Search

Abstract According to the recently proposed omnigenic theory, all expressed genes in a relevant tissue are contributing directly or indirectly to the manifestation of complex disorders such as autism. Thus, holistic approaches can be complementary in studying genetics of these complex disorders to focusing on a limited number of candidate genes. Gene interaction networks can be used for holistic studies of the omnigenic nature of autism. We used Louvain clustering on tissue-specific gene interaction networks and their subgraphs exclusively containing autism-related genes to study the effects of peripheral gene interactions. We observed that the autism gene clusters are significantly weaker connected to each other and the peripheral genes in non-neuronal tissues than in brain-related tissues. The biological functions of the brain clusters correlated well with previous findings on autism, such as synaptic signaling, regulation of DNA methylation, or regulation of lymphocyte activation, however, on the other tissues they did not enrich as significantly. Furthermore, ASD subjects with disruptive mutations in specific gene clusters show phenotypical differences compared to other disruptive variants carrying ASD individuals. Our results strengthen the omnigenic theory and can advance our understanding of the genetic background of autism.

One hundred and six Rétköz and 48 Váh valley samples were collected from the contact zones of Hungarian-Slovakian territories and were genotyped for Y-chromosomal haplotypes and haplogroups. The results were compared with contemporary and archaic data from published sources. The genetic composition of the Rétköz population from Hungary and the Váh valley population from Slovakia indicates different histories. In the Rétköz population, the paternal lineages that were also found in the Hungarian Conquerors, such as R1a-Z93, N-M46, Q-M242, and R1b-L23, were better preserved. These haplogroups occurred in 10% of the population. The population of the Váh valley, however, is characterized by the complete absence of these haplogroups. Our study did not detect a genetic link between the Váh valley population and the Hungarian Conquerors; the genetic composition of the Váh valley population is similar to that of the surrounding Indo-European populations. The Hungarian Rétköz males shared common haplotypes with ancient Xiongnu, ancient Avar, Caucasian Avar, Abkhazian, Balkarian, and Circassian males within haplogroups R1a-Z93, N1c-M46, and R1b-L23, indicating a common genetic footprint. Another difference between the two studied Hungarian populations can be concluded from the Fst-based MDS plot. The Váh valley, in the western part of the Hungarian-Slovakian contact zone, is genetically closer to the Western Europeans. In contrast, Rétköz is in the eastern part of that zone and therefore closer to the Eastern Europeans.

DiGeorge Syndrome (DGS) Critical Region 8 (DGCR8) is a primary candidate gene in they DGS. The DGCR8 microprocessor complex subunit is an essential cofactor in the canonical miRNA biogenesis which is involved in diverse cellular functions such as cell fate decisions, apoptosis and different signaling pathways. However, the role of DGCR8 in these processes or development of DGS is not fully understood. Here we present a heterozygous DGCR8 mutant human embryonic stem cell line (HuES9DGCR8+/−) created by the CRISPR/Cas9 system. The generated HuES9DGCR8+/− cells maintain normal karyotype, morphology, pluripotency and differentiation capacity into all three germ layers.

Autism spectrum disorder (ASD) is a heterogeneous neuropsychiatric condition traditionally defined by core symptoms in social behavior, speech/communication, repetitive behavior, and restricted interests. Beyond the core symptoms, autism has strong association with other disorders such as intellectual disability (ID), epilepsy, schizophrenia among many others. This paper outlines a theory of ASD with capacity to connect heterogeneous “core” symptoms, medical and psychiatric comorbidities as well as other etiological theories of autism in a unifying cognitive framework rooted in neuroscience and genetics. Cognition is embedded into an ever-developing structure modified by experiences, including the outcomes of environment influencing behaviors. The key constraint of cognition is that the brain can handle only 7±2 relevant variables at a time, whereas sensory variables, i.e., the number of sensory neurons is orders of magnitude larger. As a result, (a) the extraction, (b) the encoding, and (c) the capability for the efficient cognitive manipulation of the relevant variables, and (d) the compensatory mechanisms that counteract computational delays of the distributed components are critical. We outline our theoretical model to describe a Cartesian Factor (CF) forming, autoencoder-like cognitive mechanism which breaks combinatorial explosion and is accelerated by internal reinforcing machineries and discuss the neural processes that support CF formation. Impairments in any of these aspects may disrupt learning, cognitive manipulation, decisions on interactions, and execution of decisions. We suggest that social interactions are the most susceptible to combinations of diverse small impairments and can be spoiled in many ways that pile up. Comorbidity is experienced, if any of the many potential impairments is relatively strong. We consider component spoiling impairments as the basic colors of autism, whereas the combinations of individual impairments make the palette of autism. We put forth arguments on the possibility of dissociating the different main elements of the impairments that can appear together. For example, impairments of generalization (domain general learning) and impairments of dealing with many variable problems, such as social situations may appear independently and may mutually enhance their impacts. We also consider mechanisms that may lead to protection.

