Cold storage and cryopreservation methods for spermatozoa of the sea urchins Lytechinus pictus and Strongylocentrotus purpuratus.

BACKGROUND: Sea urchins have contributed greatly to knowledge of fertilization, embryogenesis, and cell biology. However, until now, they have not been genetic model organisms because of their long generation times and lack of tools for husbandry and gene manipulation. We recently established the sea urchin Lytechinus pictus, as a multigenerational model Echinoderm, because of its relatively short generation time of 4-6 months and ease of laboratory culture. To take full advantage of this new multigenerational species, methods are needed to biobank and share genetically modified L. pictus sperm. RESULTS: Here, we describe a method, based on sperm ion physiology that maintains L. pictus and Strongylocentrotus purpuratus sperm fertilizable for at least 5-10 weeks when stored at 0°C. We also describe a new method to cryopreserve sperm of both species. Sperm of both species can be frozen and thawed at least twice and still give rise to larvae that undergo metamorphosis. CONCLUSIONS: The simple methods we describe work well for both species, achieving >90% embryo development and producing larvae that undergo metamorphosis to juvenile adults. We hope that these methods will be useful to others working on marine invertebrate sperm.

Converging and Diverging Cerebellar Pathways for Motor and Social Behaviors in Mice.

Evidence from clinical and preclinical studies has shown that the cerebellum contributes to cognitive functions, including social behaviors. Now that the cerebellum's role in a wider range of behaviors has been confirmed, the question arises whether the cerebellum contributes to social behaviors via the same mechanisms with which it modulates movements. This review seeks to answer whether the cerebellum guides motor and social behaviors through identical pathways. It focuses on studies in which cerebellar cells, synapses, or genes are manipulated in a cell-type specific manner followed by testing of the effects on social and motor behaviors. These studies show that both anatomically restricted and cerebellar cortex-wide manipulations can lead to social impairments without abnormal motor control, and vice versa. These studies suggest that the cerebellum employs different cellular, synaptic, and molecular pathways for social and motor behaviors. Future studies warrant a focus on the diverging mechanisms by which the cerebellum contributes to a wide range of neural functions.

Agrobacterium tumefaciens: a Transformative Agent for Fundamental Insights into Host-Microbe Interactions, Genome Biology, Chemical Signaling, and Cell Biology.

Agrobacterium tumefaciens incites the formation of readily visible macroscopic structures known as crown galls on plant tissues that it infects. Records from biologists as early as the 17th century noted these unusual plant growths and began examining the basis for their formation. These studies eventually led to isolation of the infectious agent, A. tumefaciens, and decades of study revealed the remarkable mechanisms by which A. tumefaciens causes crown gall through stable horizontal genetic transfer to plants. This fundamental discovery generated a barrage of applications in the genetic manipulation of plants that is still under way. As a consequence of the intense study of A. tumefaciens and its role in plant disease, this pathogen was developed as a model for the study of critical processes that are shared by many bacteria, including host perception during pathogenesis, DNA transfer and toxin secretion, bacterial cell-cell communication, plasmid biology, and more recently, asymmetric cell biology and composite genome coordination and evolution. As such, studies of A. tumefaciens have had an outsized impact on diverse areas within microbiology and plant biology that extend far beyond its remarkable agricultural applications. In this review, we attempt to highlight the colorful history of A. tumefaciens as a study system, as well as current areas that are actively demonstrating its value and utility as a model microorganism.

Analysis of structural variation among inbred mouse strains.

