sequencing in 14 MD patients and six healthy controls, with the aim of identifying an MD methylation signature and potential disease mechanisms. We observed a high number of differentially methylated CpGs (DMC) when comparing MD patients to controls (n= 9545), several of them in hearing loss genes, such as PCDH15, ADGRV1 and CDH23. Bioinformatic analyses of DMCs and cis-regulatory regions predicted phenotypes related to abnormal excitatory postsynaptic currents, abnormal NMDA-mediated receptor currents and abnormal glutamate-mediated receptor currents when comparing MD to controls. Moreover, we identified various DMCs in genes previously associated with cochleovestibular phenotypes in mice. We have also found 12 undermethylated regions (UMR) that were exclusive to MD, including two UMR in an inter CpG island in the PHB gene. We suggest that the DNA methylation signature allows distinguishing between MD patients and controls. The enrichment analysis confirms previous findings of a chronic inflammatory process underlying MD.

Individual factors including age, BMI and heritable factors underlie temperature variation in sickness and in health: an observational, multi-cohort study

Background Ageing affects immunity, potentially altering fever response to infection. We assess effects of biological variables on basal temperature, and during COVID-19 infection, proposing an updated temperature threshold for older adults ≥65 years. Methods Participants were from four cohorts: 1089 unaffected adult TwinsUK volunteers; 520 adults with emergency admission to a London hospital with RT-PCR confirmed SARS-CoV-2 infection; 757 adults with emergency admission to a Birmingham hospital with RT-PCR confirmed SARS-CoV-2 infection and 3972 adult community-based COVID Symptom Study participants self-reporting a positive RT-PCR test. Heritability was assessed using saturated and univariate ACE models; mixed-effect and multivariable linear regression examined associations between temperature, age, sex and BMI; multivariable logistic regression examined associations between fever (≥37.8°C) and age; receiver operating characteristic (ROC) analysis was used to identify temperature threshold for adults ≥ 65 years. Results Among unaffected volunteers, lower BMI (p=0.001), and increasing age (p<0.001) associated with lower basal temperature. Basal temperature showed a heritability of 47% 95% Confidence Interval 18-57%). In COVID-19+ participants, increasing age was associated with lower temperatures in Birmingham and community-based cohorts (p<0.001). For each additional year of age, participants were 1% less likely to demonstrate a fever ≥37.8°C (OR 0.99; p<0.001). Combining healthy and COVID-19+ participants, a temperature of 37.4°C in adults ≥65 years had similar sensitivity and specificity to 37.8°C in adults <65 years for discriminating infection. Conclusions Ageing affects temperature in health and acute infection, with significant heritability, indicating genetic factors contribute to temperature regulation. Our observations suggest a lower threshold (37.4°C/97.3°F) for identifying fever in older adults ≥65 years.

DNA Methylation Signature in Mononuclear Cells and Proinflammatory Cytokines May Define Molecular Subtypes in Sporadic Meniere Disease

Meniere Disease (MD) is a multifactorial disorder of the inner ear characterized by vertigo attacks associated with sensorineural hearing loss and tinnitus with a significant heritability. Although MD has been associated with several genes, no epigenetic studies have been performed in MD. Here we performed whole genome bisulfite sequencing in 14 MD patients and 6 healthy controls, with the aim of identifying a MD methylation signature and potential disease mechanisms. We observed a high number of differentially methylated CpGs (DMC) when comparing MD patients to controls (N= 9,545), several of them in hearing loss genes such as PCDH15, ADGRV1 and CDH23. Bioinformatic analyses of DMCs and cis-regulatory regions predicted phenotypes related to abnormal excitatory postsynaptic currents, abnormal NMDA-mediated receptor currents and abnormal glutamate-mediated receptor currents when comparing MD to controls. Moreover, we identified various DMCs in genes previously associated with cochleovestibular phenotypes in mice. We have also found 12 undermethylated regions (UMR) that were exclusive to MD, including 2 UMR in an inter CpG island in the PHB gene. We suggest that the DNA methylation signature allows to distinguish between MD patients and controls. The enrichment analysis confirms previous findings of a chronic inflammatory process underlying MD.

High-resolution genetic mapping of the mucosa-associated gut microbiome in hybrid mice provides novel insight on the impact of host genetics

Determining the forces that shape diversity in host-associated bacterial communities is critical to understanding the evolution and maintenance of meta- organisms. To gain novel insight on the genetics of gut microbial traits, we employed a powerful approach using inbred lines derived from the hybrid zone of two incipient house mouse species. We identify a high number of mucosa-associated bacterial taxa with significant heritability estimates, particularly for 16S rRNA transcript-based traits. Interestingly, heritability estimates also positively correlate with cospeciation rate estimates. Association mapping identifies 443 loci influencing 123 taxa, whose narrow genomic intervals enable promising individual candidate genes and pathways to be pinpointed. These results indicate a unique genetic architecture for cospeciating taxa, a clear enrichment for several classes of human disease, and identify important functional categories including innate immunity and G-protein-coupled receptors, whose role in host-microbe interactions diverge as new species form.

