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bioRxiv2017

Draft genomes of the fungal pathogen Phellinus noxius in Hong Kong

The fungal pathogen Phellinus noxius is the underlying cause of brown root rot, a disease with causing tree mortality globally, causing extensive damage in urban areas and crop plants. This disease currently has no cure, and despite the global epidemic, little is known about the pathogenesis and virulence of this pathogen.\n\nUsing Ion Torrent PGM, Illumina MiSeq and PacBio RSII sequencing platforms with various genome assembly methods, we produced the draft genome sequences of four P. noxius strains isolated from infected trees in Hong Kong to further understand the pathogen and identify the mechanisms behind the aggressive nature and virulence of this fungus. The resulting genomes ranged from 30.8Mb to 31.8Mb in size, and of the four sequences, the YTM97 strain was chosen to produce a high-quality Hong Kong strain genome sequence, resulting in a 31Mb final assembly with 457 scaffolds, an N50 length of 275,889 bp and 96.2% genome completeness. RNA-seq of YTM97 using Illumina HiSeq400 was performed for improved gene prediction. AUGUSTUS and Genemark-ES prediction programs predicted 9,887 protein-coding genes which were annotated using GO and Pfam databases. The encoded carbohydrate active enzymes revealed large numbers of lignolytic enzymes present, comparable to those of other white-rot plant pathogens. In addition, P. noxius also possessed larger numbers of cellulose, xylan and hemicellulose degrading enzymes than other plant pathogens. Searches for virulence genes was also performed using PHI-Base and DFVF databases revealing a host of virulence-related genes and effectors. The combination of non-specific host range, unique carbohydrate active enzyme profile and large amount of putative virulence genes could explain the reasons behind the aggressive nature and increased virulence of this plant pathogen.\n\nThe draft genome sequences presented here will provide references for strains found in Hong Kong. Together with emerging research, this information could be used for genetic diversity and epidemiology research on a global scale as well as expediting our efforts towards discovering the mechanisms of pathogenicity of this devastating pathogen.

genomics↗

bioRxiv2017

Effects of Spatial Heterogeneity on Transmission Potential in Vectorial-Contact Networks: A Comparison of Three Aedes aegypti Control Strategies

Dengue, chikungunya and zika are all transmitted by the Aedes aegypti mosquito. Despite the strong influence of host spatial distribution and movement patterns on the ability of mosquito vectors to transmit pathogens, there is little understanding how these complex interactions modify the spread of disease in spatially heterogeneous populations. In light of present fears of a worldwide zika epidemic, and failures to eradicate dengue and chikungunya; there is a pressing need to get a better picture of how high-resolution details such as human movement in a small landscape, modify the patterns of transmission of these diseases and how different mosquito-control interventions could be affected by these movements.\n\nIn this work we use a computational agent-based model (ABM) to simulate mosquito-human interactions in two different levels of spatial heterogeneity, with human movement, and in the presence of three mosquito-control interventions (spatial spraying, the release of Wolbachia-infected mosquitoes and release of insects with dominant lethal gene). To analyse the results from each of these experiments we examined mosquito population dynamics and host to host contact networks that emerged from the distribution of consecutive bites across humans. We then compared results across experiments to understand the differential effectiveness of different interventions in both the presence and absence of spatial heterogeneities, and analysed network measures of epidemiological relevance (degree probability distributions, mean path length, network density and small-worldness).\n\nFrom our experiments we conclude that spatial heterogeneity greatly influences how a pathogen may spread in a host population when mediated by a mosquito vector, and that these important heterogeneities also strongly affect effectiveness of interventions. Finally, we demonstrate that these host to host vectorial-contact networks can provide operationally important information to inform selection of optimal vector-control strategies.\n\nAuthor SummaryMosquito-borne diseases transmission patterns arise from the complex interactions between hosts and vector. Because these interactions are influenced by host and vector behaviour, spatial constraints, and other factors they are amongst the most difficult to understand. In this work, we use our computational agent-based model: SoNA3BS; to simulate two spatially different settings in the presence and absence of three different mosquito-control interventions: fogging, the release of Wolbachia-infected mosquitoes and the release of insects with dominant lethal gene. Throughout these simulations, we record mosquito population dynamics and mosquito bites on persons. We then compare mosquito population dynamics to the vectorial-contact networks (that emerge from subsequent mosquito bites between humans) and, after performing these comparisons, we proceeded to show that even when mosquito population sizes are almost equal in both spatial settings, the resulting vectorial-contact networks are radically different. This has profound implications in our understanding of how mosquito-borne diseases spread in human populations and is relevant to the effective use of resources allocated to stop these pathogens from causing more harm in human populations.

