A systems biology approach uncovers cell-specific gene regulatory effects of genetic associations in multiple sclerosis

Genome-wide association studies (GWAS) have identified more than 50,000 unique associations with common human traits. While this represents a substantial step forward, establishing the biology underlying these associations has proven extremely difficult. Even determining which cell types and which particular gene(s) are relevant continues to be a challenge. Here, we conduct a cell-specific pathway analysis of the latest GWAS in multiple sclerosis (MS), which had analyzed a total of 47,351 cases and 68,284 healthy controls and found more than 200 non-MHC genome-wide associations. Our analysis identifies pan immune cell as well as cell-specific susceptibility genes in T cells, B cells and monocytes. Finally, genotype-level data from 2,370 patients and 412 controls is used to compute intraindividual and cell-specific susceptibility pathways that offer a biological interpretation of the individual genetic risk to MS. This approach could be adopted in any other complex trait for which genome-wide data is available.Peer reviewe

Investigation of common, low-frequency and rare genome-wide variation in anorexia nervosa

Correction: Volume: 23 Issue: 9 DOI: 10.1038/mp.2017.202 Published: SEP 2018Anorexia nervosa (AN) is a complex neuropsychiatric disorder presenting with dangerously low body weight, and a deep and persistent fear of gaining weight. To date, only one genome-wide significant locus associated with AN has been identified. We performed an exome-chip based genome-wide association studies (GWAS) in 2158 cases from nine populations of European origin and 15 485 ancestrally matched controls. Unlike previous studies, this GWAS also probed association in low-frequency and rare variants. Sixteen independent variants were taken forward for in silico and de novo replication (11 common and 5 rare). No findings reached genome-wide significance. Two notable common variants were identified: rs10791286, an intronic variant in OPCML (P = 9.89 x 10(-6)), and rs7700147, an intergenic variant (P = 2.93 x 10(-5)). No low-frequency variant associations were identified at genome-wide significance, although the study was well-powered to detect low-frequency variants with large effect sizes, suggesting that there may be no AN loci in this genomic search space with large effect sizes.Peer reviewe

Genome-wide association study meta-analysis of suicide death and suicidal behavior

Suicide is a worldwide health crisis. We aimed to identify genetic risk variants associated with suicide death and suicidal behavior. Meta-analysis for suicide death was performed using 3765 cases from Utah and matching 6572 controls of European ancestry. Meta-analysis for suicidal behavior using data across five cohorts (n = 8315 cases and 256,478 psychiatric or populational controls of European ancestry) was also performed. One locus in neuroligin 1 (NLGN1) passing the genome-wide significance threshold for suicide death was identified (top SNP rs73182688, with p = 5.48 x 10(-8) before and p = 4.55 x 10(-8) after mtCOJO analysis conditioning on MDD to remove genetic effects on suicide mediated by MDD). Conditioning on suicidal attempts did not significantly change the association strength (p = 6.02 x 10(-8)), suggesting suicide death specificity. NLGN1 encodes a member of a family of neuronal cell surface proteins. Members of this family act as splice site-specific ligands for beta-neurexins and may be involved in synaptogenesis. The NRXN-NLGN pathway was previously implicated in suicide, autism, and schizophrenia. We additionally identified ROBO2 and ZNF28 associations with suicidal behavior in the meta-analysis across five cohorts in gene-based association analysis using MAGMA. Lastly, we replicated two loci including variants near SOX5 and LOC101928519 associated with suicidal attempts identified in the ISGC and MVP meta-analysis using the independent FinnGen samples. Suicide death and suicidal behavior showed positive genetic correlations with depression, schizophrenia, pain, and suicidal attempt, and negative genetic correlation with educational attainment. These correlations remained significant after conditioning on depression, suggesting pleiotropic effects among these traits. Bidirectional generalized summary-data-based Mendelian randomization analysis suggests that genetic risk for the suicidal attempt and suicide death are both bi-directionally causal for MDD.Peer reviewe

