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Schizophrenia is a mental disorder constituting different symptom clusters. Its high heterogeneity in both pathophysiology and clinical manifestations hampered effective prevention and treatment. It has long been recognized that one of the core features of schizophrenia is its intellectual decline. Using the proxy-phenotype method (PPM), we tried to identify core genes, the expression of which in the dorsal lateral prefrontal cortex (DLPFC) showed a genetic dependence between intelligence (IT) and schizophrenia (SCZ). The result revealed ten genes of genetic dependence in their genetic expression in DLPFC between IT and schizophrenia. Further, a clustering analysis using the expression matrix of these ten genes identified four biotypes in our patient group. Subsequent phenotypic profiling of these four biotypes indicated a significant difference in working memory capacity, the gray matter volume (GMV) of five brain regions (lLimbicA_TempPole_2, rLimbicA_TempPole_2 rLimbicB_OFC_1, rContA_IPS_1 and rContB_PFClv_1), structural network and psychopathology. An in-vitro investigation of the biological functions of these core genes indicated their potentially critical role in neuronal growth, especially in dendritic spines. Our current study employed a novel statistical approach to identify the core genes associated with IT and explore the possibility of using the expression knowledge of these core genes to reduce the heterogeneity of schizophrenia. The results pinpointed one biotype that exhibited significant deficits in working memory, GMV in limbic and prefrontal areas, and also showed psychopathology of core negative symptom and worse outcomes.

The last decades of research in schizophrenia witnessed a shift of etiological speculation from neurotransmitters to inflammation. However, identifying definite inflammatory effectors of schizophrenia remains elusive due to confounding factors such as medication and metabolic status. To tackle this issue, we carried out omnigenic-based Mendelian randomization (MR) analysis to explore the inflammatory responses of schizophrenia and the brain morphological consequences caused by these SCZ-triggering inflammation responses. Our results identified seven SCZ-triggering inflammation markers, with P values surviving the Bonferroni multiple comparisons (B_NGF, P = 1.45 × 10−8; GROA (CXCL1) P = 1.15 × 10−4; IL8, P = 3.64 × 10−7; MCSF, P = 9.30 × 10−4; MCP3 (CCL7), P = 1.3 × 10−6; TNF_β, P = 3.63 × 10−4; CRP, P = 1.71 × 10−32). Further, three of them, GROA (CXCL1), IL8 and CRP, could lead to significant linear change rate of brain morphologies, especially white matter in both cerebral and cerebellum. Our study is the first to use an omnigenic conceptual framework to capture the immune pathology of schizophrenia. Although future studies adopting a different methodology are needed to validate our results, our study provides another piece of evidence that extensive and low-grade neuroinflammation exists in schizophrenia and that some of these inflammation markers could be potential targets for the precise diagnosis and treatment of schizophrenia.

Deciphering the relationships between genes and complex traits could help us better understand the biological mechanisms leading to phenotypic variations and disease onset. Univariate gene-based analyses are widely used to characterize gene-phenotype relationships, but are subject to the influence of confounders. Furthermore, while some genes directly contribute to traits variations, others may exert their effects through other genes. How to quantify individual genes’ direct and indirect effects on complex traits remains an important yet challenging question. We presented a novel framework (BN-GWAS) to decipher the total and direct causal effects of individual genes using imputed gene expression data from GWAS and raw gene expression from GTEx. The study was partially motivated by the quest to differentiate “core” genes (genes with direct causal effect on the phenotype) from “peripheral” ones. Our proposed framework is based on a Bayesian network (BN) approach, which produces a directed graph showing the relationship between genes and the phenotype. The approach aims to uncover the overall causal structure, to examine the role of individual genes and quantify the direct and indirect effects by each gene. An important advantage and novelty of the proposed framework is that it allows gene expression and disease trait(s) to be evaluated in different samples, significantly improving the flexibility and applicability of the approach. It uses IDA and jointIDA incorporating a novel p-value-based regularization approach to quantify the causal effects (including total causal effects, direct causal effects, and medication effects) of genes. The proposed approach can be extended to decipher the joint causal network of 2 or more traits, and has high specificity and precision (a.k.a., positive predictive value), making it particularly useful for selecting genes for follow-up studies. We verified the feasibility and validity of the proposed framework by extensive simulations and applications to 52 traits across 14 tissues in the UK Biobank (UKBB). Split-half replication and stability selection analyses were performed to demonstrate the accuracy and efficiency of our proposed method to identify causally relevant genes. The identified (direct) causal genes were found to be significantly enriched for genes highlighted in the OpenTargets database, and the enrichment was stronger than achieved by conventional univariate gene-based tests. Encouragingly, many enriched pathways were supported by the literature, and some of the enriched drugs have been tested or used to treat patients in clinical practice. Our proposed framework provides a powerful way to prioritize genes with large direct or indirect causal effects and to estimate the ‘variable importance’ of such genes.

