Biology subjects

Gordon, S.

Publications and source records attributed to Gordon, S..

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bioRxiv2021

Exosomal transmission of α-synuclein initiates Parkinson's disease-like pathology

The intercellular transmission of -synuclein is proposed to be involved in the pathogenesis of Parkinsons disease (PD)1. Supporting this transmission hypothesis, -synuclein has been identified to act as a prion2 and has been found in cerebrospinal fluid (CSF), blood, and saliva3. However, the mechanism required to initiate the pathogenic spread of -synuclein in the body that results in PD remains unclear. Here we identify a mechanism for the loading of -synuclein into exosomes, resulting in prion-like transmission that is mediated by the ubiquitin ligase activator, Ndfip1. Risk factors associated with PD, including metal toxicity, lysosome dysfunction and pesticide exposure,4 stimulate the upregulation of Ndfip1 and increase the loading of -synuclein into exosomes. We used this pathway to promote the loading of endogenous -synuclein into exosomes, that when intranasally delivered to either wild type or M83 transgenic mice, resulted in Parkinsons-like pathology including motor impairments and brain amyloids. Recipient cells require -synuclein for pathogenesis, as delivery of exosomes containing -synuclein to Snca knockout mice did not generate brain amyloids or Parkinsons-like motor impairments. Our results demonstrate a novel mechanism to initiate the prion-like spread of -synuclein in exosomes, following exposure to risk factors for PD.

neuroscience↗

bioRxiv2021

During natural viewing, neural processing of visual targets continues throughout saccades

Relatively little is known about visual processing during free-viewing visual search in realistic dynamic environments. Free-viewing is characterized by frequent saccades. During saccades, visual processing is thought to be inhibited, yet we know that the pre-saccadic visual content can modulate post-saccadic processing. To better understand these processes in a realistic setting, we study here saccades and neural responses elicited by the appearance of visual targets in a realistic virtual environment. While subjects were being driven through a 3D virtual town they were asked to discriminate between targets that appear on the road. We found that the presence of a target enhances early occipital as well as late frontocentral saccade-related responses. The earlier potential, shortly after 125ms post-saccade onset, was enhanced for targets that appeared in peripheral vision as compared to central vision, suggesting that fast peripheral processing initiated before saccade onset. The later potential, at 195ms post-saccade onset, was strongly modulated by the visibility of the target with a spatial distribution reminiscent of the classic P300 response. Together these results suggest that, during natural viewing, neural processing of the pre-saccadic visual stimulus continues throughout the saccade, apparently unencumbered by saccadic inhibition.

neuroscience↗

bioRxiv2020

Functional succinate dehydrogenase deficiency is a pathognomonic adverse feature of clear cell renal cancer

