Effects Of Genetic Predisposition Research Articles

Longitudinal Transcriptomic Analysis of Human Cortical Spheroids Identifies Axonal Dysregulation in the Prenatal Brain as a Mediator of Genetic Risk for Schizophrenia

BackgroundSchizophrenia (SCZ) has a known neurodevelopmental etiology, but limited access to human prenatal brain tissue hampers the investigation of basic disease mechanisms in early brain development. Here, we elucidate the molecular mechanisms contributing to SCZ risk in a disease-relevant model of the prenatal human brain. MethodsWe generated induced pluripotent stem cell–derived organoids, termed human cortical spheroids (hCSs), from a large, genetically stratified sample of 14 SCZ cases and 14 age- and sex-matched controls. The hCSs were differentiated for 150 days, and comprehensive molecular characterization across 4 time points was carried out. ResultsThe transcriptional and cellular architecture of hCSs closely resembled that of fetal brain tissue at 10 to 24 postconception weeks, showing strongest spatial overlap with frontal regions of the cerebral cortex. A total of 3520 genes were differentially modulated between SCZ and control hCSs across organoid maturation, displaying a significant contribution of genetic loading, an overrepresentation of risk genes for autism spectrum disorder and SCZ, and the strongest enrichment for axonal processes in all hCS stages. The two axon guidance genes SEMA7A and SEMA5A, the first a promoter of synaptic functions and the second a repressor, were downregulated and upregulated, respectively, in SCZ hCSs. This expression pattern was confirmed at the protein level and replicated in a large postmortem sample. ConclusionsApplying a disease-relevant model of the developing fetal brain, we identified consistent dysregulation of axonal genes as an early risk factor for SCZ, providing novel insights into the effects of genetic predisposition on the neurodevelopmental origins of the disorder.

The effects of genetic predisposition to criminal behaviour

In the field of genetic research on criminal behaviour is the fact that the magnitude of genetic effects depends on social circumstances and other environmental factors. All major adoption studies of criminal behaviour have shown that genetic risk is amplified in the presence of adverse environmental factors viewed differently; the substantial genetic risk for criminal offending may be ameliorated in low risk environments. The nature of these environmentally based protective factors need greater attention in future genetic research on crime and aggression. The fact that genetic predispositions exist for criminal offending does in no way imply that environmental factors are unimportant, nor that effective treatment and prevention programs cannot be developed and implemented to reduce the chances that an individual will engage in law-breaking or other antisocial behaviours.

Difference between early onset and late-onset pediatric ulcerative colitis.

Early onset pediatric ulcerative colitis (EO-UC) is distinguished from late-onset pediatric ulcerative colitis (LO-UC) by the effects of genetic predisposition, but there have been few reports on the clinical features of EO-UC in Asia. To describe and compare the presentation and disease course of EO-UC (age range, 0-7 years) with those of LO-UC (age range, 8-15 years), we retrospectively analyzed 63 children with UC who had been diagnosed between January 2004 and March 2014 at Saitama Children's Medical Center in Japan. Ten patients (16%) had EO-UC, and 53 (84%) had LO-UC. All patients in the EO-UC group and 70% in the LO-UC group had pancolitis (P = 0.05). The period from onset to diagnosis was 9.0 ± 14.1 months for EO-UC and 2.6 ± 3.5 months for LO-UC (P < 0.01). The prevalence of extra-intestinal complications at diagnosis was significantly higher for EO-UC than for LO-UC (50% vs 11%, respectively; P < 0.01). There were no significant differences in the use of corticosteroids, immunomodulators, immunosuppressants, or surgical risk between the groups but, in the EO-UC group, only one patient was treated with cytapheresis and none was treated with anti-tumor necrosis factor (TNF-α) antibodies. The EO-UC group had a higher incidence of pancolitis, longer diagnostic delay, and more extra-intestinal manifestations than the LO-UC group. Diagnosis and treatment may therefore be slightly more difficult for EO-UC than for LO-UC.