bioinformatics↗

bioRxiv2017

Reproducibility and repeatability of six high-throughput 16S rDNA sequencing protocols for microbiota profiling

Culture-independent molecular techniques and advances in next generation sequencing (NGS) technologies make large-scale epidemiological studies on microbiota feasible. A challenge using NGS is to obtain high reproducibility and repeatability, which is mostly attained through robust amplification. We aimed to assess the reproducibility of saliva microbiota by comparing triplicate samples. The microbiota was produced with simplified in-house 16S amplicon assays taking advantage of large number of barcodes. The assays included primers with Truseq (TS-tailed) or Nextera (NX-tailed) adapters and either with dual index or dual index plus a 6-nt internal index. All amplification protocols produced consistent microbial profiles for the same samples. Although, in our study, reproducibility was highest for the TS-tailed method. Five replicates of a single sample, prepared with the TS-tailed 1-step protocol without internal index sequenced on the HiSeq platform provided high alpha-diversity and low standard deviation (mean Shannon and Inverse Simpson diversity was 3.19 {+/-} 0.097 and 13.56 {+/-} 1.634 respectively). Large-scale profiling of microbiota can consistently be produced by all 16S amplicon assays. The TS-tailed-1S dual index protocol is preferred since it provides repeatable profiles on the HiSeq platform and are less labour intensive.

microbiology↗

bioRxiv2017

Pydigree: a python library for manipulation and forward-time simulation and of genetic datasets

The development of software for working with data from population genetics or genetic epidemiology often requires substantial time spent implementing common procedures. Pydigree is a cross-platform Python 3 library that contains efficient, user friendly implementations for many of these common functions, and support for input from common file formats. Developers can combine the functions and data structures to rapidly implement programs handling genetic data. Pydigree presents a useful environment for development of applications for genetic data or rapid prototyping before reimplementation in a higher-performance language.\n\nPydigree is freely available under an open source license. Stable sources can be found in the Python Package Index at https://pypi.python.org/pypi/pydigree/, and development sources can be downloaded at https://github.com/jameshicks/pydigree/

bioinformatics↗

bioRxiv2017

A Pilot Randomized Trial of Oral Magnesium Supplementation on Supraventricular Arrhythmias

