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206 results on '"RISK LOCI"'

1. The construction of a novel prognostic prediction model for glioma based on GWAS-identified prognostic-related risk loci

Author: Wei Jie, Li Yujie, Zhou Wenqian, Ma Xiaoya, Hao Jie, Wen Ting, Li Bin, Jin Tianbo, and Hu Mingjun
Subjects: glioma prognosis, gwas, risk loci, prognostic prediction model, lasso cox regression, nomogram, Medicine
Abstract: Glioma is a highly malignant brain tumor with a grim prognosis. Genetic factors play a role in glioma development. While some susceptibility loci associated with glioma have been identified, the risk loci associated with prognosis have received less attention. This study aims to identify risk loci associated with glioma prognosis and establish a prognostic prediction model for glioma patients in the Chinese Han population.
Published: 2024
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2. Integrative splicing-quantitative-trait-locus analysis reveals risk loci for non-small-cell lung cancer.

Author: Wang, Yuzhuo, Ding, Yue, Liu, Su, Wang, Cheng, Zhang, Erbao, Chen, Congcong, Zhu, Meng, Zhang, Jing, Zhu, Chen, Ji, Mengmeng, Dai, Juncheng, Jin, Guangfu, Hu, Zhibin, Shen, Hongbing, and Ma, Hongxia
Subjects: *NON-small-cell lung carcinoma, *LUNGS, *LOCUS (Genetics), *ALTERNATIVE RNA splicing, *RISK assessment, *GENETIC variation
Abstract: Splicing quantitative trait loci (sQTLs) have been demonstrated to contribute to disease etiology by affecting alternative splicing. However, the role of sQTLs in the development of non-small-cell lung cancer (NSCLC) remains unknown. Thus, we performed a genome-wide sQTL study to identify genetic variants that affect alternative splicing in lung tissues from 116 individuals of Chinese ancestry, which resulted in the identification of 1,385 sQTL-harboring genes (sGenes) containing 378,210 significant variant-intron pairs. A comprehensive characterization of these sQTLs showed that they were enriched in actively transcribed regions, genetic regulatory elements, and splicing-factor-binding sites. Moreover, sQTLs were largely distinct from expression quantitative trait loci (eQTLs) and showed significant enrichment in potential risk loci of NSCLC. We also integrated sQTLs into NSCLC GWAS datasets (13,327 affected individuals and 13,328 control individuals) by using splice-transcriptome-wide association study (spTWAS) and identified alternative splicing events in 19 genes that were significantly associated with NSCLC risk. By using functional annotation and experiments, we confirmed an sQTL variant, rs35861926, that reduced the risk of lung adenocarcinoma (rs35861926-T, OR = 0.88, 95% confidence interval [CI]: 0.82–0.93, p = 1.87 × 10−5) by promoting FARP1 exon 20 skipping to downregulate the expression level of the long transcript FARP1 -011. Transcript FARP1 -011 promoted the migration and proliferation of lung adenocarcinoma cells. Overall, our study provided informative lung sQTL resources and insights into the molecular mechanisms linking sQTL variants to NSCLC risk. [Display omitted] This study provided a comprehensive catalog of splicing quantitative trait loci (sQTLs) in lung tissues. Integrative sQTL analysis revealed risk loci for non-small-cell lung cancer. Further experiments confirmed that rs35861926 could reduce lung adenocarcinoma risk by promoting FARP1 exon 20 skipping to downregulate the expression level of transcript FARP1 -011. [ABSTRACT FROM AUTHOR]
Published: 2023
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3. A Swedish Familial Genome-Wide Haplotype Analysis Identified Five Novel Breast Cancer Susceptibility Loci on 9p24.3, 11q22.3, 15q11.2, 16q24.1 and Xq21.31.

Author: Barnekow, Elin, Hasslow, Johan, Liu, Wen, Bryant, Patrick, Thutkawkorapin, Jessada, Wendt, Camilla, Czene, Kamila, Hall, Per, Margolin, Sara, and Lindblom, Annika
Subjects: *LOCUS (Genetics), *BREAST cancer, *BRCA genes, *GENOME-wide association studies, *HAPLOTYPES, *DISEASE risk factors, CANCER susceptibility
Abstract: Most breast cancer heritability is unexplained. We hypothesized that analysis of unrelated familial cases in a GWAS context could enable the identification of novel susceptibility loci. In order to examine the association of a haplotype with breast cancer risk, we performed a genome-wide haplotype association study using a sliding window analysis of window sizes 1–25 SNPs in 650 familial invasive breast cancer cases and 5021 controls. We identified five novel risk loci on 9p24.3 (OR 3.4; p 4.9 × 10−11), 11q22.3 (OR 2.4; p 5.2 × 10−9), 15q11.2 (OR 3.6; p 2.3 × 10−8), 16q24.1 (OR 3; p 3 × 10−8) and Xq21.31 (OR 3.3; p 1.7 × 10−8) and confirmed three well-known loci on 10q25.13, 11q13.3, and 16q12.1. In total, 1593 significant risk haplotypes and 39 risk SNPs were distributed on the eight loci. In comparison with unselected breast cancer cases from a previous study, the OR was increased in the familial analysis in all eight loci. Analyzing familial cancer cases and controls enabled the identification of novel breast cancer susceptibility loci. [ABSTRACT FROM AUTHOR]
Published: 2023
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4. NEK1 and STMN2 short tandem repeat lengths are not associated with Australian amyotrophic lateral sclerosis risk.

Author: Grima, Natalie, Henden, Lyndal, Fearnley, Liam G., Rowe, Dominic B., D'Silva, Susan, Pamphlett, Roger, Adams, Lorel, Kiernan, Matthew C., Mazumder, Srestha, Timmins, Hannah C., Zoing, Margaret, Bahlo, Melanie, Blair, Ian P., and Williams, Kelly L.
Abstract: Sporadic amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with a complex genetic architecture. The lengths of two short tandem repeats (STRs), at the NEK1 and STMN2 loci, were recently associated with ALS risk in cohorts of European descent. The STMN2 STR was proposed to be predictive of clinical features including the age of onset and disease duration in bulbar onset cases. We sought to investigate NEK1 and STMN2 STR lengths in a cohort of Australian sporadic ALS cases (n = 608) and neurologically healthy controls (n = 4689) of European ancestry. ExpansionHunter was used to determine NEK1 and STMN2 STR length genotypes from whole-genome sequencing data followed by PCR validation of predicted lengths. No significant association was identified between sporadic ALS risk and the length of either STR. Further, neither NEK1 nor STMN2 STR lengths were indicative of the age of onset or disease duration. We report that the NEK1 and STMN2 STRs were not associated with ALS risk or clinical features in this Australian sporadic ALS cohort. [ABSTRACT FROM AUTHOR]
Published: 2022
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5. Post-GWAS functional characterisation of colorectal cancer risk loci

Author: Ooi, Li Yin, Dunlop, Malcolm, Weller, Richard, and Farrington, Susan
Subjects: 616.99, colorectal cancer, risk loci, functional studies
Abstract: Large bowel cancer, or colorectal cancer (CRC) is the third most common cause of cancer worldwide and the fourth biggest cause of cancer mortality. Twin studies have shown that the heritable contribution is ~35%, with ~5% of cases due to rare, high-penetrance mutations. In the last decade, the use of genome-wide association studies on large, well-characterised case-control cohorts of CRC has facilitated the identification of over 25 common genetic variants that carry with them an increased predisposition to colorectal cancer, invoking the common-disease common variant paradigm. As almost all of these variants lie within non-coding regions, the underlying causal mechanism is to-date poorly understood for the majority of these loci, and it is thought that they mediate risk by influencing gene expression levels. To test this hypothesis, an agnostic approach that utilises expression quantitative trait loci (eQTL) analysis was first carried on 115 normal colorectal mucosa samples and 59 peripheral blood mononuclear cells (PBMC). As these heritable variation on gene expression are likely to be subtle, there is a strong emphasis on the technical methodology to minimise experimentally-induced non-biological variations, including the extraction of high-quality RNA from primary tissue, the selection and validation of reference genes for normalisation of gene expression quantification, as well as internal validation of the samples and data processing. Thereafter, the association between the 25 CRC risk variants and the expression of their cis-genes were examined systematically, demonstrating that ten of these variants are also tissue-specific eQTLs. This intermediate phenotype strongly suggests that they confer risk, at least in part, by modifying regulatory mechanisms. One of the best eQTL associations (Xp22.2) is investigated in further detail to reveal a novel indel polymorphism (Indel24) at the distal promoter region of target gene SHROOM2 that influenced both transcript abundance and CRC risk more than the original tagging SNP. Functional verification with gene reporter assays indicated that Indel24 displays differential allelic control over transcriptional activity. Further in silico analysis and mutations to the reporter gene constructs provided evidence that Indel24 modulates transcription by modifying the spacing between CCAAT motifs and the consequent binding affinity of NF-Y transcription factor. siRNA depletion of NF-Y was associated with a reduction in transcriptional activity of the Indel24 gene construct as well as endogenous SHROOM2, which is strongly supportive of the interaction between Indel24 and NF-Y in the transcriptional activation of SHROOM2. Preliminary evidence is suggestive of SHROOM2 being expressed at the top of the intestinal epithelial crypt and playing a role in cell cycle regulation. Hypothesis-driven approaches can also be of utility in demonstrating functionality of CRC risk variants, complementing the hypothesis-free approach of eQTL analysis. Guided by a recently discovered gene-environment interaction between the 16q22.1 risk variant and circulating vitamin D levels, the influence of the rs9929218 SNP on CDH1 gene expression was examined, in relation to the expression of putative regulatory genes derived from in silico analysis and studies of other target genes. Although there was no direct association between rs9929218 and CDH1 expression, there were multiple two-way interactions that were together suggestive of rs9929218 influencing the VDR/FOXO4 regulation of CDH1. This provides functional support for the mechanism underlying the epidemiological observation of the gene-environment interaction between 16q22.1 and vitamin D, and demonstrates a candidate-based approach in deciphering the link between genetic locus and CRC susceptibility. In summary, the research presented in this thesis has validated the experimental rationale of utilising expression studies of normal colorectal mucosa to hone in on the molecular mechanisms and susceptibility genes underlying the association between common genetic variation and CRC risk.
Published: 2016

6. Discovery of Novel Genetic Risk Loci for Acute Central Serous Chorioretinopathy and Genetic Pleiotropic Effect With Age-Related Macular Degeneration

Author: Lei Feng, Si Chen, Huatuo Dai, Rajkumar Dorajoo, Jianjun Liu, Jinfeng Kong, Xianyong Yin, and Yunqing Ren
Subjects: central serous chorioretinopathy, gene, association, pleiotropic effect, risk loci, age-related macular degeneration, Biology (General), QH301-705.5
Abstract: BackgroundCentral serous chorioretinopathy (CSC) is a severe and heterogeneous chorioretinal disorder. Shared clinical manifestations between CSC and age-related macular degeneration (AMD) and the confirmation of CFH as genetic risk locus for both CSC and AMD suggest possible common pathophysiologic mechanisms between two diseases.MethodsTo advance the understanding of genetic susceptibility of CSC and further investigate genetic pleiotropy between CSC and AMD, we performed genetic association analysis of 38 AMD-associated single nucleotide polymorphisms (SNPs) in a Chinese CSC cohort, consisting of 464 patients and 548 matched healthy controls.ResultsTwelve SNPs were found to be associated with CSC at nominal significance (p < 0.05), and four SNPs on chromosomes 1, 4, and 15 showed strong associations whose evidences surpassed Bonferroni (BF)-corrected significance [rs1410996, odds ratios (OR) = 1.47, p = 2.37 × 10–5; rs1329428, OR = 1.40, p = 3.32 × 10–4; rs4698775, OR = 1.45, p = 2.20 × 10–4; and rs2043085, OR = 1.44, p = 1.91 × 10–4]. While the genetic risk effects of rs1410996 and rs1329428 (within the well-established locus CFH) are correlated (due to high LD), rs4698775 on chromosome 4 and rs2043085 on chromosome 15 are novel risk loci for CSC. Polygenetic risk score (PRS) constructed by using three independent SNPs (rs1410996, rs4698775, and rs2043085) showed highly significant association with CSC (p = 2.10 × 10–7), with the top 10% of subjects with high PRS showing 6.39 times higher risk than the bottom 10% of subjects with lowest PRS. Three SNPs were also found to be associated with clinic manifestations of CSC patients. In addition, by comparing the genetic effects (ORs) of these 38 SNPs between CSC and AMD, our study revealed significant, but complex genetic pleiotropic effect between the two diseases.ConclusionBy discovering two novel genetic risk loci and revealing significant genetic pleiotropic effect between CSC and AMD, the current study has provided novel insights into the role of genetic composition in the pathogenesis of CSC.
Published: 2021
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7. Targeted sequencing of Parkinson's disease loci genes highlights SYT11, FGF20 and other associations.

Author: Rudakou, Uladzislau, Yu, Eric, Krohn, Lynne, Ruskey, Jennifer A, Asayesh, Farnaz, Dauvilliers, Yves, Spiegelman, Dan, Greenbaum, Lior, Fahn, Stanley, Waters, Cheryl H, Dupré, Nicolas, Rouleau, Guy A, Hassin-Baer, Sharon, Fon, Edward A, Alcalay, Roy N, and Gan-Or, Ziv
Subjects: *PARKINSON'S disease, *GENES, *MOLECULAR probes, *LINKAGE disequilibrium, *PROMOTERS (Genetics), *GENE targeting, *RESEARCH, *GENETIC mutation, *GROWTH factors, *RESEARCH methodology, *GENETIC polymorphisms, *MEDICAL cooperation, *EVALUATION research, *COMPARATIVE studies, *DISEASE susceptibility, *RESEARCH funding, *CALCIUM-binding proteins
Abstract: Genome-wide association studies (GWAS) have identified numerous loci associated with Parkinson's disease. The specific genes and variants that drive the associations within the vast majority of these loci are unknown. We aimed to perform a comprehensive analysis of selected genes to determine the potential role of rare and common genetic variants within these loci. We fully sequenced 32 genes from 25 loci previously associated with Parkinson's disease in 2657 patients and 3647 controls from three cohorts. Capture was done using molecular inversion probes targeting the exons, exon-intron boundaries and untranslated regions (UTRs) of the genes of interest, followed by sequencing. Quality control was performed to include only high-quality variants. We examined the role of rare variants (minor allele frequency < 0.01) using optimized sequence Kernel association tests. The association of common variants was estimated using regression models adjusted for age, sex and ethnicity as required in each cohort, followed by a meta-analysis. After Bonferroni correction, we identified a burden of rare variants in SYT11, FGF20 and GCH1 associated with Parkinson's disease. Nominal associations were identified in 21 additional genes. Previous reports suggested that the SYT11 GWAS association is driven by variants in the nearby GBA gene. However, the association of SYT11 was mainly driven by a rare 3' UTR variant (rs945006601) and was independent of GBA variants (P = 5.23 × 10-5 after exclusion of all GBA variant carriers). The association of FGF20 was driven by a rare 5' UTR variant (rs1034608171) located in the promoter region. The previously reported association of GCH1 with Parkinson's disease is driven by rare non-synonymous variants, some of which are known to cause dopamine-responsive dystonia. We also identified two LRRK2 variants, p.Arg793Met and p.Gln1353Lys, in 10 and eight controls, respectively, but not in patients. We identified common variants associated with Parkinson's disease in MAPT, TMEM175, BST1, SNCA and GPNMB, which are all in strong linkage disequilibrium with known GWAS hits in their respective loci. A common coding PM20D1 variant, p.Ile149Val, was nominally associated with reduced risk of Parkinson's disease (odds ratio 0.73, 95% confidence interval 0.60-0.89, P = 1.161 × 10-3). This variant is not in linkage disequilibrium with the top GWAS hits within this locus and may represent a novel association. These results further demonstrate the importance of fine mapping of GWAS loci, and suggest that SYT11, FGF20, and potentially PM20D1, BST1 and GPNMB should be considered for future studies as possible Parkinson's disease-related genes. [ABSTRACT FROM AUTHOR]
Published: 2021
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8. SNP-based pathway enrichment analysis for genome-wide association studies

Author: Weng, Lingjie, Macciardi, Fabio, Subramanian, Aravind, Guffanti, Guia, Potkin, Steven G, Yu, Zhaoxia, and Xie, Xiaohui
Subjects: false discovery rate, 7 common diseases, risk loci, schizophrenia, genes, population, variants, set, replication, network
Abstract: BackgroundRecently we have witnessed a surge of interest in using genome-wide association studies (GWAS) to discover the genetic basis of complex diseases. Many genetic variations, mostly in the form of single nucleotide polymorphisms (SNPs), have been identified in a wide spectrum of diseases, including diabetes, cancer, and psychiatric diseases. A common theme arising from these studies is that the genetic variations discovered by GWAS can only explain a small fraction of the genetic risks associated with the complex diseases. New strategies and statistical approaches are needed to address this lack of explanation. One such approach is the pathway analysis, which considers the genetic variations underlying a biological pathway, rather than separately as in the traditional GWAS studies. A critical challenge in the pathway analysis is how to combine evidences of association over multiple SNPs within a gene and multiple genes within a pathway. Most current methods choose the most significant SNP from each gene as a representative, ignoring the joint action of multiple SNPs within a gene. This approach leads to preferential identification of genes with a greater number of SNPs.ResultsWe describe a SNP-based pathway enrichment method for GWAS studies. The method consists of the following two main steps: 1) for a given pathway, using an adaptive truncated product statistic to identify all representative (potentially more than one) SNPs of each gene, calculating the average number of representative SNPs for the genes, then re-selecting the representative SNPs of genes in the pathway based on this number; and 2) ranking all selected SNPs by the significance of their statistical association with a trait of interest, and testing if the set of SNPs from a particular pathway is significantly enriched with high ranks using a weighted Kolmogorov-Smirnov test. We applied our method to two large genetically distinct GWAS data sets of schizophrenia, one from European-American (EA) and the other from African-American (AA). In the EA data set, we found 22 pathways with nominal P-value less than or equal to 0.001 and corresponding false discovery rate (FDR) less than 5%. In the AA data set, we found 11 pathways by controlling the same nominal P-value and FDR threshold. Interestingly, 8 of these pathways overlap with those found in the EA sample. We have implemented our method in a JAVA software package, called SNP Set Enrichment Analysis (SSEA), which contains a user-friendly interface and is freely available at http://cbcl.ics.uci.edu/SSEA.ConclusionsThe SNP-based pathway enrichment method described here offers a new alternative approach for analysing GWAS data. By applying it to schizophrenia GWAS studies, we show that our method is able to identify statistically significant pathways, and importantly, pathways that can be replicated in large genetically distinct samples.
Published: 2011

9. A variant in FTO gene shows association with histological ulceration in cutaneous melanoma.

Author: Kalo, Eric, Güvenç, Canan, Marasigan, Vivien, Lambrechts, Diether, Oord, Joost, and Garmyn, Marjan
Subjects: *MELANOMA, *CYCLIN-dependent kinase inhibitor-2A, *BONFERRONI correction, *ONE-way analysis of variance, *SINGLE nucleotide polymorphisms, *PROGRESSION-free survival
Abstract: The association between the nine selected SNPs and ulceration status by genotype in melanoma are summarized in Table. Relationship between the nine selected SNPs and ulceration status by genotype in malignant melanoma after adjustment for host factors - age and gender The role of germline SNPs in predicting melanoma ulceration risk has remained generally unexplored. [Extracted from the article]
Published: 2020
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10. Comprehensive analysis of colorectal cancer-risk loci and survival outcome: A prognostic role for CDH1 variants.