Perinatal infections and cerebral palsy

There are many causes of cerebral palsy (CP) apart from hypoxic events during the perinatal period. Perinatal infections and systemic inflammatory response syndrome of the mother and infant can affect the development of CP significantly. The majority of premature infants are vulnerable to CP and the association between intraamniotic infections, preterm rupture of fetal membranes and the effect of preterm birth predispose the infant to CP. Incidence of intraventricular hemorrhage, white matter disease and periventricular leukomalacia has increased after preterm labor resulting from intraamniotic infections. Bacterial vaginosis, fever, periodontal disease of the mother, as well as bacterial, viral, protozoan and fungal infections of the newborn infant are effective during the development of CP. The balance between proinflammatory and anti-inflammatory cytokines and the combined effects of genetic predisposition, hypoxia, cytokines and bacterial products may initiate the unfavorable process. Treatments directed towards cytokines and bacterial products have not been effective until now. Fetuses and neonates should be protected from perinatal infections as much as possible and all infections should be treated promptly in order to prevent short-term and long-term adverse outcomes.

Epigenetic mechanisms of endothelial dysfunction in type 2 diabetes.

The development of type-2 diabetes mellitus (T2DM) and its complications is largely due to the complex interaction between genetic factors and environmental influences, mainly dietary habits and lifestyle, which can either accelerate or slow down disease progression. Recent findings suggest the potential involvement of epigenetic mechanisms as a crucial interface between the effects of genetic predisposition and environmental factors. The common denominator of environmental factors promoting T2DM development and progression is that they trigger an inflammatory response, promoting inflammation-mediated insulin resistance and endothelial dysfunction. Proinflammatory stimuli, including hyperglycemia, oxidative stress, and other inflammatory mediators, can affect epigenetic mechanisms, altering the expression of specific genes in target cells without changes in underlying DNA sequences. DNA methylation and post-translational histone modifications (PTHMs) are the most extensively investigated epigenetic mechanisms. Over the past few years, non-coding RNA, including microRNAs (miRNAs), have also emerged as key players in gene expression modulation. MiRNAs can be actively released or shed by cells in the bloodstream and taken up in active form by receiving cells, acting as efficient systemic communication tools. The miRNAs involved in modulation of inflammatory pathways (inflammamiRs), such as miR-146a, and those highly expressed in endothelial lineages and hematopoietic progenitor cells (angiomiRs), such as miR-126, are the most extensively studied circulating miRNAs in T2DM. However, data on circulating miRNA signatures associated with specific diabetic complications are still lacking. Since immune cells and endothelial cells are primarily involved in the vascular complications of T2DM, their relative contribution to circulating miRNA signatures needs to be elucidated. An integrated approach encompassing different epigenetic mechanisms would have the potential to provide new mechanistic insights into the genesis of diabetes and its severe vascular complications and identify a panel of epigenetic markers with diagnostic/prognostic and therapeutic relevance.

Abstract 4831: Additive and multiplicative gene-environment interactions for colorectal cancer risk.

Abstract Background: Genetic and environmental factors influence colorectal cancer (CRC) risk. Previous studies have provided additional etiologic insight by examining multiplicative gene-environment interactions for individual susceptibility loci. However, individual loci confer only modest risks, which may limit statistical power and clinical significance. A genetic risk score comprising known CRC loci may provide a more comprehensive assessment of risk. Further, there is a paucity of data on the role of additive gene-environment interactions, which may have greater public health implications than multiplicative interactions. We thus evaluated both additive and multiplicative interactions between a genetic risk score and 15 key environmental factors on risk of CRC. Methods: We conducted an analysis of 10,491 CRC cases and 10,725 controls of European ancestry in 7 cohort and 6 case-control studies participating in the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO) or Colon Cancer Family Registry (CCFR). To provide a global measure of genetic predisposition, information across multiple risk variants was combined by calculating a genetic risk score based on 24 polymorphisms near 21 genetic loci identified in previous genome-wide association studies. For the genetic score and environmental factors, the reference category corresponded to that associated with lower CRC risk. We tested for additive interactions by estimating relative excess risk due to interactions (RERIs) using logistic regression; for multiplicative interactions we used an empirical-Bayes approach. Nominal P values ≤ 0.05 were considered statistically significant. Results: After adjustment for age, sex, center, study, principal components, and total energy, as appropriate, we observed super-additive gene-environment interactions for CRC risk between the genetic risk score and body mass index (RERI=0.15; 95% CI: 0.00-0.31), ever smoking (RERI=0.14; 95% CI: 0.00-0.28), pack-years of smoking (RERI=0.23; 95% CI: 0.05-0.41), postmenopausal hormone therapy use (RERI=0.38; 95% CI: 0.17-0.59), and intake of processed meat (RERI=0.23; 95% CI: 0.06-0.40). Of the 15 environmental risk factors, 12 showed RERIs &amp;gt; 0 – suggesting an overall trend toward super-additive interactions for these factors. In addition, we observed evidence of sub-multiplicative interactions for use of aspirin and non-steroidal anti-inflammatory drugs. There were no other statistically significant multiplicative interactions. Conclusions: We observed evidence for super-additive effects of genetic predisposition and environmental risk factors on risk of CRC. Our findings suggest that certain environmental risk factors have stronger effects on absolute risk among individuals with higher genetic risk of CRC. If confirmed in future studies, these results may have implications for targeted prevention strategies. Citation Format: Mengmeng Du, Sonja I. Berndt, Hermann Brenner, Bette J. Caan, Peter T. Campbell, Graham Casey, Andrew Chan, Jenny Chang-Claude, Stephen J. Chanock, Nilanjan Chatterjee, David V. Conti, David Duggan, Jane C. Figueiredo, Steven Gallinger, Jian Gong, Robert W. Haile, Tabitha A. Harrison, Richard B. Hayes, Michael Hoffmeister, John L. Hopper, Li Hsu, Thomas J. Hudson, Carolyn M. Hutter, Eric J. Jacobs, Mark A. Jenkins, Shuo Jiao, Laurence N. Kolonel, Peter Kraft, Loic Le Marchand, Mathieu Lemire, Yi Lin, Noralane M. Lindor, Polly A. Newcomb, John D. Potter, Robert E. Schoen, Fredrick R. Schumacher, Daniela Seminara, Martha L. Slattery, Stephen N. Thibodeau, Cornelia M. Ulrich, Aung Ko Win, Emily White, Brent W. Zanke, Ulrike Peters. Additive and multiplicative gene-environment interactions for colorectal cancer risk. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4831. doi:10.1158/1538-7445.AM2013-4831