BackgroundReduced succinate dehydrogenase (SDH) activity resulting in adverse succinate accumulation was previously thought to be relevant only in 0.05-0.5% of kidney cancers associated with germline SDH mutations (categorized SDH-deficient Renal Cell Carcinoma in the 2016 WHO classification) ResultsWe show that under-expression of SDH subunits resulting in accumulation of oncogenic succinate is a common feature in clear cell renal cell carcinoma (ccRCC) tumors during pathogenesis and progression, with a marked adverse impact on survival in a large cohort (n=516) of ccRCC patients. From a mechanistic standpoint, we show that von Hippel-Lindau (VHL) loss induced hypoxia-inducible factor (HIF) dependent upregulation of mir-210 in ccRCC causes direct inhibition of the SDHD transcript. We demonstrate that reduced expression of SDH subunits is associated with genome-wide increase in methylation and enhancement of epithelial mesenchymal transition (EMT) in ccRCC tumors, consistent with succinate-induced inhibition of TET activity and increase in invasiveness/ migratory ability of ccRCC cells. TET-2 inhibition-induced global regulatory DNA hypermethylation drives SDH loss-induced enrichment of EMT. SDH subunits under-expression had a striking association with CDHI (E-cadherin) loss in ccRCC tumors, in keeping with succinate-induced CDH1 hypermethylation and under-expression in ccRCC cells. Next, in conformity with recombinant TET-2 fluorescence quenching dynamics with succinate and ascorbic acid (AA, a TET enzyme co-factor), AA treatment led to reversal of succinate-induced inhibition of TET activity, CDH1 hypermethylation and under-expression, as well as enhanced invasiveness in ccRCC cells. Furthermore, using immunohistochemical analysis and artificial intelligence quantitation, we report that ccRCC is characterized by a marked loss of ascorbic acid transporter SLC23A1 [median percent positive cells in ccRCC primary tumors (n=104) and normal kidney cortex (n=7) was 0.7 and 32.4 respectively; p=0.0012]. Lower SLC23A1 was associated with worse survival in ccRCC (TCGA). Lastly, intravenous AA significantly prolonged survival in a metastatic ccRCC xenograft model with increased succinate and reduced SLC23A1 expression. ConclusionsTaken together, these findings strongly indicate that functional SDH deficiency is a pathognomonic adverse feature of ccRCC (which accounts for [~]80% of all kidney cancers), and that the WHO category SDH-deficient RCC should be re-named SDH germline mutation-associated RCC. Furthermore, oncogenic accumulation of succinate can be abrogated by TET modulation with AA. STATEMENT OF SIGNIFICANCEIn this study, we show that under-expression of succinate dehydrogenase (SDH) subunits resulting in the accumulation of oncogenic succinate is a common, adverse, epigenetic modulating feature occurring in a vast majority of clear cell renal cell carcinoma (ccRCC), during pathogenesis and progression. Functional SDH deficiency is therefore a pathognomonic feature of ccRCC (which accounts for [~]80% of all kidney cancers), and not just limited to the 0.05-0.5% of kidney cancer patients with germline SDH mutations. Based on the findings reported, we propose that the SDH-deficient RCC category in the 2016 WHO classification of kidney tumors be renamed SDH germline mutation-associated RCC. Furthermore, we demonstrate that oncogenic accumulation of succinate in ccRCC can be countered by TET modulation with ascorbic acid, and that ccRCC is characterized by a marked loss of ascorbic acid transporter SLC23A1. O_FIG O_LINKSMALLFIG WIDTH=172 HEIGHT=200 SRC="FIGDIR/small/188433v2_ufig1.gif" ALT="Figure 1"> View larger version (28K): org.highwire.dtl.DTLVardef@728d5eorg.highwire.dtl.DTLVardef@9f2e24org.highwire.dtl.DTLVardef@8e7011org.highwire.dtl.DTLVardef@15f8d33_HPS_FORMAT_FIGEXP M_FIG Graphical abstract depicting the consequential adverse downregulation of Succinate Dehydrogenase in ccRCC and its central role in oxidative phosphorylation C_FIG

cancer biology↗

bioRxiv2020

Geographic mosaic of selection by avian predators on hindwing warning colour in a polymorphic aposematic moth

Warning signals are predicted to develop signal monomorphism via positive frequency-dependent selection (+FDS) albeit many aposematic systems exhibit signal polymorphism. To understand this mismatch, we conducted a large-scale predation experiment in four locations, among which the frequencies of hindwing warning coloration of aposematic Arctia plantaginis differ. Here we show that selection by avian predators on warning colour is predicted by local morph frequency and predator community composition. We found +FDS to be strongest in monomorphic Scotland, and in contrast, lowest in polymorphic Finland, where different predators favour different male morphs. +FDS was also found in Georgia, where the predator community was the least diverse, whereas in the most diverse avian community in Estonia, hardly any models were attacked. Our results support the idea that spatial variation in predator and prey communities alters the strength or direction of selection on warning signals, thus facilitating a geographic mosaic of selection.

ecology↗

bioRxiv2020

Activation of JUN in fibroblasts promotes pro-fibrotic programme and modulates protective immunity

In pulmonary fibrosis, the transcription factor JUN is highly expressed in the fibrotic foci. Its induction in adult mice drives lung fibrosis, which is abrogated by administration of anti-CD47. Here, we use high-dimensional mass cytometry to profile protein expression and the secretome of individual fibroblasts and leukocytes from pulmonary fibrosis patients. We show that JUN is activated in fibroblasts derived from fibrotic lungs which also demonstrated increased CD47 and PD-L1 expression. Using ATAC-seq and ChIP-seq, we found that activation of JUN in fibroblasts rendered enhancers of CD47 and PD-L1 accessible, an observation that reporter assays corroborated. Meanwhile we detected increased IL-6 signaling which amplified both JUN-mediated CD47-enhancer activity and protein expression in fibrotic lung fibroblasts. Using an in vivo mouse model of fibrosis, we found two distinct mechanisms by which blocking IL-6, CD47, and PD-L1 reversed fibrosis--increased phagocytosis of profibrotic fibroblasts and elimination of suppressive effects on adaptive immunity. Our results identify specific immune mechanisms that promote the fibrotic process and suggest a complementary therapeutic approach that could be used alongside conventional anti-fibrotics for pulmonary fibrosis diseases.