THE EFFECTIVENESS OF FISHBOWL METHOD ON STUDENTS’ SPEAKING SKILL AT THE SECOND GRADE STUDENTS OF SMA N 8 CIREBON

AYU WULANDARI. THE EFFECTIVENESS OF FISHBOWL METHOD ON STUDENTS’ SPEAKING SKILL AT THE SECOND GRADE STUDENTS OF SMA N 8 CIREBON In Indonesia English has drawn up by government as foreign language that the students should master English language. In fact, the students still have weakness in skill of English, especially in speaking skill. In this thesis, the writer focuses on the students’ speaking skill as Y variable that they have any weakness to master speaking skill. And the writer focuses on the fishbowl method as the X variable that will help student to practice speaking English. The aims of this research are to find out the students’ responses towards the application of fishbowl method, to find out the students’ achievement of speaking skill before and after using the application of fishbowl method and to find out the effectiveness of fishbowl method to improve the students’ speaking skill Looking forward the problem in speaking skill that students have the weakness in this skill thus the writer offered fishbowl method which can be effective teaching tools for modeling group processes that can improve the students’ speaking skill and more active in classroom to practice speaking English. The research design is quantitative research and experiment research. To know the response the application of fishbowl method, the writer uses questionnaire. To know the students’ achievement speaking skill, the writer uses two tests, pretest and posttest. The data was analyzed statistically by using Microsoft Excel, ANA test4 and SPSS program V 2.2.0. The result of the students’ response towards the application of fishbowl method is 1237 with the percentage 82,5 %, it can be categorized strong response. And the result of the students’ achievement in speaking skill between experimental class and control class where Gain of experiment class get the mean score 0.26, but the N-Gain of control class get the mean score 0.12 so that the deviation is 0.14. It means that the experiment class is better than control class in improving the students’ speaking skill. Then conclusion of this thesis is that the alternative hypothesis (Ha) is received and the Null Hypothesis (Ho) is refused where t-test < t-table or <0.05. It means that there is any significant effectiveness of using fishbowl method to improve students’ speaking skill the second grade students of SMA N 8 Cirebon

Apolipoprotein E4 Polymorphism and Outcomes from Traumatic Brain Injury : A Living Systematic Review and Meta-Analysis

The mortality of traumatic brain injury (TBI) has been largely static despite advances in monitoring and imaging techniques. Substantial variance exists in outcome, not fully accounted for by baseline characteristics or injury severity, and genetic factors likely play a role in this variance. The aims of this systematic review were to examine the evidence for a link between the apolipoprotein E4 (APOE4) polymorphism and TBI outcomes and where possible, to quantify the effect size via meta-analysis. We searched EMBASE, MEDLINE, CINAHL, and gray literature in December 2017. We included studies of APOE genotype in relation to functional adult TBI outcomes. Methodological quality was assessed using the Quality in Prognostic Studies Risk of Bias Assessment Instrument and the prognostic studies adaptation of the Grading of Recommendations Assessment, Development and Evaluation tool. In addition, we contacted investigators and included an additional 160 patients whose data had not been made available for previous analyses, giving a total sample size of 2593 patients. Meta-analysis demonstrated higher odds of a favorable outcome following TBI in those not possessing an ApoE e4 allele compared with e4 carriers and homozygotes (odds ratio 1.39, 95% confidence interval 1.05 to 1.84; p = 0.02). The influence of APOE4 on neuropsychological functioning following TBI remained uncertain, with multiple conflicting studies. We conclude that the ApoE e4 allele confers a small risk of poor outcome following TBI, with analysis by TBI severity not possible based on the currently available published data. Further research into the long-term neuropsychological impact and risk of dementia is warranted.Peer reviewe

Complement genes contribute sex-biased vulnerability in diverse disorders

Many common illnesses, for reasons that have not been identified, differentially affect men and women. For instance, the autoimmune diseases systemic lupus erythematosus (SLE) and Sjogren's syndrome affect nine times more women than men1, whereas schizophrenia affects men with greater frequency and severity relative to women(2). All three illnesses have their strongest common genetic associations in the major histocompatibility complex (MHC) locus, an association that in SLE and Sjogren's syndrome has long been thought to arise from alleles of the human leukocyte antigen (HLA) genes at that locus(3-6). Here we show that variation of the complement component 4 (C4) genes C4A and C4B, which are also at the MHC locus and have been linked to increased risk for schizophrenia(7), generates 7-fold variation in risk for SLE and 16-fold variation in risk for Sjogren's syndrome among individuals with common C4 genotypes, with C4A protecting more strongly than C4B in both illnesses. The same alleles that increase risk for schizophrenia greatly reduce risk for SLE and Sjogren's syndrome. In all three illnesses, C4 alleles act more strongly in men than in women: common combinations of C4A and C4B generated 14-fold variation in risk for SLE, 31-fold variation in risk for Sjogren's syndrome, and 1.7-fold variation in schizophrenia risk among men (versus 6-fold, 15-fold and 1.26-fold variation in risk among women, respectively). At a protein level, both C4 and its effector C3 were present at higher levels in cerebrospinal fluid and plasma(8,9) in men than in women among adults aged between 20 and 50 years, corresponding to the ages of differential disease vulnerability. Sex differences in complement protein levels may help to explain the more potent effects of C4 alleles in men, women's greater risk of SLE and Sjogren's syndrome and men's greater vulnerability to schizophrenia. These results implicate the complement system as a source of sexual dimorphism in vulnerability to diverse illnesses.Peer reviewe

Association of the MYOC p.(Gln368Ter) Variant With Glaucoma in a Finnish Population