BACKGROUND: 'Long read' sequencing methods have been used to identify previously uncharacterized structural variants that cause human genetic diseases. Therefore, we investigated whether long read sequencing could facilitate genetic analysis of murine models for human diseases. RESULTS: The genomes of six inbred strains (BTBR T + Itpr3tf/J, 129Sv1/J, C57BL/6/J, Balb/c/J, A/J, SJL/J) were analyzed using long read sequencing. Our results revealed that (i) Structural variants are very abundant within the genome of inbred strains (4.8 per gene) and (ii) that we cannot accurately infer whether structural variants are present using conventional short read genomic sequence data, even when nearby SNP alleles are known. The advantage of having a more complete map was demonstrated by analyzing the genomic sequence of BTBR mice. Based upon this analysis, knockin mice were generated and used to characterize a BTBR-unique 8-bp deletion within Draxin that contributes to the BTBR neuroanatomic abnormalities, which resemble human autism spectrum disorder. CONCLUSION: A more complete map of the pattern of genetic variation among inbred strains, which is produced by long read genomic sequencing of the genomes of additional inbred strains, could facilitate genetic discovery when murine models of human diseases are analyzed.

Genetically engineered mouse models of FK506-binding protein 5.

FK506 binding protein 51 (FKBP51) is a molecular chaperone that influences stress response. In addition to having an integral role in the regulation of steroid hormone receptors, including glucocorticoid receptor, FKBP51 has been linked with several biological processes including metabolism and neuronal health. Genetic and epigenetic alterations in the gene that encodes FKBP51, FKBP5, are associated with increased susceptibility to multiple neuropsychiatric disorders, which has fueled much of the research on this protein. Because of the complexity of these processes, animal models have been important in understanding the role of FKBP51. This review examines each of the current mouse models of FKBP5, which include whole animal knockout, conditional knockout, overexpression, and humanized mouse models. The generation of each model and observational details are discussed, including behavioral phenotypes, molecular changes, and electrophysiological alterations basally and following various challenges. While much has been learned through these models, there are still many aspects of FKBP51 biology that remain opaque and future studies are needed to help illuminate these current gaps in knowledge. Overall, FKBP5 continues to be an exciting potential target for stress-related disorders.

Impact of inclusion non-additive effects on genome-wide association and variance's components in Scottish black sheep.

CONTEXT: It's well-documented that most economic traits have a complex genetic structure that is controlled by additive and non-additive gene actions. Hence, knowledge of the underlying genetic architecture of such complex traits could aid in understanding how these traits respond to the selection in breeding and mating programs. Computing and having estimates of the non-additive effect for economic traits in sheep using genome-wide information can be important because; non-additive genes play an important role in the prediction accuracy of genomic breeding values and the genetic response to the selection. AIM: This study aimed to assess the impact of non-additive effects (dominance and epistasis) on the estimation of genetic parameters for body weight traits in sheep. METHODS: This study used phenotypic and genotypic belonging to 752 Scottish Blackface lambs. Three live weight traits considered in this study were included in body weight at 16, 20, and 24 weeks). Three genetic models including additive (AM), additive + dominance (ADM), and additive + dominance + epistasis (ADEM), were used. KEY RESULTS: The narrow sense heritability for weight at 16 weeks of age (BW16) were 0.39, 0.35, and 0.23, for 20 weeks of age (BW20) were 0.55, 0.54, and 0.42, and finally for 24 weeks of age (BW24) were 0.16, 0.12, and 0.02, using the AM, ADM, and ADEM models, respectively. The additive genetic model significantly outperformed the non-additive genetic model (p < 0.01). The dominance variance of the BW16, BW20, and BW24 accounted for 38, 6, and 30% of the total phenotypic, respectively. Moreover, the epistatic variance accounted for 39, 0.39, and 47% of the total phenotypic variances of these traits, respectively. In addition, our results indicated that the most important SNPs for live weight traits are on chromosomes 3 (three SNPS including s12606.1, OAR3_221188082.1, and OAR3_4106875.1), 8 (OAR8_16468019.1, OAR8_18067475.1, and OAR8_18043643.1), and 19 (OAR19_18010247.1), according to the genome-wide association analysis using additive and non-additive genetic model. CONCLUSIONS: The results emphasized that the non-additive genetic effects play an important role in controlling body weight variation at the age of 16-24 weeks in Scottish Blackface lambs. IMPLICATIONS: It is expected that using a high-density SNP panel and the joint modeling of both additive and non-additive effects can lead to better estimation and prediction of genetic parameters.