immunology↗

bioRxiv2019

Genetic Association Study of Childhood Aggression across raters, instruments and age

Childhood aggressive behavior (AGG) has a substantial heritability of around 50%. Here we present a genome-wide association meta-analysis (GWAMA) of childhood AGG, in which all phenotype measures across childhood ages from multiple assessors were included. We analyzed phenotype assessments for a total of 328 935 observations from 87 485 children aged between 1.5 and 18 years, while accounting for sample overlap. We also meta-analyzed within subsets of the data - i.e. within rater, instrument and age. SNP-heritability for the overall meta-analysis (AGGoverall) was 3.31% (SE=0.0038). We found no genome-wide significant SNPs for AGGoverall. The gene-based analysis returned three significant genes: ST3GAL3 (P=1.6E-06), PCDH7 (P=2.0E-06) and IPO13 (P=2.5E-06). All three genes have previously been associated with educational traits. Polygenic scores based on our GWAMA significantly predicted aggression in a holdout sample of children (variance explained = 0.44%) and in retrospectively assessed childhood aggression (variance explained = 0.20%). Genetic correlations (rg) among rater-specific assessment of AGG ranged from rg =0.46 between self- and teacher-assessment to rg =0.81 between mother- and teacher-assessment. We obtained moderate to strong rgs with selected phenotypes from multiple domains, but hardly with any of the classical biomarkers thought to be associated with AGG. Significant genetic correlations were observed with most psychiatric and psychological traits (range |rg| : 0.19 - 1.00), except for obsessive-compulsive disorder. Aggression had a negative genetic correlation (rg =~ -0.5) with cognitive traits and age at first birth. Aggression was strongly genetically correlated with smoking phenotypes (range |rg| : 0.46 - 0.60). The genetic correlations between aggression and psychiatric disorders were weaker for teacher-reported AGG than for mother- and self-reported AGG. The current GWAMA of childhood aggression provides a powerful tool to interrogate the rater-specific genetic etiology of AGG.

genomics↗

bioRxiv2019

Shared Genetic Risk between Eating Disorder- and Substance-Use-Related Phenotypes: Evidence from Genome-Wide Association Studies

Eating disorders and substance use disorders frequently co-occur. Twin studies reveal shared genetic variance between liabilities to eating disorders and substance use, with the strongest associations between symptoms of bulimia nervosa (BN) and problem alcohol use (genetic correlation [rg], twin-based=0.23-0.53). We estimated the genetic correlation between eating disorder and substance use and disorder phenotypes using data from genome-wide association studies (GWAS). Four eating disorder phenotypes (anorexia nervosa [AN], AN with binge-eating, AN without binge-eating, and a BN factor score), and eight substance-use-related phenotypes (drinks per week, alcohol use disorder [AUD], smoking initiation, current smoking, cigarettes per day, nicotine dependence, cannabis initiation, and cannabis use disorder) from eight studies were included. Significant genetic correlations were adjusted for variants associated with major depressive disorder (MDD). Total sample sizes per phenotype ranged from ~2,400 to ~537,000 individuals. We used linkage disequilibrium score regression to calculate single nucleotide polymorphism-based genetic correlations between eating disorder and substance-use-related phenotypes. Significant positive genetic associations emerged between AUD and AN (rg=0.18; false discovery rate q=0.0006), cannabis initiation and AN (rg=0.23; q<0.0001), and cannabis initiation and AN with binge-eating (rg=0.27; q=0.0016). Conversely, significant negative genetic correlations were observed between three non-diagnostic smoking phenotypes (smoking initiation, current smoking, and cigarettes per day) and AN without binge-eating (rgs=-0.19 to -0.23; qs<0.04). The genetic correlation between AUD and AN was no longer significant after co-varying for MDD loci. The patterns of association between eating disorder- and substance-use-related phenotypes highlights the potentially complex and substance-specific relationships between these behaviors.