Author: Summers, Matthew G., Maughan, Timothy S., Kaplan, Richard, Law, Philip J., Houlston, Richard S., Escott-Price, Valentina, and Cheadle, Jeremy P.
Subjects: *COLON tumors, *CONFIDENCE intervals, *GENES, *GENETIC polymorphisms, *RISK assessment, *STATISTICS, *SURVIVAL, *TUMOR markers, *PROPORTIONAL hazards models, *ODDS ratio, *GENOTYPES, *DISEASE risk factors, RECTUM tumors
Abstract: Genome-wide association studies have identified common single nucleotide polymorphisms (SNPs) at 83 loci associated with colorectal cancer (CRC) risk in European populations. Because germline variation can also influence patient outcome, we studied the relationship between these SNPs and CRC survivorship. For the 83 risk loci, 10 lead SNPs were directly genotyped, 72 were imputed and 1 was not genotyped nor imputed, in 1948 unrelated patients with advanced CRC from the clinical trials COIN and COIN–B (oxaliplatin and fluoropyrimidine chemotherapy ± cetuximab). A Cox survival model was used for each variant, and variants classified by pathway, adjusting for known prognostic factors. We imposed a Bonferroni threshold of P = 6.6 × 10−4 for multiple testing. We carried out meta-analyses of published risk SNPs associated with survival. Univariate analysis identified six SNPs associated with overall survival (OS) (P < 0.05); however, only rs9939049 in CDH1 remained significant beyond the Bonferroni threshold (Hazard Ratio [HR] 1.44, 95% Confidence Intervals [CI]: 1.21–1.71, P = 5.0 × 10−5). Fine mapping showed that rs12597188 was the most significant SNP at this locus and remained significant after adjustment for known prognostic factors beyond multiple testing thresholds (HR 1.23, 95% CI: 1.13–1.34, P = 1.9 × 10−6). rs12597188 was also associated with poor response to therapy (OR 0.61, 95% CI: 0.42–0.87, P = 6.6 × 10−3). No combinations of SNPs within pathways were more significantly associated with survival compared with single variants alone, and no other risk SNPs were associated with survival in meta-analyses. The CRC susceptibility SNP rs9939049 in CDH1 influences patient survival and warrants further evaluation as a prognostic biomarker. • Analysed 83 colorectal cancer (CRC)-risk loci in 1948 patients with advanced CRC for prognostic outcome. • CDH1 variants were highly associated with overall survival in multivariate analysis. • Patients with rs12597188 minor alleles had a decrease in life expectancy of 5 months. • rs12597188 was also associated with poor response to therapy. • CDH1 (E-cadherin) involved in epithelial to mesenchymal transition during metastasis. [ABSTRACT FROM AUTHOR]
Published: 2020
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11. Psychopathy subdomains in violent offenders with and without a psychotic disorder

Author: Bell, Christina, Tesli, Natalia, Gurholt, Tiril Pedersen, Rokicki, Jaroslav, Hjell, Gabriela, Fischer-Vieler, Thomas, Melle, Ingrid, Agartz, Ingrid, Andreassen, Ole, Ringen, Petter Andreas, Rasmussen, Kirsten, Dahl, Hilde, Friestad, Christine, and Haukvik, Unn Kristin Hansen
Subjects: Genetics & Heredity, Science & Technology, NECROSIS-FACTOR-ALPHA, VARIANTS, AMYLOID-BETA, RISK LOCI, Psychiatry and Mental health, PREDICTION MODELS, IMPUTATION, GENOME-WIDE ASSOCIATION, Life Sciences & Biomedicine, METAANALYSIS, GENERATION, RESPONSES
Abstract: Background Violence in psychosis has been linked to antisocial behavior and psychopathy traits. Psychopathy comprises aspects of interpersonal, affective, lifestyle, and antisocial traits which may be differently involved in violent offending by persons with psychotic disorders. We explored psychopathy subdomains among violent offenders with and without a psychotic disorder. Methods 46 males, with a history of severe violence, with (n = 26; age 35.85 ± 10.34 years) or without (n = 20; age 39.10 ± 11.63 years) a diagnosis of a psychotic disorder, were assessed with the Psychopathy Checklist-Revised (PCL-R). PCL-R was split into subdomains following the four-facet model. Group differences in total and subdomain scores were analyzed with a general linear model with covariates. Results Total PCL-R scores did not differ between the groups (p = 0.61, Cohen’s d = 0.17). The violent offenders without psychotic disorders had higher facet 2 scores than the patient group with psychotic disorders (p = 0.029, Cohen’s d = 0.77). Facet 1, 3, or 4 scores did not differ between the groups. Controlling for age did not alter the results. Conclusion Patients with a psychotic disorder and a history of severe violence have lower affective psychopathy scores than violent offenders without psychotic disorders. This observation may point toward distinct underlying mechanisms for violence and may provide a target for focused treatment and prevention.
Published: 2022

12. SNCA 3′ UTR Genetic Variants in Patients with Parkinson’s Disease

Author: Antonela Blažeković, Kristina Gotovac Jerčić, and Fran Borovečki
Subjects: Parkinson’s disease, 3′ UTR, alpha-synuclein, PINK1, linkage disequilibrium, risk loci, Microbiology, QR1-502
Abstract: The SNCA (Synuclein Alpha) gene represents a major risk gene for Parkinson’s disease (PD) and SNCA polymorphisms have been associated with the common sporadic form of PD. Numerous Genome-Wide Association Studies showed strong signals located in the SNCA 3′ UTR (untranslated region) region indicating that variants in 3′ UTRs of PD-associated genes could contribute to neurodegeneration and may regulate the risk for PD. Genetic variants in 3′ UTR can affect miRNA activity and consequently change the translation process. The aim of this study was to access the differences in 3′ UTR variants of SNCA genes in a cohort of PD patients and control subjects from Croatia. The cohort consisted of 52 PD patients and 23 healthy control subjects. Differences between 3′ UTR allele and genotype frequencies were accessed through next generation sequencing approach from whole blood samples. In our study, we identified four previously reported single nucleotide polymorphisms (SNPs) and one insertion in the 3′ UTR region of SNCA gene, namely rs1045722, rs3857053, rs577490090, rs356165, and rs777296100, and five variants not reported in the literature, namely rs35270750, rs529553259, rs377356638, rs571454522, and rs750347645. Our results indicate a significantly higher occurrence of the rs571454522 variant in the PD population. To the best of our knowledge, this variant has not been reported until now in the literature. We analyzed our results in the context of previous research, creating a brief overview of the importance of 3′ UTR variants of the SNCA gene. Further studies will be needed to gain a more profound insight regarding their role in PD development, which will help to assess the role and impact of post-transcriptional regulation on disease pathology.
Published: 2021
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13. Bromodomain protein 4 discriminates tissue-specific super-enhancers containing disease-specific susceptibility loci in prostate and breast cancer

Author: Verena Zuber, Francesco Bettella, Aree Witoelar, the PRACTICAL Consortium, the CRUK GWAS, the BCAC Consortium, the TRICL Consortium, Ole A. Andreassen, Ian G. Mills, and Alfonso Urbanucci
Subjects: BRD4, Genome-wide association studies, SNPs, Functional annotation, Chromatin, Risk loci, Biotechnology, TP248.13-248.65, Genetics, QH426-470
Abstract: Abstract Background Epigenetic information can be used to identify clinically relevant genomic variants single nucleotide polymorphisms (SNPs) of functional importance in cancer development. Super-enhancers are cell-specific DNA elements, acting to determine tissue or cell identity and driving tumor progression. Although previous approaches have been tried to explain risk associated with SNPs in regulatory DNA elements, so far epigenetic readers such as bromodomain containing protein 4 (BRD4) and super-enhancers have not been used to annotate SNPs. In prostate cancer (PC), androgen receptor (AR) binding sites to chromatin have been used to inform functional annotations of SNPs. Results Here we establish criteria for enhancer mapping which are applicable to other diseases and traits to achieve the optimal tissue-specific enrichment of PC risk SNPs. We used stratified Q-Q plots and Fisher test to assess the differential enrichment of SNPs mapping to specific categories of enhancers. We find that BRD4 is the key discriminant of tissue-specific enhancers, showing that it is more powerful than AR binding information to capture PC specific risk loci, and can be used with similar effect in breast cancer (BC) and applied to other diseases such as schizophrenia. Conclusions This is the first study to evaluate the enrichment of epigenetic readers in genome-wide associations studies for SNPs within enhancers, and provides a powerful tool for enriching and prioritizing PC and BC genetic risk loci. Our study represents a proof of principle applicable to other diseases and traits that can be used to redefine molecular mechanisms of human phenotypic variation.
Published: 2017
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14. A Perception on Genome-Wide Genetic Analysis of Metabolic Traits in Arab Populations

Author: Prashantha Hebbar, Jehad Ahmed Abubaker, Mohamed Abu-Farha, Jaakko Tuomilehto, Fahd Al-Mulla, and Thangavel Alphonse Thanaraj
Subjects: Arab population, type 2 diabetes, genome-wide association studies, risk loci, Kuwait, Euro-centric risk variants, Diseases of the endocrine glands. Clinical endocrinology, RC648-665
Abstract: Despite dedicated nation-wide efforts to raise awareness against the harmful effects of fast-food consumption and sedentary lifestyle, the Arab population continues to struggle with an increased risk for metabolic disorders. Unlike the European population, the Arab population lacks well-established genetic risk determinants for metabolic disorders, and the transferability of established risk loci to this population has not been satisfactorily demonstrated. The most recent findings have identified over 240 genetic risk loci (with ~400 independent association signals) for type 2 diabetes, but thus far only 25 risk loci (ADAMTS9, ALX4, BCL11A, CDKAL1, CDKN2A/B, COL8A1, DUSP9, FTO, GCK, GNPDA2, HMG20A, HNF1A, HNF1B, HNF4A, IGF2BP2, JAZF1, KCNJ11, KCNQ1, MC4R, PPARγ, SLC30A8, TCF7L2, TFAP2B, TP53INP1, and WFS1) have been replicated in Arab populations. To our knowledge, large-scale population- or family-based association studies are non-existent in this region. Recently, we conducted genome-wide association studies on Arab individuals from Kuwait to delineate the genetic determinants for quantitative traits associated with anthropometry, lipid profile, insulin resistance, and blood pressure levels. Although these studies led to the identification of novel recessive variants, they failed to reproduce the established loci. However, they provided insights into the genetic architecture of the population, the applicability of genetic models based on recessive mode of inheritance, the presence of genetic signatures of inbreeding due to the practice of consanguinity, and the pleiotropic effects of rare disorders on complex metabolic disorders. This perspective presents analysis strategies and study designs for identifying genetic risk variants associated with diabetes and related traits in Arab populations.
Published: 2019
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15. Analysis of the genetic component of systemic sclerosis in Iranian and Turkish populations through a genome-wide association study.

Author: González-Serna, David, López-Isac, Elena, Yilmaz, Neslihan, Gharibdoost, Farhad, Jamshidi, Ahmadreza, Kavosi, Hoda, Poursani, Shiva, Farsad, Faraneh, Direskeneli, Haner, Saruhan-Direskeneli, Guhrer, Vargas, Sofia, Sawalha, Amr H, Brown, Matthew A, Yavuz, Sule, Mahmoudi, Mahdi, and Martin, Javier
Subjects: *ALLELES, *AMINO acids, *COMPARATIVE studies, *DNA, *GENOMES, *STATISTICS, *DATA analysis, *SYSTEMIC scleroderma, *ODDS ratio, *GENOTYPES, *DIAGNOSIS
Abstract: Objectives SSc is an autoimmune disease characterized by alteration of the immune response, vasculopathy and fibrosis. Most genetic studies on SSc have been performed in European-ancestry populations. The aim of this study was to analyse the genetic component of SSc in Middle Eastern patients from Iran and Turkey through a genome-wide association study. Methods This study analysed data from a total of 834 patients diagnosed with SSc and 1455 healthy controls from Iran and Turkey. DNA was genotyped using high-throughput genotyping platforms. The data generated were imputed using the Michigan Imputation Server, and the Haplotype Reference Consortium as a reference panel. A meta-analysis combining both case–control sets was conducted by the inverse variance method. Results The highest peak of association belonged to the HLA region in both the Iranian and Turkish populations. Strong and independent associations between the classical alleles HLA-DRB1*11: 04 [ P = 2.10 × 10−24, odds ratio (OR) = 3.14] and DPB1*13: 01 (P = 5.37 × 10−14, OR = 5.75) and SSc were observed in the Iranian population. HLA-DRB1*11: 04 (P = 4.90 × 10−11, OR = 2.93) was the only independent signal associated in the Turkish cohort. An omnibus test yielded HLA-DRB1 58 and HLA-DPB1 76 as relevant amino acid positions for this disease. Concerning the meta-analysis, we also identified two associations close to the genome-wide significance level outside the HLA region, corresponding to IRF5-TNPO3 rs17424921-C (P = 1.34 × 10−7, OR = 1.68) and NFKB1 rs4648133-C (P = 3.11 × 10−7, OR = 1.47). Conclusion We identified significant associations in the HLA region and suggestive associations in IRF5-TNPO3 and NFKB1 loci in Iranian and Turkish patients affected by SSc through a genome-wide association study and an extensive HLA analysis. [ABSTRACT FROM AUTHOR]
Published: 2019
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16. A Perception on Genome-Wide Genetic Analysis of Metabolic Traits in Arab Populations.

Author: Hebbar, Prashantha, Abubaker, Jehad Ahmed, Abu-Farha, Mohamed, Tuomilehto, Jaakko, Al-Mulla, Fahd, and Thanaraj, Thangavel Alphonse
Subjects: GENOMES, POPULATION, METABOLIC disorders, SEDENTARY lifestyles, BLOOD pressure
Abstract: Despite dedicated nation-wide efforts to raise awareness against the harmful effects of fast-food consumption and sedentary lifestyle, the Arab population continues to struggle with an increased risk for metabolic disorders. Unlike the European population, the Arab population lacks well-established genetic risk determinants for metabolic disorders, and the transferability of established risk loci to this population has not been satisfactorily demonstrated. The most recent findings have identified over 240 genetic risk loci (with ~400 independent association signals) for type 2 diabetes, but thus far only 25 risk loci (ADAMTS9 , ALX4, BCL11A, CDKAL1, CDKN2A/B , COL8A1, DUSP9, FTO, GCK, GNPDA2, HMG20A, HNF1A, HNF1B, HNF4A, IGF2BP2, JAZF1, KCNJ11, KCNQ1, MC4R, PPAR γ , SLC30A8, TCF7L2, TFAP2B, TP53INP1 , and WFS1) have been replicated in Arab populations. To our knowledge, large-scale population- or family-based association studies are non-existent in this region. Recently, we conducted genome-wide association studies on Arab individuals from Kuwait to delineate the genetic determinants for quantitative traits associated with anthropometry, lipid profile, insulin resistance, and blood pressure levels. Although these studies led to the identification of novel recessive variants, they failed to reproduce the established loci. However, they provided insights into the genetic architecture of the population, the applicability of genetic models based on recessive mode of inheritance, the presence of genetic signatures of inbreeding due to the practice of consanguinity, and the pleiotropic effects of rare disorders on complex metabolic disorders. This perspective presents analysis strategies and study designs for identifying genetic risk variants associated with diabetes and related traits in Arab populations. [ABSTRACT FROM AUTHOR]
Published: 2019
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17. New insights into the genetic etiology of Alzheimer's disease and related dementias