Lessons from the Vietnam Head Injury Study

Event Abstract Back to Event Lessons from the Vietnam Head Injury Study Jordan Grafman1* 1 National Institute of Neurological Disorders and Stroke, Cognitive Neuroscience Section, United States The Vietnam Head Injury Study is a prospective long-term study of several hundred military veterans who suffered mostly penetrating Traumatic Brain Injuries (pTBI) in combat in Vietnam. In this presentation, I will review the importance of such studies for improving our understanding of brain-behaviour relationships, recovery of function after brain injury, and neuroplasticity. I will first describe our early results focusing on the influence of pre-injury ability on outcome, the importance of social skills in predicting outcome, and briefly touch upon the unique effects of pTBI compared to closed head injuries on behaviour. The last part of the presentation will emphasize our more recent results examining the effects of focal brain injury on the occurrence of post-traumatic stress disorder, the effects of genetic predisposition on outcome, and how many of the results we have obtained helped generate a model of prefrontal cortex functions. Keywords: frontal lobes, neuroplasticity, Penetrating Traumatic Brain Injury, Recovery of Function Conference: Karolinska Institutet 200 years anniversary Symposium on Traumatic Injuries in the Nervous System, Stockholm, Sweden, 15 Sep - 16 Sep, 2010. Presentation Type: Presentation Topic: Traumatic Injuries in the Nervous System Citation: Grafman J (2010). Lessons from the Vietnam Head Injury Study. Front. Neurol. Conference Abstract: Karolinska Institutet 200 years anniversary Symposium on Traumatic Injuries in the Nervous System. doi: 10.3389/conf.fneur.2010.56.00017 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 03 Sep 2010; Published Online: 21 Sep 2010. * Correspondence: Dr. Jordan Grafman, National Institute of Neurological Disorders and Stroke, Cognitive Neuroscience Section, Bethesda, Maryland, United States, jgrafman@northwestern.edu Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Jordan Grafman Google Jordan Grafman Google Scholar Jordan Grafman PubMed Jordan Grafman Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.