genetics↗

bioRxiv2019

Mycobacterium riyadhense clinical isolates provide insights into ancestry and adaptive evolution in tuberculosis

Current evolutionary scenarios posit the emergence of Mycobacterium tuberculosis, the deadliest bacterial pathogen for humans globally, from an environmental saprophyte through a cumulative process of genome adaptation. Mycobacterium riyadhense is a novel non-tuberculous mycobacterium (NTM) that is being increasingly isolated from human clinical cases with tuberculosis (TB)-like symptoms in various parts of the world. We provide evidence here that M. riyadhense is likely a missing link in our understanding of the evolution of M. tuberculosis. To elucidate the genomic hallmarks that define the evolutionary relationship between M. riyadhense and other mycobacterial species, including members of the Mycobacterium tuberculosis complex (MTBC), eight clinical isolates of M. riyadhense were sequenced and analyzed. We show, among other features, that M. riyadhense shares a large number of conserved orthologues with the MTBC; contains linear and circular plasmids carrying type IV and type VII secretion systems; and shows expansion of toxin/anti-toxin pairs. We conclude that M. riyadhense is an emerging mycobacterial pathogen that shares a common ancestor with members of the MTBC and that can serve as an experimental model to study the evolution and pathogenesis of tubercle bacilli.\n\nAuthor summaryMycobacterium tuberculosis is one of the most prolific infectious killers in humans and is a member of the Mycobacterium tuberculosis complex (MTBC) - a group of genetically related pathogens that cause tuberculosis (TB) in mammalian species. It is postulated that MTBC has evolved from a free-living environmental ancestor into an obligate pathogen. In this evolutionary context, a comprehensive understanding of the genomic hallmarks of the free-living environmental ancestors of the MTBC is of particular scientific interest for better understanding of the evolution of the MTBC. Mycobacterium riyadhense is a novel environmental mycobacterium, first isolated in 2009 in a hospital in Riyadh, that is increasingly being isolated from clinical cases with typical tuberculosis (TB)-like symptoms in humans. In this study, we report the characterization of eight clinical isolates of M. riyadhense, compare their genomes to members of the MTBC, and provide a comprehensive insight into the adaptive changes associated with the evolution of the MTBC from environmental mycobacteria. We show that M. riyadhense is one of the closest known environmental mycobacteria related to the MTBC, and we provide several lines of molecular evidence that M. riyadhense is likely the missing link in the evolution of M. tuberculosis. It shares a common ancestor with members of the MTBC that have evolved through a process of genome reduction, expansion of toxin/antitoxin (T/A) gene systems, and ultimately host adaptation.

evolutionary biology↗

bioRxiv2019

Pneumococcal Colonisation is an Asymptomatic Event in Healthy Adults using an Experimental Human Colonisation Model.

IntroductionPneumococcal colonisation is regarded as a pre-requisite for developing pneumococcal disease. In children previous studies have reported colonisation to be a symptomatic event and described a relationship between symptom severity/frequency and colonisation density. The evidence for this in adults is lacking in the literature. This study uses an experimental human pneumococcal challenge model to explore whether pneumococcal colonisation (or co-colonisation with a respiratory virus) is a symptomatic event in healthy adults.\n\nMethodsHealthy volunteers aged 18-50 were recruited and inoculated intra-nasally with either Streptococcus pneumoniae (serotypes 6B, 23F) or saline as a control. Respiratory viral swabs were obtained prior to inoculation. Nasal and non-nasal symptoms were then assessed using a modified Likert score between 1 (no symptoms) to 7 (cannot function). The rate of symptoms reported between groups was compared and a correlation analysis performed.\n\nResultsData from 54 participants were analysed. 46 were inoculated with S. pneumoniae (29 with 6B, 17 with 23F) and 8 received saline. In total, 14 became experimentally colonised (30.4%), all of which were inoculated with 6B serotype. There was no statistically significant difference in nasal (p= 0.45) or non-nasal symptoms (p=0.28) between the pneumococcal inoculation group and the saline group. There was no direct correlation between colonisation density and symptom severity in those who were colonised. In the 22% (12/52) who were co-colonised with pneumococcus and respiratory viruses there was no statistical difference in either nasal or non-nasal symptoms (virus positive p=0.74 and virus negative p=1.0).\n\nConclusionPneumococcal colonisation is asymptomatic in healthy adults, regardless of bacterial density or viral co-colonisation.