BackgroundMagnesium is believed to have a physiologic role in cardiac contractility, and evidence from epidemiologic and clinical studies has suggested that low serum concentrations of magnesium may be associated with increased risk of atrial fibrillation (AF).\n\nObjectiveAs part of the planning effort for a large randomized trial to prevent AF with magnesium supplementation, we conducted a 12-week pilot study to assess adherence to oral magnesium supplementation and matching placebo, estimate the effect on circulating magnesium concentrations, and evaluate the feasibility of using an ambulatory monitoring device (ZioPatch) for assessing premature atrial contractions (PACs), a predictor of AF.\n\nDesignDouble-blind randomized pilot clinical trial comparing supplementation with 400 mg magnesium oxide daily (versus placebo) over 12 weeks of follow-up. The ZioPatch was applied for 14 days at baseline and the end of follow-up. Adherence to the assigned treatment, and changes in PACs, serum magnesium concentration, glucose and blood pressure were assessed.\n\nResultsA total of 59 participants, 73% women and average age 62 years, were randomized. 98% of participants completed follow-up. Those assigned to the magnesium supplement took 75% of tablets as compared to 83% for those in the placebo group. Change in magnesium concentrations was significantly greater for those given magnesium supplement compared to placebo (0.07; 95% confidence interval (CI): 0.03, 0.12 mEq/L; p = 0.002). ZioPatch was worn for an average of 13.0 of the requested 14 days at baseline; at the end of follow-up, the average number of days of monitoring was 13.0 days for the magnesium supplement group and 12.7 days for the placebo group. For log PAC burden (episodes per hour), the average change from baseline was -0.05 (95% CI: -0.31, 0.20) for those randomized to magnesium supplement and 0.04 (95% CI: -0.24, 0.31) for those randomized to placebo (p=0.79 for difference). Gastrointestinal problems were reported by 50% of participants in the magnesium supplement group and 7% in the placebo group. Only one person in the magnesium supplement group and none in the placebo group experienced adverse events which led to treatment discontinuation.\n\nConclusionsIn this pilot randomized clinic trial, although gastrointestinal side effects to the magnesium supplement were common, adherence, measured by pill counts, was very good and, as a consequence, magnesium concentrations were greater for those randomly assigned to the magnesium supplement compared to placebo. Participant acceptance of the planned monitoring with ZioPatch was also very good. While the difference in the change in PACs was not significant, this pilot study was small, short-term, and did not include participants at high risk of AF. Thus, we could not reliably evaluate the effect of magnesium supplementation on PACs.\n\nClinicaltrials.gov registrationNCT02837328

clinical trials↗

bioRxiv2017

Identifying the phenotypic effect of rare variants by including between-pedigree coancestry in variance components linkage analysis

The contribution of rare variants to disease burden has become an important focus in genetic epidemiology. These effects are difficult to detect in population-based datasets, and as a result, interest in family-based study designs has resurfaced. Linkage analysis tools will need to be updated to accommodate the scale of data generated by modern genotyping and sequencing technologies.\n\nIn conventional linkage analysis individuals in different pedigrees are assumed to be independent of each other. However, cryptic relatedness is often present in populations and haplotypes that harbor rare variants may be shared between pedigrees as well as within them.\n\nWith millions of polymorphisms, Identity-by-descent (IBD) states across the genome can now be inferred without use of pedigree information. This is done by identifying long runs of identical-by-state genotypes which are unlikely to arise without IBD. Previously, IBD had to be estimated in pedigrees from recombination events in a sparse set of markers.\n\nWe present a method for variance-components linkage that can incorporate large number of markers and allows for between-pedigree relatedness. We replace the IBD matrix generated from pedigree-based analysis with one generated from a genotype-based method. All pedigrees in a dataset are considered jointly, allowing between-pedigree IBD to be included in the model.\n\nIn simulated data, we show that power is increased in the scenario when there is a haplotype shared IBD between members of different pedigrees. If there is no between-pedigree IBD, the analysis reduces to conventional variance-components analysis. By determining IBD states by long runs of dense IBS genotypes, linkage signals can be determined from their physical position, allowing more precise localization.

genetics↗

bioRxiv2017

Antimicrobial resistant Klebsiella pneumoniae carriage and infection in specialized geriatric care wards linked to acquisition in the referring hospital

