What does the environment have to do with autism? | Ensia

Rapid GWAS of thousands of phenotypes for 337,000 samples in the UK Biobank — Neale lab

 "The UK Biobank recently released genome-wide association data on ~500,000 individuals. The genotype data for these samples have been cleaned, imputed and released to the scientific community. This public release of data represents an extraordinary advance for genetics, pushing the envelope for data sharing and rapid uptake by the research community. These data will be used for novel discovery of disease-associated genes, in the development of new methods, and to serve as an example for how future efforts in genetics and biology ought to proceed.

To further enhance the value of this resource, we have performed a basic association test on ~337,000 unrelated individuals of British ancestry for over 2,000 of the available phenotypes. We’re making these results available for browsing through several portals, including the Global Biobank Engine where they will appear soon. They are also available for download here.

We have decided not to write a scientific article for publication based on these analyses. Rather, we have described the data processing in a detailed blog post linked to the underlying code repositories. The decision to eschew scientific publication for the basic association analysis is rooted in our view that we will continue to work on and analyze these data and, as a result, writing a paper would not reflect the current state of the scientific work we are performing. Our goal here is to make these results available as quickly as possible, for any geneticist, biologist or curious citizen to explore. This is not to suggest that we will not write any papers on these data, but rather only write papers for those activities that involve novel method development or more complex analytic approaches. A univariate genome-wide association analysis is now a relatively well-established activity, and while the scale of this is a bit grander than before, that in and of itself is a relatively perfunctory activity. Simply put, let the data be free.

We do view these results as likely to change as we continue to refine the quality control analyses and as we continue to dig into the results themselves. Nevertheless, we’ve started to use them in a variety of downstream analyses and for other scientific projects and hope that others find them useful too."

'via Blog this'

Researchers see popular herbicide (Atrazine) affecting health across generations

 First, the good news. Washington State University researchers have found that a rat exposed to a popular herbicide while in the womb developed no diseases and showed no apparent health effects aside from lower weight.
Now, the weird news. The grand-offspring of that rat did have more disease, as did a great-grand offspring third generation.
"The third generation had multiple diseases and much more frequently than the third generation of unexposed ," said Michael Skinner, a Washington State University professor of biological sciences. At work, says Skinner, are epigenetic inheritance changes that turn genes on and off, often because of environmental influences.Writing this week in the journal PLOS ONE, Skinner reports exposing pregnant rats to atrazine, a commonly used herbicide on corn crops across the Midwest. Manufactured by Syngenta, the hormone-disrupting compound has been banned in Europe, where it was found contaminating water, while the Environmental Protection Agency permits its use in the U.S. It has been found in water systems serving 30 million Americans in 28 states, according to an Environmental Working Group survey of municipal water records.After Skinner and his colleagues exposed pregnant female rats to the herbicide, their first generation of offspring showed no ill effects but weighed less than rats in a control group. Rats bred from them had increased testis disease and altered sperm production, mammary tumors in both males and females, early-onset puberty in the males and lower-weight females. Their offspring—the great-grand offspring of the exposed rats—also had more testis disease, plus early onset puberty in females, hyperactivity and leaner male and female physiques.
When Skinner and his colleagues looked at sperm of the offspring, they found epimutations, or alterations in the methyl groups that stick to DNA and affect its activation.

'via Blog this'

Antibiotic-induced perturbations in microbial diversity during post-natal development alters amyloid pathology in an aged APP SWE /PS1 ΔE9 murine model of Alzheimer’s disease | Scientific Reports

Recent evidence suggests the commensal microbiome regulates host immunity and influences brain function; findings that have ramifications for neurodegenerative diseases. In the context of Alzheimer’s disease (AD), we previously reported that perturbations in microbial diversity induced by life-long combinatorial antibiotic (ABX) selection pressure in the APPSWE/PS1ΔE9 mouse model of amyloidosis is commensurate with reductions in amyloid-β (Aβ) plaque pathology and plaque-localised gliosis. Considering microbiota-host interactions, specifically during early post-natal development, are critical for immune- and neuro-development we now examine the impact of microbial community perturbations induced by acute ABX exposure exclusively during this period in APPSWE/PS1ΔE9 mice. We show that early post-natal (P) ABX treatment (P14-P21) results in long-term alterations of gut microbial genera (predominantly Lachnospiraceae and S24-7) and reduction in brain Aβ deposition in aged APPSWE/PS1ΔE9 mice. These mice exhibit elevated levels of blood- and brain-resident Foxp3+ T-regulatory cells and display an alteration in the inflammatory milieu of the serum and cerebrospinal fluid. Finally, we confirm that plaque-localised microglia and astrocytes are reduced in ABX-exposed mice. These findings suggest that ABX-induced microbial diversity perturbations during post-natal stages of development coincide with altered host immunity mechanisms and amyloidosis in a murine model of AD.