microbiology↗

bioRxiv2018

Experimental Human Challenge Reveals Distinct Mechanisms of Acquisition or Protection Against Pneumococcal Colonization

Colonization of the upper respiratory tract with Streptococcus pneumoniae is the precursor of pneumococcal pneumonia and invasive disease. Following exposure, however, it is unclear which human immune mechanisms determine whether a pathogen will colonize. We used a human challenge model to investigate host-pathogen interactions in the first hours and days following intranasal exposure to Streptococcus pneumoniae. Using a novel home sampling method, we measured early immune responses and bacterial density dynamics in the nose and saliva after pneumococcal exposure. We found that nasal colonization can take up to 24 hours to become established. Also, two distinct bacterial clearance profiles were associated with protection: nasal clearers with immediate clearance of bacteria in the nose by the activity of pre-existent mucosal neutrophils and saliva clearers with detectable pneumococcus in saliva at one-hour post challenge and delayed clearance mediated by an inflammatory response and increased neutrophil activity 24 hours post bacterial encounter.

immunology↗

bioRxiv2018

Transparency reduces predator detection in chemically protected clearwing butterflies

1. Predation is an important selective pressure and some prey have evolved warning colour signals advertising unpalatability (i.e. aposematism) as an antipredator strategy. Unexpectedly, some butterfly species from the unpalatable tribe Ithomiini possess transparent wings, an adaptation rare on land but common in water where it helps avoiding predator detection.\n\n2. We tested if transparency of butterfly wings was associated with decreased detectability by predators, by comparing four butterfly species exhibiting different degrees of transparency, ranging from fully opaque to largely transparent. We tested our prediction using using both wild birds and humans in behavioural experiments. Vision modelling predicted detectability to be similar for these two predator types.\n\n3. In concordance with predictions, more transparent species were almost never the first detected items and were detected less often than the opaque species by both birds and humans, suggesting that transparency enhances crypsis. However, humans could learn to better detect the most transparent species over time. Our study demonstrates for the first time that transparency on land likely decreases detectability by visual predators.

evolutionary biology↗

bioRxiv2018

Common genetic variants contribute to risk of rare severe neurodevelopmental disorders

There are thousands of rare human disorders caused by a single deleterious, protein-coding genetic variant 1. However, patients with the same genetic defect can have different clinical presentation 2-4, and some individuals carrying known disease-causing variants can appear unaffected 5. What explains these differences? Here, we show in a cohort of 6,987 children with heterogeneous severe neurodevelopmental disorders expected to be almost entirely monogenic that 7.7% of variance in risk is attributable to inherited common genetic variation. We replicated this genome wide common variant burden by showing that it is over-transmitted from parents to children in an independent sample of 728 trios from the same cohort. Our common variant signal is significantly positively correlated with genetic predisposition to fewer years of schooling, decreased intelligence, and risk of schizophrenia. We found that common variant risk was not significantly different between individuals with and without a known protein-coding diagnostic variant, suggesting that common variant risk is not confined to patients without a monogenic diagnosis. In addition, previously published common variant scores for autism, height, birth weight, and intracranial volume were all correlated with those traits within our cohort, suggesting that phenotypic expression in individuals with monogenic disorders is affected by the same variants as the general population. Our results demonstrate that common genetic variation affects both overall risk and clinical presentation in disorders typically considered to be monogenic.

genetics↗

bioRxiv2018

Trans-ancestral GWAS of alcohol dependence reveals common genetic underpinnings with psychiatric disorders

Liability to alcohol dependence (AD) is heritable, but little is known about its complex polygenic architecture or its genetic relationship with other disorders. To discover loci associated with AD and characterize the relationship between AD and other psychiatric and behavioral outcomes, we carried out the largest GWAS to date of DSM - IV diagnosed AD. Genome - wide data on 14,904 individuals with AD and 37,944 controls from 28 case / control and family - based studies were meta - analyzed, stratified by genetic ancestry (European, N = 46,568; African; N = 6,280). Independent, genome - wide significant effects of different ADH1B variants were identified in European (rs1229984; p = 9.8E - 13) and African ancestries (rs2066702; p = 2.2E - 9). Significant genetic correlations were observed with schizophrenia, ADHD, depression, and use of cigarettes and cannabis. There was only modest genetic correlation with alcohol consumption and inconsistent associations with problem drinking. The genetic underpinnings of AD only partially overlap with those for alcohol consumption, underscoring the genetic distinction between pathological and non - pathological drinking behaviors.