Dyskinesias are characterized by abnormal repetitive involuntary movements due to dysfunctional neuronal activity. Although levodopa-induced dyskinesia, characterized by tic-like abnormal involuntary movements, has no clinical treatment for Parkinson’s disease patients, animal studies indicate that Riluzole, which interferes with glutamatergic neurotransmission, can improve the phenotype. The rat model of Levodopa-Induced Dyskinesia is a unilateral lesion with 6-hydroxydopamine in the medial forebrain bundle, followed by the repeated administration of levodopa. The molecular pathomechanism of Levodopa-Induced Dyskinesia is still not deciphered; however, the implication of epigenetic mechanisms was suggested. In this study, we investigated the striatum for DNA methylation alterations under chronic levodopa treatment with or without co-treatment with Riluzole. Our data show that the lesioned and contralateral striata have nearly identical DNA methylation profiles. Chronic levodopa and levodopa + Riluzole treatments led to DNA methylation loss, particularly outside of promoters, in gene bodies and CpG poor regions. We observed that several genes involved in the Levodopa-Induced Dyskinesia underwent methylation changes. Furthermore, the Riluzole co-treatment, which improved the phenotype, pinpointed specific methylation targets, with a more than 20% methylation difference relative to levodopa treatment alone. These findings indicate potential new druggable targets for Levodopa-Induced Dyskinesia.

Abstract Alzheimer’s disease (AD) is a multifactorial disease with both genetic and environmental factors contributing to its etiology. Previous evidence has implicated disturbed insulin signaling as a key mechanism that plays a role in both neurodegenerative diseases such as AD and comorbid somatic diseases such as diabetes mellitus type 2 (DM2). In this study, we analysed available genome-wide association studies (GWASs) of AD and somatic insulin-related diseases and conditions (SID), i.e., DM2, metabolic syndrome and obesity, to identify genes associated with both AD and SID that could increase our insights into their molecular underpinnings. We then performed functional enrichment analyses of these genes. Subsequently, using (additional) GWAS data, we conducted shared genetic etiology analyses between AD and SID, on the one hand, and blood and cerebrospinal fluid (CSF) metabolite levels on the other hand. Further, integrating all these analysis results with elaborate literature searches, we built a molecular landscape of the overlap between AD and SID. From the landscape, multiple functional themes emerged, including insulin signaling, estrogen signaling, synaptic transmission, lipid metabolism and tau signaling. We also found shared genetic etiologies between AD/SID and the blood/CSF levels of multiple metabolites, pointing towards “energy metabolism” as a key metabolic pathway that is affected in both AD and SID. Lastly, the landscape provided leads for putative novel drug targets for AD (including MARK4, TMEM219, FKBP5, NDUFS3 and IL34) that could be further developed into new AD treatments.

Abstract Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by the death of motor neurons, the aetiology of which is essentially unknown. Here, we present an integrative epigenomic study in blood samples from seven clinically characterised sporadic ALS patients to elucidate molecular factors associated with the disease. We used clinical exome sequencing (CES) to study DNA variants, DNA-RNA hybrid immunoprecipitation sequencing (DRIP-seq) to assess R-loop distribution, and reduced representation bisulfite sequencing (RRBS) to examine DNA methylation changes. The above datasets were combined to create a comprehensive repository of genetic and epigenetic changes associated with the ALS cases studied. This repository is well-suited to unveil new correlations within individual patients and across the entire patient cohort. The molecular attributes described here are expected to guide further mechanistic studies on ALS, shedding light on the underlying genetic causes and facilitating the development of new epigenetic therapies to combat this life-threatening disease.

IntroductionPreeclampsia (PE) is a severe obstetrical syndrome characterized by new-onset hypertension and proteinuria and it is often associated with fetal intrauterine growth restriction (IUGR). PE leads to long-term health complications, so early diagnosis would be crucial for timely prevention. There are multiple etiologies and subtypes of PE, and this heterogeneity has hindered accurate identification in the presymptomatic phase. Recent investigations have pointed to the potential role of small regulatory RNAs in PE, and these species, which travel in extracellular vesicles (EVs) in the circulation, have raised the possibility of non-invasive diagnostics. The aim of this study was to investigate the behavior of exosomal regulatory small RNAs in the most severe subtype of PE with IUGR.MethodsWe isolated exosomal EVs from first-trimester peripheral blood plasma samples of women who later developed preterm PE with IUGR (n=6) and gestational age-matched healthy controls (n=14). The small RNA content of EVs and their differential expression were determined by next-generation sequencing and further validated by quantitative real-time PCR. We also applied the rigorous exceRpt bioinformatics pipeline for small RNA identification, followed by target verification and Gene Ontology analysis.ResultsOverall, >2700 small RNAs were identified in all samples and, of interest, the majority belonged to the RNA interference (RNAi) pathways. Among the RNAi species, 16 differentially expressed microRNAs were up-regulated in PE, whereas up-regulated and down-regulated members were equally found among the six identified Piwi-associated RNAs. Gene ontology analysis of the predicted small RNA targets showed enrichment of genes in pathways related to immune processes involved in decidualization, placentation and embryonic development, indicating that dysregulation of the induced small RNAs is connected to the impairment of immune pathways in preeclampsia development. Finally, the subsequent validation experiments revealed that the hsa_piR_016658 piRNA is a promising biomarker candidate for preterm PE associated with IUGR.DiscussionOur rigorously designed study in a homogeneous group of patients unraveled small RNAs in circulating maternal exosomes that act on physiological pathways dysregulated in preterm PE with IUGR. Therefore, our small RNA hits are not only suitable biomarker candidates, but the revealed biological pathways may further inform us about the complex pathology of this severe PE subtype.