BackgroundKlebsiella pneumoniae is a leading cause of extended-spectrum beta-lactamase (ESBL) producing hospital-associated infections, for which elderly patients are at increased risk.\n\nMethodsWe conducted a 1-year prospective cohort study, in which a third of patients admitted to two geriatric wards in a specialized hospital were recruited and screened for carriage of K. pneumoniae by microbiological culture. Clinical isolates were monitored via the hospital laboratory. Colonizing and clinical isolates were subjected to whole genome sequencing and antimicrobial susceptibility testing.\n\nResultsK. pneumoniae throat carriage prevalence was 4.1%, rectal carriage 10.8% and ESBL carriage 1.7%. K. pneumoniae infection incidence was 1.2%. The isolates were diverse, and most patients were colonized or infected with a unique phylogenetic lineage, with no evidence of transmission in the wards. ESBL strains carried blaCTX-M-15 and belonged to clones associated with hospital-acquired ESBL infections in other countries (ST29, ST323, ST340).\n\nOne also carried the carbapenemase blaIMP-26. Genomic and epidemiological data provided evidence that ESBL strains were acquired in the referring hospital. Nanopore sequencing also identified strain-to-strain transmission of a blaCTX-M-15 FIBK/FIIK plasmid in the referring hospital.\n\nConclusionsThe data suggest the major source of K. pneumoniae was the patients own gut microbiome, but ESBL strains were acquired in the referring hospital. This highlights the importance of the wider hospital network to understanding K. pneumoniae risk and infection control. Rectal screening for ESBL organisms upon admission to geriatric wards could help inform patient management and infection control in such facilities.\n\nSummaryPatients own gut microbiota were the major source of K. pneumoniae, but extended-spectrum beta-lactamase strains were acquired in the referring hospital. This highlights the potential for rectal screening, and the importance of the wider hospital network, for local risk management.

microbiology↗

bioRxiv2017

Population genomics of hypervirulent Klebsiella pneumoniae clonal group 23 reveals early emergence and rapid global dissemination

Since the mid-1980s there have been increasing reports of severe community-acquired pyogenic liver abscess, meningitis and bloodstream infections caused by hypervirulent Klebsiella pneumoniae, predominantly encompassing clonal group (CG) 23 serotype K1 strains. Common features of CG23 include a virulence plasmid associated with iron scavenging and hypermucoidy, and a chromosomal integrative and conjugative element (ICE) encoding the siderophore yersiniabactin and the genotoxin colibactin. Here we investigate the evolutionary history and genomic diversity of CG23 based on comparative analysis of 98 genomes. Contrary to previous reports with more limited samples, we show that CG23 comprises several deep branching sublineages dating back to the 1870s, many of which are associated with distinct chromosomal insertions of ICEs encoding yersiniabactin. We find that most liver abscess isolates (>80%) belong to a dominant sublineage, CG23-I, which emerged in the 1920s following acquisition of ICEKp10 (encoding colibactin in addition to yersiniabactin) and has undergone clonal expansion and global dissemination within the human population. The unique genomic feature of CG23-I is the production of colibactin, which has been reported previously as a promoter of gut colonisation and dissemination to the liver and brain in a mouse model of CG23 K. pneumoniae infection, and has been linked to colorectal cancer. We also identify an antibiotic-resistant subclade of CG23-I associated with sexually-transmitted infections in horses dating back to the 1980s. These data show that hypervirulent CG23 K. pneumoniae was circulating in humans for decades before the liver abscess epidemic was first recognised, and has the capacity to acquire and maintain AMR plasmids. These data provide a framework for future epidemiological and experimental studies of hypervirulent K. pneumoniae. To further support such studies we present an open access and completely sequenced human liver abscess isolate, SGH10, which is typical of the globally disseminated CG23-I sublineage.

genomics↗

bioRxiv2017

Pneumococcal vaccine impacts on the population genomics of non-typeable Haemophilus influenzae

Between 2008/09 and 2012/13 the molecular epidemiology of non-typeable Haemophilus influenzae (NTHi) carriage in children <5 years of age was determined; a period that included pneumococcal conjugate vaccine (PCV) 13 introduction. Significantly increased carriage in post-PCV13 years was observed and lineage-specific associations with S. pneumoniae were observed before and after PCV13 introduction. NTHi were characterised into eleven discrete, temporally stable lineages, congruent with current knowledge regarding the clonality of NTHi. This increase could not be linked to the expansion of a particular clone and demonstrates different dynamics to before PCV13 implementation during which time NTHi co-carried with vaccine serotype pneumococci.

microbiology↗

bioRxiv2017

Examination of the Shared Genetic Basis of Anorexia Nervosa and Obsessive-Compulsive Disorder