genetics↗

bioRxiv2017

The bovine alveolar macrophage DNA methylome is resilient to infection with Mycobacterium bovis

DNA methylation is pivotal in orchestrating gene expression patterns in various mammalian biological processes. Perturbation of the bovine alveolar macrophage (bAM) transcriptome, due to Mycobacterium bovis (M. bovis) infection, has been well documented; however, the impact of this intracellular pathogen on the bAM epigenome has not been determined. Here, whole genome bisulfite sequencing (WGBS) was used to assess the effect of M. bovis infection on the bAM DNA methylome. The methylomes of bAM infected with M. bovis were compared to those of non-infected bAM 24 hours post-infection (hpi). No differences in DNA methylation (CpG or non-CpG) were observed. Analysis of DNA methylation at proximal promoter regions uncovered >250 genes harbouring intermediately methylated (IM) promoters (average methylation of 33-66%). Gene ontology analysis, focusing on genes with low, intermediate or highly methylated promoters, revealed that genes with IM promoters were enriched for immune-related GO categories; this enrichment was not observed for genes in the high or low methylation groups. Targeted analysis of genes in the IM category confirmed the WGBS observation. This study is the first in cattle examining genome-wide DNA methylation at single nucleotide resolution in an important bovine cellular host-pathogen interaction model, providing evidence for IM promoter methylation in bAM.

genomics↗

bioRxiv2017

The Anorexia Nervosa Genetics Initiative: Overview and Methods

BackgroundGenetic factors contribute to anorexia nervosa (AN); and the first genome-wide significant locus has been identified. We describe methods and procedures for the Anorexia Nervosa Genetics Initiative (ANGI), an international collaboration designed to rapidly recruit 13000 individuals with AN as well as ancestrally matched controls. We present sample characteristics and the utility of an online eating disorder diagnostic questionnaire suitable for large-scale genetic and population research.\n\nMethodsANGI recruited from the United States (US), Australia/New Zealand (ANZ), Sweden (SE), and Denmark (DK). Recruitment was via national registers (SE, DK); treatment centers (US, ANZ, SE, DK); and social and traditional media (US, ANZ, SE). All cases had a lifetime AN diagnosis based on DSM-IV or ICD-10 criteria (excluding amenorrhea). Recruited controls had no lifetime history of disordered eating behaviors. To assess the positive and negative predictive validity of the online eating disorder questionnaire (ED100K-v1), 109 women also completed the Structured Clinical Interview for DSM-IV (SCID), Module H.\n\nResultsBlood samples and clinical information were collected from 13,364 individuals with lifetime AN and from controls. Online diagnostic phenotyping was effective and efficient; the validity of the questionnaire was acceptable.\n\nConclusionsOur multipronged recruitment approach was highly effective for rapid recruitment and can be used as a model for efforts by other groups. High online presence of individuals with AN rendered the Internet/social media a remarkably effective recruitment tool in some countries. ANGI has substantially augmented Psychiatric Genomics Consortium AN sample collection. ANGI is a registered clinical trial: clinicaltrials.gov NCT01916538; https://clinicaltrials.gov/ct2/show/NCT01916538?cond=Anorexia+Nervosa&draw=1&rank=3.

genetics↗

bioRxiv2017

Higher genetic risk for schizophrenia is associated with living in urban and populated areas

Social stress in urban life has been proposed as an environmental risk factor associated with the increased prevalence of schizophrenia in urban compared to rural areas. However, the potential genetic contributions to this relationship have been largely ignored.\n\nUsing a community-based sample of 15,544 adults living in Australia, we found higher genetic loading for schizophrenia in participants living in more densely populated (p-value=5.69*10-5) or less remote areas (p-value=0.003). Mendelian Randomization suggested that high schizophrenia genetic risk is a causal factor in chosing to live in denser (p-value=0.046) and less remote areas (p-value=0.044).\n\nOur results support the hypothesis of selective migration to more urban environments by people at higher genetic risk for schizophrenia and suggest a need to refine the social stress model for schizophrenia by including genetic influences on where people choose to live.

genetics↗