Diverse stem cells for periodontal tissue formation and regeneration.

The periodontium is comprised of multiple units of mineralized and nonmineralized tissues including the cementum on the root surface, the alveolar bone, periodontal ligament (PDL), and the gingiva. PDL contains a variety of cell populations including mesenchymal stem/progenitor cells (MSCs) termed PDLSCs, which contribute to periodontal regeneration. Recent studies utilizing mouse genetic models shed light on the identities of these mesenchymal progenitors in their native environment, particularly regarding how they contribute to homeostasis and repair of the periodontium. The current concept is that mesenchymal progenitors in the PDL are localized to the perivascular niche. Single-cell RNA sequencing (scRNA-seq) analyses reveal heterogeneity and cell-type specific markers of cells in the periodontium, as well as their developmental relationship with precursor cells in the dental follicle. The characteristics of PDLSCs and their diversity in vivo are now beginning to be unraveled thanks to insights from mouse genetic models and scRNA-seq analyses, which aid to uncover the fundamental properties of stem cells in the human PDL. The new knowledge will be highly important for developing more effective stem cell-based regenerative therapies to repair periodontal tissues in the future.

Synaptic pathology in Huntington's disease: Beyond the corticostriatal pathway.

Huntington's disease (HD) is a heritable, fatal neurodegenerative disorder caused by a mutation in the Huntingtin gene. It is characterized by chorea, as well as cognitive and psychiatric symptoms. Histopathologically, there is a massive loss of striatal projection neurons and less but significant loss in other areas throughout the cortico-basal ganglia-thalamocortical (CBGTC) loop. The mutant huntingtin protein has been implicated in numerous functions, including an important role in synaptic transmission. Most studies on anatomical and physiological alterations in HD have focused on striatum and cerebral cortex. However, based on recent CBGTC projectome evidence, the need to study other pathways has become increasingly clear. In this review, we examine the current status of our knowledge of morphological and electrophysiological alterations of those pathways in animal models of HD. Based on recent studies, there is accumulating evidence that synaptic disconnection, particularly along excitatory pathways, is pervasive and almost universal in HD, thus supporting a critical role of the huntingtin protein in synaptic transmission.

Genetic Manipulation in Mucorales and New Developments to Study Mucormycosis.

The study of the Mucoralean fungi physiology is a neglected field that the lack of effective genetic tools has hampered in the past. However, the emerging fungal infection caused by these fungi, known as mucormycosis, has prompted many researchers to study the pathogenic potential of Mucorales. The main reasons for this current attraction to study mucormycosis are its high lethality, the lack of effective antifungal drugs, and its recent increased incidence. The most contemporary example of the emergence character of mucormycosis is the epidemics declared in several Asian countries as a direct consequence of the COVID-19 pandemic. Fortunately, this pressure to understand mucormycosis and develop new treatment strategies has encouraged the blossoming of new genetic techniques and methodologies. This review describes the history of genetic manipulation in Mucorales, highlighting the development of methods and how they allowed the main genetic studies in these fungi. Moreover, we have emphasized the recent development of new genetic models to study mucormycosis, a landmark in the field that will configure future research related to this disease.

Utility of Human Relevant Preclinical Animal Models in Navigating NAFLD to MAFLD Paradigm.

Fatty liver disease is an emerging contributor to disease burden worldwide. The past decades of work established the heterogeneous nature of non-alcoholic fatty liver disease (NAFLD) etiology and systemic contributions to the pathogenesis of the disease. This called for the proposal of a redefinition in 2020 to that of metabolic dysfunction-associated fatty liver disease (MAFLD) to better reflect the current understanding of the disease. To date, several clinical cohort studies comparing NAFLD and MAFLD hint at the relevancy of the new nomenclature in enriching for patients with more severe hepatic injury and extrahepatic comorbidities. However, the underlying systemic pathogenesis is still not fully understood. Preclinical animal models have been imperative in elucidating key biological mechanisms in various contexts, including intrahepatic disease progression, interorgan crosstalk and systemic dysregulation. Furthermore, they are integral in developing novel therapeutics against MAFLD. However, substantial contextual variabilities exist across different models due to the lack of standardization in several aspects. As such, it is crucial to understand the strengths and weaknesses of existing models to better align them to the human condition. In this review, we consolidate the implications arising from the change in nomenclature and summarize MAFLD pathogenesis. Subsequently, we provide an updated evaluation of existing MAFLD preclinical models in alignment with the new definitions and perspectives to improve their translational relevance.