Studies conducted in psychotic disorders have shown that DNA-methylation (DNAm) is sensitive to the impact of Childhood Adversity (CA). However, whether it mediates the association between CA and psychosis is yet to be explored. Epigenome-wide association studies (EWAS) using the Illumina Infinium-Methylation EPIC array in peripheral blood tissue from 366 First-episode of psychosis and 517 healthy controls was performed. Polyvictimization scores were created for abuse, neglect, and composite adversity with the Childhood Trauma Questionnaire (CTQ). Regressions examining (I) CTQ scores with psychosis; (II) with DNAm EWAS level and (III), then between DNAm and caseness, adjusted for a variety of confounders were conducted. Divide-Aggregate Composite-null Test for the composite null hypothesis of no mediation effect was conducted. Enrichment analyses were conducted with missMethyl package and the KEGG database. Our results show that CA was associated with psychosis (Composite: OR = 3.09; p =

Despite many methodological studies on the global heritability estimation of complex traits, very few methods have been designed to dissect local heritability accurately. A precise local heritability would provide a high-resolution map for precision medicine. We report an effective heritability estimator (EHE) for local heritability estimation using p values from genome-wide association studies (GWAS). With a directly converting marginal heritability to the effective one, EHE shows higher accuracy and is the only method correctly calculating standard errors of local heritability estimation among the four compared methods. Importantly, EHE can be directly used to estimate the conditional heritability of nearby regions or genes in which the redundant heritability can be cleaned. The conditional heritability estimation procedure can be supervised by tissue-specific expression profiles to prioritize and quantify functionally more important genes of complex phenotypes. Applying EHE to 42 complex traits from the UK biobank, we found that heritability density in lncRNA genes tends to be higher than protein-coding genes, and genes pleiotropic to more phenotypes are not enriched for more heritability among candidate susceptibility genes. EHE provides an efficient way to finely and precisely dissect the genetic architecture of complex phenotypes.

Hirschsprung disease (HSCR) is characterized by the absence of enteric neurons caused by the defects of enteric neural crest cells (ENCCs), leading to intestinal obstruction. Here, using iPSC-based models of HSCR and single-cell transcriptomic analysis, we identified a core gene set of 118 genes commonly dysregulated in all HSCR-ENCCs, with HDAC1 found to be a master regulator of these genes. Furthermore, upregulation of RNA splicing mediators and enhanced alternative splicing events were associated with severe form of HSCR. In particular, the higher inclusion rate of exon 9 in PTBP1 and the perturbed expression of a PTBP1-target, PKM, were significantly enriched in these HSCR-ENCCs, and associated with the defective oxidative-phosphorylation (OXPHOS) and impaired neurogenesis. Hedgehog-induced OXPHOS significantly enhanced the survival and differentiation capacity of HSCR-ENCCs. In sum, we have defined the core factors underpinning HSCR disease and demonstrated the implications of OXPHOS in ENCC development and HSCR pathogenesis.