IMPORTANCE The c.1102C>T, p.(Gln368Ter) variant in themyocilin (MYOC) gene is a known risk allele for glaucoma. It is the most common MYOC risk variant for glaucoma among individuals of European ancestry, and its prevalence is highest in Finland. Furthermore, exfoliation syndrome has high prevalence in Scandinavia, making the Finnish population ideal to study the association of the variant with different types of glaucoma. OBJECTIVES To examine the association and penetrance of MYOC p.(Gln368Ter) (rs74315329) variant with different types of glaucoma in a Finnish population. DESIGN, SETTING, AND PARTICIPANTS This genetic association study included individuals of Finnish ancestry in the FinnGen project. The participants were collected from Finnish biobanks, and the disease end points were defined using nationwide registries. The MYOC c.1102C>T variant was either directly genotyped or imputed with microarrays. Recruitment of samples to FinnGen was initiated in 2017, and data analysis was performed between December 2019 and May 2020. MAIN OUTCOMES AND MEASURES The main outcomes were odds ratios (ORs) and penetrance with different types of glaucoma and in different age groups. RESULTS A total of 218 792 individuals were included in this study (mean [SD] age 52.4 [17.5] years; 123 579 women [56.5%]), including 8591 (3.9%) with glaucoma, 3412 (1.6%) with primary open-angle glaucoma, 1515 (0.7%) with exfoliation glaucoma, 892 (0.4%) with normal-tension glaucoma, and 4766 (2.2%) with suspected glaucoma. The minor allele frequency of MYOC p.(Gln368Ter) was 0.28%. Individuals with the heterozygous variant had higher odds of primary open-angle glaucoma (OR, 3.36; 95% CI, 2.55-4.37), overall glaucoma (OR, 2.58; 95% CI, 2.12-3.13), suspected glaucoma (OR, 2.53; 95% CI, 1.93-3.26), exfoliation glaucoma (OR, 2.61; 95% CI, 1.60-4.02), and undergoing glaucoma-related operations (OR, 5.45; 95% CI, 2.95-9.28). The penetrance of heterozygous MYOC p.(Gln368Ter) was 5.2% in individuals with primary open-angle glaucoma, 9.6% in individuals with glaucoma, 5.4% in individuals with suspected glaucoma, and 1.9% in individuals with exfoliation glaucoma. There was no significant association with normal-tension glaucoma (OR, 1.69; 95% CI, 0.72-3.35). CONCLUSIONS AND RELEVANCE This genetic association study found that the MYOC p.(Gln368Ter) variant was associated with exfoliation glaucoma. The association with normal-tension glaucoma could not be replicated. These findings suggest that MYOC p.(Gln368Ter) was associated with open-angle glaucoma and exfoliation glaucoma in a Finnish population.Peer reviewe

Mapping and characterization of structural variation in 17,795 human genomes

Structural variants in more than 17,000 human genomes are mapped and characterized using whole-genome sequencing, showing how this type of variation contributes to rare deleterious coding and noncoding alleles. A key goal of whole-genome sequencing for studies of human genetics is to interrogate all forms of variation, including single-nucleotide variants, small insertion or deletion (indel) variants and structural variants. However, tools and resources for the study of structural variants have lagged behind those for smaller variants. Here we used a scalable pipeline(1)to map and characterize structural variants in 17,795 deeply sequenced human genomes. We publicly release site-frequency data to create the largest, to our knowledge, whole-genome-sequencing-based structural variant resource so far. On average, individuals carry 2.9 rare structural variants that alter coding regions; these variants affect the dosage or structure of 4.2 genes and account for 4.0-11.2% of rare high-impact coding alleles. Using a computational model, we estimate that structural variants account for 17.2% of rare alleles genome-wide, with predicted deleterious effects that are equivalent to loss-of-function coding alleles; approximately 90% of such structural variants are noncoding deletions (mean 19.1 per genome). We report 158,991 ultra-rare structural variants and show that 2% of individuals carry ultra-rare megabase-scale structural variants, nearly half of which are balanced or complex rearrangements. Finally, we infer the dosage sensitivity of genes and noncoding elements, and reveal trends that relate to element class and conservation. This work will help to guide the analysis and interpretation of structural variants in the era of whole-genome sequencing.Peer reviewe

Dissecting the contribution of single nucleotide polymorphisms in CCR9 and CCL25 genomic regions to the celiac disease phenotype

Purpose and objectives: Given their role in homing immune cells to the intestine, CC motif chemokine receptor 9 (CCR9) and its specific ligand CC motif chemokine ligand 25 (CCL25) are interesting candidate genes for celiac disease. These genes are located in regions previously shown to be associated with or linked to celiac disease, but no investigations on their association with various celiac disease phenotypes have so far been conducted. Here we studied such associations of both genotyped and imputed single nucleotide polymorphisms (SNPs) with either regulatory function or exonic location of the CCR9 and CCL25 loci. Results: Exploiting a carefully phenotyped cohort of 625 celiac disease patients and 1817 non-celiac controls, we identified that multiple SNPs with predicted regulatory function (RegulomeDB score 0.05). Conclusions: We conclude that SNPs in the region of CCR9 and CCL25 with predicted functional effect or exonic localization likely contribute only modestly to various celiac disease phenotypes.Peer reviewe