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Diverse functions associate with non-coding polymorphisms shared between humans and chimpanzees

BMC ECOLOGY AND EVOLUTION 2022年第1期22卷 68-68页

作者： Velazquez-Arcelay, Keila Benton, Mary Lauren Capra, John A. Vanderbilt Univ Dept Biol Sci Nashville TN 37235 USA Baylor Univ Dept Comp Sci Waco TX USA Vanderbilt Univ Dept Biomed Informat Genet Inst Nashville TN 37235 USA Vanderbilt Univ Dept Comp Sci Genet Inst Nashville TN 37235 USA Vanderbilt Univ Ctr Struct Biol Nashville TN 37235 USA Univ Calif San Francisco Bakar Computat Hlth Sci Inst San Francisco CA 94143 USA Univ Calif San Francisco Dept Epidemiol & Biostat San Francisco CA 94143 USA

Background Long-term balancing selection (LTBS) can maintain allelic variation at a locus over millions of years and through speciation events. variants shared between species in the state of identity-by-descent, hereafter "trans-species polymorphisms", can result from LTBS, often due to host-pathogen interactions. For instance, the major histocompatibility complex (MHC) locus contains TSPs present across primates. Several hundred candidate LTBS regions have been identified in humans and chimpanzees;however, because many are in non-protein-coding regions of the genome, the functions and potential adaptive roles for most remain unknown. Results We integrated diverse genomic annotations to explore the functions of 60 previously identified regions with multiple shared polymorphisms (SPs) between humans and chimpanzees, including 19 with strong evidence of LTBS. We analyzed genome-wide functional assays, expression quantitative trait loci (eQTL), genome-wide association studies (GWAS), and phenome-wide association studies (PheWAS) for all the regions. We identify functional annotations for 59 regions, including 58 with evidence of gene regulatory function from GTEx or functional genomics data and 19 with evidence of trait association from GWAS or PheWAS. As expected, the SPs associate in humans with many immune system phenotypes, including response to pathogens, but we also find associations with a range of other phenotypes, including body size, alcohol intake, cognitive performance, risk-taking behavior, and urate levels. Conclusions The diversity of traits associated with non-coding regions with multiple SPs support previous hypotheses that functions beyond the immune system are likely subject to LTBS. Furthermore, several of these trait associations provide support and candidate genetic loci for previous hypothesis about behavioral diversity in human and chimpanzee populations, such as the importance of variation in risk sensitivity.

关键词： Trans-species polymorphisms Balancing selection Long-term balancing selection non-coding variants Phenome-wide association study

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Systematic investigation of allelic regulatory activity of schizophrenia-associated common variants

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CELL GENOMICS 2023年第10期3卷 100404-100404页

作者： McAfee, Jessica C. Lee, Sool Lee, Jiseok Bell, Jessica L. Krupa, Oleh Davis, Jessica Insigne, Kimberly Bond, Marielle L. Zhao, Nanxiang Boyle, Alan P. Phanstiel, Douglas H. Love, Michael I. Stein, Jason L. Ruzicka, W. Brad Davila-Velderrain, Jose Kosuri, Sriram Won, Hyejung Univ N Carolina Dept Genet Chapel Hill NC 27599 USA Univ N Carolina Neurosci Ctr Chapel Hill NC 27599 USA Univ N Carolina Curriculum Genet & Mol Biol Chapel Hill NC 27599 USA Univ N Carolina Curriculum Bioinformat & Computat Biol Chapel Hill NC 27599 USA Univ Calif Los Angeles Dept Chem & Biochem Los Angeles CA 90095 USA Univ Calif Los Angeles UCLA DOE Inst Genom & Prote Los Angeles CA 90095 USA Univ Calif Los Angeles Mol Biol Inst Los Angeles CA 90095 USA Univ Calif Los Angeles Quantitat & Computat Biol Inst Los Angeles CA 90095 USA Univ Calif Los Angeles Eli & Edythe Broad Ctr Regenerat Med & Stem Cell Los Angeles CA 90095 USA Univ Michigan Dept Computat Med & Bioinformat Ann Arbor MI 48109 USA Univ Michigan Dept Human Genet Ann Arbor MI 48109 USA Univ N Carolina Thurston Arthrit Res Ctr Chapel Hill NC 27599 USA Univ N Carolina Dept Cell Biol & Physiol Chapel Hill NC 27599 USA Univ N Carolina Dept Biostat Chapel Hill NC 27599 USA McLean Hosp Lab Epigenom Human Psychopathol Belmont MA 02178 USA Harvard Med Sch Boston MA 02115 USA Broad Inst MIT & Harvard Cambridge MA 02142 USA Human Technopole Viale Rita Levi Montalcini 1 I-20157 Milan Italy