Background Jumping to conclusions (JTC) is a well-established reasoning and data gathering bias found in patients with psychosis even at illness onset (First Episode Psychosis, FEP). Preliminary work in this field focused primarily on the association with delusions, although jumping to conclusions has also been found in non-deluded schizophrenia patients after remission, and in individual with at risk mental state. Moreover, psychotic patients tend to show impairments in social cognition, struggling in identifying, processing and interpreting social clues. Deficits in facial emotion recognition (FER) – a key component of the construct – represent a well-replicated finding in schizophrenia. Furthermore, deficits in global facial affect recognition have been found in FEP with the same severity as at further stages, especially for anger recognition. The present study aims to measure JTC and FER bias in a sample of FEP recruited across 5 European countries, compared with healthy controls. Methods Data on JTC (Beads task 60:40), FER (Degraded Facial Recognition task – DFAR) and socio-demographics have been analysed in a sample of 643 FEP and 1019 population controls recruited as part as the EU-GEI study across UK, Netherlands, France, Spain, and Italy. IQ scores were used to exclude cases and controls with current IQ

Background Current diagnostic models of psychosis have been questioned since Kraepelin’s original dichotomy of dementia praecox and manic depression. Indeed, increasing evidence has suggested that a dimensional approach might be a valid alternative platform for research. However, while an increasing number of studies have investigated how environmental risk factors for affective and non-affective psychosis map onto symptom dimensions, only a few have examined these dimensions in relation to genetic variants as summarised by Polygenic Risk Score (PRS). Furthermore, no studies have examined the putative effect of PRS for Schizophrenia (SZ), Bipolar Disorder (BP), and Major Depressive Disorder (MDD) on previously identified general and specific symptom dimensions. At the same time, only one study has investigated how symptoms vary according to epidemiological factors such as living in urban neighbourhoods. The objectives of this study were to: 1) test whether a bi-factor model statistically fits the conceptualization of psychosis as composed of general and specific dimensions; 2) examine the extent to which SZ, BP, and MDD PRSs explain the phenotypic variance due to general and specific dimensions; 3) test the hypothesis that the general psychosis dimension would be more severe in highly urban environments. Methods We used clinical and epidemiological data from the EUropean network of national schizophrenia networks studying Gene-Environment Interactions (EUGEI) study, including 2322 First Episode Psychosis (FEP) patients recruited in 17 sites across 6 countries. Genetic variants were collectively analyzed for 800 individuals. The following analysis steps were performed: 1) Psychopathology items were analysed using multidimensional item response modelling in MPlus to estimate unidimensional, multidimensional, and bi-factor models of psychosis. Model fit statistics included Log-Likelihood, and Akaike and Bayesian Information Criteria to compare these models. 2) SZ, BP, and MDD PRSs for general and specific dimensions were built using PRSice. Summary statistics from large case-control mega-analyses from the Psychiatric Genomics Consortium were used as base data sets and general and specific dimension scores were used as discovery data sets. Individuals’ number of risk alleles in the discovery sample was weighted by the log odds ratio from the base samples, accounting for population stratification, and summed into the three PRSs. 3) Multilevel regression analysis was used in STATA 14 to examine the variance in general dimension due to the population density levels across the sites. Results A bi-factor solution, composed of one general and five specific symptom dimensions, showed the best model fit statistics. Higher SZ PRS score was associated with higher scores on positive dimensions (β= 0.27, t=2.11, p

