Association of nutritional glycaemic indices with global DNA methylation patterns: results from the Moli-sani cohort

Background: High dietary glycaemic index (GI) and load (GL) have been associated with increased risk of various cardiometabolic conditions. Among the molecular potential mechanisms underlying this relationship, DNA methylation has been studied, but a direct link between high GI and/or GL of diet and global DNA methylation levels has not been proved yet. We analyzed the associations between GI and GL and global DNA methylation patterns within an Italian population. Results: Genomic DNA methylation (5mC) and hydroxymethylation (5hmC) levels were measured in 1080 buffy coat samples from participants of the Moli-sani study (mean(SD) = 54.9(11.5) years; 52% women) via ELISA. A 188-item Food Frequency Questionnaire was used to assess food intake and dietary GI and GL for each participant were calculated. Multiple linear regressions were used to investigate the associations between dietary GI and GL and global 5mC and 5hmC levels, as well as the proportion of effect explained by metabolic and inflammatory markers. We found negative associations of GI with both 5mC (β (SE) = - 0.073 (0.027), p = 0.007) and 5hmC (- 0.084 (0.030), p = 0.006), and of GL with 5mC (- 0.14 (0.060), p = 0.014). Circulating biomarkers did not explain the above-mentioned associations. Gender interaction analyses revealed a significant association of the gender-x-GL interaction with 5mC levels, with men showing an inverse association three times as negative as in women (interaction β (SE) = - 0.16 (0.06), p = 0.005). Conclusions: Our findings suggest that global DNA methylation and hydroxymethylation patterns represent a biomarker of carbohydrate intake. Based on the differential association of GL with 5mC between men and women, further gender-based separate approaches are warranted

Genomic Overlap between Platelet Parameters Variability and Age at Onset of Parkinson Disease

With the increasing burden of common neurodegenerative disorders and their long-hypothesized link with platelet biology, genomic approaches have been recently used to investigate the presence of a shared genetic basis between neurodegenerative risk and platelet parameters, reporting a significant though moderate genetic correlation between Parkinson Disease (PD) risk and platelet distribution width, an index of platelet size variability. Here, we investigated the genetic overlap of platelet parameters with an endophenotype of PD, age-at-onset (PD-AAO). First, we applied a Linkage Disequilibrium (LD)-score regression to the summary statistics of a large independent Genome Wide Association Study (GWAS) previously conducted, to estimate the co-heritability based on common genetic variants. Then, we analyzed multitrait single-variant associations to identify novel loci associated with both PD-AAO and mean platelet volume (MPV). Finally, we performed gene and gene-set enrichment analyses of these associations. We observed a statistically significant genetic correlation between MPV and PD-AAO (rg (SE) = −0.215 (0.082); p = 0.009). The multitrait analysis revealed eight novel variants associated with PD-AAO and 33 with MPV. The genes most significantly enriched for associations with PD-AAO included ARHGEF3 (Rho Guanine Nucleotide Exchange Factor 3), previously associated with depression, and KALRN (Kalirin RhoGEF Kinase), encoding a PINK1 interactor previously implicated in schizophrenia, Alzheimer Disease and PD itself. Interestingly, these genes were also identified in the analysis of MPV. The most significant gene-set enrichments shared between MPV and PD-AAO were observed for coagulation- and megakaryopoiesis-related pathways. These findings provide novel hints into the common genetic basis of PD endophenotypes, platelet biology and its neuropsychiatric comorbidities, paving the way for investigating common underlying mechanisms

Genomic overlap between age at onset of Parkinson Disease and blood platelet parameters variability

Common neurodegenerative disorders have been long-hypothesized to be linked with blood platelet biology. Genomic approaches have been recently used to unravel a possibly shared genetic basis between neurodegenerative risk and platelet parameters. A significant though moderate genetic correlation between Parkinson Disease (PD) risk and an index of platelet size variability, has been reported

A Multi-Trait Association Analysis of Brain Disorders and Platelet Traits Identifies Novel Susceptibility Loci for Major Depression, Alzheimer’s and Parkinson’s Disease