Genome-wide association studies (GWASs) have successfully identified 145 genomic regions that contribute to schizophrenia risk, but linkage disequilibrium makes it challenging to discern causal variants. We per-formed a massively parallel reporter assay (MPRA) on 5,173 fine-mapped schizophrenia GWAS variants in primary human neural progenitors and identified 439 variants with allelic regulatory effects (MPRA-positive variants). Transcription factor binding had modest predictive power, while fine-map posterior probability, enhancer overlap, and evolutionary conservation failed to predict MPRA-positive variants. Furthermore, 64% of MPRA-positive variants did not exhibit expressive quantitative trait loci signature, suggesting that MPRA could identify yet unexplored variants with regulatory potentials. To predict the combinatorial effect of MPRA-positive variants on gene regulation, we propose an accessibility-by-contact model that combines MPRA-measured allelic activity with neuronal chromatin architecture.

关键词： MPRA schizophrenia GWAS non-coding variants accessibility-by-contact model variant function high-throughput reporter assay gene regulation chromatin architecture eQTL

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Characterization and in silico analyses of the BRCA1/2 variants identified in individuals with personal and/or family history of BRCA-related cancers

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INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES 2020年第0期162卷 1166-1177页

作者： Pirim, Dilek Kaya, Niyazi Yildirim, Elif Uz Sag, Sebnem Ozemri Temel, Sehime Gulsun Bursa Uludag Univ Dept Mol Biol & Genet Bursa Turkey Bursa Uludag Univ Inst Nat & Appl Sci Dept Mol Biol & Genet Bursa Turkey Bursa Uludag Univ Fac Med Dept Med Genet TR-16059 Bursa Turkey Bursa Uludag Univ Inst Hlth Sci Dept Translat Med Bursa Turkey Bursa Uludag Univ Fac Med Dept Histol & Embryol Bursa Turkey

Pathogenic variants in the coding regions of the BRCA1/2 lead dysfunctional or nonfunctional BRCA proteins however the contribution of non-coding BRCA1/2 variants to BRCA-related disease risk has not been fully elucidated. Thus, we characterized the functional impact of both coding and non-coding BRCA1/2 variants identified in individuals with personal and/or family history of BRCA-related cancers. The data were produced by resequencing the exons and exon-intron junctions of the BRCA1/2 in 125 individuals and were comprehensively analyzed by using bioinformatics tools and databases. A total of 96 variants (59 coding and 37 non-coding) including 7 novel variants were identified and analyzed for their functional importance. We identified 11 missense variants that potentially affect protein function;22 variants were likely to alter different types of posttranslational modifications. Also, multiple non-coding BRCA1/2 variants were found to reside in the critical regulatory regions that have the potential to act as eQTLs and affect alternative splicing. The results of our study shed light on the possible contributions of not only coding variants but also non-coding BRCA1/2 variants in BRCRA-related cancers. Further investigation is required to fully understand their potential associations with phenotypes which may ultimately lead their utilization on cancer management as a biomarker. (c) 2020 Elsevier B.V. All rights reserved.

关键词： BRCA1/2 In silico analyses non-coding variants BRCA-related cancer Next-generation sequencing

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GCH1 variants contribute to the risk and earlier age-at-onset of Parkinson's disease:a two-cohort case-control study

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Translational Neurodegeneration 2020年第3期9卷 409-420页

作者： Hong-xu Pan Yu-wen Zhao Jun-pu Mei Zheng-huan Fang Yige Wang Xun Zhou Yang-jie Zhou Rui Zhang Kai-lin Zhang Li Jiang Qian Zeng Yan He Zheng Wang Zhen-hua Liu Qian Xu Qi-ying Sun Yang Yang Ya-cen Hu Ya-se Chen Juan Du Li-fang Lei Hai-nan Zhang Chun-yu Wang Xin-xiang Yan Lu Shen Hong Jiang Jie-qiong Tan Jin-chen Li Bei-sha Tang Ji-feng Guo Department of Neurology Xiangya HospitalCentral South UniversityChangsha 410008China National Clinical Research Center for Geriatric Disorders Xiangya HospitalCentral South UniversityChangsha 410008China Centre for Medical Genetics and Hunan Key Laboratory of Medical Genetics School of Life SciencesCentral South UniversityChangsha 410008China Department of Geriatrics Xiangya HospitalCentral South UniversityChangsha 410008China Department of Neurology The Third Xiangya HospitalCentral South UniversityChangsha 410013China Department of Neurology The Second Xiangya HospitalCentral South UniversityChangsha 410011China Key Laboratory of Hunan Province in Neurodegenerative Disorders Central South UniversityChangsha 410008China