Studies help explain link between autism, severe infection during pregnancy

 "Mothers who experience an infection severe enough to require hospitalization during pregnancy are at higher risk of having a child with autism. Two new studies from MIT and the University of Massachusetts Medical School shed more light on this phenomenon and identify possible approaches to preventing it.

In research on mice, the researchers found that the composition of bacterial populations in the mother's digestive tract can influence whether maternal infection leads to autistic-like behaviors in offspring. They also discovered the specific brain changes that produce these behaviors."

'via Blog this'

Toxoplasma Modulates Signature Pathways of Human Epilepsy, Neurodegeneration & Cancer | Scientific Reports

life cycle of Toxoplasma gondii
life cycle of Toxoplasma gondii (Photo credit: Wikipedia)
 One third of humans are infected lifelong with the brain-dwelling, protozoan parasite, Toxoplasma gondii. Approximately fifteen million of these have congenital toxoplasmosis. Although neurobehavioral disease is associated with seropositivity, causality is unproven. To better understand what this parasite does to human brains, we performed a comprehensive systems analysis of the infected brain: We identified susceptibility genes for congenital toxoplasmosis in our cohort of infected humans and found these genes are expressed in human brain. Transcriptomic and quantitative proteomic analyses of infected human, primary, neuronal stem and monocytic cells revealed effects on neurodevelopment and plasticity in neural, immune, and endocrine networks. These findings were supported by identification of protein and miRNA biomarkers in sera of ill children reflecting brain damage and T. gondii infection. These data were deconvoluted using three systems biology approaches: “Orbital-deconvolution” elucidated upstream, regulatory pathways interconnecting human susceptibility genes, biomarkers, proteomes, and transcriptomes. “Cluster-deconvolution” revealed visual protein-protein interaction clusters involved in processes affecting brain functions and circuitry, including lipid metabolism, leukocyte migration and olfaction. Finally, “disease-deconvolution” identified associations between the parasite-brain interactions and epilepsy, movement disorders, Alzheimer’s disease, and cancer. This “reconstruction-deconvolution” logic provides templates of progenitor cells’ potentiating effects, and components affecting human brain parasitism and diseases."

T. Gondii interactome 

'via Blog this'

Blocking sweet taste receptors can help body fight off sinus infections: Researchers identify amino acids that hold the key to the process -- ScienceDaily

 Bitter taste receptors in the upper airway are a first line of defense against sinus infections, but their ability to kill harmful toxins and pathogens is blocked when the sweet taste receptors are also stimulated. While glucose and other sugars are known to trigger these sweet taste receptors, researchers at the Perelman School of Medicine of the University of Pennsylvania have now shown amino acids can also have that effect. This new understanding could help pave the way toward new treatments for chronic sinus infections. The researchers published their findings in the journal Science Signaling this week."

Here's the paper:- Bacterial d-amino acids suppress sinonasal innate immunity through sweet taste receptors in solitary chemosensory cells

Gene-environment interaction study for BMI reveals interactions between genetic factors and physical activity, alcohol consumption and socioeconomic status

 "Previous genome-wide association studies (GWAS) have identified hundreds of genetic loci to be associated with body mass index (BMI) and risk of obesity. Genetic effects can differ between individuals depending on lifestyle or environmental factors due to gene-environment interactions. In this study, we examine gene-environment interactions in 362,496 unrelated participants with Caucasian ancestry from the UK Biobank resource. A total of 94 BMI-associated SNPs, selected from a previous GWAS on BMI, were used to construct weighted genetic scores for BMI (GSBMI). Linear regression modeling was used to estimate the effect of gene-environment interactions on BMI for 131 lifestyle factors related to: dietary habits, smoking and alcohol consumption, physical activity, socioeconomic status, mental health, sleeping patterns, as well as female-specific factors such as menopause and childbirth. In total, 15 lifestyle factors were observed to interact with GSBMI, of which alcohol intake frequency, usual walking pace, and Townsend deprivation index, a measure of socioeconomic status, were all highly significant (p = 1.45*10−29, p = 3.83*10−26, p = 4.66*10−11, respectively). Interestingly, the frequency of alcohol consumption, rather than the total weekly amount resulted in a significant interaction. The FTO locus was the strongest single locus interacting with any of the lifestyle factors. However, 13 significant interactions were also observed after omitting the FTO locus from the genetic score. Our analyses indicate that many lifestyle factors modify the genetic effects on BMI with some groups of individuals having more than double the effect of the genetic score. However, the underlying causal mechanisms of gene-environmental interactions are difficult to deduce from cross-sectional data alone and controlled experiments are required to fully characterise the causal factors."