Author: Bellenguez, C., Küçükali, F., Jansen, I. E., Kleineidam, L., Moreno-Grau, S., Amin, N., Naj, A. C., Campos-Martin, R., Grenier-Boley, B., Andrade, V., Holmans, P. A., Boland, A., Damotte, V., van der Lee, S. J., Costa, M. R., Kuulasmaa, T., Yang, Q., de Rojas, I., Bis, J. C., Yaqub, A., Prokic, I., Chapuis, J., Ahmad, S., Giedraitis, V., Aarsland, D., Garcia-Gonzalez, P., Abdelnour, C., Alarcón-Martín, E., Alcolea, D., Alegret, M., Alvarez, I., Álvarez, V., Armstrong, N. J., Tsolaki, A., Antúnez, C., Appollonio, I., Arcaro, M., Archetti, S., Pastor, A. A., Arosio, B., Athanasiu, L., Bailly, H., Banaj, N., Baquero, M., Barral, S., Beiser, A., Pastor, A. B., Below, J. E., Benchek, P., Benussi, L., Berr, C., Besse, C., Bessi, V., Binetti, G., Bizarro, A., Blesa, R., Boada, M., Boerwinkle, E., Borroni, B., Boschi, S., Bossù, P., Bråthen, G., Bressler, J., Bresner, C., Brodaty, H., Brookes, K. J., Brusco, L. I., Buiza-Rueda, D., Bûrger, K., Burholt, V., Bush, W. S., Calero, M., Cantwell, L. B., Chene, G., Chung, J., Cuccaro, M. L., Carracedo, Á., Cecchetti, R., Cervera-Carles, L., Charbonnier, C., Chen, H. -H., Chillotti, C., Ciccone, S., Claassen, J. A. H. R., Clark, C., Conti, E., Corma-Gómez, A., Costantini, E., Custodero, C., Daian, D., Dalmasso, M. C., Daniele, A., Dardiotis, E., Dartigues, J. -F., de Deyn, P. P., de Paiva Lopes, K., de Witte, L. D., Debette, S., Deckert, J., del Ser, T., Denning, N., Destefano, A., Dichgans, M., Diehl-Schmid, J., Diez-Fairen, M., Rossi, P. D., Djurovic, S., Duron, E., Düzel, E., Dufouil, C., Eiriksdottir, G., Engelborghs, S., Escott-Price, V., Espinosa, A., Ewers, M., Faber, K. M., Fabrizio, T., Nielsen, S. F., Fardo, D. W., Farotti, L., Fenoglio, C., Fernández-Fuertes, M., Ferrari, R., Ferreira, C. B., Ferri, E., Fin, B., Fischer, P., Fladby, T., Fließbach, K., Fongang, B., Fornage, M., Fortea, J., Foroud, T. M., Fostinelli, S., Fox, N. C., Franco-Macías, E., Bullido, M. J., Frank-García, A., Froelich, L., Fulton-Howard, B., Galimberti, D., García-Alberca, J. M., García-González, P., Garcia-Madrona, S., Garcia-Ribas, G., Ghidoni, R., Giegling, I., Giorgio, G., Goate, A. M., Goldhardt, O., Gomez-Fonseca, D., González-Pérez, A., Graff, C., Grande, G., Green, E., Grimmer, T., Grünblatt, E., Grunin, M., Gudnason, V., Guetta-Baranes, T., Haapasalo, A., Hadjigeorgiou, G., Haines, J. L., Hamilton-Nelson, K. L., Hampel, H., Hanon, O., Hardy, J., Hartmann, A. M., Hausner, L., Harwood, J., Heilmann-Heimbach, S., Helisalmi, S., Heneka, M. T., Hernández, I., Herrmann, M. J., Hoffmann, P., Holmes, C., Holstege, H., Vilas, R. H., Hulsman, M., Humphrey, J., Biessels, G. J., Jian, X., Johansson, C., Jun, G. R., Kastumata, Y., Kauwe, J., Kehoe, P. G., Kilander, L., Ståhlbom, A. K., Kivipelto, M., Koivisto, A., Kornhuber, J., Kosmidis, M. H., Kukull, W. A., Kuksa, P. P., Kunkle, B. W., Kuzma, A. B., Lage, C., Laukka, E. J., Launer, L., Lauria, A., Lee, C. -Y., Lehtisalo, J., Lerch, O., Lleó, A., Longstreth, W., Lopez, O., de Munain, A. L., Love, S., Löwemark, M., Luckcuck, L., Lunetta, K. L., Ma, Y., Macías, J., Macleod, C. A., Maier, W., Mangialasche, F., Spallazzi, M., Marquié, M., Marshall, R., Martin, E. R., Montes, A. M., Rodríguez, C. M., Masullo, C., Mayeux, R., Mead, S., Mecocci, P., Medina, M., Meggy, A., Mehrabian, S., Mendoza, S., Menéndez-González, M., Mir, P., Moebus, S., Mol, M., Molina-Porcel, L., Montrreal, L., Morelli, L., Moreno, F., Morgan, K., Mosley, T., Nöthen, M. M., Muchnik, C., Mukherjee, S., Nacmias, B., Ngandu, T., Nicolas, G., Nordestgaard, B. G., Olaso, R., Orellana, A., Orsini, M., Ortega, G., Padovani, A., Paolo, C., Papenberg, G., Parnetti, L., Pasquier, F., Pastor, P., Peloso, G., Pérez-Cordón, A., Pérez-Tur, J., Pericard, P., Peters, O., Pijnenburg, Y. A. L., Pineda, J. A., Piñol-Ripoll, G., Pisanu, C., Polak, T., Popp, J., Posthuma, D., Priller, J., Puerta, R., Quenez, O., Quintela, I., Thomassen, J. Q., Rábano, A., Rainero, I., Rajabli, F., Ramakers, I., Real, L. M., Reinders, M. J. T., Reitz, C., Reyes-Dumeyer, D., Ridge, P., Riedel-Heller, S., Riederer, P., Roberto, N., Rodriguez-Rodriguez, E., Rongve, A., Allende, I. R., Rosende-Roca, M., Royo, J. L., Rubino, E., Rujescu, D., Sáez, M. E., Sakka, P., Saltvedt, I., Sanabria, Á., Sánchez-Arjona, M. B., Sanchez-Garcia, F., Juan, P. S., Sánchez-Valle, R., Sando, S. B., Sarnowski, C., Satizabal, C. L., Scamosci, M., Scarmeas, N., Scarpini, E., Scheltens, P., Scherbaum, N., Scherer, M., Schmid, M., Schneider, A., Schott, J. M., Selbæk, G., Seripa, D., Serrano, M., Sha, J., Shadrin, A. A., Skrobot, O., Slifer, S., Snijders, G. J. L., Soininen, H., Solfrizzi, V., Solomon, A., Song, Y. E., Sorbi, S., Sotolongo-Grau, O., Spalletta, G., Spottke, A., Squassina, A., Stordal, E., Tartan, J. P., Tárraga, L., Tesí, N., Thalamuthu, A., Thomas, T., Tosto, G., Traykov, L., Tremolizzo, L., Tybjærg-Hansen, A., Uitterlinden, A., Ullgren, A., Ulstein, I., Valero, S., Valladares, O., Broeckhoven, C. V., Vance, J., Vardarajan, B. N., van der Lugt, A., Dongen, J. V., van Rooij, J., van Swieten, J., Vandenberghe, R., Verhey, F., Vidal, J. -S., Vogelgsang, J., Vyhnalek, M., Wagner, M., Wallon, D., Wang, L. -S., Wang, R., Weinhold, L., Wiltfang, J., Windle, G., Woods, B., Yannakoulia, M., Zare, H., Zhao, Y., Zhang, X., Zhu, C., Zulaica, M., Laczo, J., Matoska, V., Serpente, M., Assogna, F., Piras, F., Ciullo, V., Shofany, J., Ferrarese, C., Andreoni, S., Sala, G., Zoia, C. P., Zompo, M. D., Benussi, A., Bastiani, P., Takalo, M., Natunen, T., Laatikainen, T., Tuomilehto, J., Antikainen, R., Strandberg, T., Lindström, J., Peltonen, M., Abraham, R., Al-Chalabi, A., Bass, N. J., Brayne, C., Brown, K. S., Collinge, J., Craig, D., Deloukas, P., Fox, N., Gerrish, A., Gill, M., Gwilliam, R., Harold, D., Hollingworth, P., Johnston, J. A., Jones, L., Lawlor, B., Livingston, G., Lovestone, S., Lupton, M., Lynch, A., Mann, D., Mcguinness, B., Mcquillin, A., O’Donovan, M. C., Owen, M. J., Passmore, P., Powell, J. F., Proitsi, P., Rossor, M., Shaw, C. E., Smith, A. D., Gurling, H., Todd, S., Mummery, C., Ryan, N., Lacidogna, G., Adarmes-Gómez, A., Mauleón, A., Pancho, A., Gailhajenet, A., Lafuente, A., Macias-García, D., Martín, E., Pelejà, E., Carrillo, F., Merlín, I. S., Garrote-Espina, L., Vargas, L., Carrion-Claro, M., Marín, M., Labrador, M., Buendia, M., Alonso, M. D., Guitart, M., Moreno, M., Ibarria, M., Periñán, M., Aguilera, N., Gómez-Garre, P., Cañabate, P., Escuela, R., Pineda-Sánchez, R., Vigo-Ortega, R., Jesús, S., Preckler, S., Rodrigo-Herrero, S., Diego, S., Vacca, A., Roveta, F., Salvadori, N., Chipi, E., Boecker, H., Laske, C., Perneczky, R., Anastasiou, C., Janowitz, D., Malik, R., Anastasiou, A., Parveen, K., López-García, S., Antonell, A., Mihova, K. Y., Belezhanska, D., Weber, H., Kochen, S., Solis, P., Medel, N., Lisso, J., Sevillano, Z., Politis, D. G., Cores, V., Cuesta, C., Ortiz, C., Bacha, J. I., Rios, M., Saenz, A., Abalos, M. S., Kohler, E., Palacio, D. L., Etchepareborda, I., Kohler, M., Novack, G., Prestia, F. A., Galeano, P., Castaño, E. M., Germani, S., Toso, C. R., Rojo, M., Ingino, C., Mangone, C., Rubinsztein, D. C., Teipel, S., Fievet, N., Deramerourt, V., Forsell, C., Thonberg, H., Bjerke, M., Roeck, E. D., Martínez-Larrad, M. T., Olivar, N., Cano, A., Macias, J., Maroñas, O., Nuñez-Llaves, R., Olivé, C., Adarmes-Gómez, A. D., Amer-Ferrer, G., Antequera, M., Burguera, J. A., Casajeros, M. J., Martinez de Pancorbo, M., Hevilla, S., Espinosa, M. A. L., Legaz, A., Manzanares, S., Marín-Muñoz, J., Marín, T., Martínez, B., Martínez, V., Martínez-Lage Álvarez, P., Iriarte, M. M., Periñán-Tocino, M. T., Real de Asúa, D., Rodrigo, S., Sastre, I., Vicente, M. P., Vivancos, L., Epelbaum, J., Hannequin, D., Campion, D., Deramecourt, V., Tzourio, C., Brice, A., Dubois, B., Williams, A., Thomas, C., Davies, C., Nash, W., Dowzell, K., Morales, A. C., Bernardo-Harrington, M., Turton, J., Lord, J., Brown, K., Vardy, E., Fisher, E., Warren, J. D., Ryan, N. S., Guerreiro, R., Uphill, J., Bass, N., Heun, R., Kölsch, H., Schürmann, B., Lacour, A., Herold, C., Powell, J., Patel, Y., Hodges, A., Becker, T., Warden, D., Wilcock, G., Clarke, R., Ben-Shlomo, Y., Hooper, N. M., Pickering-Brown, S., Sussams, R., Warner, N., Bayer, A., Heuser, I., Drichel, D., Klopp, N., Mayhaus, M., Riemenschneider, M., Pinchler, S., Feulner, T., Gu, W., van den Bussche, H., Hüll, M., Frölich, L., Wichmann, H. -E., Jöckel, K. -H., O’Donovan, M., Owen, M., Bahrami, S., Bosnes, I., Selnes, P., Bergh, S., Palotie, A., Daly, M., Jacob, H., Matakidou, A., Runz, H., John, S., Plenge, R., Mccarthy, M., Hunkapiller, J., Ehm, M., Waterworth, D., Fox, C., Malarstig, A., Klinger, K., Call, K., Behrens, T., Loerch, P., Mäkelä, T., Kaprio, J., Virolainen, P., Pulkki, K., Kilpi, T., Perola, M., Partanen, J., Pitkäranta, A., Kaarteenaho, R., Vainio, S., Turpeinen, M., Serpi, R., Laitinen, T., Mäkelä, J., Kosma, V. -M., Kujala, U., Tuovila, O., Hendolin, M., Pakkanen, R., Waring, J., Riley-Gillis, B., Liu, J., Biswas, S., Diogo, D., Marshall, C., Hu, X., Gossel, M., Graham, R., Cummings, B., Ripatti, S., Schleutker, J., Arvas, M., Carpén, O., Hinttala, R., Kettunen, J., Mannermaa, A., Laukkanen, J., Julkunen, V., Remes, A., Kälviäinen, R., Peltola, J., Tienari, P., Rinne, J., Ziemann, A., Esmaeeli, S., Smaoui, N., Lehtonen, A., Eaton, S., Lahdenperä, S., van Adelsberg, J., Michon, J., Kerchner, G., Bowers, N., Teng, E., Eicher, J., Mehta, V., Gormley, P., Linden, K., Whelan, C., Xu, F., Pulford, D., Färkkilä, M., Pikkarainen, S., Jussila, A., Blomster, T., Kiviniemi, M., Voutilainen, M., Georgantas, B., Heap, G., Rahimov, F., Usiskin, K., Lu, T., Oh, D., Kalpala, K., Miller, M., Mccarthy, L., Eklund, K., Palomäki, A., Isomäki, P., Pirilä, L., Kaipiainen-Seppänen, O., Huhtakangas, J., Lertratanakul, A., Hochfeld, M., Bing, N., Gordillo, J. 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A., Ollila, T., Seitsonen, S., Uusitalo, H., Aaltonen, V., Uusitalo-Järvinen, H., Luodonpää, M., Hautala, N., Loomis, S., Strauss, E., Podgornaia, A., Hoffman, J., Tasanen, K., Huilaja, L., Hannula-Jouppi, K., Salmi, T., Peltonen, S., Koulu, L., Harvima, I., Wu, Y., Choy, D., Pussinen, P., Salminen, A., Salo, T., Rice, D., Nieminen, P., Palotie, U., Siponen, M., Suominen, L., Mäntylä, P., Gursoy, U., Anttonen, V., Sipilä, K., Davis, J. W., Quarless, D., Petrovski, S., Wigmore, E., Chen, C. -Y., Bronson, P., Tsai, E., Huang, Y., Maranville, J., Shaikho, E., Mohammed, E., Wadhawan, S., Kvikstad, E., Caliskan, M., Chang, D., Bhangale, T., Pendergrass, S., Holzinger, E., Chen, X., Hedman, Å., King, K. 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P., Brein, G., Awaisa, G., Shcherban, A., Donner, K., Loukola, A., Laiho, P., Sistonen, T., Kaiharju, E., Laukkanen, M., Järvensivu, E., Lähteenmäki, S., Männikkö, L., Wong, R., Mattsson, H., Hiekkalinna, T., Paajanen, T., Pärn, K., Gracia-Tabuenca, J., Abner, E., Adams, P. M., Aguirre, A., Albert, M. S., Albin, R. L., Allen, M., Alvarez, L., Apostolova, L. G., Arnold, S. E., Asthana, S., Atwood, C. S., Ayres, G., Baldwin, C. T., Barber, R. C., Barnes, L. L., Beach, T. G., Becker, J. T., Beecham, G. W., Beekly, D., Benitez, B. A., Bennett, D., Bertelson, J., Margaret, F. E., Bird, T. D., Blacker, D., Boeve, B. F., Bowen, J. D., Boxer, A., Brewer, J., Burke, J. R., Burns, J. M., Buxbaum, J. D., Cairns, N. J., Cao, C., Carlson, C. S., Carlsson, C. M., Carney, R. M., Carrasquillo, M. M., Chasse, S., Chesselet, M. -F., Chesi, A., Chin, N. A., Chui, H. C., Craft, S., Crane, P. K., Cribbs, D. H., Crocco, E. A., Cruchaga, C., Cullum, M., Darby, E., Davis, B., De Jager, P. 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M, Rossi, P, Djurovic, S, Duron, E, Düzel, E, Dufouil, C, Eiriksdottir, G, Engelborghs, S, Escott-Price, V, Espinosa, A, Ewers, M, Faber, K, Fabrizio, T, Nielsen, S, Fardo, D, Farotti, L, Fenoglio, C, Fernández-Fuertes, M, Ferrari, R, Ferreira, C, Ferri, E, Fin, B, Fischer, P, Fladby, T, Fließbach, K, Fongang, B, Fornage, M, Fortea, J, Foroud, T, Fostinelli, S, Fox, N, Franco-Macías, E, Bullido, M, Frank-García, A, Froelich, L, Fulton-Howard, B, Galimberti, D, García-Alberca, J, García-González, P, Garcia-Madrona, S, Garcia-Ribas, G, Ghidoni, R, Giegling, I, Giorgio, G, Goate, A, Goldhardt, O, Gomez-Fonseca, D, González-Pérez, A, Graff, C, Grande, G, Green, E, Grimmer, T, Grünblatt, E, Grunin, M, Gudnason, V, Guetta-Baranes, T, Haapasalo, A, Hadjigeorgiou, G, Haines, J, Hamilton-Nelson, K, Hampel, H, Hanon, O, Hardy, J, Hartmann, A, Hausner, L, Harwood, J, Heilmann-Heimbach, S, Helisalmi, S, Heneka, M, Hernández, I, Herrmann, M, Hoffmann, P, Holmes, C, Holstege, H, Vilas, R, Hulsman, M, Humphrey, J, Biessels, G, Jian, X, Johansson, C, Jun, G, Kastumata, Y, Kauwe, J, Kehoe, P, Kilander, L, Ståhlbom, A, Kivipelto, M, Koivisto, A, Kornhuber, J, Kosmidis, M, Kukull, W, Kuksa, P, Kunkle, B, Kuzma, A, Lage, C, Laukka, E, Launer, L, Lauria, A, Lee, C, Lehtisalo, J, Lerch, O, Lleó, A, Longstreth, W, Lopez, O, de Munain, A, Love, S, Löwemark, M, Luckcuck, L, Lunetta, K, Ma, Y, Macías, J, Macleod, C, Maier, W, Mangialasche, F, Spallazzi, M, Marquié, M, Marshall, R, Martin, E, Montes, A, Rodríguez, C, Masullo, C, Mayeux, R, Mead, S, Mecocci, P, Medina, M, Meggy, A, Mehrabian, S, Mendoza, S, Menéndez-González, M, Mir, P, Moebus, S, Mol, M, Molina-Porcel, L, Montrreal, L, Morelli, L, Moreno, F, Morgan, K, Mosley, T, Nöthen, M, Muchnik, C, Mukherjee, S, Nacmias, B, Ngandu, T, Nicolas, G, Nordestgaard, B, Olaso, R, Orellana, A, Orsini, M, Ortega, G, Padovani, A, Paolo, C, Papenberg, G, Parnetti, L, Pasquier, F, Pastor, P, Peloso, G, Pérez-Cordón, A, Pérez-Tur, J, Pericard, P, Peters, O, Pijnenburg, Y, Pineda, J, Piñol-Ripoll, G, Pisanu, C, Polak, T, Popp, J, Posthuma, D, Priller, J, Puerta, R, Quenez, O, Quintela, I, Thomassen, J, Rábano, A, Rainero, I, Rajabli, F, Ramakers, I, Real, L, Reinders, M, Reitz, C, Reyes-Dumeyer, D, Ridge, P, Riedel-Heller, S, Riederer, P, Roberto, N, Rodriguez-Rodriguez, E, Rongve, A, Allende, I, Rosende-Roca, M, Royo, J, Rubino, E, Rujescu, D, Sáez, M, Sakka, P, Saltvedt, I, Sanabria, Á, Sánchez-Arjona, M, Sanchez-Garcia, F, Juan, P, Sánchez-Valle, R, Sando, S, Sarnowski, C, Satizabal, C, Scamosci, M, Scarmeas, N, Scarpini, E, Scheltens, P, Scherbaum, N, Scherer, M, Schmid, M, Schneider, A, Schott, J, Selbæk, G, Seripa, D, Serrano, M, Sha, J, Shadrin, A, Skrobot, O, Slifer, S, Snijders, G, Soininen, H, Solfrizzi, V, Solomon, A, Song, Y, Sorbi, S, Sotolongo-Grau, O, Spalletta, G, Spottke, A, Squassina, A, Stordal, E, Tartan, J, Tárraga, L, Tesí, N, Thalamuthu, A, Thomas, T, Tosto, G, Traykov, L, Tremolizzo, L, Tybjærg-Hansen, A, Uitterlinden, A, Ullgren, A, Ulstein, I, Valero, S, Valladares, O, Broeckhoven, C, Vance, J, Vardarajan, B, van der Lugt, A, Dongen, J, van Rooij, J, van Swieten, J, Vandenberghe, R, Verhey, F, Vidal, J, Vogelgsang, J, Vyhnalek, M, Wagner, M, Wallon, D, Wang, L, Wang, R, Weinhold, L, Wiltfang, J, Windle, G, Woods, B, Yannakoulia, M, Zare, H, Zhao, Y, Zhang, X, Zhu, C, Zulaica, M, Andreoni, S, Ferrarese, C, Sala, G, Zoia, C, Farrer, L, Psaty, B, Ghanbari, M, Raj, T, Sachdev, P, Mather, K, Jessen, F, Ikram, M, de Mendonça, A, Hort, J, Tsolaki, M, Pericak-Vance, M, Amouyel, P, Williams, J, Frikke-Schmidt, R, Clarimon, J, Deleuze, J, Rossi, G, Seshadri, S, Andreassen, O, Ingelsson, M, Hiltunen, M, Sleegers, K, Schellenberg, G, van Duijn, C, Sims, R, van der Flier, W, Ruiz, A, Ramirez, A, Lambert, J, VU University medical center, Amsterdam Neuroscience - Neurodegeneration, Neurology, Human genetics, Amsterdam Neuroscience - Complex Trait Genetics, Amsterdam Neuroscience - Compulsivity, Impulsivity & Attention, APH - Personalized Medicine, APH - Methodology, Bellenguez, Céline [0000-0002-1240-7874], Küçükali, Fahri [0000-0002-3835-9639], Amin, Najaf [0000-0002-8944-1771], Holmans, Peter A [0000-0003-0870-9412], van der Lee, Sven J [0000-0003-1606-8643], Costa, Marcos R [0000-0002-4928-2163], Kuulasmaa, Teemu [0000-0002-1795-7314], Yang, Qiong [0000-0002-3658-1375], de Rojas, Itziar [0000-0002-2148-381X], Bis, Joshua C [0000-0002-3409-1110], Yaqub, Amber [0000-0002-3579-8054], Prokic, Ivana [0000-0002-0370-1473], Chapuis, Julien [0000-0002-5802-2857], Ahmad, Shahzad [0000-0002-8658-3790], Giedraitis, Vilmantas [0000-0003-3423-2021], Garcia-Gonzalez, Pablo [0000-0003-0125-5403], Alcolea, Daniel [0000-0002-3819-3245], Alvarez, Ignacio [0000-0002-8537-3935], Tsolaki, Anthoula [0000-0002-5563-7776], Baquero, Miquel [0000-0002-6861-1831], Pastor, Ana Belén [0000-0001-9637-4688], Berr, Claudine [0000-0001-5254-7655], Bessi, Valentina [0000-0002-6176-3584], Boada, Mercè [0000-0003-2617-3009], Bossù, Paola [0000-0002-1432-0078], Bråthen, Geir [0000-0003-3224-7983], Bressler, Jan [0000-0001-6578-4772], Bresner, Catherine [0000-0003-2673-9762], Brodaty, Henry [0000-0001-9487-6617], Brookes, Keeley J [0000-0003-2427-2513], Burholt, Vanessa [0000-0002-6789-127X], Bush, William S [0000-0002-9729-6519], Calero, Miguel [0000-0001-5366-3324], Chung, Jaeyoon [0000-0002-6431-9454], Cervera-Carles, Laura [0000-0003-2286-200X], Costantini, Emanuele [0000-0002-1096-8221], Dalmasso, Maria Carolina [0000-0002-4901-9955], de Paiva Lopes, Katia [0000-0002-0240-0126], de Witte, Lot D [0000-0002-7235-9958], Debette, Stéphanie [0000-0001-8675-7968], Del Ser, Teodoro [0000-0001-9806-7083], Dichgans, Martin [0000-0002-0654-387X], Diehl-Schmid, Janine [0000-0002-7745-1382], Diez-Fairen, Mónica [0000-0003-1882-0309], Djurovic, Srdjan [0000-0002-8140-8061], Dufouil, Carole [0000-0003-2442-4476], Escott-Price, Valentina [0000-0003-1784-5483], Ewers, Michael [0000-0001-5231-1714], Fabrizio, Tagliavini [0000-0003-1039-7315], Fladby, Tormod [0000-0002-9984-9797], Fornage, Myriam [0000-0003-0677-8158], Fox, Nick C [0000-0002-6660-657X], Bullido, María J [0000-0002-6477-1117], Froelich, Lutz [0000-0003-1494-0813], Galimberti, Daniela [0000-0002-9284-5953], García-Alberca, Jose Maria [0000-0003-2951-6644], Goate, Alison M [0000-0002-0576-2472], González-Pérez, Antonio [0000-0001-9771-5982], Green, Emma [0000-0002-8687-5590], Grünblatt, Edna [0000-0001-8505-7265], Gudnason, Vilmundur [0000-0001-5696-0084], Haapasalo, Annakaisa [0000-0003-0959-2957], Harwood, Janet [0000-0002-3225-0069], Heilmann-Heimbach, Stefanie [0000-0003-1057-465X], Herrmann, Martin J [0000-0001-9970-2122], Holstege, Henne [0000-0002-7688-3087], Biessels, Geert Jan [0000-0001-6862-2496], Jian, Xueqiu [0000-0002-0313-6494], Johansson, Charlotte [0000-0002-5351-1950], Jun, Gyungah R [0000-0002-3230-8697], Kastumata, Yuriko [0000-0002-0188-8094], Kehoe, Patrick G [0000-0002-7542-1139], Kornhuber, Johannes [0000-0002-8096-3987], Kosmidis, Mary H [0000-0001-8790-1220], Lage, Carmen [0000-0003-1703-121X], Launer, Lenore [0000-0002-3238-7612], Lee, Chien-Yueh [0000-0002-4304-974X], Lleó, Alberto [0000-0002-2568-5478], Lopez, Oscar [0000-0002-8546-8256], de Munain, Adolfo Lopez [0000-0002-9509-4032], Lunetta, Kathryn L [0000-0002-9268-810X], Ma, Yiyi [0000-0002-3609-8877], MacLeod, Catherine A [0000-0002-9314-7380], Marquié, Marta [0000-0002-0660-0950], Montes, Angel Martín [0000-0002-1694-786X], Mead, Simon [0000-0002-4326-1468], Medina, Miguel [0000-0002-7016-5340], Menéndez-González, Manuel [0000-0002-5218-0774], Mol, Merel [0000-0003-2533-2530], Morgan, Kevin [0000-0002-8217-2396], Nöthen, Markus M [0000-0002-8770-2464], Muchnik, Carolina [0000-0002-1542-3706], Nacmias, Benedetta [0000-0001-9338-9040], Nicolas, Gael [0000-0001-9391-7800], Nordestgaard, Børge G [0000-0002-1954-7220], Pasquier, Florence [0000-0001-9880-9788], Pastor, Pau [0000-0002-7493-8777], Peloso, Gina [0000-0002-5355-8636], Pérez-Cordón, Alba [0000-0002-6028-0791], Pérez-Tur, Jordi [0000-0002-9111-1712], Pericard, Pierre [0000-0001-8167-6448], Pineda, Juan A [0000-0002-3751-0296], Pisanu, Claudia [0000-0002-9151-4319], Posthuma, Danielle [0000-0001-7582-2365], Puerta, Raquel [0000-0002-1191-5893], Quenez, Olivier [0000-0002-8273-8505], Thomassen, Jesper Qvist [0000-0003-3484-9531], Real, Luis M [0000-0003-4932-7429], Reinders, Marcel JT [0000-0002-1148-1562], Reitz, Christiane [0000-0001-8757-7889], Riedel-Heller, Steffi [0000-0003-4321-6090], Rodriguez-Rodriguez, Eloy [0000-0001-7742-677X], Rongve, Arvid [0000-0002-0476-4134], Sáez, María Eugenia [0000-0001-9299-2534], Saltvedt, Ingvild [0000-0002-7897-9808], Juan, Pascual Sánchez [0000-0002-6081-8037], Sarnowski, Chloé [0000-0002-6090-7099], Satizabal, Claudia L [0000-0002-1115-4430], Schott, Jonathan M [0000-0003-2059-024X], Selbæk, Geir [0000-0001-6511-8219], Shadrin, Alexey A [0000-0002-7467-250X], Soininen, Hilkka [0000-0002-2785-9937], Solfrizzi, Vincenzo [0000-0002-8524-0315], Song, Yeunjoo [0000-0002-7452-3731], Sotolongo-Grau, Oscar [0000-0002-9679-0670], Spalletta, Gianfranco [0000-0002-7432-4249], Squassina, Alessio [0000-0001-7415-7607], Stordal, Eystein [0000-0002-2443-7923], Tosto, Giuseppe [0000-0001-7075-8245], Uitterlinden, Andre [0000-0002-7276-3387], Valladares, Otto [0000-0001-8055-2187], Broeckhoven, Christine Van [0000-0003-0183-7665], Vidal, Jean-Sébastien [0000-0001-6770-0720], Vogelgsang, Jonathan [0000-0001-9326-8193], Wagner, Michael [0000-0003-2589-6440], Wallon, David [0000-0002-2634-7198], Wiltfang, Jens [0000-0003-1492-5330], Woods, Bob [0000-0002-6781-651X], Yannakoulia, Mary [0000-0003-2171-7337], Zare, Habil [0000-0001-5902-6238], Zhang, Xiaoling [0000-0001-8237-1857], Farrer, Lindsay A [0000-0001-5533-4225], Psaty, Bruce M [0000-0002-7278-2190], Ghanbari, Mohsen [0000-0002-9476-7143], Raj, Towfique [0000-0002-9355-5704], Sachdev, Perminder [0000-0002-9595-3220], Mather, Karen [0000-0003-4143-8941], Ikram, M Arfan [0000-0003-0372-8585], Tsolaki, Magda [0000-0002-2072-8010], Pericak-Vance, Margaret A [0000-0001-7283-8804], Amouyel, Philippe [0000-0001-9088-234X], Williams, Julie [0000-0002-4069-0259], Frikke-Schmidt, Ruth [0000-0003-4084-5027], Seshadri, Sudha [0000-0001-6135-2622], Andreassen, Ole A [0000-0002-4461-3568], Sleegers, Kristel [0000-0002-0283-2332], van Duijn, Cornelia M [0000-0002-2374-9204], Sims, Rebecca [0000-0002-3885-1199], van der Flier, Wiesje M [0000-0001-8766-6224], Ramirez, Alfredo [0000-0003-4991-763X], Lambert, Jean-Charles [0000-0003-0829-7817], Apollo - University of Cambridge Repository, Complex Trait Genetics, Clinical sciences, Neuroprotection & Neuromodulation, Pathologic Biochemistry and Physiology, Clinical Biology, Epidemiology, Internal Medicine, Psychiatrie & Neuropsychologie, RS: MHeNs - R1 - Cognitive Neuropsychiatry and Clinical Neuroscience, MUMC+: MA Med Staf Spec Psychiatrie (9), UAM. Departamento de Biología Molecular, University of Helsinki, Department of Neurosciences, HUS Internal Medicine and Rehabilitation, Timo Strandberg / Principal Investigator, Department of Medicine, Clinicum, HUS Neurocenter, Neurologian yksikkö, Centre of Excellence in Complex Disease Genetics, HUS Abdominal Center, Institut Pasteur, Institut National de la Santé et de la Recherche Médicale (France), European Commission, LabEx DISTALZ, Pérez-Tur, Jordi, University Children’s Hospital Basel (Suiza), INSERM (Francia), Lille Métropole Communauté Urbaine, Government of France (Francia), EADB, GR@ACE, DEGESCO, EADI, GERAD, Demgene, FinnGen, ADGC, CHARGE, Holmans, Peter A. [0000-0003-0870-9412], van der Lee, Sven J. [0000-0003-1606-8643], Costa, Marcos R. [0000-0002-4928-2163], Bis, Joshua C. [0000-0002-3409-1110], Brookes, Keeley J. [0000-0003-2427-2513], Bush, William S. [0000-0002-9729-6519], de Witte, Lot D. [0000-0002-7235-9958], del Ser, Teodoro [0000-0001-9806-7083], Fox, Nick C. [0000-0002-6660-657X], Bullido, María J. [0000-0002-6477-1117], Goate, Alison M. [0000-0002-0576-2472], Herrmann, Martin J. [0000-0001-9970-2122], Jun, Gyungah R. [0000-0002-3230-8697], Kehoe, Patrick G. [0000-0002-7542-1139], Kosmidis, Mary H. [0000-0001-8790-1220], Lunetta, Kathryn L. [0000-0002-9268-810X], MacLeod, Catherine A. [0000-0002-9314-7380], Nöthen, Markus M. [0000-0002-8770-2464], Nordestgaard, Børge G. [0000-0002-1954-7220], Pineda, Juan A. [0000-0002-3751-0296], Real, Luis M. [0000-0003-4932-7429], Reinders, Marcel J. T. [0000-0002-1148-1562], Satizabal, Claudia L. [0000-0002-1115-4430], Schott, Jonathan M. [0000-0003-2059-024X], Shadrin, Alexey A. [0000-0002-7467-250X], Farrer, Lindsay A. [0000-0001-5533-4225], Psaty, Bruce M. [0000-0002-7278-2190], Ikram, M. Arfan [0000-0003-0372-8585], Pericak-Vance, Margaret A. [0000-0001-7283-8804], Andreassen, Ole A. [0000-0002-4461-3568], van Duijn, Cornelia M. [0000-0002-2374-9204], van der Flier, Wiesje M. [0000-0001-8766-6224], and Molecular Neuroscience and Ageing Research (MOLAR)
Subjects: tau Proteins/genetics, Alzheimer`s disease Donders Center for Medical Neuroscience [Radboudumc 1], Neurologi, MED/03 - GENETICA MEDICA, 45/43, Medizin, Stress-related disorders Donders Center for Medical Neuroscience [Radboudumc 13], genetics [Alzheimer Disease], Genome-Wide Association Study, Humans, tau Proteins, Alzheimer Disease, Cognitive Dysfunction, VARIANTS, pathology [Alzheimer Disease], Tau Proteins, Settore BIO/13 - Biologia Applicata, Cognitive Dysfunction/psychology, 692/699/375/365/1283, IMPUTATION, article, 1184 Genetics, developmental biology, physiology, Biología y Biomedicina / Biología, AMYLOID-BETA, Settore MED/26 - NEUROLOGIA, Neurology, psychology [Cognitive Dysfunction], Medical Genetics, Human, Neuroscience(all), 631/208/205/2138, All institutes and research themes of the Radboud University Medical Center, SDG 3 - Good Health and Well-being, ddc:570, Genetics, Genetic Predisposition to Disease, GENOME-WIDE ASSOCIATION, METAANALYSIS, Medicinsk genetik, MED/26 - NEUROLOGIA, Alzheimer Disease/genetics, neurology, tau Protein, NECROSIS-FACTOR-ALPHA, RISK LOCI, genetics [tau Proteins], PREDICTION MODELS, Human medicine, GENERATION, RESPONSES
Abstract: 25 páginas, 6 figuras, 2 tablas, Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele., This work was funded by a grant (EADB) from the EU Joint Programme – Neurodegenerative Disease Research. INSERM UMR1167 is also funded by the INSERM, Institut Pasteur de Lille, Lille Métropole Communauté Urbaine and French government’s LABEX DISTALZ program (development of innovative strategies for a transdisciplinary approach to AD). Full consortium acknowledgements and funding are in the Supplementary Not
Published: 2022