Modern simulation utilities for genetic analysis.

BACKGROUND: Statistical geneticists employ simulation to estimate the power of proposed studies, test new analysis tools, and evaluate properties of causal models. Although there are existing trait simulators, there is ample room for modernization. For example, most phenotype simulators are limited to Gaussian traits or traits transformable to normality, while ignoring qualitative traits and realistic, non-normal trait distributions. Also, modern computer languages, such as Julia, that accommodate parallelization and cloud-based computing are now mainstream but rarely used in older applications. To meet the challenges of contemporary big studies, it is important for geneticists to adopt new computational tools. RESULTS: We present TraitSimulation, an open-source Julia package that makes it trivial to quickly simulate phenotypes under a variety of genetic architectures. This package is integrated into our OpenMendel suite for easy downstream analyses. Julia was purpose-built for scientific programming and provides tremendous speed and memory efficiency, easy access to multi-CPU and GPU hardware, and to distributed and cloud-based parallelization. TraitSimulation is designed to encourage flexible trait simulation, including via the standard devices of applied statistics, generalized linear models (GLMs) and generalized linear mixed models (GLMMs). TraitSimulation also accommodates many study designs: unrelateds, sibships, pedigrees, or a mixture of all three. (Of course, for data with pedigrees or cryptic relationships, the simulation process must include the genetic dependencies among the individuals.) We consider an assortment of trait models and study designs to illustrate integrated simulation and analysis pipelines. Step-by-step instructions for these analyses are available in our electronic Jupyter notebooks on Github. These interactive notebooks are ideal for reproducible research. CONCLUSION: The TraitSimulation package has three main advantages. (1) It leverages the computational efficiency and ease of use of Julia to provide extremely fast, straightforward simulation of even the most complex genetic models, including GLMs and GLMMs. (2) It can be operated entirely within, but is not limited to, the integrated analysis pipeline of OpenMendel. And finally (3), by allowing a wider range of more realistic phenotype models, TraitSimulation brings power calculations and diagnostic tools closer to what investigators might see in real-world analyses.

The Atg16l1 gene: characterization of wild type, knock-in, and knock-out phenotypes in rats.

ATG16L1 is a ubiquitous autophagy gene responsible, in part, for formation of the double-membrane bound autophagosome that delivers unwanted cellular debris and intracellular pathogens to the lysosome for degradation. A single, nonsynonymous adenine to guanine polymorphism resulting in a threonine to alanine amino acid substitution (T300A) directly preceded by a caspase cleavage site (DxxD) causes an increased susceptibility to Crohn's disease (CD) in humans. The mechanism behind this increased susceptibility is still being elucidated, however, the amino acid change caused by this point mutation results in increased ATG16L1 protein sensitivity to caspase 3-mediated cleavage. To generate novel rat strains carrying genetic alterations in the rat Atg16l1 gene, we first characterized the wild-type rat gene. We identified four alternative splice variants with tissue-specific expression. Using CRISPR-Cas9 genome editing technology, we developed a knock-in rat model for the human ATG16L1 T300A CD risk polymorphism, as well as a knock-out rat model to evaluate the role of Atg16l1 in autophagy as well as its potential effect on CD susceptibility. These are the first reported rat strains with alterations of the Atg16l1 gene. Consistent with studies of the effects of human ATG16L1 polymorphisms, models exhibit morphological abnormalities in both Paneth and goblet cells, but do not develop spontaneous intestinal permeability or inflammatory bowel disease. Analysis of the gut microbiota does not show inherent differences in bacterial composition between wild-type and genetically modified animals. These Atg16l1 strains are valuable new animal models for the study of both autophagy and CD susceptibility.