'via Blog this'

Peripheral inflammatory markers in Alzheimer’s disease: a systematic review and meta-analysis of 175 studies | Journal of Neurology, Neurosurgery & Psychiatry

 Objectives Increasing evidence suggests that inflammation is involved in Alzheimer’s disease (AD) pathology. This study quantitatively summarised the data on peripheral inflammatory markers in patients with AD compared with healthy controls (HC).

 Methods Original reports containing measurements of peripheral inflammatory markers in AD patients and HC were included for meta-analysis. Standardised mean differences were calculated using a random effects model. Meta-regression and exploration of heterogeneity was performed using publication year, age, gender, Mini-Mental State Examination (MMSE) scores, plasma versus serum measurements and immunoassay type.

Results A total of 175 studies were combined to review 51 analytes in 13 344 AD and 12 912 HC patients. Elevated peripheral interleukin (IL)-1β, IL-2, IL-6, IL-18, interferon-γ, homocysteine, high-sensitivity C reactive protein, C-X-C motif chemokine-10, epidermal growth factor, vascular cell adhesion molecule-1, tumour necrosis factor (TNF)-α converting enzyme, soluble TNF receptors 1 and 2, α1-antichymotrypsin and decreased IL-1 receptor antagonist and leptin were found in patients with AD compared with HC. IL-6 levels were inversely correlated with mean MMSE scores.

Conclusions These findings suggest that AD is accompanied by a peripheral inflammatory response and that IL-6 may be a useful biological marker to correlate with the severity of cognitive impairment. Further studies are needed to determine the clinical utility of these markers."

'via Blog this'

Depression is a physical illness which could be treated with anti-inflammatory drugs, scientists suggest

 "Depression could be treated using anti-inflammatory drugs, scientists now believe, after determining that it is a physical illness caused by a faulty immune system.

Around one in 13 people in Britain suffers from anxiety or depression and last year the NHS issued 64.7 million prescriptions for antidepressants, double the amount given out a decade ago.

Current treatment is largely centred around restoring mood-boosting chemicals in the brain, such as serotonin, but experts now think an overactive immune system triggers inflammation throughout the entire body, sparking feelings of hopelessness, unhappiness and fatigue.

It may be a symptom of the immune system failing to switch off after a trauma or illness, and is a similar to the low mood people often experience when they are fighting a virus, like flu."

'via Blog this'

Folic acid may mitigate autism risk from pesticides

 "In the paper, which used data from the Childhood Autism Risks from Genetics and the Environment (CHARGE) study, researchers looked at 296 children between 2 and 5 who had been diagnosed with ASD and 220 who had developed typically. Mothers were interviewed about their household pesticide exposure during pregnancy, as well as their folic acid and B vitamin intake. The team also linked data from California Pesticide Use reports, which provide important details about agricultural spraying, with the mothers' addresses.
Mothers who took less than 800 micrograms and encountered household pesticides had a much higher estimated risk of having a child who developed an ASD than moms who took 800 micrograms of folic acid or more and were not exposed to pesticides. The associated risk increased for women exposed repeatedly. Women with low folic acid intake who were exposed to agricultural pesticides during a window from three months before conception to three months afterward also were at higher estimated risk."

'via Blog this'

Commensal bacteria make GPCR ligands that mimic human signalling molecules : Nature : Nature Research

  "Commensal bacteria are believed to have important roles in human health. The mechanisms by which they affect mammalian physiology remain poorly understood, but bacterial metabolites are likely to be key components of host interactions. Here we use bioinformatics and synthetic biology to mine the human microbiota for N-acyl amides that interact with G-protein-coupled receptors (GPCRs). We found that N-acyl amide synthase genes are enriched in gastrointestinal bacteria and the lipids that they encode interact with GPCRs that regulate gastrointestinal tract physiology. Mouse and cell-based models demonstrate that commensal GPR119 agonists regulate metabolic hormones and glucose homeostasis as efficiently as human ligands, although future studies are needed to define their potential physiological role in humans. Our results suggest that chemical mimicry of eukaryotic signalling molecules may be common among commensal bacteria and that manipulation of microbiota genes encoding metabolites that elicit host cellular responses represents a possible small-molecule therapeutic modality (microbiome-biosynthetic gene therapy)."