18. Dissecting the limited genetic overlap of Parkinson's and Alzheimer's disease

Author: Andersen, Maren Stolp, Tan, Manuela, Holtman, Inge R., Hardy, John, Pihlstrøm, Lasse, and Molecular Neuroscience and Ageing Research (MOLAR)
Subjects: Neurons, INSIGHTS, Alzheimer Disease, IMPACT, General Neuroscience, Humans, Parkinson Disease, Microglia, Neurology (clinical), GENOME-WIDE ASSOCIATION, RISK LOCI, Genome-Wide Association Study
Abstract: Parkinson's disease and Alzheimer's disease show overlapping features both clinically and neuropathologically and elucidating shared mechanisms could have important implications for therapeutic strategies. Evidence for genetic overlap is limited, although enrichment of heritability in genomic regions relevant to microglia has been demonstrated in both disorders. Using summary statistics from genome-wide association studies, we assessed genetic covariance stratified by cell types and local genetic correlation between Parkinson's and Alzheimer's disease. Significant covariance was observed for neurons only (p = 0.00046), and local genetic correlation was significant only in the human leukocyte antigen region (p = 1.0e-05). Our findings support a minor genetic overlap between these two disorders.
Published: 2022

19. A Swedish Familial Genome-Wide Haplotype Analysis Identified Five Novel Breast Cancer Susceptibility Loci on 9p24.3, 11q22.3, 15q11.2, 16q24.1 and Xq21.31

Author: Elin Barnekow, Johan Hasslow, Wen Liu, Patrick Bryant, Jessada Thutkawkorapin, Camilla Wendt, Kamila Czene, Per Hall, Sara Margolin, and Annika Lindblom
Subjects: GRIA4, haplotype, Cancer och onkologi, TGIF2LX, Organic Chemistry, familial, General Medicine, Catalysis, Computer Science Applications, Inorganic Chemistry, risk loci, breast cancer, Cancer and Oncology, SMARCA2, GWAS, Physical and Theoretical Chemistry, Molecular Biology, Spectroscopy
Abstract: Most breast cancer heritability is unexplained. We hypothesized that analysis of unrelated familial cases in a GWAS context could enable the identification of novel susceptibility loci. In order to examine the association of a haplotype with breast cancer risk, we performed a genome-wide haplotype association study using a sliding window analysis of window sizes 1–25 SNPs in 650 familial invasive breast cancer cases and 5021 controls. We identified five novel risk loci on 9p24.3 (OR 3.4; p 4.9 × 10−11), 11q22.3 (OR 2.4; p 5.2 × 10−9), 15q11.2 (OR 3.6; p 2.3 × 10−8), 16q24.1 (OR 3; p 3 × 10−8) and Xq21.31 (OR 3.3; p 1.7 × 10−8) and confirmed three well-known loci on 10q25.13, 11q13.3, and 16q12.1. In total, 1593 significant risk haplotypes and 39 risk SNPs were distributed on the eight loci. In comparison with unselected breast cancer cases from a previous study, the OR was increased in the familial analysis in all eight loci. Analyzing familial cancer cases and controls enabled the identification of novel breast cancer susceptibility loci.
Published: 2023

20. A reference human induced pluripotent stem cell line for collaborative studies

Author: Pantazis, Caroline B, Yang, Andrian, Lara, Erika, McDonough, Justin A, Blauwendraat, Cornelis, Peng, Lirong, Oguro, Hideyuki, Kanaujiya, Jitendra, Zou, Jizhong, Sebesta, David, Pratt, Gretchen, Cross, Erin, Blockwick, Jeffrey, Buxton, Philip, Kinner-Bibeau, Lauren, Medura, Constance, Tompkins, Christopher, Hughes, Stephen, Santiana, Marianita, Faghri, Faraz, Nalls, Mike A, Vitale, Daniel, Ballard, Shannon, Qi, Yue A, Ramos, Daniel M, Anderson, Kailyn M, Stadler, Julia, Narayan, Priyanka, Papademetriou, Jason, Reilly, Luke, Nelson, Matthew P, Aggarwal, Sanya, Rosen, Leah U, Kirwan, Peter, Pisupati, Venkat, Coon, Steven L, Scholz, Sonja W, Priebe, Theresa, Ottl, Miriam, Dong, Jian, Meijer, Marieke, Janssen, Lara JM, Lourenco, Vanessa S, van der Kant, Rik, Crusius, Dennis, Paquet, Dominik, Raulin, Ana-Caroline, Bu, Guojun, Held, Aaron, Wainger, Brian J, Gabriele, Rebecca MC, Casey, Jackie M, Wray, Selina, Abu-Bonsrah, Dad, Parish, Clare L, Beccari, Melinda S, Cleveland, Don W, Li, Emmy, Rose, Indigo VL, Kampmann, Martin, Aristoy, Carles Calatayud, Verstreken, Patrik, Heinrich, Laurin, Chen, Max Y, Schule, Birgitt, Dou, Dan, Holzbaur, Erika LF, Zanellati, Maria Clara, Basundra, Richa, Deshmukh, Mohanish, Cohen, Sarah, Khanna, Richa, Raman, Malavika, Nevin, Zachary S, Matia, Madeline, Van Lent, Jonas, Timmerman, Vincent, Conklin, Bruce R, Chase, Katherine Johnson, Zhang, Ke, Funes, Salome, Bosco, Daryl A, Erlebach, Lena, Welzer, Marc, Kronenberg-Versteeg, Deborah, Lyu, Guochang, Arenas, Ernest, Coccia, Elena, Sarrafha, Lily, Ahfeldt, Tim, Marioni, John C, Skarnes, William C, Cookson, Mark R, Ward, Michael E, and Merkle, Florian T
Subjects: Science & Technology, Cell Biology, DOPAMINE NEURONS, RISK LOCI, GENE, DISEASE, DIRECTIONAL GENOMIC HYBRIDIZATION, COPY NUMBER, DIFFERENTIATION, Cell & Tissue Engineering, HETEROGENEITY, Life Sciences & Biomedicine, A-BETA, GENERATION
Abstract: Human induced pluripotent stem cell (iPSC) lines are a powerful tool for studying development and disease, but the considerable phenotypic variation between lines makes it challenging to replicate key findings and integrate data across research groups. To address this issue, we sub-cloned candidate human iPSC lines and deeply characterized their genetic properties using whole genome sequencing, their genomic stability upon CRISPR-Cas9-based gene editing, and their phenotypic properties including differentiation to commonly used cell types. These studies identified KOLF2.1J as an all-around well-performing iPSC line. We then shared KOLF2.1J with groups around the world who tested its performance in head-to-head comparisons with their own preferred iPSC lines across a diverse range of differentiation protocols and functional assays. On the strength of these findings, we have made KOLF2.1J and its gene-edited derivative clones readily accessible to promote the standardization required for large-scale collaborative science in the stem cell field. ispartof: CELL STEM CELL vol:29 issue:12 pages:1685-+ ispartof: location:United States status: published
Published: 2022

21. Alzheimer’s disease-related transcriptional sex differences in myeloid cells

Author: Isabelle Coales, Stergios Tsartsalis, Nurun Fancy, Maria Weinert, Daniel Clode, David Owen, Paul M. Matthews, Medical Research Council (MRC), and UK DRI Ltd
Subjects: Male, MENOPAUSE, Immunology, BETA, IMMUNITY, ANK1, MICROGLIA, Cellular and Molecular Neuroscience, Neuroinflammation, Alzheimer Disease, Humans, Myeloid Cells, Neurodegeneration, Aged, Sex Characteristics, Science & Technology, Neurology & Neurosurgery, Estradiol, General Neuroscience, Neurosciences, 1103 Clinical Sciences, RISK LOCI, Neurology, 1107 Immunology, Sex, Female, Neurosciences & Neurology, 1109 Neurosciences, Life Sciences & Biomedicine
Abstract: Sex differences have been identified in many diseases associated with dysregulated immune responses, including Alzheimer’s disease (AD), for which approximately two-thirds of patients are women. An accumulating body of research indicates that microglia may play a causal role in the pathogenesis of this disease. We hypothesised that sex differences in the transcriptome of human myeloid cells may contribute to the sex difference observed in AD prevalence. To explore this, we assessed bulk and single-nuclear RNA sequencing data sets generated from four human derived myeloid cell populations: post-mortem microglial nuclei, peripheral monocytes, monocyte-derived macrophages (MDMs) and induced pluripotent stem cell derived microglial-like cells (MGLs). We found that expression of AD risk genes, gene signatures associated with the inflammatory response in AD, and genes related to proinflammatory immune responses were enriched in microglial nuclei isolated from aged female donors without ante-mortem neurological disease, relative to those from males. In addition, these inflammation-associated gene sets were found to be enriched in peripheral monocytes isolated from postmenopausal women and in MDMs obtained from premenopausal individuals relative to age-matched males. Expression of these gene sets did not differ in MDMs derived from women whose blood was sampled across the menstrual cycle or in MGLs cultured with 17β-oestradiol. This suggests that the observed gene set enrichments in myeloid cells from women were not being driven by acute hormonal influences. Together, these data support the hypothesis that the increased prevalence of AD in women may be partly explained by a myeloid cell phenotype biased towards expression of biological processes relevant to AD.
Published: 2022