Background: Robust evidence has demonstrated that cannabis use increases the risk to develop psychotic disorders. However, a limited number of studies have investigated if and how cannabis use influences psychopathology profiles at first episode psychosis (FEP). Based on the evidence that dopamine dysfunction contributes to explain positive symptoms in psychosis, and that the main cannabis’ psychoactive component, Δ9-Tetrahydrocannabinol (THC), modulates the dopamine system, we hypothesise that: 1) positive symptoms at FEP are more common among psychotic patients who used cannabis compared with never users; 2) this association is a dose-response relationship. Methods: We analyzed a sample of 1130 FEP patients as part of the EUGEI study, recruited across six countries. The MRC Socio-demographic Schedule was used to collect sociodemographic information. Psychopathology was assessed with the OPerational CRITeria (OPCRIT), and symptom items were analyzed using Mplus to estimate a multidimensional model of psychosis. The Cannabis Experience Questionnaire modified version (CEQmv) was administered to collect information on cannabis, and different patterns of use were computed based on frequency of consumption and type of cannabis, as a proxy of exposure to THC. Results: The lifetime rate of cannabis use was 63%. Fifty-five percent of cannabis users consumed mostly high-potency cannabis, and 46% showed a daily frequency. Mixed-effects linear regression revealed that frequency of cannabis use was associated with the positive symptom dimension score. Daily users of high-potency cannabis presented with the strongest association (Β=0.19, 95%CI=0.02–0.38), even after gender, age, ethnicity, other drug use, and study site were controlled for. Discussion: Our results show that patients with a history of daily use of high potency cannabis express more positive symptoms at psychosis onset, even after taking into account other substance use and relevant sociodemographic factors.

Our study aimed to identify possible single nucleotide polymorphisms (SNPs) via a genome-wide association study (GWAS) approach and a candidate gene platform that were associated with lumbar developmental spinal stenosis (DSS). Southern Chinese population-based study volunteers were assessed (age range: 18-55 years). DSS was defined as the anteroposterior bony spinal canal diameter on T1-weighted axial MRI of L1 to S1. Genotyping was performed using the Illumina HumanOmniZhongHua-8 BeadChip. Using the canal diameter as the quantitative trait, genomic statistical analyses was performed. A total of 469 subjects were recruited. The mean axial AP measurements noted were: L1: 21.8 mm, L2: 21.9 mm, L3: 22.4 mm, L4: 20.2 mm, L5: 19.6 mm, and S1: 17.3 mm. Q-Q plots of genome-wide associations found significant differences in L4 and L5 measurements. More significant SNPs were found on chromosomes 8, 11, and 18. Low-density lipoprotein receptor-related protein 5 on chromosome 11 was found to be an important functional gene in canal bony development via candidate gene approach. We found two clusters in the findings with one including the upper levels (L1-L4) and the other the lower levels (L5 and S1). This is the first GWAS addressing DSS. The presence of multiple SNPs suggests a multi-factorial origin of DSS. Further analyses noted region-specific genetic predisposition, delineating distinct upper to lower lumbar regions of DSS. With better understanding of the DSS phenotype and genetic markers, the at-risk population can be identified early, preventative measures can be initiated, lifestyle/activity modification can be implemented, and more novel and precision-based therapeutics can be developed. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:1262-1268, 2018.

Supplemental Figures and Tables. Supplemental Figures S1â S14 and Tables S1â S14. (PDF 3992 kb)

Supplementary information. (DOC 653 kb)

Supplementary Methods and Material. (DOCX 51Â kb)

Background Adolescent idiopathic scoliosis (AIS) is a common rotational deformity of the spine that presents in children worldwide, yet its etiology is poorly understood. Recent genome-wide association studies (GWAS) have identified a few candidate risk loci. One locus near the chromosome 10q24.31 LBX1 gene (OMIM #604255) was originally identified by a GWAS of Japanese subjects and replicated in additional Asian populations. To extend this result, and to create larger AIS cohorts for the purpose of large-scale meta-analyses in multiple ethnicities, we formed a collaborative group called the International Consortium for Scoliosis Genetics (ICSG). Methods Here, we report the first ICSG study, a meta-analysis of the LBX1 locus in six Asian and three non-Asian cohorts. Results We find significant evidence for association of this locus with AIS susceptibility in all nine cohorts. Results for seven cohorts containing both genders yielded P=1.22×10–43 for rs11190870, and P=2.94×10–48 for females in all nine cohorts. Comparing the regional haplotype structures for three populations, we refined the boundaries of association to a ∼25 kb block encompassing the LBX1 gene. The LBX1 protein, a homeobox transcription factor that is orthologous to the Drosophila ladybird late gene, is involved in proper migration of muscle precursor cells, specification of cardiac neural crest cells, and neuronal determination in developing neural tubes. Conclusions Our results firmly establish the LBX1 region as the first major susceptibility locus for AIS in Asian and non-Hispanic white groups, and provide a platform for larger studies in additional ancestral groups.