'via Blog this'

‘Adrenaline’ of Immune System Discovered

Scientists at the Champalimaud Centre for the Unknown and the Instituto de Medicina Molecular, in Lisbon, Portugal, have discovered that neurons located at mucosal tissues can immediately detect an infection in the organism, promptly producing a substance that acts as an “adrenaline rush” for immune cells. Under the effect of this signal, immune cells rapidly become poised to fight the infection and repair the damage caused to surrounding tissues. These totally novel results have been published online in the journal Nature on September 6, 2017.

Published in Nature:- Neuronal regulation of type 2 innate lymphoid cells via neuromedin U” by Vânia Cardoso, Julie Chesné, Hélder Ribeiro, Bethania García-Cassani, Tânia Carvalho, Tiffany Bouchery, Kathleen Shah, Nuno L. Barbosa-Morais, Nicola Harris & Henrique Veiga-Fernandes in Nature. Published online September 6 2017 doi:10.1038/nature23469

A Human Mixture Risk Assessment for Neurodevelopmental Toxicity Associated with Polybrominated Diphenyl Ethers Used as Flame Retardants

The European Food Safety Authority recently concluded that the exposure of small children (1–3 y old) to brominated diphenyl ether (BDE)-99 may exceed acceptable levels defined in relation to neurodevelopmental toxicity in rodents. The flame retardant BDE-209 may release BDE-99 and other lower brominated BDEs through biotic and abiotic degradation, and all age groups are exposed not only to BDE-209 and -99 but also to a cocktail of BDE congeners with evidence of neurodevelopmental toxicity. The possible risks from combined exposures to these substances have not been evaluated.

We performed a congener-specific mixture risk assessment (MRA) of human exposure to combinations of BDE-209 and other BDEs based on estimated exposures via diet and dust intake and on measured levels in biologic samples.

We employed the Hazard Index (HI) method by using BDE congener-specific reference doses for neurodevelopmental toxicity.

Our HI analysis suggests that combined exposures to polybrominated diphenyl ethers (PBDEs) may exceed acceptable levels in breastfeeding infants (0–3 mo old) and in small children (1–3 y old), even for moderate (vs. high) exposure scenarios. Our estimates also suggest that acceptable levels of combined PBDEs may be exceeded in adults whose diets are high in fish. Small children had the highest combined exposures, with some estimated body burdens that were similar to body burdens associated with developmental neurotoxicity in rodents.

Our estimates corroborate reports from several recent epidemiological studies of associations between PBDE exposures and neurobehavioral outcomes, and they support the inclusion of BDE-209 in the persistent organic pollutant (POP) convention as well as the need for strategies to reduce exposures to PBDE mixtures, including maximum residue limits for PBDEs in food and measures for limiting the release of PBDEs from consumer waste. "

'via Blog this'

Cancer Onset May Be Caused by Immune System Fighting Viruses | GEN

 "The development of an advanced immune system to fight off microbial pathogens is a considerable part of the evolutionary success of multicellular organisms. Yet, like most success stories there is always a flip side. New evidence from investigators at the University of Colorado (CU) Cancer Center shows how the action of various immunity-based enzymes can spill over onto the host genome when trying to fight off various viral pathogens—ultimately leading to cancer-causing DNA mutations. Findings from the new study were published recently in Viruses, in an article entitled “Roles of APOBEC3A and APOBEC3B in Human Papillomavirus Infection and Disease Progression.”"

Lithium in Drinking Water May Lower Dementia Risk

  "Higher long-term lithium exposure from drinking water may be associated with a lower incidence of dementia, a large population-based study suggests.
"This is the first study ever investigating the association between lithium in drinking water and onset of dementia," Lars Vedel Kessing, MD, DMSc, from the University of Copenhagen, Denmark, told Medscape Medical News.
"If confirmed by others, tablets of lithium in microdose could be used among individuals at high risk of developing Alzheimer's disease, including those with a family history or certain genetic variations," Dr Kessing added.
The study was published online August 23 in JAMA Psychiatry."