Background:Common and rare variants of guanosine triphosphate cyclohydrolase 1(GCH1)gene may play important roles in Parkinson's disease(PD).However,there is a lack of comprehensive analysis of GCH1 genotypes,especially in non-coding *** aim of this study was to explore the genetic characteristics of GCH1,including rare and common variants in coding and non-coding regions,in a large population of PD patients in Chinese mainland,as well as the phenotypic characteristics of GCH1 variant ***:In the first cohort of this case-control study,we performed whole-exome sequencing in 1555 patients with early-onset or familial PD and 2234 healthy controls;then in the second cohort,whole-genome sequencing was performed in sporadic late-onset PD samples(1962 patients),as well as 1279 *** at target GCH1 regions were extracted,and then genetic and detailed phenotypic data were analyzed using regression models and the sequence kernel association *** also performed a meta-analysis to correlate deleterious GCH1 variants with age at onset(AAO)in PD ***:For coding variants,we identified a significant burden of GCH1 deleterious variants in early-onset or familial PD cases compared to controls(1.2%VS 0.1%,P<0.0001).In the analysis of possible regulatory variants in GCH1 non-coding regions,rs12323905(P=0.001,odds ratio=1.19,95%CI 1.07-1.32)was significantly associated with PD,and variant sets in untranslated regions and intron regions,GCH1 brain-specific expression quantitative trait loci,and two possible promoter/enhancer(GH14J054857 and GH14J054880)were suggestively associated with *** phenotype correlation analysis revealed that the carriers of GCH1 deleterious variants manifested younger AAO(P<0.0001),and had milder motor symptoms,milder fatigue symptoms and more autonomic nervous ***-analysis of six studies demonstrated 6.4-year earlier onset in GCH1 deleterious variant carriers(P=0.0009).Conclusions:The results

关键词： Parkinson's disease Age at onset GCH1 Deleterious variants non-coding variants

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A semi-supervised deep learning approach for predicting the functional effects of genomic non-coding variations

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BMC BIOINFORMATICS 2021年第SUPPL 6期22卷 128-128页

作者： Jia, Hao Park, Sung-Joon Nakai, Kenta Univ Tokyo Dept Comp Sci Bunkyo Ku 7-3-1 Hongo Tokyo 1138656 Japan Univ Tokyo Human Genome Ctr Inst Med Sci Minato Ku 4-6-1 Shirokanedai Tokyo 1088639 Japan

Background Understanding the functional effects of non-coding variants is important as they are often associated with gene-expression alteration and disease development. Over the past few years, many computational tools have been developed to predict their functional impact. However, the intrinsic difficulty in dealing with the scarcity of data leads to the necessity to further improve the algorithms. In this work, we propose a novel method, employing a semi-supervised deep-learning model with pseudo labels, which takes advantage of learning from both experimentally annotated and unannotated data. Results We prepared known functional non-coding variants with histone marks, DNA accessibility, and sequence context in GM12878, HepG2, and K562 cell lines. Applying our method to the dataset demonstrated its outstanding performance, compared with that of existing tools. Our results also indicated that the semi-supervised model with pseudo labels achieves higher predictive performance than the supervised model without pseudo labels. Interestingly, a model trained with the data in a certain cell line is unlikely to succeed in other cell lines, which implies the cell-type-specific nature of the non-coding variants. Remarkably, we found that DNA accessibility significantly contributes to the functional consequence of variants, which suggests the importance of open chromatin conformation prior to establishing the interaction of non-coding variants with gene regulation. Conclusions The semi-supervised deep learning model coupled with pseudo labeling has advantages in studying with limited datasets, which is not unusual in biology. Our study provides an effective approach in finding non-coding mutations potentially associated with various biological phenomena, including human diseases.

关键词： non-coding variants Epigenome Semi-supervised learning Deep learning Pseudo label

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Beyond association: successes and challenges in linking non-coding genetic variation to functional consequences that modulate Alzheimer's disease risk

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MOLECULAR NEURODEGENERATION 2021年第1期16卷 27-27页

作者： Novikova, Gloriia Andrews, Shea J. Renton, Alan E. Marcora, Edoardo Icahn Sch Med Mt Sinai Dept Neurosci Ronald M Loeb Ctr Alzheimers Dis New York NY 10029 USA Icahn Sch Med Mt Sinai Dept Genet & Genom Sci New York NY 10029 USA