Intervening to Reduce Risk

Behavior There have been many discussions of how genes and environment might interact in the context of human behavior. Brody et al. have studied the effects of a randomized behavioral intervention on adolescents who have a genetic polymorphism associated with the initiation of risky behavior. Roughly 600 11-year-olds were randomly assigned to the Strong African American Families (SAAF) program or to a control group. The SAAF group (and their caregivers, usually mothers) participated in separate and joint training sessions on parenting practices, stress management, dealing with racism, setting goals, and norms for the use of alcohol and other substances. Sessions occurred over the course of 1 year, and the initiation of risky behaviors was assessed at the beginning of the program and for the next 2.5 years. Two years later, saliva samples were collected to look for a polymorphism in the promoter region of the serotonin transporter. Possession of a short form of the allele has been associated previously with impulsivity, substance abuse, and early sexual activity. In the control group, adolescents with the short allele were twice as likely to have engaged in risky behaviors as those assigned to the SAAF group or those with the long allele in either group. Only one genetic polymorphism was examined, and the results need to be confirmed in a variety of populations; however, this provides further evidence of the value of this intervention and the mutability of the effects of genetic predisposition. Child Devel. 80 , 645 (2009).

Mean diffusivity: A biomarker for CSF-related disease and genetic liability effects in schizophrenia

Mean diffusivity (MD), the rotationally invariant magnitude of water diffusion that is greater in cerebrospinal fluid (CSF) and smaller in organized brain tissue, has been suggested to reflect schizophrenia-associated cortical atrophy. Regional changes, associations with CSF, and the effects of genetic predisposition towards schizophrenia, however, remain uncertain. Six-direction diffusion tensor imaging DTI and high-resolution structural images were obtained from 26 schizophrenia patients, 36 unaffected first-degree patient relatives, 20 control subjects and 32 control relatives ( N = 114). Registration procedures aligned diffusion tensor imaging (DTI) data across imaging modalities. MD was averaged within lobar regions and the cingulate and superior temporal gyri. CSF volume and MD were highly correlated. Significant bilateral temporal, and superior temporal MD increases were observed in schizophrenia compared with unrelated control probands. First-degree relatives of schizophrenia probands showed larger MD measures compared with controls within bilateral superior temporal regions with CSF volume correction. Superior temporal lobe brain tissue deficits and proximal CSF enlargements are widely documented in schizophrenia. Larger MD indices in patients and their relatives may thus reflect similar pathophysiological mechanisms. However, persistence of regional MD effects after controlling for CSF volume, suggests that MD is a sensitive biological marker of disease and genetic liability, characterizing at least partially distinct aspects of brain structural integrity.

Interacting Effects of Genetic Predisposition and Depression on Adolescent Smoking Progression

Interacting Effects of Genetic Predisposition and Depression on Adolescent Smoking Progression

Effects of genetic predisposition on proinsulin responses in Asian Indians

This study was done in adult offspring of two diabetic (NIDDM) parents (ODP) to look for changes in specific insulin (insulin) and proinsulin responses due to strong familial background and also in different states of glucose intolerance. Equal numbers (20 in each group) of ODP with normal glucose tolerance (NGT), impaired glucose tolerance (IGT) and diabetes (DM) were chosen. Twenty, age and BMI matched healthy controls, without family history of diabetes, were also studied for comparison. Plasma specific insulin and proinsulin were measured by radioimmunoassays in fasting and 120′ plasma samples collected during the GTT. Proinsulin to insulin ratio were calculated. Insulin resistance (IR-HOMA) was calculated. In NGT, fasting proinsulin–insulin ratio was significantly higher than the control value ( P=0.023). Insulin values at 120′ was higher than control values, though it did not reach statistical significance. Proinsulin at 120′ was higher than controls (P=0.016). In IGT, the fasting proinsulin to insulin ratio, the 120′ proinsulin and insulin values were higher than controls ( P=0.048, 0.0013 and 0.0001, respectively). Fasting proinsulin–insulin ratio in IGT was similar to the value in NGT. In diabetic subjects proinsulin concentrations were significantly higher than controls at fasting ( P=0.0004), and 120′ ( P=0.0007). The fasting values were higher compared to NGT also ( P=0.037). Proinsulin–insulin ratios were higher than the values in controls ( P=0.0008), IGT ( P=0.047) and NGT ( P=0.05). Diabetic subjects had higher fasting insulin values compared to the control values although between the groups no statistical significance was found ( P=0.22 by Kruscall Wallis test). At 120′ both insulin and proinsulin values increased from NGT to IGT, but with development of diabetes a reduction was seen in the responses. Insulin resistance (IR-HOMA) increased steadily from NGT to diabetes. The difference between NGT and controls in IR was not statistically significant. This study of Asian Indian offspring of diabetic parents has shown that genetic predisposition to diabetes resulted in increased proinsulin to insulin ratio at the fasting state. Absolute hyperproinsulinaemia occurred only with development of diabetes.