The individuality of shape asymmetries of the human cerebral cortex

Asymmetries of the cerebral cortex are found across diverse phyla and occur at multiple spatial scales, from the global morphology of the two hemispheres to fine-grained sulcal and gyral anatomy. Cortical asymmetries are particularly pronounced in humans and have important implications for brain function and disease. However, most studies conflate asymmetries in regional size and shape and only consider effects at fairly fine-grained resolutions, such as image voxels or a priori regions-of-interest. As such, whether asymmetries are preferentially expressed at specific spatial resolutions over others remains unclear. Here, we apply a spectral shape analysis to magnetic resonance imaging (MRI) data from three independent samples to derive a multiscale description of asymmetries in cortical shape that is distinct from regional size-related descriptors such as volume or thickness. We show that our proposed shape asymmetry signature (SAS) is a highly individualized feature, akin to a cortical fingerprint, that more accurately identifies individuals than size-based descriptors or measures of inter-regional functional coupling of brain activity. Notably, individual identifiability is optimal at coarse spatial scales (~37 mm wavelength), and shape asymmetries at specific scales show differences between males and females but are unrelated to the handedness. We further demonstrate that while unihemispheric shape descriptors show significant heritability at coarse scales, the SAS are determined primarily by unique environmental effects across all scales considered. Our findings thus identify coarse-scale scale asymmetries of cortical shape as being highly unique to individuals, sexually dimorphic, and largely driven by stochastic environmental influences.

Compared Heritability of Chronotype Instruments in a Single Population Sample

It is well established that the oldest chronotype questionnaire, the morningness-eveningness questionnaire (MEQ), has significant heritability, and several associations have been reported between MEQ score and polymorphisms in candidate clock genes, a number of them reproducibly across populations. By contrast, there are no reports of heritability and genetic associations for the Munich chronotype questionnaire (MCTQ). Recent genome-wide association studies (GWAS) from large cohorts have reported multiple associations with chronotype as assessed by a single self-evaluation question. We have taken advantage of the availability of data from all these instruments from a single sample of 597 participants from the Brazilian Baependi Heart Study. The family-based design of the cohort allowed us to calculate the heritability (h2) for these measures. Heritability values for the best-fitted models were 0.37 for MEQ, 0.32 for MCTQ, and 0.28 for single-question chronotype (MEQ Question 19). We also calculated the heritability for the two major factors recently derived from MEQ, “Dissipation of sleep pressure” (0.32) and “Build-up of sleep pressure” (0.28). This first heritability comparison of the major chronotype instruments in current use provides the first quantification of the genetic component of MCTQ score, supporting its future use in genetic analysis. Our findings also suggest that the single chronotype question that has been used for large GWAS analyses captures a larger proportion of the dimensions of chronotype than previously thought.

Heritability of 2D:4D finger length ratio

A Chuvashian population-based sample included 802 males and 738 females (mean age 46.98±17.10 and 48.65±16.62 years, correspondingly). Age, basic demographics, anthropometric data, reproductive indices, and x-rays of both hands were collected. Results and discussion. Familial correlations of FLR traits showed no significant correlation for spouses, however, parent-offspring (0.15-0.28, p<0.001) and sibling correlations (0.13-0.38, p<0.009) were found significant. Heritability (H2) of visual classification of FLR was 0.36 for the left and 0.28 for the right hand; finger ratio was 0.55 and 0.66, respectively; the ray ratio was 0.49 and 0.59, respectively, thus indicating the existence of a clear familial aggregation of FLR variation in the Chuvashian pedigrees, which cannot be explained by pure common environmental effects. Conclusion. Results of our study suggest the familial aggregations of finger ratio variation (for all traits) in Chuvashian pedigrees. Further research should focus on the biological mechanisms of the relationship between FLR and aging.

3D facial phenotyping by biometric sibling matching used in contemporary genomic methodologies

The analysis of contemporary genomic data typically operates on one-dimensional phenotypic measurements (e.g. standing height). Here we report on a data-driven, family-informed strategy to facial phenotyping that searches for biologically relevant traits and reduces multivariate 3D facial shape variability into amendable univariate measurements, while preserving its structurally complex nature. We performed a biometric identification of siblings in a sample of 424 children, defining 1,048 sib-shared facial traits. Subsequent quantification and analyses in an independent European cohort (n = 8,246) demonstrated significant heritability for a subset of traits (0.17–0.53) and highlighted 218 genome-wide significant loci (38 also study-wide) associated with facial variation shared by siblings. These loci showed preferential enrichment for active chromatin marks in cranial neural crest cells and embryonic craniofacial tissues and several regions harbor putative craniofacial genes, thereby enhancing our knowledge on the genetic architecture of normal-range facial variation.