However, Lithium in drug form does not appear to affect Alzheimer's disease


Association Between Lithium Use and Risk of Alzheimer's Disease.

'via Blog this'

Numerous uncharacterized and highly divergent microbes which colonize humans are revealed by circulating cell-free DNA

 Through massive shotgun sequencing of circulating cell-free DNA from the blood of more than 1,000 independent samples, we identified hundreds of new bacteria and viruses which represent previously unidentified members of the human microbiome. Previous studies targeted specific niches such as feces, skin, or the oral cavity, whereas our approach of using blood effectively enables sampling of the entire body and reveals the colonization of niches which have been previously inaccessible. We were thus able to discover that the human body contains a vast and unexpected diversity of microbes, many of which have highly divergent relationships to the known tree of life."

'via Blog this'

Autism Linked to Mitochondrial DNA Variation, Possible Cause Gains Traction | GEN

 : "Looking beyond the nuclear genome, researchers have found further evidence that the nearby mitochondrial genome, often overlooked, could be an underlying cause of autism spectrum disorder (ASD). The study reported an association between ancient mitochondrial DNA (mtDNA) variants and ASD and was published August 23 in JAMA Psychiatry.

“What we discovered is that a very significant proportion of the risk of developing autism correlates with the mitochondrial DNA variants, not the nuclear variants, so that implies then that mitochondrial energetics might be the cause, or a major factor, in the etiology of this disease,” senior study author Douglas Wallace, Ph.D., told GEN. Wallace is the director of the Center for Mitochondrial and Epigenomic Medicine at The Children’s Hospital of Philadelphia Research Institute.

Wallace continued, explaining, “The brain uses 20% of all the energy that our body generates but is only 2% to 3% of our body’s weight; therefore, subtle changes in mitochondrial energy production should have a disproportionate effect on the brain.”"

Here's the paper

Association Between Mitochondrial DNA Haplogroup Variation and Autism Spectrum Disorders

'via Blog this'

Human Gut-Derived Commensal Bacteria Suppress CNS Inflammatory and Demyelinating Disease: Cell Reports

•A human gut bacterium has potential as a therapy for multiple sclerosis (MS)

•P. histicola can suppress disease in a preclinical animal model of MS

•P. histicola suppresses disease by inducing CD4+ FoxP3+ regulatory T cells

The human gut is colonized by a large number of microorganisms (∼1013 bacteria) that support various physiologic functions. A perturbation in the healthy gut microbiome might lead to the development of inflammatory diseases, such as multiple sclerosis (MS). Therefore, gut commensals might provide promising therapeutic options for treating MS and other diseases. We report the identification of human gut-derived commensal bacteria, Prevotella histicola, which can suppress experimental autoimmune encephalomyelitis (EAE) in a human leukocyte antigen (HLA) class II transgenic mouse model. P. histicola suppresses disease through the modulation of systemic immune responses. P. histicola challenge led to a decrease in pro-inflammatory Th1 and Th17 cells and an increase in the frequencies of CD4+FoxP3+ regulatory T cells, tolerogenic dendritic cells, and suppressive macrophages. Our study provides evidence that the administration of gut commensals may regulate a systemic immune response and may, therefore, have a possible role in treatment strategies for MS."

'via Blog this'

Common antiseptic ingredients de-energize cells and impair hormone response

 "A new in-vitro study by University of California, Davis, researchers indicates that quaternary ammonium compounds, or "quats," used as antimicrobial agents in common household products inhibit mitochondria, the powerhouses of the cell, as well as estrogenic functions in cells. Their findings will appear online Aug. 22 in Environmental Health Perspectives, a publication of the National Institute of Environmental Health Sciences.

Quats are used as antiseptics in toothpastes, mouthwashes, lozenges, nasal sprays, eye drops, shampoos, lotions, intravaginal spermicidal sponges and household cleaners, to name a few.
"Disinfectants that we are putting on and in our bodies, and using in our environment, have been shown to inhibit mitochondrial energy production and the cellular estrogen response," said biochemist Gino Cortopassi in the UC Davis School of Veterinary Medicine. "This raises concern because exposure to other mitochondrial-inhibiting drugs, such as rotenone and MPTP, is associated with increased risk for Parkinson's disease.""


In Vitro Evaluation of Mitochondrial Function and Estrogen Signaling in Cell Lines Exposed to the Antiseptic Cetylpyridinium Chloride