The nature of the self: Neural analyses and heritability estimates of self-evaluations in middle childhood.

How neural correlates of self-concept are influenced by environmental versus genetic factors is currently not fully understood. We investigated heritability estimates of behavioral and neural correlates of self-concept in middle childhood since this phase is an important time window for taking on new social roles in academic and social contexts. To do so, a validated self-concept fMRI task was applied in a twin sample of 345 participants aged between 7 and 9 years. In the self-concept condition, participants were asked to indicate whether academic and social traits applied to them whereas the control condition required trait categorization. The self-processing activation analyses (n = 234) revealed stronger medial prefrontal cortex (mPFC) activation for self than for control conditions. This effect was more pronounced for social-self than academic self-traits, whereas stronger dorsolateral prefrontal cortex (DLPFC) activation was observed for academic versus social self-evaluations. Behavioral genetic modeling (166 complete twin pairs) revealed that 25-52% of the variation in academic self-evaluations was explained by genetic factors, whereas 16-49% of the variation in social self-evaluations was explained by shared environmental factors. Neural genetic modeling (91 complete twin pairs) for variation in mPFC and anterior prefrontal cortex (PFC) activation for academic self-evaluations confirmed genetic and unique environmental influences, whereas anterior PFC activation for social self-evaluations was additionally influenced by shared environmental influences. This indicates that environmental context possibly has a larger impact on the behavioral and neural correlates of social self-concept at a young age. This is the first study demonstrating in a young twin sample that self-concept depends on both genetic and environmental factors, depending on the specific domain.

Unveiling diversity of stem cells in dental pulp and apical papilla using mouse genetic models: a literature review.

The dental pulp, a non-mineralized connective tissue uniquely encased within the cavity of the tooth, provides a niche for diverse arrays of dental mesenchymal stem cells. Stem cells in the dental pulp, including dental pulp stem cells (DPSCs), stem cells from human exfoliated deciduous teeth (SHEDs) and stem cells from apical papilla (SCAPs), have been isolated from human tissues with an emphasis on their potential application to regenerative therapies. Recent studies utilizing mouse genetic models shed light on the identities of these mesenchymal progenitor cells derived from neural crest cells (NCCs) in their native conditions, particularly regarding how they contribute to homeostasis and repair of the dental tissue. The current concept is that at least two distinct niches for stem cells exist in the dental pulp, e.g., the perivascular niche and the perineural niche. The precise identities of these stem cells and their niches are now beginning to be unraveled thanks to sophisticated mouse genetic models, which lead to better understanding of the fundamental properties of stem cells in the dental pulp and the apical papilla in humans. The new knowledge will be highly instrumental for developing more effective stem cell-based regenerative therapies to repair teeth in the future.

[Molecular genetics of human hypertension]. / Molekulargenetik der humanen Hypertonie.

A genetic influence on blood pressure was demonstrated more than 100 years ago and a simple Mendelian inheritance was initially presumed. Platt and Pickering conducted a lively debate on this topic. Platt favored the idea that a single gene or only a few genes were responsible for high blood pressure. Pickering presented research results, which supported the assumption that many genes exerted an influence on blood pressure. This was all in a period when it was not even known what genes were. Genome-wide association studies (GWAS) according to the Pickering model have identified > 500 blood pressure relevant gene loci, which are distributed over the whole genome. Each individual gene exerts only a small effect on blood pressure. The dark horses of hypertension research are the secondary causes. In pheochromocytoma, primary aldosteronism, Cushing's syndrome and even fibromuscular dysplasia (renovascular hypertension) the results indicate that a genetic cause regularly underlies secondary hypertension. This would therefore also partially confirm Platt's theory. In the meantime, a multitude of forms of hypertension have been described with a genetic inheritance according to Mendel. Each of these genetic variants exerts a considerable influence on blood pressure. A multitude of novel physiological mechanisms were explained by this. These findings will become therapeutically important. Therefore, it is incumbent upon clinicians to be optimally informed about these research results.