In response to reported schizophrenia linkage findings on chromosomes 3, 6 and 8, fourteen research groups genotyped 14 microsatellite markers in an unbiased, collaborative (New) sample of 403-567 informative pedigrees per marker, and in the Original sample which produced each finding (the Johns Hopkins University sample of 46-52 informative pedigrees for chromosomes 3 and 8, and the Medical College of Virginia sample of 156-191 informative pedigrees for chromosome 6). Primary planned analyses (New sample) were two-point heterogeneity lod score (lod2) tests (dominant and recessive affected-only models), and multipoint affected sibling pair (ASP) analysis, with a narrow diagnostic model (DSM-IIIR schizophrenia and schizoaffective disorders). Regions with positive results were also analyzed in the Original and Combined samples. There was no evidence for linkage on chromosome 3. For chromosome 6, ASP maximum lod scores (MLS) were 2.19 (New sample, nominal p = 0.001) and 2.68 (Combined sample, p = .0004). For chromosome 8, maximum lod2 scores (tests of linkage with heterogeneity) were 2.22 (New sample, p = .0014) and 3.06 (Combined sample, p = .00018). Results are interpreted as inconclusive but suggestive of linkage in the latter two regions. We discuss possible reasons for failing to achieve a conclusive result in this large sample. Design issues and limitations of this type of collaborative study are discussed, and it is concluded that multicenter follow-up linkage studies of complex disorders can help to direct research efforts toward promising regions.

Several groups have reported weak evidence for linkage between schizophrenia and genetic markers located on chromosome 22q using the lod score method of analysis. However these findings involved different genetic markers and methods of analysis, and so were not directly comparable. To resolve this issue we have performed a combined analysis of genotypic data from the marker D22S278 in multiply affected schizophrenic families derived from 11 independent research groups worldwide. This marker was chosen because it showed maximum evidence for linkage in three independent datasets (Vallada et al., Am J Med Genet 60:139-146, 1995; Polymeropoulos et al., Neuropsychiatr Genet 54:93-99, 1994; Lasseter et al., Am J Med Genet, 60:172-173, 1995. Using the affected sib-pair method as implemented by the program ESPA, the combined dataset showed 252 alleles shared compared with 188 alleles not share (chi-square 9.31, 1df, P = 0.001) where parental genotype data was completely known. When sib-pairs for whom parental data was assigned according to probability were included the number of alleles shared was 514.1 compared with 437.8 not shared (chi-square 6.12, 1df, P = 0.006). Similar results were obtained when a likelihood ratio method for sib-pair analysis was used. These results indicate that may be a susceptibility locus for schizophrenia at 22q12.