22. Association of <italic>CDKN2A/CDKN2B</italic> with inflammatory bowel disease in Koreans.

Author: Lee, Ho‐su, Lee, Soo Bin, Kim, Byoung Mok, Hong, Myunghee, Jung, Seulgi, Hong, Jeonghoon, Baek, Jiwon, Han, Buhm, Oh, Seak Hee, Kim, Kyung Mo, Park, Sang Hyoung, Yang, Suk‐kyun, Ye, Byong Duk, and Song, Kyuyoung
Subjects: *CYCLIN-dependent kinase inhibitor-2A, *INFLAMMATORY bowel diseases, *KOREANS, *GENETIC regulation, *GENOMES, *GENETICS
Abstract: Abstract: Background and Aim: CDKN2A/CDKN2B locus on 9p21 is reported to be associated with various diseases, including cancer and cardiovascular and inflammatory diseases. Significant downregulation of CDKN2B‐AS1 in inflamed colon tissue of inflammatory bowel disease (IBD) cases was reported in Europeans. This study aimed to confirm the suggestive association of CDKN2A/CDKN2B with IBD identified in our recent genome‐wide association study (GWAS). Methods: We examined the association of CDKN2A/CDKN2B locus with IBD in an additional sample of 574 IBD cases and 542 controls, totaling 4068 cases and 8074 controls. In silico study was performed at various levels for functional annotation of the causal variant. Co‐localization of the GWAS association signals and the corresponding expression quantitative trait loci in IBD‐related tissues was evaluated using eCAVIAR. Results: An expanded GWAS showed genome‐wide significant association of rs3731257 at 9p21 with IBD (odds ratio = 1.17, 95% confidence interval = 1.12–1.22, Pcombined = 5.68 × 10−9) and Crohn's disease (odds ratio = 1.22, 95% confidence interval = 1.15–1.28, Pcombined = 8.85 × 10−9) in the Korean population. Co‐localization study suggested that both CDKN2B‐AS1 and CDKN2A might be functionally associated with the locus in the small intestine. Conclusions: rs3731257 in CDKN2A/CDKN2B is an IBD‐susceptible locus in Koreans, with a suggestive role for small intestine‐specific gene regulation. Our findings suggested that alterations of the CDKN2A/CDKN2B locus could affect the pathophysiology of IBD. [ABSTRACT FROM AUTHOR]
Published: 2018
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23. Estrogen-related receptor gamma regulates mitochondrial and synaptic genes and modulates vulnerability to synucleinopathy

Author: S. N. Fox, L. J. McMeekin, C. H. Savage, K. L. Joyce, S. M. Boas, M. S. Simmons, C. B. Farmer, J. Ryan, L. Pereboeva, K. Becker, J. Auwerx, S. Sudarshan, J. Ma, A. Lee, R. C. Roberts, D. K. Crossman, A. Kralli, and R. M. Cowell
Subjects: risk loci, fibrils, Cellular and Molecular Neuroscience, dysfunction, Neurology, err-gamma, alpha-synuclein, expression, genome-wide association, parkinsons-disease, Neurology (clinical), dopamine, transcriptional control
Abstract: Many studies implicate mitochondrial dysfunction as a key contributor to cell loss in Parkinson disease (PD). Previous analyses of dopaminergic (DAergic) neurons from patients with Lewy-body pathology revealed a deficiency in nuclear-encoded genes for mitochondrial respiration, many of which are targets for the transcription factor estrogen-related receptor gamma (Esrrg/ERRγ). We demonstrate that deletion of ERRγ from DAergic neurons in adult mice was sufficient to cause a levodopa-responsive PD-like phenotype with reductions in mitochondrial gene expression and number, that partial deficiency of ERRγ hastens synuclein-mediated toxicity, and that ERRγ overexpression reduces inclusion load and delays synuclein-mediated cell loss. While ERRγ deletion did not fully recapitulate the transcriptional alterations observed in postmortem tissue, it caused reductions in genes involved in synaptic and mitochondrial function and autophagy. Altogether, these experiments suggest that ERRγ-deficient mice could provide a model for understanding the regulation of transcription in DAergic neurons and that amplifying ERRγ-mediated transcriptional programs should be considered as a strategy to promote DAergic maintenance in PD.
Published: 2022

24. Distributed genetic architecture across the hippocampal formation implies common neuropathology across brain disorders

Author: Shahram Bahrami, Kaja Nordengen, Alexey A. Shadrin, Oleksandr Frei, Dennis van der Meer, Anders M. Dale, Lars T. Westlye, Ole A. Andreassen, Tobias Kaufmann, Psychiatry 2, RS: MHeNs - R2 - Mental Health, and Psychiatrie & Neuropsychologie
Subjects: Brain Diseases, GLYCINERGIC INHIBITION, Multidisciplinary, RECEPTOR, SEGMENTATION, General Physics and Astronomy, General Chemistry, Hippocampus, Polymorphism, Single Nucleotide, RISK LOCI, General Biochemistry, Genetics and Molecular Biology, White People, PARKINSONS-DISEASE, Genetic Loci, Humans, GENOME-WIDE ASSOCIATION, PLASTICITY, METAANALYSIS, SYSTEM, Genome-Wide Association Study, RESPONSES
Abstract: Despite its major role in complex human functions across the lifespan, most notably navigation, learning and memory, much of the genetic architecture of the hippocampal formation is currently unexplored. Here, through multivariate genome-wide association analysis in volumetric data from 35,411 white British individuals, we reveal 177 unique genetic loci with distributed associations across the hippocampal formation. We identify genetic overlap with eight brain disorders with typical onset at different stages of life, where common genes suggest partly age- and disorder-independent mechanisms underlying hippocampal pathology.The hippocampus has been associated with memory traits and a variety of neurodegenerative and psychiatric disorders. Here, the authors have done a multivariate GWAS revealing 177 genetic loci, and overlap with various brain disorders may suggest partly age- and disorder-independent mechanisms underlying hippocampal pathology.
Published: 2022

25. Association study reveals novel risk loci for sporadic inclusion body myositis.

Author: Johari, M., Arumilli, M., Palmio, J., Savarese, M., Tasca, G., Mirabella, M., Sandholm, N., Lohi, H., Hackman, P., and Udd, B.
Subjects: *MYOSITIS, *MUSCLE diseases, *NONARTICULAR rheumatism, *HLA histocompatibility antigens, *SINGLE nucleotide polymorphisms
Abstract: Background and purpose The aim was to identify potential genetic risk factors associated with sporadic inclusion body myositis ( sIBM). Methods An association based case−control approach was utilized on whole exome sequencing data of 30 Finnish sIBM patients and a control cohort ( n = 193). A separate Italian cohort of sIBM patients ( n = 12) was used for evaluation of the results. Results Seven single nucleotide polymorphisms were identified in five genes that have a considerably higher observed frequency in Finnish sIBM patients compared to the control population, and the previous association of the genetic human leukocyte antigen region was confirmed. Conclusions All seven identified variants could individually or in combination increase the susceptibility for sIBM. [ABSTRACT FROM AUTHOR]
Published: 2017
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26. Bromodomain protein 4 discriminates tissue-specific super-enhancers containing disease-specific susceptibility loci in prostate and breast cancer.

Author: Zuber, Verena, Bettella, Francesco, Witoelar, Aree, Andreassen, Ole A., Mills, Ian G., and Urbanucci, Alfonso
Subjects: *BREAST cancer risk factors, *SINGLE nucleotide polymorphisms, *CANCER invasiveness, *CHROMATIN, *EPIGENETICS
Abstract: Background: Epigenetic information can be used to identify clinically relevant genomic variants single nucleotide polymorphisms (SNPs) of functional importance in cancer development. Super-enhancers are cell-specific DNA elements, acting to determine tissue or cell identity and driving tumor progression. Although previous approaches have been tried to explain risk associated with SNPs in regulatory DNA elements, so far epigenetic readers such as bromodomain containing protein 4 (BRD4) and super-enhancers have not been used to annotate SNPs. In prostate cancer (PC), androgen receptor (AR) binding sites to chromatin have been used to inform functional annotations of SNPs. Results: Here we establish criteria for enhancer mapping which are applicable to other diseases and traits to achieve the optimal tissue-specific enrichment of PC risk SNPs. We used stratified Q-Q plots and Fisher test to assess the differential enrichment of SNPs mapping to specific categories of enhancers. We find that BRD4 is the key discriminant of tissuespecific enhancers, showing that it is more powerful than AR binding information to capture PC specific risk loci, and can be used with similar effect in breast cancer (BC) and applied to other diseases such as schizophrenia. Conclusions: This is the first study to evaluate the enrichment of epigenetic readers in genome-wide associations studies for SNPs within enhancers, and provides a powerful tool for enriching and prioritizing PC and BC genetic risk loci. Our study represents a proof of principle applicable to other diseases and traits that can be used to redefine molecular mechanisms of human phenotypic variation. [ABSTRACT FROM AUTHOR]
Published: 2017
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27. A meta-analysis of reflux genome-wide association studies in 6750 Northern Europeans from the general population.

Author: Bonfiglio, F., Hysi, P. G., Ek, W., Karhunen, V., Rivera, N. V., Männikkö, M., Nordenstedt, H., Zucchelli, M., Bresso, F., Williams, F., Tornblom, H., Magnusson, P. K., Pedersen, N. L., Ronkainen, J., Schmidt, P. T., and D'Amato, M.
Subjects: *GENOMES, *META-analysis, *PSYCHOMETRICS, *GASTROESOPHAGEAL reflux, *HEARTBURN
Abstract: Background Gastroesophageal reflux disease ( GERD), the regurgitation of gastric acids often accompanied by heartburn, affects up to 20% of the general population. Genetic predisposition is suspected from twin and family studies but gene-hunting efforts have so far been scarce and no conclusive genome-wide study has been reported. We exploited data available from general population samples, and studied self-reported reflux symptoms in relation to genome-wide single nucleotide polymorphism ( SNP) genotypes. Methods We performed a GWAS meta-analysis of three independent population-based cohorts from Sweden, Finland, and UK. GERD cases (n=2247) and asymptomatic controls (n=4503) were identified using questionnaire-derived symptom data. Upon stringent quality controls, genotype data for more than 2.5M markers were used for association testing. Bioinformatic characterization of genomic regions associated with GERD included gene-set enrichment analysis ( GSEA), in silico prediction of genetic risk effects on gene expression, and computational analysis of drug-induced gene expression signatures using Connectivity Map ( cMap). Key results We identified 30 GERD suggestive risk loci (P≤5×10−5), with concordant risk effects in all cohorts, and predicted functional effects on gene expression in relevant tissues. GSEA revealed involvement of GERD risk genes in biological processes associated with the regulation of ion channel and cell adhesion. From cMap analysis, omeprazole had significant effects on GERD risk gene expression, while antituberculosis and anti-inflammatory drugs scored highest among the repurposed compounds. Conclusions We report a large-scale genetic study of GERD, and highlight genes and pathways that contribute to further our understanding of its pathogenesis and therapeutic opportunities. [ABSTRACT FROM AUTHOR]
Published: 2017
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28. Sharing lessons learnt across European cardiovascular research consortia

Author: Jeanette Erdmann, Heribert Schunkert, Marijke Bijker-Schreurs, Ivana Bobeldijk-Pastorova, Lisette de Jong, Jan Albert Kuivenhoven, and Alain J. van Gool
Subjects: 0301 basic medicine, Pharmacology, Biomedical Research, business.industry, Cardiovascular research, MEDLINE, Metabolic Disorders Radboud Institute for Molecular Life Sciences [Radboudumc 6], Public relations, RISK LOCI, Europe, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, Drug Development, Work (electrical), Cardiovascular Diseases, 030220 oncology & carcinogenesis, Drug Discovery, Humans, Molecular Targeted Therapy, business, Disease treatment, Independent research
Abstract: Research consortia in Europe often compete with each other for skills, human and technical resources and, eventually, recognition of the scientific impact of their work. In response to the same EU Horizon2020 call, we received funding for our research project proposals to identify and validate novel drug targets for cardiovascular disease treatment. Each consortium followed a unique and independent research strategy. However, as coordinators of these consortia we envisioned we could increase impact, outcomes and efficiency by intensifying our interaction. At an agreed stage during our projects we chose to share our knowledge, vision and ideas. In this paper we present what we learned, in the hope that future consortia will see the benefits of this approach.
Published: 2020

29. Sharing lessons learnt across European cardiovascular research consortia

Subjects: RISK LOCI
Abstract: Research consortia in Europe often compete with each other for skills, human and technical resources and, eventually, recognition of the scientific impact of their work. In response to the same EU Horizon2020 call, we received funding for our research project proposals to identify and validate novel drug targets for cardiovascular disease treatment. Each consortium followed a unique and independent research strategy. However, as coordinators of these consortia we envisioned we could increase impact, outcomes and efficiency by intensifying our interaction. At an agreed stage during our projects we chose to share our knowledge, vision and ideas. In this paper we present what we learned, in the hope that future consortia will see the benefits of this approach.
Published: 2020

30. GCH1 Deficiency Activates Brain Innate Immune Response and Impairs Tyrosine Hydroxylase Homeostasis

Author: Hannah Larbalestier, Marcus Keatinge, Lisa Watson, Emma White, Siri Gowda, Wenbin Wei, Katjusa Koler, Svetlana A. Semenova, Adam M. Elkin, Neal Rimmer, Sean T. Sweeney, Julie Mazzolini, Dirk Sieger, Winston Hide, Jonathan McDearmid, Pertti Panula, Ryan B. MacDonald, Oliver Bandmann, Department of Anatomy, Medicum, Helsinki In Vivo Animal Imaging Platform (HAIP), Pertti Panula / Principal Investigator, and Neuroscience Center
Subjects: Tyrosine 3-Monooxygenase, DYSTONIA, Parkinson's disease, microglia, 3124 Neurology and psychiatry, Animals, Genetically Modified, DOPAMINE, PARKINSONS-DISEASE, tyrosine hydroxylase, Animals, Homeostasis, GTP CYCLOHYDROLASE-I, Genetic Predisposition to Disease, GENOME-WIDE ASSOCIATION, GTP Cyclohydrolase, Research Articles, SUBSTANTIA-NIGRA, NITRIC-OXIDE, Sequence Analysis, RNA, Dopaminergic Neurons, General Neuroscience, 3112 Neurosciences, Brain, Parkinson Disease, GTP cyclohydrolase 1, zebrafish, MICROGLIAL ACTIVATION, RISK LOCI, Immunity, Innate, MODEL, tetrahydrobiopterin
Abstract: The Parkinson's disease (PD) risk gene GTP cyclohydrolase 1 (GCH1) catalyzes the rate-limiting step in tetrahydrobiopterin (BH4) synthesis, an essential cofactor in the synthesis of monoaminergic neurotransmitters. To investigate the mechanisms by which GCH1 deficiency may contribute to PD, we generated a loss of function zebrafishgch1mutant (gch1–/–), using CRISPR/Cas technology.gch1–/–zebrafish develop marked monoaminergic neurotransmitter deficiencies by 5 d postfertilization (dpf), movement deficits by 8 dpf and lethality by 12 dpf. Tyrosine hydroxylase (Th) protein levels were markedly reduced without loss of ascending dopaminergic (DAergic) neurons. L-DOPA treatment ofgch1–/–larvae improved survival without ameliorating the motor phenotype. RNAseq ofgch1–/–larval brain tissue identified highly upregulated transcripts involved in innate immune response. Subsequent experiments provided morphologic and functional evidence of microglial activation ingch1–/–. The results of our study suggest that GCH1 deficiency may unmask early, subclinical parkinsonism and only indirectly contribute to neuronal cell death via immune-mediated mechanisms. Our work highlights the importance of functional validation for genome-wide association studies (GWAS) risk factors and further emphasizes the important role of inflammation in the pathogenesis of PD.SIGNIFICANCE STATEMENTGenome-wide association studies have now identified at least 90 genetic risk factors for sporadic Parkinson's disease (PD). Zebrafish are an ideal tool to determine the mechanistic role of genome-wide association studies (GWAS) risk genes in a vertebrate animal model. The discovery of GTP cyclohydrolase 1 (GCH1) as a genetic risk factor for PD was counterintuitive, GCH1 is the rate-limiting enzyme in the synthesis of dopamine (DA), mutations had previously been described in the non-neurodegenerative movement disorder dopa-responsive dystonia (DRD). Rather than causing DAergic cell death (as previously hypothesized by others), we now demonstrate that GCH1 impairs tyrosine hydroxylase (Th) homeostasis and activates innate immune mechanisms in the brain and provide evidence of microglial activation and phagocytic activity.
Published: 2022

31. Missing lnc(RNAs) in Alzheimer's Disease?

Author: Rafaela Policarpo and Constantin d’Ydewalle
Subjects: Genetics & Heredity, EXPRESSION, MICRORNA-125B, Science & Technology, PROMOTES, COMMON VARIANTS, PROTEIN, QH426-470, Alzheimer's disease, LONG NONCODING RNAS, RISK LOCI, long non-coding RNAs, Genetics, gene expression, GENOME-WIDE ASSOCIATION, CD33, Alzheimer’s disease, Life Sciences & Biomedicine, Genetics (clinical), A-BETA
Abstract: With the ongoing demographic shift towards increasingly elderly populations, it is estimated that approximately 150 million people will live with Alzheimer's disease (AD) by 2050. By then, AD will be one of the most burdensome diseases of this and potentially next centuries. Although its exact etiology remains elusive, both environmental and genetic factors play crucial roles in the mechanisms underlying AD neuropathology. Genome-wide association studies (GWAS) identified genetic variants associated with AD susceptibility in more than 40 different genomic loci. Most of these disease-associated variants reside in non-coding regions of the genome. In recent years, it has become clear that functionally active transcripts arise from these non-coding loci. One type of non-coding transcript, referred to as long non-coding RNAs (lncRNAs), gained significant attention due to their multiple roles in neurodevelopment, brain homeostasis, aging, and their dysregulation or dysfunction in neurological diseases including in AD. Here, we will summarize the current knowledge regarding genetic variations, expression profiles, as well as potential functions, diagnostic or therapeutic roles of lncRNAs in AD. We postulate that lncRNAs may represent the missing link in AD pathology and that unraveling their role may open avenues to better AD treatments. ispartof: GENES vol:13 issue:1 ispartof: location:Switzerland status: published
Published: 2022

32. A simple and efficient algorithm for genome‐wide homozygosity analysis in disease

Author: Wei Liu, Jinhui Ding, Jesse Raphael Gibbs, Sue Jane Wang, John Hardy, and Andrew Singleton
Subjects: disease network, homozygous segments, risk loci, statistical algorithm, whole‐genome screening, Biology (General), QH301-705.5, Medicine (General), R5-920
Abstract: Abstract Here we propose a simple statistical algorithm for rapidly scoring loci associated with disease or traits due to recessive mutations or deletions using genome‐wide single nucleotide polymorphism genotyping case–control data in unrelated individuals. This algorithm identifies loci by defining homozygous segments of the genome present at significantly different frequencies between cases and controls. We found that false positive loci could be effectively removed from the output of this procedure by applying different physical size thresholds for the homozygous segments. This procedure is then conducted iteratively using random sub‐datasets until the number of selected loci converges. We demonstrate this method in a publicly available data set for Alzheimer's disease and identify 26 candidate risk loci in the 22 autosomes. In this data set, these loci can explain 75% of the genetic risk variability of the disease.
Published: 2009
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33. SNCA 3′ UTR Genetic Variants in Patients with Parkinson’s Disease