Among candidate neurodegenerative/neuropsychiatric risk-predictive biomarkers, platelet count, mean platelet volume and platelet distribution width have been associated with the risk of major depressive disorder (MDD), Alzheimer’s disease (AD) and Parkinson’s disease (PD) through epidemiological and genomic studies, suggesting partial co-heritability. We exploited these relationships for a multi-trait association analysis, using publicly available summary statistics of genome-wide association studies (GWASs) of all traits reported above. Gene-based enrichment tests were carried out, as well as a network analysis of significantly enriched genes. We analyzed 4,540,326 single nucleotide polymorphisms shared among the analyzed GWASs, observing 149 genome-wide significant multi-trait LD-independent associations (p −8) for AD, 70 for PD and 139 for MDD. Among these, 27 novel associations were detected for AD, 34 for PD and 40 for MDD. Out of 18,781 genes with annotated variants within ±10 kb, 62 genes were enriched for associations with AD, 70 with PD and 125 with MDD (p −6). Of these, seven genes were novel susceptibility loci for AD (EPPK1, TTLL1, PACSIN2, TPM4, PIF1, ZNF689, AZGP1P1), two for PD (SLC26A1, EFNA3) and two for MDD (HSPH1, TRMT61A). The resulting network showed a significant excess of interactions (enrichment p = 1.0 × 10−16). The novel genes that were identified are involved in the organization of cytoskeletal architecture (EPPK1, TTLL1, PACSIN2, TPM4), telomere shortening (PIF1), the regulation of cellular aging (ZNF689, AZGP1P1) and neurodevelopment (EFNA3), thus, providing novel insights into the shared underlying biology of brain disorders and platelet parameters

Assessing Genetic Overlap Between Platelet Parameters and Neurodegenerative Disorders

Neurodegenerative disorders such as Parkinson's disease (PD) and Alzheimer's disease (AD) suffer from the lack of risk-predictive circulating biomarkers, and clinical diagnosis occurs only when symptoms are evident. Among potential biomarkers, platelet parameters have been associated with both disorders. However, these associations have been scarcely investigated at the genetic level. Here, we tested genome-wide coheritability based on common genetic variants between platelet parameters and PD/AD risk, through Linkage Disequilibrium Score Regression. This revealed a significant genetic correlation between platelet distribution width (PDW), an index of platelet size variability, and PD risk (rg [SE] = 0.080 [0.034]; p = 0.019), which was confirmed by a summary-summary polygenic score analysis, where PDW explained a small but significant proportion PD risk (<1%). AD risk showed no significant correlations, although a negative trend was observed with PDW (rg [SE] =-0.088 [0.053]; p=0.096), in line with previous epidemiological reports. These findings suggest the existence of limited shared genetic bases between PDW and PD and warrant further investigations to clarify the genes involved in this relation. Additionally, they suggest that the association between platelet parameters and AD risk is more environmental in nature, prompting an investigation into which factors may influence these traits

NMU DNA methylation in blood is associated with metabolic and inflammatory indices: results from the Moli-sani study

Neuromedin U (NMU) is a neuropeptide involved in gut-brain axis, energy balance and immune response. We aimed at analysing the association between NMU epigenetic variability and metabolic indices and the potential mediating role of low-grade inflammation in a general population of Italian adults. NMU Blood DNA methylation levels at two CpG islands (NMU76 and NMU32) were analysed using pyrosequencing in a randomly selected sub-cohort of 1,160 subjects from the Moli-sani study ( 6535years; 49.20% men). Multivariable regressions adjusted for age, sex, smoking, alcohol and vegetable consumption were performed to estimate the associations between methylation and metabolic phenotypes (BMI, waist-to-hip ratio, blood pressure, glucose, HOMA-IR, lipids, lipoprotein(a) and apolipoproteins). Mediation analysis was performed to identify the influence of low-grade inflammation in the association using a composite index based on C reactive protein, granulocyte-to-lymphocyte ratio (GLR), platelet and white blood cell counts (INFLA-score). Using principal component analysis four methylation factors were identified: NMU76-F1, NMU76-F2, NMU32-F1 and NMU32-F2. NMU76-F1 was FDR significantly associated with total cholesterol (for 1 SD increase: \u3b2 = 4.5 \ub1 1.4 mg/dL of, R2 = 10.8%, p = 0.001), ApoB (0.03 \ub1 0.01 g/L, 12.2%, p = 0.0004), with INFLA-score (1.05 \ub1 0.22, p = 2.7E-6) and GLR (-0.27 \ub1 0.03, 30.4%, p = 1.3E-20). GLR and lymphocyte number mediate the association of NMU76-F1 with cholesterol (24.0% of total effect, Sobel p = 0.013) and ApoB (42.6%, p = 9E-7), respectively. These findings suggest that NMU promoter methylation patterns could mark a pathway linking lipids with haematopoiesis and systemic inflammation

