Autism spectrum disorders (ASDs) and autistic traits in the general population may share genetic susceptibility factors. In this study, we investigated such potential overlap based on common genetic variants. We developed and validated a self-report questionnaire of autistic traits in adults. We then conducted genome-wide association studies (GWASs) of six trait scores derived from the questionnaire through exploratory factor analysis in 1981 adults from the general population. Using the results from the Psychiatric Genomics Consortium GWAS of ASDs, we observed genetic sharing between ASDs and the autistic traits 'childhood behavior', 'rigidity' and 'attention to detail'. Gene-set analysis subsequently identified 'rigidity' to be significantly associated with a network of ASD gene-encoded proteins that regulates neurite outgrowth. Gene-wide association with the well-established ASD gene MET reached significance. Taken together, our findings provide evidence for an overlapping genetic and biological etiology underlying ASDs and autistic population traits, which suggests that genetic studies in the general population may yield novel ASD genes.
Parkinson’s disease is caused by a complex interplay of genetic and environmental factors. Although a number of independent molecular pathways and processes have been associated with familial Parkinson’s disease, a common mechanism underlying especially sporadic Parkinson’s disease is still largely unknown. In order to gain further insight into the etiology of Parkinson’s disease, we here conducted genetic network and literature analyses to integrate the top-ranked findings from thirteen published genome-wide association studies of Parkinson’s disease (involving 13.094 cases and 47.148 controls) and other genes implicated in (familial) Parkinson’s disease, into a molecular interaction landscape. The molecular Parkinson’s disease landscape harbors four main biological processes—oxidative stress response, endosomal-lysosomal functioning, endoplasmic reticulum stress response, and immune response activation—that interact with each other and regulate dopaminergic neuron function and death, the pathological hallmark of Parkinson’s disease. Interestingly, lipids and lipoproteins are functionally involved in and influenced by all these processes, and affect dopaminergic neuron-specific signaling cascades. Furthermore, we validate the Parkinson’s disease -lipid relationship by genome-wide association studies data-based polygenic risk score analyses that indicate a shared genetic risk between lipid/lipoprotein traits and Parkinson’s disease. Taken together, our findings provide novel insights into the molecular pathways underlying the etiology of (sporadic) Parkinson’s disease and highlight a key role for lipids and lipoproteins in Parkinson’s disease pathogenesis, providing important clues for the development of disease-modifying treatments of Parkinson’s disease.
Heterozygous mutations or deletions in the human Euchromatin histone methyltransferase 1 (EHMT1) gene cause Kleefstra syndrome, a neurodevelopmental disorder that is characterized by autistic-like features and severe intellectual disability (ID). Neurodevelopmental disorders including ID and autism may be related to deficits in activity-dependent wiring of brain circuits during development. Although Kleefstra syndrome has been associated with dendritic and synaptic defects in mice and Drosophila, little is known about the role of EHMT1 in the development of cortical neuronal networks. Here we used micro-electrode arrays and whole-cell patch-clamp recordings to investigate the impact of EHMT1 deficiency at the network and single cell level. We show that EHMT1 deficiency impaired neural network activity during the transition from uncorrelated background action potential firing to synchronized network bursting. Spontaneous bursting and excitatory synaptic currents were transiently reduced, whereas miniature excitatory postsynaptic currents were not affected. Finally, we show that loss of function of EHMT1 ultimately resulted in less regular network bursting patterns later in development. These data suggest that the developmental impairments observed in EHMT1-deficient networks may result in a temporal misalignment between activity-dependent developmental processes thereby contributing to the pathophysiology of Kleefstra syndrome.