Anorexia nervosa (AN) and obsessive-compulsive disorder (OCD) are often comorbid and likely to share genetic risk factors. Hence, we examine their shared genetic background using a crossdisorder GWAS meta-analysis of 3,495 AN cases, 2,688 OCD cases and 18,013 controls. We confirmed a high genetic correlation between AN and OCD (rg = 0.49 {+/-} 0.13, p = 9.07x10-7) and a sizable SNP heritability (SNP h2 = 0.21 {+/-} 0.02) for the cross-disorder phenotype. Although no individual loci reached genome-wide significance, the cross-disorder phenotype showed strong positive genetic correlations with other psychiatric phenotypes (e.g., bipolar disorder, schizophrenia, neuroticism) and negative correlations with metabolic phenotypes (e.g., BMI, triglycerides). Follow-up analyses revealed that although AN and OCD overlap heavily in their shared risk with other psychiatric phenotypes, the relationship with metabolic and anthropometric traits is markedly stronger for AN than for OCD. We further tested whether shared genetic risk for AN/OCD was associated with particular tissue or cell-type gene expression patterns and found that the basal ganglia and medium spiny neurons were most enriched for AN/OCD risk, consistent with neurobiological findings for both disorders. Our results confirm and extend genetic epidemiological findings of shared risk between AN and OCD and suggest that larger GWASs are warranted.

genetics↗

bioRxiv2017

The impact of HIV-1 within-host evolution on transmission dynamics

The adaptive potential of HIV-1 is a vital mechanism to evade host immune responses and antiviral treatment. However, high evolutionary rates during persistent infection can impair transmission efficiency and alter disease progression in the new host, resulting in a delicate trade-off between within-host virulence and between-host infectiousness. This trade-off is visible in the disparity in evolutionary rates at within-host and between-host levels, and preferential transmission of ancestral donor viruses. Understanding the impact of within-host evolution for epidemiological studies is essential for the design of preventive and therapeutic measures. Herein, we review recent theoretical and experimental work that generated new insights into the complex link between within-host evolution and between-host fitness, revealing temporal and selective processes underlying the structure and dynamics of HIV-1 transmission.

microbiology↗

bioRxiv2017

Leishmania naiffi and Leishmania guyanensis reference genomes highlight genome structure and gene content evolution in the Viannia subgenus

The unicellular protozoan parasite Leishmania causes the neglected tropical disease leishmaniasis, affecting 12 million people in 98 countries. In South America where the Viannia subgenus predominates, so far only L. (Viannia) braziliensis and L. (V.) panamensis have been sequenced, assembled and annotated as reference genomes. Addressing this deficit in molecular information can inform species typing, epidemiological monitoring and clinical treatment. Here, L. (V.) naiffi and L. (V.) guyanensis genomic DNA was sequenced to assemble these two genomes as draft references from short sequence reads. The methods used were tested using short sequence reads for L. braziliensis M2904 against its published reference as a comparison. This assembly and annotation pipeline identified 70 additional genes not annotated on the original M2904 reference. Phylogenetic and evolutionary comparisons of L. guyanensis and L. naiffi with ten other Viannia genomes revealed four traits common to all Viannia: aneuploidy, 22 orthologous groups of genes absent in other Leishmania subgenera, elevated TATE transposon copies, and a high NADH-dependent fumarate reductase gene copy number. Within the Viannia, there were limited structural changes in genome architecture specific to individual species: a 45 Kb amplification on chromosome 34 was present in all bar L. lainsoni, L. naiffi had a higher copy number of the virulence factor leishmanolysin, and laboratory isolate L. shawi M8408 had a possible minichromosome derived from the 3 end of chromosome 34. This combination of genome assembly, phylogenetics and comparative analysis across an extended panel of diverse Viannia has uncovered new insights into the origin and evolution of this subgenus and can help improve diagnostics for leishmaniasis surveillance.

genomics↗

bioRxiv2017

Global phylogenomics of multidrug-resistant Staphylococcus aureus sequence type 772: the Bengal Bay clone