Developmental Requirement of Homeoprotein Otx2 for Specific Habenulo-Interpeduncular Subcircuits.

The habenulo-interpeduncular system (HIPS) is now recognized as a critical circuit modulating aversion, reward, and social behavior. There is evidence that dysfunction of this circuit leads to psychiatric disorders. Because psychiatric diseases may originate in developmental abnormalities, it is crucial to investigate the developmental mechanisms controlling the formation of the HIPS. Thus far, this issue has been the focus of limited studies. Here, we explored the developmental processes underlying the formation of the medial habenula (MHb) and its unique output, the interpeduncular nucleus (IPN), in mice independently of their gender. We report that the Otx2 homeobox gene is essential for the proper development of both structures. We show that MHb and IPN neurons require Otx2 at different developmental stages and, in both cases, Otx2 deletion leads to disruption of HIPS subcircuits. Finally, we show that Otx2+ neurons tend to be preferentially interconnected. This study reveals that synaptically connected components of the HIPS, despite radically different developmental strategies, share high sensitivity to Otx2 expression.SIGNIFICANCE STATEMENT Brain reward circuits are highly complex and still poorly understood. In particular, it is important to understand how these circuits form as many psychiatric diseases may arise from their abnormal development. This work shows that Otx2, a critical evolutionary conserved gene implicated in brain development and a predisposing factor for psychiatric diseases, is required for the formation of the habenulo-interpeduncular system (HIPS), an important component of the reward circuit. Otx2 deletion affects multiple processes such as proliferation and migration of HIPS neurons. Furthermore, neurons expressing Otx2 are preferentially interconnected. Therefore, Otx2 expression may represent a code that specifies the connectivity of functional subunits of the HIPS. Importantly, the Otx2 conditional knock-out animals used in this study might represent a new genetic model of psychiatric diseases.

Zebrafish models of impulsivity and impulse control disorders.

Impulse control disorders (ICDs) are characterized by generalized difficulty controlling emotions and behaviors. ICDs are a broad group of the central nervous system (CNS) disorders including conduct disorder, intermittent explosive, oppositional-defiant disorder, antisocial personality disorder, kleptomania, pyromania and other illnesses. Although they all share a common feature (aberrant impulsivity), their pathobiology is complex and poorly understood. There are also currently no ICD-specific therapies to treat these illnesses. Animal models are a valuable tool for studying ICD pathobiology and potential therapies. The zebrafish (Danio rerio) has become a useful model organism to study CNS disorders due to high genetic and physiological homology to mammals, and sensitivity to various pharmacological and genetic manipulations. Here, we summarize experimental models of impulsivity and ICD in zebrafish and highlight their growing translational significance. We also emphasize the need for further development of zebrafish ICD models to improve our understanding of their pathogenesis and to search for novel therapeutic treatments.

Effects of Pharmacologically Targeting Neuroimmune Pathways on Alcohol Drinking in Mice Selectively Bred to Drink to Intoxication.