Nasopharyngeal carcinoma (NPC) is a malignancy of epithelial origin. The etiology of NPC is complex and includes multiple genetic and environmental factors. We employed case-control analysis to study the association of chromosome 6p regions with NPC. In total, 360 subjects and 360 healthy controls were included, and 233 single nucleotide polymorphisms (SNPs) on 6p were examined. Significant single-marker associations were found for SNPs rs2267633 (p = 4.49610 -5), rs2076483 (most significant, p = 3.36610 -5), and rs29230 (p = 1.43610 -4). The highly associated genes were the gamma-amino butyric acid B receptor 1 (GABBR1), human leukocyte antigen (HLA-A), and HLA complex group 9 (HCG9). Haplotypic associations were found for haplotypes AAA (located within GABBR1, p-value = 6.46610 -5) and TT (located within HLA-A, p = 0.0014). Further investigation of the homozygous genotype frequencies between cases and controls suggested that micro-deletion regions occur in GABBR1 and neural precursor cell expressed developmentally down-regulated 9 (NEDD9). Quantitative real-time polymerase chain reaction (qPCR) using 11 pairs of NPC biopsy samples confirmed the significant decline in GABBR1 and NEDD9 mRNA expression in the cancer tissues compared to the adjacent non-tumor tissue (p, published_or_final_version

Cigarette consumption and smoking cessation are influenced in part by genes. Personality traits have also been implicated in the aetiology of smoking. Neuroticism, a personality trait with a heritable component, correlates well with anxiety and depression, increasing the risk of being a smoker and decreasing the chance of smoking cessation. Several prior studies in non-British populations have given conflicting results as to whether some genetic polymorphisms affect the relationship between smoking and neuroticism. This study investigated the influence of serotonin transporter (5HTTLPR) genotypes on a composite measure of neuroticism and cigarette consumption/smoking cessation in a British population. Although neuroticism was significantly associated with cigarette consumption and smoking cessation, genotype did not affect this relationship. Our results do not support initial interest in utilising 5HTTLPR genotypes in combination with neuroticism ratings for predicting outcome in smoking cessation clinical settings.

A collaboration involving four groups of investigators (Johns Hopkins University/Massachusetts Institute of Technology; Medical College of Virginia/The Health Research Board, Dublin; Institute of Psychiatry, London/University of Wales, Cardiff; Centre National de la Recherche Scientifique, Paris) was organized to confirm results suggestive of a schizophrenia susceptibility locus on chromosome 22 identified by the JHU/MIT group after a random search of the genome. Diagnostic, laboratory, and analytical reliability exercises were conducted among the groups to ensure uniformity of procedures. Data from genotyping of 3 dinucleotide repeat polymorphisms (at the loci D22S268, IL2RB, D22S307) for a combined replication sample of 256 families, each having 2 or more affected individuals with DNA, were analysed using a complex autosomal dominant model. This study provided no evidence for linkage or heterogeneity for the region 22q12-q13 under this model. We conclude that if this region confers susceptibility to schizophrenia, it must be in only a small proportion of families. Collaborative efforts to obtain large samples must continue to play an important role in the genetic search for clues to complex psychiatric disorders such as schizophrenia.

33 Background Twin, population and animal studies suggest that genetic factors are important in stroke. To date all research in humans has used case control (CC) methods to determine association between candidate genes and stroke. Alternative approaches include linkage analysis with the advantage of allowing detection of novel genes and transmission disequilibrium testing, which uses internal family controls e.g.parents(TDT) or unaffected sibs (S-TDT)to reduce the risk of population stratification which is a problem in case control studies. Despite theoretical benefits, the feasiblity of these methods remains unknown. Methods Family history was prospectively determined in 727 consecutive cerebrovascular patients and 623 age matched controls. Patients with suspected Mendelian syndromes were excluded. Parent and sibling status (alive or dead and the presence of stroke)was documented. The data was used to model the number of stroke patients required for the different study designs. Results Family history of young stroke (≤65)was an independent risk factor for ischaemic stroke OR 1.45 (95% CI 1.01–2.09) p=0.05, early onset proband stroke (≤65) OR 2.22(1.42–3.50)p=0.0005 and stroke due to large vessel disease OR 1.75 (1.09–2.83) p=0.02. In the age group Conclusion This study supports the role of independent genetic risk factors in stroke which have greater influence in young individuals. Novel approaches are potentially feasible, although linkage studies and TDT would require large scale multicentre collaborations.