The global spread of antimicrobial resistance has been well documented in Gram-negative bacteria and healthcare-associated epidemic pathogens, often emerging from regions with heavy antimicrobial use. However, the degree to which similar processes occur with Gram-positive bacteria in the community setting is less well understood. Here we demonstrate the recent origin and global spread from the Indian subcontinent of a multidrug resistant Staphylococcus aureus lineage, sequence type 772 (Bengal Bay clone). Short-term outbreaks occurred following intercontinental transmission, typically associated with travel and family contacts, but ongoing endemic transmission was uncommon. Instrumental in the emergence of a single dominant clade in the early 1990s was the acquisition of a multidrug resistance integrated plasmid that did not appear to incur a significant fitness cost. The Bengal Bay clone therefore combines the multidrug resistance of traditional healthcare-associated clones with the epidemiological and virulence potential of community-associated clones.

genomics↗

bioRxiv2017

Human Herpes Virus 6 (HHV-6) - Pathogen or Passenger? A pilot study of clinical laboratory data and next generation sequencing

ABSTRACT\n\nBackgroundHuman herpes virus 6 (HHV-6) is a ubiquitous organism that can cause a variety of clinical syndromes ranging from short-lived rash and fever through to life-threatening encephalitis.\n\nObjectivesWe set out to generate observational data regarding the epidemiology of HHV-6 infection in clinical samples from a UK teaching hospital and to compare different diagnostic approaches.\n\nStudy designFirst, we scrutinized HHV-6 detection in samples submitted to our hospital laboratory through routine diagnostic pathways. Second, we undertook a pilot study using Illumina next generation sequencing (NGS) to determine the frequency of HHV-6 in CSF and respiratory samples that were initially submitted to the laboratory for other diagnostic tests.\n\nResultsOf 72 samples tested for HHV-6 by PCR at the request of a clinician, 24 (33%) were positive for HHV-6. The majority of these patients were under the care of the haematology team (30/41, 73%), and there was a borderline association between HHV-6 detection and both Graft versus Host Disease (GvHD) and Central nervous system (CNS) disease (p=0.05 in each case). We confirmed detection of HHV-6 DNA using NGS in 4/20 (20%) CSF and respiratory samples.\n\nConclusionsHHV-6 is common in clinical samples submitted from a high-risk haematology population, and enhanced screening of this group should be considered. NGS can be used to identify HHV-6 from a complex microbiomee, but further controls are required to define the sensitivity and specificity, and to correlate these results with clinical disease. Our results underpin ongoing efforts to develop NGS technology for viral diagnostics.

microbiology↗

bioRxiv2017

Going through the motions: incorporating movement analyses into disease research

Though epidemiology dates back to the 1700s, most mathematical representations of epidemics still use transmission rates averaged at the population scale, especially for wildlife diseases. In simplifying the contact process, we ignore the heterogeneities in host movements that complicate the real world, and overlook their impact on spatiotemporal patterns of disease burden. Movement ecology offers a set of tools that help unpack the transmission process, letting researchers more accurately model how animals within a population interact and spread pathogens. Analytical techniques from this growing field can also help expose the reverse process: how infection impacts movement behaviors, and therefore other ecological processes like feeding, reproduction, and dispersal. Here, we synthesize the contributions of movement ecology in disease research, with a particular focus on studies that have successfully used movement-based methods to quantify individual heterogeneity in exposure and transmission risk. Throughout, we highlight the rapid growth of both disease and movement ecology, and comment on promising but unexplored avenues for research at their overlap. Ultimately, we suggest, including movement empowers ecologists to pose new questions expanding our understanding of host-pathogen dynamics, and improving our predictive capacity for wildlife and even human diseases.

ecology↗

bioRxiv2017

Δ9-tetrahydrocannabinol Attenuates Oxycodone Self-Administration Under Extended Access Conditions