De novo missense variants in phosphatidylinositol kinase PIP5KIγ underlie a neurodevelopmental syndrome associated with altered phosphoinositide signaling

: Phosphoinositides (PIs) are membrane phospholipids produced through the local activity of PI kinases and phosphatases that selectively add or remove phosphate groups from the inositol head group. PIs control membrane composition and play key roles in many cellular processes including actin dynamics, endosomal trafficking, autophagy, and nuclear functions. Mutations in phosphatidylinositol 4,5 bisphosphate [PI(4,5)P2] phosphatases cause a broad spectrum of neurodevelopmental disorders such as Lowe and Joubert syndromes and congenital muscular dystrophy with cataracts and intellectual disability, which are thus associated with increased levels of PI(4,5)P2. Here, we describe a neurodevelopmental disorder associated with an increase in the production of PI(4,5)P2 and with PI-signaling dysfunction. We identified three de novo heterozygous missense variants in PIP5K1C, which encodes an isoform of the phosphatidylinositol 4-phosphate 5-kinase (PIP5KIγ), in nine unrelated children exhibiting intellectual disability, developmental delay, acquired microcephaly, seizures, visual abnormalities, and dysmorphic features. We provide evidence that the PIP5K1C variants result in an increase of the endosomal PI(4,5)P2 pool, giving rise to ectopic recruitment of filamentous actin at early endosomes (EEs) that in turn causes dysfunction in EE trafficking. In addition, we generated an in vivo zebrafish model that recapitulates the disorder we describe with developmental defects affecting the forebrain, including the eyes, as well as craniofacial abnormalities, further demonstrating the pathogenic effect of the PIP5K1C variants

De novo missense variants in phosphatidylinositol kinase PIP5KIγ underlie a neurodevelopmental syndrome associated with altered phosphoinositide signaling

: Phosphoinositides (PIs) are membrane phospholipids produced through the local activity of PI kinases and phosphatases that selectively add or remove phosphate groups from the inositol head group. PIs control membrane composition and play key roles in many cellular processes including actin dynamics, endosomal trafficking, autophagy, and nuclear functions. Mutations in phosphatidylinositol 4,5 bisphosphate [PI(4,5)P2] phosphatases cause a broad spectrum of neurodevelopmental disorders such as Lowe and Joubert syndromes and congenital muscular dystrophy with cataracts and intellectual disability, which are thus associated with increased levels of PI(4,5)P2. Here, we describe a neurodevelopmental disorder associated with an increase in the production of PI(4,5)P2 and with PI-signaling dysfunction. We identified three de novo heterozygous missense variants in PIP5K1C, which encodes an isoform of the phosphatidylinositol 4-phosphate 5-kinase (PIP5KIγ), in nine unrelated children exhibiting intellectual disability, developmental delay, acquired microcephaly, seizures, visual abnormalities, and dysmorphic features. We provide evidence that the PIP5K1C variants result in an increase of the endosomal PI(4,5)P2 pool, giving rise to ectopic recruitment of filamentous actin at early endosomes (EEs) that in turn causes dysfunction in EE trafficking. In addition, we generated an in vivo zebrafish model that recapitulates the disorder we describe with developmental defects affecting the forebrain, including the eyes, as well as craniofacial abnormalities, further demonstrating the pathogenic effect of the PIP5K1C variants