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.

Background: Acute ischemic stroke (AIS) represents one of the principal causes of neurological morbidity and mortality worldwide. For a prompt and efficient cerebral blood restoration, intravenous treatment with rt-PA is often combined with mechanical thrombectomy (MT) which provides cerebral thrombi (CT) as study material, allowing the investigation of its cellular composition, morphological and histopathological features. Indeed, the determination of stroke etiology, typically defined by the TOAST classification, is paramount for prognostic factors, outcome, and management of the event. Aim of the study is therefore to highlight and analyze gene expression profiles in thrombotic tissue and peripheral blood (PB) in the comparison between strokes of cardioembolic (CE) and atherosclerotic (LAA) origin. Methods: We performed gene expression profiles of 92 patients. CT were stored in RNA later and RNA was extracted by PAX gene blood miRNA kit. The global gene expression profile was assessed by Affymetrix technology using GeneChip Human Transcriptome Array 2.0 combined with Affymetrix Transcriptome Analysis Console (TAC) Software. Results: Currently, we focused our attention on CT data analysis. The analysis revealed a significant difference (p-value<0.05 and FoldChange=2 as threshold) in gene expression when comparing LAA and CE stroke. In particular, from CT of atherosclerotic origin emerges an overexpression of 1766 genes. Prominent among them are genes such as MMP-9, TGFB, TGFBR and CXCL1, primarily involved in neutrophil-mediated immunity, Blood-Brain Barrier (BBB) disruption processes, and associated with atherosclerotic plaque instability and related to poor neurological outcome, suggesting a deleterious role in human brain injury. As concerns CE patients, 57 genes mainly involved in transcriptional regulatory processes turn out to be significantly overexpressed. Conclusions: Transcriptome profiling is a powerful weapon for revealing expression patterns associated with complex disorders. The variation of gene expression profiles confirmed and extended several known pathophysiological mechanisms and may be one way of delineating different stroke etiology.