Alongside their function in primary haemostasis and thrombo-inflammation, platelets are increasingly considered a bridge between mental, immunological and coagulation-related disorders. This review focuses on the link between platelets and the pathophysiology of major depressive disorder (MDD) and its most frequent comorbidities. Platelet- and neuron-shared proteins involved in MDD are functionally described. Platelet-related studies performed in the context of MDD, cardiovascular disease, and major neurodegenerative, neuropsychiatric and neurodevelopmental disorders are transversally presented from an epidemiological, genetic and functional point of view. To provide a complete scenario, we report the analysis of original data on the epidemiological link between platelets and depression symptoms suggesting moderating and interactive effects of sex on this association. Epidemiological and genetic studies discussed suggest that blood platelets might also be relevant biomarkers of MDD prediction and occurrence in the context of MDD comorbidities. Finally, this review has the ambition to formulate some directives and perspectives for future research on this topic.

Background The laminin alpha 5 gene (LAMA5) plays a master role in the maintenance and function of the extracellular matrix (ECM) in mammalian tissues, which is critical in developmental patterning, stem cell niches, cancer and genetic diseases. Its mutations have never been reported in human disease so far. The aim of this study was to associate the first mutation in LAMA5 gene to a novel multisystem syndrome. Methods A detailed characterisation of a three-generation family, including clinical, biochemical, instrumental and morphological analysis, together with genetics and expression (WES and RNAseq) studies, was performed. Results The heterozygous LAMA5 mutation c.9418G>A (p.V3140M) was associated with skin anomalies, impaired scarring, night blindness, muscle weakness, osteoarthritis, joint and internal organs ligaments laxity, malabsorption syndrome and hypothyroidism. We demonstrated that the mutation alters the amount of LAMA5 peptides likely derived from protein cleavage and perturbs the activation of the epithelial-mesenchymal signalling, producing an unbalanced expression of Sonic hedgehog and GLI1, which are upregulated in cells from affected individuals, and of ECM proteins (COL1A1, MMP1 and MMP3), which are strongly inhibited. Studies carried out using human skin biopsies showed alteration of dermal papilla with a reduction of the germinative layer and an early arrest of hair follicle downgrowth. The knock-in mouse model, generated in our laboratory, shows similar changes in the tissues studied so far. Conclusions This is the first report of a disease phenotype associated with LAMA5 mutation in humans.

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 < 5 × 10⁻⁸) 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 < 2.7 × 10⁻⁶). 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.

The KALRN gene (encoding kalirin) has been implicated in several neuropsychiatric and neurodegenerative disorders. However, genetic evidence supporting this implication is limited and targeted epigenetic analyses are lacking. Here, we tested associations between epigenetic variation in KALRN and interindividual variation in depressive symptoms (PHQ9) and cognitive (MoCA) performance, in an Italian population cohort (N = 2409; mean (SD) age: 67 (9) years; 55% women). First, we analyzed the candidate region chr3:124584826–124584886 (hg38), within the KALRN promoter, through pyrosequencing of 1385 samples. Then, we widened the investigated region by analyzing 137 CpGs annotated to the whole gene, rescued from epigenome-wide (Illumina EPIC) data from 1024 independent samples from the same cohort. These were tested through stepwise regression models adjusted for age, sex, circulating leukocytes fractions, education, prevalent health conditions and lifestyles. We observed no statistically significant associations with methylation levels in the three CpGs tested through pyrosequencing, or in the gene-wide association analysis with MoCA score. However, we observed a statistically significant association between PHQ9 and cg13549966 (chr3:124106738; β (Standard Error) = 0.28 (0.08), Bonferroni-corrected p = 0.025), located close to the transcription start site of the gene. This association was driven by a polychoric factor tagging somatic depressive symptoms (β (SE) = 0.127 (0.064), p = 0.048). This evidence underscores the importance of studying epigenetic variation within the KALRN gene and the role that it may play in brain diseases, particularly in atypical depression, which is often characterized by somatic symptoms.

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.

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 (≥35years; 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: β = 4.5 ± 1.4 mg/dL of, R² = 10.8%, p = 0.001), ApoB (0.03 ± 0.01 g/L, 12.2%, p = 0.0004), with INFLA-score (1.05 ± 0.22, p = 2.7E-6) and GLR (-0.27 ± 0.03, 30.4%, p = 1.3E-20). GLR and lymphocyte numbers 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.