Author: Borovečki, Antonela Blažeković, Kristina Gotovac Jerčić, and Fran
Subjects: Parkinson’s disease, 3′ UTR, alpha-synuclein, PINK1, linkage disequilibrium, risk loci, next generation sequencing, single nucleotide polymorphism
Abstract: The SNCA (Synuclein Alpha) gene represents a major risk gene for Parkinson’s disease (PD) and SNCA polymorphisms have been associated with the common sporadic form of PD. Numerous Genome-Wide Association Studies showed strong signals located in the SNCA 3′ UTR (untranslated region) region indicating that variants in 3′ UTRs of PD-associated genes could contribute to neurodegeneration and may regulate the risk for PD. Genetic variants in 3′ UTR can affect miRNA activity and consequently change the translation process. The aim of this study was to access the differences in 3′ UTR variants of SNCA genes in a cohort of PD patients and control subjects from Croatia. The cohort consisted of 52 PD patients and 23 healthy control subjects. Differences between 3′ UTR allele and genotype frequencies were accessed through next generation sequencing approach from whole blood samples. In our study, we identified four previously reported single nucleotide polymorphisms (SNPs) and one insertion in the 3′ UTR region of SNCA gene, namely rs1045722, rs3857053, rs577490090, rs356165, and rs777296100, and five variants not reported in the literature, namely rs35270750, rs529553259, rs377356638, rs571454522, and rs750347645. Our results indicate a significantly higher occurrence of the rs571454522 variant in the PD population. To the best of our knowledge, this variant has not been reported until now in the literature. We analyzed our results in the context of previous research, creating a brief overview of the importance of 3′ UTR variants of the SNCA gene. Further studies will be needed to gain a more profound insight regarding their role in PD development, which will help to assess the role and impact of post-transcriptional regulation on disease pathology.
Published: 2021
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34. Generalizability of GWA-Identified Genetic Risk Variants for Metabolic Traits to Populations from the Arabian Peninsula

Author: Fahd Al-Mulla, Prashantha Hebbar, Mohamed Abu-Farha, Thangavel Alphonse Thanaraj, Jehad Abubaker, and Arshad Channanath
Subjects: Linkage disequilibrium, Context (language use), Genome-wide association study, Consanguinity, Review, Biology, QH426-470, Linkage Disequilibrium, Metabolic Diseases, Risk Factors, Genetics, Humans, GWAS, Genetic Predisposition to Disease, Arab ancestry, Allele frequency, Qatar, Genetics (clinical), population diversity, social sciences, transferability of risk loci, Heritability, Lipid Metabolism, Arabs, risk loci, Genetics, Population, Kuwait, Evolutionary biology, Gene-Environment Interaction, metabolic traits, Inbreeding, Imputation (genetics), geographic locations, Genome-Wide Association Study
Abstract: The Arabian Peninsula, located at the nexus of Africa, Europe, and Asia, was implicated in early human migration. The Arab population is characterized by consanguinity and endogamy leading to inbreeding. Global genome-wide association (GWA) studies on metabolic traits under-represent the Arab population. Replicability of GWA-identified association signals in the Arab population has not been satisfactorily explored. It is important to assess how well GWA-identified findings generalize if their clinical interpretations are to benefit the target population. Our recent study from Kuwait, which performed genome-wide imputation and meta-analysis, observed 304 (from 151 genes) of the 4746 GWA-identified metabolic risk variants replicable in the Arab population. A recent large GWA study from Qatar found replication of 30 GWA-identified lipid risk variants. These complementing studies from the Peninsula increase the confidence in generalizing metabolic risk loci to the Arab population. However, both the studies reported a low extent of transferability. In this review, we examine the observed low transferability in the context of differences in environment, genetic correlations (allele frequencies, linkage disequilibrium, effect sizes, and heritability), and phenotype variance. We emphasize the need for large-scale GWA studies on deeply phenotyped cohorts of at least 20,000 Arab individuals. The review further presents GWA-identified metabolic risk variants generalizable to the Arab population.
Published: 2021

35. rs641738C>T nearMBOAT7is associated with liver fat, ALT and fibrosis in NAFLD: A meta-analysis

Author: Medicina, Medikuntza, Teo, Kevin, Abeysekera, Kushala W.M., Adams, Leon, Aigner, Elmar, Anstee, Quentin M., Bañales Asurmendi, Jesús María, Banerjee, Rajarshi, Basu, Priyadarshi, Berg, Thomas, Bhatnagar, Pallav, Buch, Stephan, Canbay, Ali, Caprio, Sonia, Chatterjee, Ankita, Chen, Yii-Der Ida, Chowdhury, Abhijit, Daly, Ann K., Datz, Christian, De Gracia Hahn, Dana, DiStefano, Johanna K., Dong, Jiawen, Duret, Amedine, EU-PNAFLD Investigators, Emdin, Connor, Fairey, Madison, Gerhard, Glenn S., GOLD Consortium, Guo, Xiuqing, Hampe, Jochen, Hickman, Matthew, Heintz, Lena, Hudert, Christian, Hunter, Harriet, Kelly, Matt, Kozlitina, Julia, Krawczyk, Marcin, Lammert, Frank, Langenberg, Claudia, Lavine, Joel, Li, Lin, Lim, Hong Kai, Loomba, Rohit, Luukkonen, Panu K., Melton, Phillip E., Mori, Trevor A., Palmer, Nicholette D., Parisinos, Constantinos A., Pillai, Sreekumar G., Qayyum, Faiza, Reichert, Matthias C., Romeo, Stefano, Rotter, Jerome I., Im, Yu Ri, Santoro, Nicola, Schafmayer, Clemens, Speliotes, Elizabeth K., Stender, Stefan, Stickel, Felix, Still, Christopher D., Strnad, Pavel, Taylor, Kent D., Tybjærg-Hansen, Anne, Umano, Giuseppina Rosaria, Utukuri, Mrudula, Valenti, Luca, Wagenknecht, Lynne E., Wareham, Nicholas J., Watanabe, Richard M., Wattacheril, Julia, Yaghootkar, Hanieh, Yki-Järvinen, Hannele, Young, Kendra A., Mann, Jake P., Medicina, Medikuntza, Teo, Kevin, Abeysekera, Kushala W.M., Adams, Leon, Aigner, Elmar, Anstee, Quentin M., Bañales Asurmendi, Jesús María, Banerjee, Rajarshi, Basu, Priyadarshi, Berg, Thomas, Bhatnagar, Pallav, Buch, Stephan, Canbay, Ali, Caprio, Sonia, Chatterjee, Ankita, Chen, Yii-Der Ida, Chowdhury, Abhijit, Daly, Ann K., Datz, Christian, De Gracia Hahn, Dana, DiStefano, Johanna K., Dong, Jiawen, Duret, Amedine, EU-PNAFLD Investigators, Emdin, Connor, Fairey, Madison, Gerhard, Glenn S., GOLD Consortium, Guo, Xiuqing, Hampe, Jochen, Hickman, Matthew, Heintz, Lena, Hudert, Christian, Hunter, Harriet, Kelly, Matt, Kozlitina, Julia, Krawczyk, Marcin, Lammert, Frank, Langenberg, Claudia, Lavine, Joel, Li, Lin, Lim, Hong Kai, Loomba, Rohit, Luukkonen, Panu K., Melton, Phillip E., Mori, Trevor A., Palmer, Nicholette D., Parisinos, Constantinos A., Pillai, Sreekumar G., Qayyum, Faiza, Reichert, Matthias C., Romeo, Stefano, Rotter, Jerome I., Im, Yu Ri, Santoro, Nicola, Schafmayer, Clemens, Speliotes, Elizabeth K., Stender, Stefan, Stickel, Felix, Still, Christopher D., Strnad, Pavel, Taylor, Kent D., Tybjærg-Hansen, Anne, Umano, Giuseppina Rosaria, Utukuri, Mrudula, Valenti, Luca, Wagenknecht, Lynne E., Wareham, Nicholas J., Watanabe, Richard M., Wattacheril, Julia, Yaghootkar, Hanieh, Yki-Järvinen, Hannele, Young, Kendra A., and Mann, Jake P.
Abstract: Background & Aims: A common genetic variant near MBOAT7 (rs641738C>T) has been previously associated with hepatic fat and advanced histology in NAFLD; however, these findings have not been consistently replicated in the literature. We aimed to establish whether rs641738C>T is a risk factor across the spectrum of NAFLD and to characterise its role in the regulation of related metabolic phenotypes through a meta-analysis. Methods: We performed a meta-analysis of studies with data on the association between rs641738C>T genotype and liver fat, NAFLD histology, and serum alanine aminotransferase (ALT), lipids or insulin. These included directly genotyped studies and population-level data from genome-wide association studies (GWAS). We performed a random effects meta-analysis using recessive, additive and dominant genetic models. Results: Data from 1,066,175 participants (9,688 with liver biopsies) across 42 studies were included in the meta-analysis. rs641738C>T was associated with higher liver fat on CT/MRI (+0.03 standard deviations [95% CI 0.02-0.05], p(z) = 4.8x10(-5)) and diagnosis of NAFLD (odds ratio [OR] 1.17 [95% CI 1.05-1.3], p(z) = 0.003) in Caucasian adults. The variant was also positively associated with presence of advanced fibrosis (OR 1.22 [95% CI 1.03-1.45], p(z) = 0.021) in Caucasian adults using a recessive model of inheritance (CC + CT vs. TT). Meta-analysis of data from previous GWAS found the variant to be associated with higher ALT (p(z) = 0.002) and lower serum triglycerides (p(z) = 1.5x10(-4)). rs641738C>T was not associated with fasting insulin and no effect was observed in children with NAFLD. Conclusions: Our study validates rs641738C>T near MBOAT7 as a risk factor for the presence and severity of NAFLD in individuals of European descent. Lay summary: Fatty liver disease is a common condition where fat builds up in the liver, which can cause liver inflammation and scarring (including 'cirrhosis'). It is closely linked to obesity and diabetes
Published: 2021

36. From Stem Cells to Populations—Using hiPSC, Next-Generation Sequencing, and GWAS to Explore the Genetic and Molecular Mechanisms of Congenital Heart Defects

Author: Broberg, Martin, Hästbacka, Johanna, Helle, Emmi, Institute for Molecular Medicine Finland, STEMM - Stem Cells and Metabolism Research Program, Faculty of Medicine, University of Helsinki, Helsinki Institute of Life Science HiLIFE, HUS Children and Adolescents, Children's Hospital, Clinicum, and Kivelä Lab
Subjects: IMPACT, massively parallel sequencing, NOTCH1 MUTATIONS, 1184 Genetics, developmental biology, physiology, EXOME, PATIENT, RISK LOCI, congenital heart disease, DISEASE, human induced pluripotent stem cells, DE-NOVO MUTATIONS, genome-wide association studies, genetics, 3111 Biomedicine, GENOME-WIDE ASSOCIATION, COPY-NUMBER VARIANTS, METAANALYSIS
Abstract: Congenital heart defects (CHD) are developmental malformations affecting the heart and the great vessels. Early heart development requires temporally regulated crosstalk between multiple cell types, signaling pathways, and mechanical forces of early blood flow. While both genetic and environmental factors have been recognized to be involved, identifying causal genes in non-syndromic CHD has been difficult. While variants following Mendelian inheritance have been identified by linkage analysis in a few families with multiple affected members, the inheritance pattern in most familial cases is complex, with reduced penetrance and variable expressivity. Furthermore, most non-syndromic CHD are sporadic. Improved sequencing technologies and large biobank collections have enabled genome-wide association studies (GWAS) in non-syndromic CHD. The ability to generate human to create human induced pluripotent stem cells (hiPSC) and further differentiate them to organotypic cells enables further exploration of genotype–phenotype correlations in patient-derived cells. Here we review how these technologies can be used in unraveling the genetics and molecular mechanisms of heart development.
Published: 2021

37. Parkinson's disease age at onset genome‐wide association study: Defining heritability, genetic loci, and α‐synuclein mechanisms

Author: Lisa M. Shulman, Hirotaka Iwaki, David A. Hinds, Jacob Gratten, Huw R. Morris, Joseph Jankovic, Costanza L. Vallerga, J. Raphael Gibbs, John Hardy, Javier Simón-Sánchez, Johan Marinus, Thomas Gasser, Peter Heutink, Alexis Brice, Andrew B. Singleton, Dena G. Hernandez, Jean-Christophe Corvol, Karl Heilbron, Donald G. Grosset, Manu Sharma, Ari Siitonen, Peter M. Visscher, Sonja W. Scholz, Pentti J. Tienari, Lynne Krohn, Mathias Toft, Manuela Tan, Johanna Eerola-Rautio, Mike A. Nalls, Jacobus J. van Hilten, Lasse Pihlstrøm, Claudia Schulte, Ziv Gan-Or, Sara Bandres-Ciga, Cornelis Blauwendraat, Hampton L. Leonard, Alastair J. Noyce, Kari Majamaa, Rainer von Coelln, N Wood, Joshua M. Shulman, Suzanne Lesage, HUS Neurocenter, Pentti Tienari / Principal Investigator, Neurologian yksikkö, Research Programs Unit, Department of Neurosciences, STEMM - Stem Cells and Metabolism Research Program, University of Helsinki, and University Management
Subjects: Male, GLUCOCEREBROSIDASE, 0301 basic medicine, Parkinson's disease, EFFICIENT, Genome-wide association study, genetics [Glucosylceramidase], 3124 Neurology and psychiatry, 0302 clinical medicine, genetics [Parkinson Disease], STATISTICAL POWER, Databases, Genetic, TMEM175, Age of Onset, LONGEVITY, Aged, 80 and over, Genetics, Parkinson Disease, Middle Aged, 3. Good health, Neurology, alpha-Synuclein, genetics [alpha-Synuclein], Glucosylceramidase, Female, GBA, age at onset, APOE, Adult, EXPRESSION, PENETRANCE, Context (language use), Biology, Leucine-Rich Repeat Serine-Threonine Protein Kinase-2, Polymorphism, Single Nucleotide, Article, Young Adult, 03 medical and health sciences, Genetic variation, Humans, Genetic Predisposition to Disease, ddc:610, Genetic variability, Allele, Alleles, METAANALYSIS, Aged, Genetic association, 3112 Neurosciences, Heritability, RISK LOCI, 030104 developmental biology, Genetic Loci, GBA MUTATIONS, genetics [Leucine-Rich Repeat Serine-Threonine Protein Kinase-2], SNCA, Neurology (clinical), Age of onset, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract: Background Increasing evidence supports an extensive and complex genetic contribution to PD. Previous genome-wide association studies (GWAS) have shed light on the genetic basis of risk for this disease. However, the genetic determinants of PD age at onset are largely unknown. Objectives To identify the genetic determinants of PD age at onset. Methods Using genetic data of 28,568 PD cases, we performed a genome-wide association study based on PD age at onset. Results We estimated that the heritability of PD age at onset attributed to common genetic variation was similar to 0.11, lower than the overall heritability of risk for PD (similar to 0.27), likely, in part, because of the subjective nature of this measure. We found two genome-wide significant association signals, one at SNCA and the other a protein-coding variant in TMEM175, both of which are known PD risk loci and a Bonferroni-corrected significant effect at other known PD risk loci, GBA, INPP5F/BAG3, FAM47E/SCARB2, and MCCC1. Notably, SNCA, TMEM175, SCARB2, BAG3, and GBA have all been shown to be implicated in alpha-synuclein aggregation pathways. Remarkably, other well-established PD risk loci, such as GCH1 and MAPT, did not show a significant effect on age at onset of PD. Conclusions Overall, we have performed the largest age at onset of PD genome-wide association studies to date, and our results show that not all PD risk loci influence age at onset with significant differences between risk alleles for age at onset. This provides a compelling picture, both within the context of functional characterization of disease-linked genetic variability and in defining differences between risk alleles for age at onset, or frank risk for disease. (c) 2019 International Parkinson and Movement Disorder Society
Published: 2019

38. Moderate-to-severe asthma in individuals of European ancestry

Subjects: HAY-FEVER, EXPRESSION, BLOOD, SUSCEPTIBILITY LOCI, ALLERGIC DISEASE, IDENTIFICATION, VARIANTS, RISK LOCI, METAANALYSIS, LUNG
Abstract: Background Few genetic studies that focus on moderate-to-severe asthma exist. We aimed to identity novel genetic variants associated with moderate-to-severe asthma, see whether previously identified genetic variants for all types of asthma contribute to moderate-to-severe asthma, and provide novel mechanistic insights using expression analyses in patients with asthma.Methods In this genome-wide association study, we used a two-stage case-control design. In stage 1, we genotyped patient-level data from two UK cohorts (the Genetics of Asthma Severity and Phenotypes [GASP] initiative and the Unbiased BIOmarkers in PREDiction of respiratory disease outcomes [U-BIOPRED] project) and used data from the UK Biobank to collect patient-level genomic data for cases and controls of European ancestry in a 1: 5 ratio. Cases were defined as having moderate-to-severe asthma if they were taking appropriate medication or had been diagnosed by a doctor. Controls were defined as not having asthma, rhinitis, eczema, allergy, emphysema, or chronic bronchitis as diagnosed by a doctor. For stage 2, an independent cohort of cases and controls (1: 5) was selected from the UK Biobank only, with no overlap with stage 1 samples. In stage 1 we undertook a genome-wide association study of moderate-to-severe asthma, and in stage 2 we followed up independent variants that reached the significance threshold of p less than 1 x 10(-6) in stage 1. We set genome-wide significance at p less than 5 x 10(-8). For novel signals, we investigated their effect on all types of asthma (mild, moderate, and severe). For all signals meeting genome-wide significance, we investigated their effect on gene expression in patients with asthma and controls.Findings We included 5135 cases and 25 675 controls for stage 1, and 5414 cases and 21 471 controls for stage 2. We identified 24 genome-wide significant signals of association with moderate-to-severe asthma, including several signals in innate or adaptive immune-response genes. Three novel signals were identified: rs10905284 in GATA3 (coded allele A, odds ratio [OR] 0.90, 95% CI 0 . 88-0.93; p=1.76 x 10(-10)), rs11603634 in the MUC5AC region (coded allele G, OR 1.09, 1.06-1.12; p=2.32 x 10(-8)), and rs560026225 near KIAA1109 (coded allele GATT, OR 1.12, 1.08-1.16; p=3.06 x 10(-9)). The MUC5AC signal was not associated with asthma when analyses included mild asthma. The rs11603634 G allele was associated with increased expression of MUC5AC mRNA in bronchial epithelial brush samples via proxy SNP rs11602802; (p=2.50 x 10(-5)) and MUC5AC mRNA was increased in bronchial epithelial samples from patients with severe asthma (in two independent analyses, p=0.039 and p=0.022).Interpretation We found substantial shared genetic architecture between mild and moderate-to-severe asthma. We also report for the first time genetic variants associated with the risk of developing moderate-to-severe asthma that regulate mucin production. Finally, we identify candidate causal genes in these loci and provide increased insight into this difficult to treat population. Copyright (c) 2018 The Author(s). Published by Elsevier Ltd.
Published: 2019