Growing nonmedical use of prescription opioids is a global problem, motivating research on ways to reduce use and combat addiction. Medical cannabis (\"medical marijuana\") legalization has been associated epidemiologically with reduced opioid harms and cannabinoids have been shown to modulate effects of opioids in animal models. This study was conducted to determine if {Delta}9-tetrahydrocannabinol (THC) enhances the behavioral effects of oxycodone.\n\nMale rats were trained to intravenously self-administer (IVSA) oxycodone (0.15 mg/kg/infusion) during 1 h, 4 h or 8 h sessions. Following acquisition rats were exposed to THC by vapor inhalation (1 h and 8 h groups) or injection (0-10 mg/kg, i.p.; all groups) prior to IVSA sessions. Fewer oxycodone infusions were obtained by rats following vaporized or injected THC compared with vehicle treatment prior to the session. Follow-up studies demonstrated parallel dose-dependent effects of THC, i.p., on self-administration of different per-infusion doses of oxycodone and a preserved loading dose early in the session. These patterns are inconsistent with behavioral suppression. Additional groups of male and female Wistar rats were assessed for nociception following inhalation of vaporized THC (50 mg/mL), oxycodone (100 mg/mL) or the combination. Tail withdrawal latency was increased more by the THC/oxycodone combination compared to either drug alone. Similar additive antinociceptive effects were produced by injection of THC (5.0 mg/kg, i.p.) and oxycodone (2.0 mg/kg, s.c.). Together these data demonstrate additive effects of THC and oxycodone and suggest the potential use of THC to enhance therapeutic efficacy, and to reduce the abuse, of opioids.

neuroscience↗

bioRxiv2018

Viral gain-of-function experiments uncover residues under diversifying selection in nature

Viral gain-of-function mutations are commonly observed in the laboratory; however, it is unknown whether those mutations also evolve in nature. We identify two key residues in the host recognition protein of bacteriophage {lambda} that are necessary to exploit a new receptor; both residues repeatedly evolved among homologs from environmental samples. Our results provide evidence for widespread host-shift evolution in nature and a proof of concept for integrating experiments with genomic epidemiology.

evolutionary biology↗

bioRxiv2018

Structural and functional influences of urban and rural childhoods on the medial prefrontal cortex

Global increases in urbanization have brought dramatic economic, environmental and social changes. However, less is understood about how these may influence disease-related brain mechanisms underlying epidemiological observations that urban birth and childhoods may increase the risk for neuropsychiatric disorders, including increased social stress and depression. In a genetically homogeneous Han Chinese adult population with divergent urban and rural birth and childhoods, we examined the structural and functional MRI neural correlates of childhood urbanicity, focusing on behavioral traits responding to social status threats, and polygenic risk for depression. Subjects with divergent rural and urban childhoods were similar in adult socioeconomic status and were genetically homogeneous. Urban childhoods, however, were associated with higher trait anxiety-depression. On structural MRI, urban childhoods were associated with relatively reduced medial prefrontal gray matter volumes. Functional medial prefrontal engagement under social status threat during working memory correlated with trait anxiety-depression in subjects with urban childhoods, to a significantly greater extent than in their rural counterparts, implicating an exaggerated physiological response to the threat context. Stress-associated medial prefrontal engagement also interacted with polygenic risk for depression, significantly predicting a differential response in individuals with urban but not rural childhoods. Developmental urbanicity thus differentially influenced medial prefrontal structure and function, at least in part through mechanisms associated with the neural processing of social status threat, trait anxiety, and genetic risk for depression, which may be factors in the association of urbanicity with adult psychopathology.\n\nSignificance StatementUrban living has been associated with social inequalities and stress. However, less is understood about the neural underpinnings by which these stressors affect disease risk, and in particular, genetic risk for depression. Leveraging urbanization in China, we studied adults with diverse urban and rural upbringings, who were genetically homogeneous and with similar current socioeconomic status, to isolate the effects of childhood urbanicity. At medial prefrontal cortex, a region critical for processing emotional stressors and social status, genetic risk for depression resulted in more deleterious function under stress in individuals with urban, but not rural childhoods. This implicates medial prefrontal cortexs critical role in brain development, integrating genetic mechanisms of stress and depression with the childhood environment.

neuroscience↗