BACKGROUND: Rodent models of high alcohol drinking offer opportunities to better understand factors for alcohol use disorders (AUD) and test potential treatments. Selective breeding was carried out to create 2 unique High Drinking in the Dark (HDID-1, HDID-2) mouse lines that represent models of genetic risk for binge-like drinking. A number of studies have indicated that neuroimmune genes are important for regulation of alcohol drinking. We tested whether compounds shown to reduce drinking in other models also reduce alcohol intake in these unique genetic lines. METHODS: We report tests of gabapentin, tesaglitazar, fenofibrate, caffeic acid phenethyl ester (CAPE), ibrutinib, and rolipram. Although these compounds have different mechanisms of action, they have all been shown to reduce inflammatory responses. We evaluated effects of these compounds on alcohol intake. In order to facilitate comparison with previously published findings for some compounds, we employed similar schedules that were previously used for that compound. RESULTS: Gabapentin increased ethanol (EtOH) binge-like alcohol drinking in female HDID-1 and HS/NPT mice. Tesaglitazar and fenofibrate did not alter 2-bottle choice (2BC) drinking in male HDID-1 or HS/NPT mice. However, tesaglitazar had no effect on DID EtOH intake but reduced blood alcohol levels (BAL), and fenofibrate increased DID intake with no effects on BAL. CAPE had no effect on EtOH intake. Ibrutinib reduced intake in female HDID-1 in initial testing, but did not reduce intake in a second week of testing. Rolipram reduced DID intake and BALs in male and female HDID-1, HDID-2, and HS/NPT mice. CONCLUSIONS: A number of compounds shown to reduce EtOH drinking in other models, and genotypes are not effective in HDID mice or their genetically heterogeneous founders, HS/NPT. The most promising compound was the PDE4 inhibitor, rolipram. These results highlight the importance of assessing generalizability when rigorously testing compounds for therapeutic development.

Genetic and Environmental Causes of Individual Differences in Borderline Personality Disorder Features and Loneliness are Partially Shared.

Loneliness is related to mental and somatic health outcomes, including borderline personality disorder. Here, we analyze the sources of variation that are responsible for the relationship between borderline personality features (including four dimensions, affective instability, identity disturbance, negative relationships, self-harm and a total score) and loneliness. Using genetically informative data from two large nonclinical samples of adult twin pairs from Australia and the Netherlands (N = 11,329), we estimate the phenotypic, genetic and environmental correlations between self-reported borderline personality features and loneliness. Individual differences in borderline personality and loneliness were best explained by additive genetic factors with heritability estimates h2 = 41% for the borderline personality total score and h2 = 36% for loneliness, with the remaining variation explained by environmental influences that were not shared by twins from the same pair. Genetic and environmental factors influencing borderline personality (total score and four subscales separately) were also partial causes of loneliness. The correlation between loneliness and the borderline personality total score was rph = .51. The genetic correlation was estimated at rg = .64 and the environmental correlation at re = .40. Our study suggests common etiological factors in loneliness and borderline personality features.

Association between MTHFR C677T/A1298C and susceptibility to autism spectrum disorders: a meta-analysis.

BACKGROUND: Autism spectrum disorder (ASD) is becoming increasingly prevalent of late. Methylenetetrahydrofolate reductase (MTHFR) has a significant role in folate metabolism. Owing to the inconsistencies and inconclusiveness on the association between MTHFR single nucleotide polymorphism (SNP) and ASD susceptibilities, a meta-analysis was conducted to settle the inconsistencies. METHODS: For this meta-analysis, a total of 15 manuscripts published up to January 26, 2020, were selected from PubMed, Google Scholar, Medline, WangFang, and CNKI databases using search terms "MTHFR" OR "methylenetetrahydrofolate reductase" AND "ASD" OR "Autism Spectrum Disorders" OR "Autism" AND "polymorphism" OR "susceptibility" OR "C677T" OR "A1298C". RESULTS: The findings of the meta-analysis indicated that MTHFR C677T polymorphism is remarkably associated with ASD in the five genetic models, viz., allelic, dominant, recessive, heterozygote, and homozygote. However, the MTHFR A1298C polymorphism was not found to be significantly related to ASD in the five genetic models. Subgroup analyses revealed significant associations of ASD with the MTHFR (C677T and A1298C) polymorphism. Sensitivity analysis showed that this meta-analysis was stable and reliable. No publication bias was identified in the associations between MTHFRC677T polymorphisms and ASD in the five genetic models, except for the one with regard to the associations between MTHFRA1298C polymorphisms and ASD in the five genetic models. CONCLUSION: This meta-analysis showed that MTHFR C677T polymorphism is a susceptibility factor for ASD, and MTHFR A1298C polymorphism is not associated with ASD susceptibility.