39. High-density genetic mapping identifies new susceptibility loci for rheumatoid arthritis

Author: Mark Caulfield, Solbritt Rantapää Dahlqvist, Eleftheria Zeggini, Michael Weedon, Paul Martin, Elaine Dennison, Patricia Munroe, Detelina Grozeva, John Isaacs, Stephen Eyre, Alex MacGregor, Kate Duffus, Andrew Hattersley, DOROTHEE DIOGO, Luis Rodriguez-Rodriguez, Steven Young-Min, Chris Wallace, Miguel Gonzalez-Gay, Tom Huizinga, Stephen Newhouse, Alexandra Zhernakova, Melanie Newport, Deborah Symmons, Lisa Jones, Michael O'Donovan, Wan-Fai Ng, Nadira Yusupovna Yuldasheva, Cyrus Cooper, Willem Ouwehand, Philip Conaghan, Gerome Breen, Lars Alfredsson, Karim Raza, Hana Lango Allen, Jane Worthington, Mark Iles, Ann Morgan, Professor David Dunger, Soumya Raychaudhuri, Panos Deloukas, Marwan Bukhari, Alastair Forbes, Allan Young, Lars Klareskog, Leonid Padyukov, Fraser Birrell, Charlie Lees, Anne Barton, Martin Tobin, Patrick Concannon, Jon Packham, Natalie Prescott, Javier Martin, Kimme Hyrich, Lude Franke, John Bowes, Ian Bruce, Chiea Chuen Khor, Stephen Rich, Miles Parkes, Sarah Hunt, Tim Bishop, Gosia Trynka, Richard Dobson, Anna Dominiczak, Cisca Wijmenga, Mark McCarthy, Cecilia Lindgren, Rene Toes, Alistair Hall, Faculteit Medische Wetenschappen/UMCG, Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Translational Immunology Groningen (TRIGR), Stem Cell Aging Leukemia and Lymphoma (SALL), Bowes, John [0000-0003-4659-031X], Zhernakova, Alexandra [0000-0002-4574-0841], Padyukov, Leonid [0000-0003-2950-5670], Toes, Rene EM [0000-0002-9618-6414], Wijmenga, Cisca [0000-0002-5635-1614], Trynka, Gosia [0000-0002-6955-9529], Franke, Lude [0000-0002-5159-8802], Alfredsson, Lars [0000-0003-1688-6697], Khor, Chiea Chuen [0000-0002-1128-4729], Concannon, Pat [0000-0002-5801-1859], Onengut-Gumuscu, Suna [0000-0002-6563-8334], Rodriguez-Rodriguez, Luis [0000-0002-2869-7861], Rantapää-Dahlqvist, Solbritt [0000-0001-8259-3863], Raychaudhuri, Soumya [0000-0002-1901-8265], Klareskog, Lars [0000-0001-9601-6186], and Apollo - University of Cambridge Repository
Subjects: EXPRESSION, Male, Arthritis, Genome-wide association study, Biology, Polymorphism, Single Nucleotide, Article, White People, Arthritis, Rheumatoid, 03 medical and health sciences, 0302 clinical medicine, Gene mapping, Polymorphism (computer science), Genetics, medicine, SNP, Humans, CORONARY-HEART-DISEASE, Genetic Predisposition to Disease, Genotyping, METAANALYSIS, 030304 developmental biology, Genetic association, Autoantibodies, Oligonucleotide Array Sequence Analysis, 030203 arthritis & rheumatology, 0303 health sciences, Chromosome Mapping, ASSOCIATION, medicine.disease, RISK LOCI, INTERLEUKIN-6 RECEPTOR, Genetic Loci, Female, SNP array, Genome-Wide Association Study
Abstract: Using the Immunochip custom SNP array, which was designed for dense genotyping of 186 loci identified through genome-wide association studies (GWAS), we analyzed 11,475 individuals with rheumatoid arthritis (cases) of European ancestry and 15,870 controls for 129,464 markers. We combined these data in a meta-analysis with GWAS data from additional independent cases (n = 2,363) and controls (n = 17,872). We identified 14 new susceptibility loci, 9 of which were associated with rheumatoid arthritis overall and five of which were specifically associated with disease that was positive for anticitrullinated peptide antibodies, bringing the number of confirmed rheumatoid arthritis risk loci in individuals of European ancestry to 46. We refined the peak of association to a single gene for 19 loci, identified secondary independent effects at 6 loci and identified association to low-frequency variants at 4 loci. Bioinformatic analyses generated strong hypotheses for the causal SNP at seven loci. This study illustrates the advantages of dense SNP mapping analysis to inform subsequent functional investigations.
Published: 2021
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40. The genetic architecture of the human thalamus and its overlap with ten common brain disorders

Author: Shahram Bahrami, Torbjørn Elvsåshagen, Lars T. Westlye, Tobias Kaufmann, Vinod Kumar, Oleksandr Frei, Dennis van der Meer, Olav B. Smeland, Alexey A. Shadrin, Ole A. Andreassen, RS: MHeNs - R2 - Mental Health, and Psychiatrie & Neuropsychologie
Subjects: 0301 basic medicine, Linkage disequilibrium, CHROMATIN-STATE DISCOVERY, THALAMOCORTICAL DYSCONNECTIVITY, General Physics and Astronomy, Genome-wide association study, Linkage Disequilibrium, 0302 clinical medicine, Thalamus, Genetics research, SCHIZOPHRENIA, Cerebral Cortex, Brain Diseases, Brain Mapping, Multidisciplinary, Mental Disorders, Brain, Magnetic Resonance Imaging, Schizophrenia, Thalamic Nuclei, EXPRESSION, Science, Quantitative Trait Loci, Single-nucleotide polymorphism, Biology, Polymorphism, Single Nucleotide, General Biochemistry, Genetics and Molecular Biology, Article, 03 medical and health sciences, Neuroimaging, medicine, Humans, Genetic Predisposition to Disease, GENOME-WIDE ASSOCIATION, METAANALYSIS, IDENTIFICATION, Genome, Human, General Chemistry, medicine.disease, RISK LOCI, Human genetics, Genetic architecture, INDIVIDUALS, 030104 developmental biology, Genetic Loci, PROJECTIONS, Diseases of the nervous system, Psychiatric disorders, Neuroscience, 030217 neurology & neurosurgery, Neurological disorders, Genome-Wide Association Study
Abstract: The thalamus is a vital communication hub in the center of the brain and consists of distinct nuclei critical for consciousness and higher-order cortical functions. Structural and functional thalamic alterations are involved in the pathogenesis of common brain disorders, yet the genetic architecture of the thalamus remains largely unknown. Here, using brain scans and genotype data from 30,114 individuals, we identify 55 lead single nucleotide polymorphisms (SNPs) within 42 genetic loci and 391 genes associated with volumes of the thalamus and its nuclei. In an independent validation sample (n = 5173) 53 out of the 55 lead SNPs of the discovery sample show the same effect direction (sign test, P = 8.6e-14). We map the genetic relationship between thalamic nuclei and 180 cerebral cortical areas and find overlapping genetic architectures consistent with thalamocortical connectivity. Pleiotropy analyses between thalamic volumes and ten psychiatric and neurological disorders reveal shared variants for all disorders. Together, these analyses identify genetic loci linked to thalamic nuclei and substantiate the emerging view of the thalamus having central roles in cortical functioning and common brain disorders., Differences in thalamic structure have been observed in several psychiatric disorders, but the genetic overlap has not been explored. Here, the authors perform a genome-wide association study on thalamic nuclei volume and find genetic loci in common between thalamic volumes and brain disorders.
Published: 2021

41. MicroRNA analysis of childhood atopic dermatitis reveals a role for miR-451a

Author: Maeve A. McAleer, Alan D. Irvine, Sanja Kezic, Reiko J. Tanaka, J. Nousbeck, Guillem Hurault, E. Kenny, K. Harte, APH - Societal Participation & Health, APH - Personalized Medicine, Coronel Institute of Occupational Health, AII - Inflammatory diseases, and British Skin Foundation
Subjects: EXPRESSION, Small RNA, RNA-sequencing, Dermatology, Biology, Real-Time Polymerase Chain Reaction, Peripheral blood mononuclear cell, DISEASE, Dermatitis, Atopic, CELL-PROLIFERATION, 030207 dermatology & venereal diseases, 03 medical and health sciences, 0302 clinical medicine, CIRCULATING MICRORNAS, children, HEPATOCELLULAR-CARCINOMA, microRNA, Gene expression, Humans, 1112 Oncology and Carcinogenesis, PROTEASOME SUBUNIT, Child, SUPPRESSION, Atopic dermatitis, LIPODYSTROPHY, Science & Technology, Gene Expression Profiling, Dermatology & Venereal Diseases, Infant, PSMB8, 1103 Clinical Sciences, RISK LOCI, Reverse transcriptase, MIR-143/145, MicroRNAs, Interleukin-6 receptor, Immunology, Leukocytes, Mononuclear, Biomarker (medicine), Life Sciences & Biomedicine
Abstract: Background MicroRNAs (miRNAs), important regulators of gene expression, have been implicated in a variety of disorders. The expression pattern of miRNAs in paediatric atopic dermatitis (AD) has not been well studied. Objectives We sought to investigate miRNA expression profiles in different blood compartments of infants with AD. Methods Small RNA and analysis with the HTG EdgeSeq system were performed to identify differentially expressed miRNAs in peripheral blood mononuclear cells (PBMCs) and plasma of infants with AD vs. age-matched healthy controls, with reverse transcription quantitative real-time polymerase chain reaction (RT-qPCR) used for validation and measurement of miRNA targets. Logistic regression models with area under the receiving operating characteristic estimation was used to evaluate the diagnostic potential of chosen miRNAs for AD. Results RNA sequencing was performed to access miRNA expression profiles in paediatric AD. We identified 10 differentially expressed miRNAs in PBMCs and eight dysregulated miRNAs in plasma of infants with AD compared with controls. Upregulated miRNAs in PBMCs included miRNAs known to be involved in inflammation: miR-223-3p, miR-126-5p and miR-143-3p. Differential expression of only one miRNA, miR-451a, was observed in both PBMCs and plasma of children with AD. Dysregulation of three miRNAs (miR-451a, miR-143-3p and miR-223-3p) was validated in larger numbers of samples and miR-451a was identified as a predictive biomarker for the early diagnosis of the disease. Experimentally verified targets of miR-451a, interleukin 6 receptor (IL6R) and proteasome subunit beta type-8 (PSMB8), were increased in patients with AD, negatively correlated with miR-451a levels and upregulated following inhibition of miR-451a in PBMCs. Conclusions In infants with AD, a distinct peripheral blood miRNA signature is seen, highlighting the systemic effects of the disease. miR-451a is uniquely expressed in different blood compartments of patients with AD and may serve as a promising novel biomarker for the early diagnosis of AD.
Published: 2021

42. Associations of ApoE Polymorphisms with Postoperative Atrial Fibrillation and Cardiac Injury in Patients with Coronary Artery Bypass Graft Surgery.

Author: Xue H, Fan L, and Liu C
Subjects: Humans, Apolipoprotein E3, Apolipoprotein E4 genetics, Apolipoproteins E genetics, Biomarkers, Coronary Artery Bypass adverse effects, Polymorphism, Genetic, Postoperative Complications epidemiology, Postoperative Complications genetics, Risk Factors, Atrial Fibrillation etiology, Atrial Fibrillation genetics
Abstract: Genetic factors may be involved in postoperative atrial fibrillation (PoAF) development and cardiac injury. However, the associations of the apolipoprotein E (ApoE) gene polymorphisms with PoAF and cardiac injury after coronary artery bypass graft surgery (CABG) remain unclear.We recruited 150 patients with CABG, comprising 92 and 58 cases for the ApoE4 and ApoE3 groups, respectively, and analyzed PoAF incidence and the levels of cardiac biomarkers, including N-terminal prohormone of brain natriuretic peptide, cardiac troponin T (cTnT), and cardiac troponin I (cTnI). The linear regression model or logistic regression analysis was applied to investigate the associations of ApoE gene polymorphisms with PoAF and biomarkers for cardiac injury.A total of 58 (38.7%) patients with CABG developed PoAF, with 40 and 18 cases in the ApoE4 and ApoE3 groups (43.5% versus 31.0%, P < 0.05), respectively. Logistic regression analysis revealed that the ApoE4 allele was an independent risk factor for PoAF (OR = 3.340, P = 0.001), while the ApoE3 allele was a protective factor for the PoAF (OR = 0.841, P = 0.043). Patients carrying the ApoE4 allele had higher levels of cTnT and cTnI than those carrying the ApoE3 allele. ApoE3 was a protective factor for cardiac injury (β = -0.220, P = 0.001), whereas ApoE4 was a risk factor for cTnI (β = 0.335, P = 0.015).Our study reveals that the ApoE allele contributes to the occurrence of PoAF and severity of cardiac injury in an allele-dependent manner, with the ApoE4 allele increasing the risk and the ApoE3 allele reducing the risk.
Published: 2023
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43. A Transcriptome-Wide Association Study Identifies Novel Candidate Susceptibility Genes for Pancreatic Cancer

Author: Zhong, Jun, Jermusyk, Ashley, Wu, Lang, Hoskins, Jason W., Collins, Irene, Mocci, Evelina, Zhang, Mingfeng, Song, Lei, Chung, Charles C., Zhang, Tongwu, Xiao, Wenming, Albanes, Demetrius, Andreotti, Gabriella, Arslan, Alan A., Babic, Ana, Bamlet, William R., Beane-Freeman, Laura, Berndt, Sonja, Borgida, Ayelet, Bracci, Paige M., Brais, Lauren, Brennan, Paul, Bueno-de-Mesquita, Bas, Buring, Julie, Canzian, Federico, Childs, Erica J., Cotterchio, Michelle, Du, Mengmeng, Duell, Eric J., Fuchs, Charles, Gallinger, Steven, Gaziano, J. Michael, Giles, Graham G., Giovannucci, Edward, Goggins, Michael, Goodman, Gary E., Goodman, Phyllis J., Haiman, Christopher, Hartge, Patricia, Hasan, Manal, Helzlsouer, Kathy J., Holly, Elizabeth A., Klein, Eric A., Kogevinas, Manolis, Kurtz, Robert J., LeMarchand, Loic, Malats, Nuria, Mannisto, Satu, Milne, Roger, Neale, Rachel E., Ng, Kimmie, Obazee, Ofure, Oberg, Ann L., Orlow, Irene, Patel, Alpa, Peters, Ulrike, Porta, Miquel, Rothman, Nathaniel, Scelo, Ghislaine, Sesso, Howard D., Severi, Gianluca, Sieri, Sabina, Silverman, Debra, Sund, Malin, Tjonneland, Anne, Thornquist, Mark D., Tobias, Geoffrey S., Trichopoulou, Antonia, Van den Eeden, Stephen K., Visvanathan, Kala, Wactawski-Wende, Jean, Wentzensen, Nicolas, White, Emily, Yu, Herbert, Yuan, Chen, Zeleniuch-Jacquotte, Anne, Hoover, Robert, Brown, Kevin, Kooperberg, Charles, Risch, Harvey A., Jacobs, Eric J., Li, Donghui, Yu, Kai, Shu, Xiao-Ou, Chanock, Stephen J., Wolpin, Brian M., Stolzenberg-Solomon, Rachael Z., Chatterjee, Nilanjan, Klein, Alison P., Smith, Jill P., Kraft, Peter, Shi, Jianxin, Petersen, Gloria M., Zheng, Wei, Amundadottir, Laufey T., Zhong, Jun, Jermusyk, Ashley, Wu, Lang, Hoskins, Jason W., Collins, Irene, Mocci, Evelina, Zhang, Mingfeng, Song, Lei, Chung, Charles C., Zhang, Tongwu, Xiao, Wenming, Albanes, Demetrius, Andreotti, Gabriella, Arslan, Alan A., Babic, Ana, Bamlet, William R., Beane-Freeman, Laura, Berndt, Sonja, Borgida, Ayelet, Bracci, Paige M., Brais, Lauren, Brennan, Paul, Bueno-de-Mesquita, Bas, Buring, Julie, Canzian, Federico, Childs, Erica J., Cotterchio, Michelle, Du, Mengmeng, Duell, Eric J., Fuchs, Charles, Gallinger, Steven, Gaziano, J. Michael, Giles, Graham G., Giovannucci, Edward, Goggins, Michael, Goodman, Gary E., Goodman, Phyllis J., Haiman, Christopher, Hartge, Patricia, Hasan, Manal, Helzlsouer, Kathy J., Holly, Elizabeth A., Klein, Eric A., Kogevinas, Manolis, Kurtz, Robert J., LeMarchand, Loic, Malats, Nuria, Mannisto, Satu, Milne, Roger, Neale, Rachel E., Ng, Kimmie, Obazee, Ofure, Oberg, Ann L., Orlow, Irene, Patel, Alpa, Peters, Ulrike, Porta, Miquel, Rothman, Nathaniel, Scelo, Ghislaine, Sesso, Howard D., Severi, Gianluca, Sieri, Sabina, Silverman, Debra, Sund, Malin, Tjonneland, Anne, Thornquist, Mark D., Tobias, Geoffrey S., Trichopoulou, Antonia, Van den Eeden, Stephen K., Visvanathan, Kala, Wactawski-Wende, Jean, Wentzensen, Nicolas, White, Emily, Yu, Herbert, Yuan, Chen, Zeleniuch-Jacquotte, Anne, Hoover, Robert, Brown, Kevin, Kooperberg, Charles, Risch, Harvey A., Jacobs, Eric J., Li, Donghui, Yu, Kai, Shu, Xiao-Ou, Chanock, Stephen J., Wolpin, Brian M., Stolzenberg-Solomon, Rachael Z., Chatterjee, Nilanjan, Klein, Alison P., Smith, Jill P., Kraft, Peter, Shi, Jianxin, Petersen, Gloria M., Zheng, Wei, and Amundadottir, Laufey T.
Abstract: Background: Although 20 pancreatic cancer susceptibility loci have been identified through genome-wide association studies in individuals of European ancestry, much of its heritability remains unexplained and the genes responsible largely unknown. Methods: To discover novel pancreatic cancer risk loci and possible causal genes, we performed a pancreatic cancer transcriptome-wide association study in Europeans using three approaches: FUSION, MetaXcan, and Summary-MulTiXcan. We integrated genome-wide association studies summary statistics from 9040 pancreatic cancer cases and 12 496 controls, with gene expression prediction models built using transcriptome data from histologically normal pancreatic tissue samples (NCI Laboratory of Translational Genomics [n = 95] and Genotype-Tissue Expression v7 [n = 174] datasets) and data from 48 different tissues (Genotype-Tissue Expression v7, n = 74-421 samples). Results: We identified 25 genes whose genetically predicted expression was statistically significantly associated with pancreatic cancer risk (false discovery rate <.05), including 14 candidate genes at 11 novel loci (1p36.12: CELA3B; 9q31.1: SMC2, SMC2-AS1; 10q23.31: RP11-80H5.9; 12q13.13: SMUG1; 14q32.33: BTBD6; 15q23: HEXA; 15q26.1: RCCD1; 17q12: PNMT, CDK12, PGAP3; 17q22: SUPT4H1; 18q11.22: RP11-888D10.3; and 19p13.11: PGPEPI) and 11 at six known risk loci (5p15.33: TERT, CLPTMIL, ZDHHCIIB; 7p14.1: INHBA; 9q34.2: ABO; 13q12.2: PDX1; 13q22.1: KLF5; and 16q23.1: WDR59, CFDP1, BCAR1, TMEM170A). The association for 12 of these genes (CELA3B, SMC2, and PNMT at novel risk loci and TERT, CLPTMIL, INHBA, ABO, PDX1, KLF5, WDR59, CFDP1, and BCAR1 at known loci) remained statistically significant after Bonferroni correction. Conclusions: By integrating gene expression and genotype data, we identified novel pancreatic cancer risk loci and candidate functional genes that warrant further investigation.
Published: 2020