Background The decline of cognitive processing speed (CPS) is a common dysfunction in persons with multiple sclerosis (MS). The Symbol Digit Modalities Test (SDMT) is widely used to formally quantify CPS. We implemented a variant of the SDMT in MS sherpa, a smartphone app for persons with MS. Objective The aim of this study was to investigate the construct validity and test-retest reliability of the MS sherpa smartphone variant of the SDMT (sSDMT). Methods We performed a validation study with 25 persons with relapsing-remitting MS and 79 healthy control (HC) subjects. In the HC group, 21 subjects were matched to the persons with MS with regard to age, gender, and education and they followed the same assessment schedule as the persons with MS (the “HC matched” group) and 58 subjects had a less intense assessment schedule to determine reference values (the “HC normative” group). Intraclass correlation coefficients (ICCs) were determined between the paper-and-pencil SDMT and its smartphone variant (sSDMT) on 2 occasions, 4 weeks apart. Other ICCs were determined for test-retest reliability, which were derived from 10 smartphone tests per study participant, with 3 days in between each test. Seven study participants with MS were interviewed regarding their experiences with the sSDMT. Results The SDMT scores were on average 12.06% higher than the sSDMT scores, with a standard deviation of 10.68%. An ICC of 0.838 was found for the construct validity of the sSDMT in the combined analysis of persons with MS and HC subjects. Average ICCs for test-retest reliability of the sSDMT for persons with MS, the HC matched group, and the HC normative group were 0.874, 0.857, and 0.867, respectively. The practice effect was significant between the first and the second test of the persons with MS and the HC matched group and trivial for all other test-retests. The interviewed study participants expressed a positive attitude toward the sSDMT, but they also discussed the importance of adapting a smartphone cognition test in accordance with the needs of the individual persons with MS. Conclusions The high correlation between sSDMT and the conventional SDMT scores indicates a very good construct validity. Similarly, high correlations underpin a very good test-retest reliability of the sSDMT. We conclude that the sSDMT has the potential to be used as a tool to monitor CPS in persons with MS, both in clinical studies and in clinical practice.
CME/CNE Information Activity Available Online: To access the article, post-test, and evaluation online, go to http://www.cmscscholar.org. Target Audience: The target audience for this activity is physicians, physician assistants, nursing professionals, and other health care providers involved in the management of patients with multiple sclerosis (MS). Learning Objectives: Accreditation Statement: In support of improving patient care, this activity has been planned and implemented by the Consortium of Multiple Sclerosis Centers (CMSC) and Delaware Media Group. The CMSC is jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC), to provide continuing education for the healthcare team. Physician Credit The CMSC designates this journal-based activity for a maximum of 0.75 AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity. Nurse Credit The CMSC designates this enduring material for 0.75 contact hour (none in the area of pharmacology). Disclosures: Editor in Chief of the International Journal of MS Care (IJMSC), has served as physician planner for this activity. He has disclosed relationships with Springer Publishing (royalty); Qr8 (receipt of intellectual property rights/patent holder); Abide Therapeutics, GW Pharma (consulting fee); Biogen (speakers' bureau); and Adamas Pharmaceuticals (contracted research).Francois Bethoux, MD, has served as reviewer for this activity. She has disclosed no relevant financial relationships.Laurie Scudder, DNP, NP, has disclosed no relevant financial relationships.Karine Wendrich, MSc, has disclosed a relationship with Orikami/MS sherpa BV (salary).Pim van Oirschot, MSc, has disclosed no relevant financial relationships.Marijn Bart Martens, PhD, has disclosed no relevant financial relationships.Marco Heerings, MANP, has disclosed relationships with Bayer (educational/consultancy activities) and MS sherpa BV (consulting fee).Peter Joseph Jongen, PhD, has disclosed no relevant financial relationships.Lotte Krabbenborg, PhD, One peer reviewer has disclosed relationships with Genentech (consulting fee, contracted research) and Novartis (contracted research). The other peer reviewers for IJMSC have disclosed no relevant financial relationships. The staff at IJMSC, CMSC, and Delaware Media Group who are in a position to influence content have disclosed no relevant financial relationships. Note: Financial relationships for some authors may have changed in the interval between listing these disclosures and publication of the article. Method of Participation: Release Date: December 1, 2019 Valid for Credit Through: December 1, 2020 In order to receive CME/CNE credit, participants must: Statements of Credit are awarded upon successful completion of the post-test with a passing score of >70% and the evaluation. Disclosure of Unlabeled Use: This educational activity may contain discussion of published and/or investigational uses of agents that are not approved by the FDA. CMSC and Delaware Media Group do not recommend the use of any agent outside of the labeled indications. The opinions expressed in the educational activity are those of the faculty and do not necessarily represent the views of CMSC or Delaware Media Group. Disclaimer: Participants have an implied responsibility to use the newly acquired information to enhance patient outcomes and their own professional development. The information presented in this activity is not meant to serve as a guideline for patient management. Any medications, diagnostic procedures, or treatments discussed in this publication should not be used by clinicians or other health-care professionals without first evaluating their patients' conditions, considering possible contraindications or risks, reviewing any applicable manufacturer's product information, and comparing any therapeutic approach with the recommendations of other authorities.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.