44. The genetics of Crohn's disease and ulcerative colitis - status quo and beyond.

Author: Ellinghaus, David, Bethune, Jörn, Petersen, Britt-Sabina, and Franke, Andre
Subjects: *GENETICS of Crohn's disease, *GENETIC research, *ULCERATIVE colitis, *GASTROINTESTINAL diseases, *GENOMES, *GENETICS
Abstract: The two major subtypes of inflammatory bowel disease (IBD), ulcerative colitis (UC, MIM#191390) and Crohn's disease (CD, MIM#266600), are chronic relapsing-remitting inflammatory disorders affecting primarily the gastrointestinal tract. Prevalence rates in North America and Europe range from 21 to 246 per 100,000 for UC and 8 to 214 per 100,000 for CD. Although CD and UC share some clinical and pathological features, they can be distinguished by localization, endoscopic appearance, histology and behavior, which suggest differences in the underlying pathophysiology. The importance of genetic risk factors in disease etiology is high and has been documented more clearly for CD than for UC (relative sibling risks λs: 15-35 for CD, 6-9 for UC). The most recent and largest genetic association study for IBD, which employed genome-wide association data for over 75,000 patients and controls, established the association of 163 susceptibility loci with IBD. Although the disease variance explained by the 163 loci only amounts to 13.6% for CD and 7.5% for UC, the identified loci and the candidate genes within yielded valuable insights into the pathogenesis of IBD and the relevant disease pathways. We here review the current research on the genetics of IBD and provide insights into on current efforts as well as suggest topics for future research. [ABSTRACT FROM AUTHOR]
Published: 2015
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45. Association of a CARD9 Gene Haplotype with Behcet's Disease in a Chinese Han Population

Author: Tingting Pang, Yizong Liu, Liying Shi, Fuzhen Li, Aize Kijlstra, Guangming Wan, Qingfeng Cao, Na Li, Liping Du, Peizeng Yang, Xin Ma, RS: MHeNs - R3 - Neuroscience, and MUMC+: MA UECM Oogartsen MUMC (9)
Subjects: Linkage disequilibrium, haplotype, LINKAGE DISEQUILIBRIUM, SUSCEPTIBILITY LOCI, CARD9 Gene, Single-nucleotide polymorphism, Genome-wide association study, Disease, Behcet's disease, INNATE, VARIANTS, ACUTE ANTERIOR UVEITIS, 03 medical and health sciences, 0302 clinical medicine, single nucleotide polymorphism, medicine, Immunology and Allergy, GENOME-WIDE ASSOCIATION, 030203 arthritis & rheumatology, Ankylosing spondylitis, business.industry, CLINICAL-FEATURES, Haplotype, ANKYLOSING-SPONDYLITIS, medicine.disease, RISK LOCI, Ophthalmology, Immunology, 030221 ophthalmology & optometry, SIGNALING PATHWAY, business, CARD9
Abstract: Purpose: To investigate the association of CARD9 gene polymorphisms with Behcet's disease (BD) and acute anterior uveitis (AAU) in a Chinese Han population. Methods: We performed a case-control association study in 480 patients with BD, 1151 patients with AAU and 1440 healthy controls. Six single nucleotide polymorphisms (SNPs) of CARD9 were genotyped, including rs4077515, rs11145769, rs59902911, rs9411205, rs4073153 and rs1135314. Results: None of the individual SNPs in the CARD9 gene showed an association with either BD or AAU. Haplotype analysis revealed a significant decrease of the frequency of a CARD9 gene haplotype CGCCA (rs4077515, rs11145769, rs59902911, rs9411205, rs4073153) in BD when compared to healthy controls (Pc = 0.012, OR = 0.585, 95%CI = 0.409 similar to 0.837). Haplotype analysis did not show an association between CARD9 and AAU. Conclusions: This study shows that a five-SNP haplotype of the CARD9 gene (CGCCA) may be a protective factor for BD with ocular involvement, but not for AAU.
Published: 2021

46. Type 2 Diabetes Is Associated With The Mtnr1B Gene, A Genetic Bridge Between Circadian Rhythm And Glucose Metabolism, In A Turkish Population

Author: Muslu Kazım Körez, Hilal Arikoglu, Funda Iscioglu, Mustafa Sait Gonen, Fatma Gokturk, Suleyman Hilmi Ipekci, Dudu Erkoc-Kaya, and Suleyman Baldane
Subjects: Blood Glucose, Male, 0301 basic medicine, Turkey, endocrine system diseases, Type 2 diabetes, Turkish population, Genome-Wide Association, 0302 clinical medicine, Susceptibility Loci, Risk Loci, Melatonin, Genetics, education.field_of_study, Han Chinese, Variants, General Medicine, Middle Aged, Circadian Rhythm, 3. Good health, Phenotype, 030220 oncology & carcinogenesis, Enpp1 Gene, Female, Adult, endocrine system, Fasting Plasma-Glucose, Population, MTNR1B gene, Single-Nucleotide Polymorphism, Single-nucleotide polymorphism, Biology, Polymorphism, Single Nucleotide, 03 medical and health sciences, Circadian Clocks, medicine, Genetic predisposition, Humans, SNP, Genetic Predisposition to Disease, education, Molecular Biology, CDKAL1, Aged, Receptor, Melatonin, MT2, Insulin-Resistance, nutritional and metabolic diseases, Single nucleotide polymorphisms, medicine.disease, 030104 developmental biology, Diabetes Mellitus, Type 2, Genetic Loci, Case-Control Studies, Blood sugar regulation, Genome-Wide Association Study
Abstract: Type 2 diabetes (T2D) is a complicated public health problem in Turkey as well as worldwide. Genome-wide approaches have been guiding in very challenging situations, such as the elucidation of genetic variations underlying complex diseases such as T2D. Despite intensive studies worldwide, few studies have determined the genetic susceptibility to T2D in Turkish populations. In this study, we investigated the effect of genes that are strongly associated with T2D in genome-wide association (GWA) studies, including MTNR1B, CDKAL1, THADA, ADAMTS9 and ENPP1, on T2D and its characteristic traits in a Turkish population. In 824 nonobese individuals (454 T2D patients and 370 healthy individuals), prominent variants of these GWA genes were genotyped by real-time PCR using the LightSNiP Genotyping Assay System. The SNP rs1387153 C/T, which is located 28 kb upstream of the MTNR1B gene, was significantly associated with T2D and fasting blood glucose levels (P < 0.05). The intronic SNP rs10830963 C/G in the MTNR1B gene was not associated with T2D, but it was associated with fasting blood glucose, HbA1C and LDL levels (P < 0.05). The other important GWA loci investigated in our study were not found to be associated with T2D or its traits. Only the SNP rs1044498 (A/C variation) in the ENPP1 gene was determined to be related to fasting blood glucose (P < 0.05). Our study suggests, consistent with the literature, that the MTNR1B locus, which has a prominent role in glucose regulation, is associated with T2D development by affecting blood glucose levels in our population., Scientific and Technological Research Council of Turkey [213S035], This study was supported by the Scientific and Technological Research Council of Turkey (213S035).
Published: 2021

47. Contribution of rare homozygous and compound heterozygous VPS13C missense mutations to dementia with Lewy bodies and Parkinson’s disease

Author: Christine Van Broeckhoven, David Crosiers, Elisabeth Hens, Patrick Cras, Sebastiaan Engelborghs, Stefanie Smolders, Stéphanie Philtjens, Bob Asselbergh, Wim Annaert, Sara Van Mossevelde, Rik Vandenberghe, Anne Sieben, Roberto Dos Santos Dias, Philippe Pals, Bavo Heeman, Yannick Vermeiren, Peter Paul De Deyn, Jean-Jacques Martin, BELNEU Consortium, Neurology, Clinical sciences, Neuroprotection & Neuromodulation, Physiotherapy, Human Physiology and Anatomy, and Pathologic Biochemistry and Physiology
Subjects: Male, Parkinson's disease, Dementia with lewy bodies, Genome-wide association study, Compound heterozygosity, Recessive inheritance, lcsh:RC346-429, FAMILIAL DEMENTIA, Missense mutation, ALZHEIMERS, Genetics, Homozygote, Brain, Parkinson Disease, Middle Aged, Nutritional Biology, PREVALENCE, Phenotype, DLB, PD, Female, Autopsy, Life Sciences & Biomedicine, Heterozygote, NEUROPATHOLOGIC ASSESSMENT, Neuroscience(all), Mutation, Missense, Biology, Lewy body disease, Pathology and Forensic Medicine, Loss-of-function, Vacuolar protein sorting 13 homolog C, Cellular and Molecular Neuroscience, VPS13C, MANAGEMENT, medicine, Humans, GENOME-WIDE ASSOCIATION, Gene, lcsh:Neurology. Diseases of the nervous system, METAANALYSIS, Aged, Science & Technology, Whole Genome Sequencing, Dementia with Lewy bodies, neurology, Research, Neurosciences, Wild type, Proteins, medicine.disease, RISK LOCI, DYSFUNCTION, Minor allele frequency, PATHOLOGY, Missense mutations, Parkinson’s disease, Human medicine, Neurosciences & Neurology, Neurology (clinical)
Abstract: Dementia with Lewy bodies (DLB) and Parkinson’s disease (PD) are clinically, pathologically and etiologically disorders embedded in the Lewy body disease (LBD) continuum, characterized by neuronal α-synuclein pathology. Rare homozygous and compound heterozygous premature termination codon (PTC) mutations in the Vacuolar Protein Sorting 13 homolog C gene (VPS13C) are associated with early-onset recessive PD. We observed in two siblings with early-onset age (VPS13C, p.Trp395Cys and p.Ala444Pro, inherited from their healthy parents in a recessive manner. In lymphoblast cells of the index patient, the missense mutations reduced VPS13C expression by 90% (p = 0.0002). Subsequent, we performed targeted resequencing of VPS13C in 844 LBD patients and 664 control persons. Using the optimized sequence kernel association test, we obtained a significant association (p = 0.0233) of rare VPS13C genetic variants (minor allele frequency ≤ 1%) with LBD. Among the LBD patients, we identified one patient with homozygous missense mutations and three with compound heterozygous missense mutations in trans position, indicative for recessive inheritance. In four patients with compound heterozygous mutations, we were unable to determine trans position. The frequency of LBD patient carriers of proven recessive compound heterozygous missense mutations is 0.59% (5/844). In autopsy brain tissue of two unrelated LBD patients, the recessive compound heterozygous missense mutations reduced VPS13C expression. Overexpressing of wild type or mutant VPS13C in HeLa or SH-SY5Y cells, demonstrated that the mutations p.Trp395Cys or p.Ala444Pro, abolish the endosomal/lysosomal localization of VPS13C. Overall, our data indicate that rare missense mutations in VPS13C are associated with LBD and recessive compound heterozygous missense mutations might have variable effects on the expression and functioning of VPS13C. We conclude that comparable to the recessive inherited PTC mutations in VPS13C, combinations of rare recessive compound heterozygous missense mutations reduce VPS13C expression and contribute to increased risk of LBD.
Published: 2021

48. The genetic basis of ankylosing spondylitis: new insights into disease pathogenesis.

Author: Tsui, Florence W. L., Tsui, Hing Wo, Akram, Ali, Haroon, Nigil, and Inman, Robert D
Subjects: ANKYLOSING spondylitis, INFLAMMATION, HLA histocompatibility antigens, HETEROGENEITY, MAJOR histocompatibility complex, INFLAMMATORY bowel diseases, IMMUNOLOGY
Abstract: Ankylosing spondylitis (AS) is a complex disease involving multiple risk factors, both genetic and environmental. AS patients are predominantly young men, and the disease is characterized by inflammation and ankylosis, mainly at the cartilage-bone interface and enthesis. HLA-B27 has been known to be the major AS-susceptibility gene for more than 40 years. Despite advances made in the past few years, progress in the search for non-human leukocyte antigen susceptibility genes has been hampered by the heterogeneity of the disease. Compared to other complex diseases, such as inflammatory bowel disease (IBD), fewer susceptibility loci have been identified in AS. Furthermore, non-major histocompatibility-complex susceptibility loci discovered, such as ERAP1 and IL23R, are likely contributors to joint inflammation. Identification and confirmation of functional variants remains a significant challenge of investigations involving genome-wide association studies (GWAS). It remains unclear why none of the AS-susceptibility genes identified in GWAS appear to be directly involved in the ankylosing process. Numerous reviews have recently been published on the genetics of AS. Therefore, aside from a brief summary of what AS GWAS has successfully achieved thus far, this review will focus on directions that could address unanswered questions raised by GWAS. [ABSTRACT FROM AUTHOR]
Published: 2014
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49. Age-of-onset information helps identify 76 genetic variants associated with allergic disease

Author: Ferreira, Manuel A R, Vonk, Judith M., Baurecht, Hansjörg, Marenholz, Ingo, Tian, Chao, Hoffman, Joshua D., Helmer, Quinta, Tillander, Annika, Ullemar, Vilhelmina, Lu, Yi, Grosche, Sarah, Ruschendorf, Franz, Granell, Raquel, Brumpton, Ben Michael, Fritsche, Lars, Bhatta, Laxmi, Gabrielsen, Maiken Elvestad, Nielsen, Jonas Bille, Zhou, Wei, Hveem, Kristian, Langhammer, Arnulf, Holmen, Oddgeir, Løset, Mari, Abecasis, Goncalo, Willer, Cristen J., Emami, Nima C., Cavazos, Taylor B., Witte, John S., Szwajda, Agnieszka, 23andMe Research Team,, collaborators of SHARE study,, Hinds, David A., Hubner, Norbert, Weidinger, Stephan, Magnusson, Patrik KE, Jorgenson, Eric, Karlsson, Robert, Paternoster, Lavinia, Boomsma, Dorret I., Almqvist, Catarina, Lee, Young-Ae, Koppelman, Gerard H., Esparza-Gordillo, Jorge, Hummel, Oliver, Hottenga, Jouke-Jan, Willemsen, Gonneke, Rodríguez, Elke, Hotze, Melanie, Franke, Andre, Matheson, Melanie C., Dharmage, Shyamali Chandrika, Arnold, Andreas, Homuth, Georg, Schmidt, Carsten O, Thompson, Philip J., Martin, Nicholas G, Duffy, David L., Novak, Natalija, Schulz, Holger, Karrasch, Stefan, Gieger, Christian, Strauch, Konstantin, Melles, Ronald B, Bouzigon, Emmanuelle, Biological Psychology, APH - Mental Health, APH - Methodology, and Groningen Research Institute for Asthma and COPD (GRIAC)
Subjects: HAY-FEVER, Male, Netherlands Twin Register (NTR), Cancer Research, Allergy, Pulmonology, Epidemiology, Eczema, Genome-wide association study, Disease, QH426-470, collaborators of the SHARE study, 0302 clinical medicine, Allergies, Medicine and Health Sciences, ATOPIC-DERMATITIS, 2.1 Biological and endogenous factors, Biologiska vetenskaper, Aetiology, Age of Onset, Child, Lung, Genetics (clinical), Rhinitis, 0303 health sciences, Allergic Diseases, Single Nucleotide, Genomics, PKC-THETA, Middle Aged, Biological Sciences, ALSPAC, II RECEPTOR, Hay fever, Female, Research Article, Allergic Rhinitis, Adult, SUSCEPTIBILITY LOCI, Adolescent, Immunology, Food Allergies, Late onset, Dermatology, Biology, 23andMe Research Team, Polymorphism, Single Nucleotide, 03 medical and health sciences, Allergic, CD200 RECEPTOR, SDG 3 - Good Health and Well-being, Clinical Research, medicine, Genome-Wide Association Studies, Genetics, Humans, GENOME-WIDE ASSOCIATION, Polymorphism, Molecular Biology, Ecology, Evolution, Behavior and Systematics, 030304 developmental biology, Asthma, Aged, Seasonal, Prevention, Inflammatory and immune system, Human Genome, Biology and Life Sciences, Computational Biology, Rhinitis, Allergic, Seasonal, Human Genetics, Rhinology, medicine.disease, Genome Analysis, RISK LOCI, Otorhinolaryngology, Cardiovascular and Metabolic Diseases, Genetic Loci, Medical Risk Factors, Expression quantitative trait loci, Genetics of Disease, T-CELLS, Nasal Diseases, Clinical Immunology, Age of onset, Clinical Medicine, 030217 neurology & neurosurgery, Developmental Biology, Genome-Wide Association Study
Abstract: Risk factors that contribute to inter-individual differences in the age-of-onset of allergic diseases are poorly understood. The aim of this study was to identify genetic risk variants associated with the age at which symptoms of allergic disease first develop, considering information from asthma, hay fever and eczema. Self-reported age-of-onset information was available for 117,130 genotyped individuals of European ancestry from the UK Biobank study. For each individual, we identified the earliest age at which asthma, hay fever and/or eczema was first diagnosed and performed a genome-wide association study (GWAS) of this combined age-of-onset phenotype. We identified 50 variants with a significant independent association (P, Author summary So far, genetic studies of allergic disease have investigated the presence of the disease rather than the age at which the first allergic symptoms develop. We aimed to identify genetic risk variants associated with the age at which symptoms of allergic disease first develop, considering information from asthma, hay fever and eczema by examining 117,130 genotyped individuals of European ancestry from the UK Biobank study. We identified 50 variants with a significant independent association (P
Published: 2020

50. A Pilot Integrative Analysis of Colonic Gene Expression, Gut Microbiota, and Immune Infiltration in Primary Sclerosing Cholangitis-Inflammatory Bowel Disease: Association of Disease With Bile Acid Pathways

Author: Gideon M. Hirschfield, Andrew D Beggs, Julian R.F. Walters, Tariq Iqbal, Richard D. Horniblow, Nicholas J. Loman, David R. Withers, Subrata Ghosh, Chris Tselepis, Georgios V. Gkoutos, Animesh Acharjee, Willem van Schaik, Mohammed Nabil Quraishi, and Amanda E. Rossiter
Subjects: Male, LIVER, endocrine system diseases, colitis, Gut flora, Gastroenterology, Inflammatory bowel disease, Transcriptome, ACTIVATION, RNA, Ribosomal, 16S, Homeostasis, TH17, Intestinal Mucosa, Bile acid, biology, digestive, oral, and skin physiology, Interleukin-17, General Medicine, dysbiosis, bioinformatics, Middle Aged, Ulcerative colitis, Up-Regulation, Autoimmune liver disease, Female, Life Sciences & Biomedicine, Signal Transduction, Adult, medicine.medical_specialty, medicine.drug_class, Colon, Cholangitis, Sclerosing, digestive system, Primary sclerosing cholangitis, Immunophenotyping, Bile Acids and Salts, Internal medicine, medicine, Humans, Colitis, GENOME-WIDE ASSOCIATION, AcademicSubjects/MED00260, Science & Technology, Gastroenterology & Hepatology, business.industry, Sequence Analysis, RNA, Immunity, Computational Biology, 1103 Clinical Sciences, Original Articles, medicine.disease, biology.organism_classification, RISK LOCI, digestive system diseases, Eccojc/1000, Gastrointestinal Microbiome, Case-Control Studies, CELLS, Th17 Cells, Colitis, Ulcerative, business, Dysbiosis
Abstract: Background Although a majority of patients with PSC have colitis [PSC-IBD; primary sclerosing cholangitis-inflammatory bowel disease], this is phenotypically different from ulcerative colitis [UC]. We sought to define further the pathophysiological differences between PSC-IBD and UC, by applying a comparative and integrative approach to colonic gene expression, gut microbiota and immune infiltration data. Methods Colonic biopsies were collected from patients with PSC-IBD [n = 10], UC [n = 10], and healthy controls [HC; n = 10]. Shotgun RNA-sequencing for differentially expressed colonic mucosal genes [DEGs], 16S rRNA analysis for microbial profiling, and immunophenotyping were performed followed by multi-omic integration. Results The colonic transcriptome differed significantly between groups [p = 0.01]. Colonic transcriptomes from HC were different from both UC [1343 DEGs] and PSC-IBD [4312 DEGs]. Of these genes, only 939 had shared differential gene expression in both UC and PSC-IBD compared with HC. Imputed pathways were predominantly associated with upregulation of immune response and microbial defense in both disease cohorts compared with HC. There were 1692 DEGs between PSC-IBD and UC. Bile acid signalling pathways were upregulated in PSC-IBD compared with UC [p = 0.02]. Microbiota profiles were different between the three groups [p = 0.01]; with inferred function in PSC-IBD also being consistent with dysregulation of bile acid metabolism. Th17 cells and IL17-producing CD4 cells were increased in both PSC-IBD and UC when compared with HC [p Conclusions Colonic transcriptomic and microbiota analysis in PSC-IBD point toward dysregulation of colonic bile acid homeostasis compared with UC. This highlights important mechanisms and suggests the possibility of novel approaches in treating PSC-IBD.
Published: 2020

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