Alzheimer's disease (AD) is the most common type of dementia, affecting millions of people worldwide;however, no disease-modifying treatments are currently available. Genome-wide association studies (GWASs) have identified more than 40 loci associated with AD risk. However, most of the disease-associated variants reside in non-coding regions of the genome, making it difficult to elucidate how they affect disease susceptibility. nonetheless, identification of the regulatory elements, genes, pathways and cell type/tissue(s) impacted by these variants to modulate AD risk is critical to our understanding of disease pathogenesis and ability to develop effective therapeutics. In this review, we provide an overview of the methods and approaches used in the field to identify the functional effects of AD risk variants in the causal path to disease risk modification as well as describe the most recent findings. We first discuss efforts in cell type/tissue prioritization followed by recent progress in candidate causal variant and gene nomination. We discuss statistical methods for fine-mapping as well as approaches that integrate multiple levels of evidence, such as epigenomic and transcriptomic data, to identify causal variants and risk mechanisms of AD-associated loci. Additionally, we discuss experimental approaches and data resources that will be needed to validate and further elucidate the effects of these variants and genes on biological pathways, cellular phenotypes and disease risk. Finally, we discuss future steps that need to be taken to ensure that AD GWAS functional mapping efforts lead to novel findings and bring us closer to finding effective treatments for this devastating disease.

关键词： Alzheimer’ s disease Myeloid cells Functional genomics Fine-mapping methods non-coding variants Gene prioritization Variant prioritization

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Genome analysis and knowledge-driven variant interpretation with TGex

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BMC MEDICAL GENOMICS 2019年第1期12卷 1-17页

作者： Dahary, Dvir Golan, Yaron Mazor, Yaron Zelig, Ofer Barshir, Ruth Twik, Michal Stein, Tsippi Iny Rosner, Guy Kariv, Revital Chen, Fei Zhang, Qiang Shen, Yiping Safran, Marilyn Lancet, Doron Fishilevich, Simon LifeMap Sci Inc Clin Genet Marshfield MA 02050 USA Weizmann Inst Sci Dept Mol Genet Rehovot Israel Tel Aviv Sourasky Med Ctr Dept Gastroenterol Tel Aviv Israel Tel Aviv Univ Fac Med Tel Aviv Israel Childrens Hosp Guangxi Zhuang Autonomous Reg Genet & Metab Cent Lab Birth Defect Prevent Res Inst Maternal & Child Hlth Hosp Nanning 530002 Peoples R China Shanghai Jiao Tong Univ Dept Med Genet & Mol Diagnost Lab Shanghai Childrens Med Ctr Sch Med Shanghai 200127 Peoples R China Harvard Med Sch Dept Neurol Div Genet & Genom Boston Childrens Hosp Boston MA 02115 USA

Background: The clinical genetics revolution ushers in great opportunities, accompanied by significant challenges. The fundamental mission in clinical genetics is to analyze genomes, and to identify the most relevant genetic variations underlying a patient's phenotypes and symptoms. The adoption of Whole Genome Sequencing requires novel capacities for interpretation of non-coding variants. Results: We present TGex, the Translational Genomics expert, a novel genome variation analysis and interpretation platform, with remarkable exome analysis capacities and a pioneering approach of non-coding variants interpretation. TGex's main strength is combining state-of-the-art variant filtering with knowledge-driven analysis made possible by VarElect, our highly effective gene-phenotype interpretation tool. VarElect leverages the widely used GeneCards knowledgebase, which integrates information from > 150 automatically-mined data sources. Access to such a comprehensive data compendium also facilitates TGex's broad variant annotation, supporting evidence exploration, and decision making. TGex has an interactive, user-friendly, and easy adaptive interface, ACMG compliance, and an automated reporting system. Beyond comprehensive whole exome sequence capabilities, TGex encompasses innovative non-coding variants interpretation, towards the goal of maximal exploitation of whole genome sequence analyses in the clinical genetics practice. This is enabled by GeneCards' recently developed GeneHancer, a novel integrative and fully annotated database of human enhancers and promoters. Examining use-cases from a variety of TGex users world-wide, we demonstrate its high diagnostic yields (42% for single exome and 50% for trios in 1500 rare genetic disease cases) and critical actionable genetic findings. The platform's support for integration with EHR and LIMS through dedicated APIs facilitates automated retrieval of patient data for TGex's customizable reporting engine, establishing a rapid

关键词： Next generation sequencing analysis Clinical variant interpretation and classification Exome sequencing Whole genome sequencing non-coding variants Biomedical knowledgebase Rare genetic diseases Hamartomatous polyposis

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Enhancer variants associated with Alzheimer's disease affect gene expression via chromatin looping

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BMC MEDICAL GENOMICS 2019年第1期12卷 1-16页

作者： Kikuchi, Masataka Hara, Norikazu Hasegawa, Mai Miyashita, Akinori Kuwano, Ryozo Ikeuchi, Takeshi Nakaya, Akihiro Osaka Univ Grad Sch Med Dept Genome Informat 2-2 Yamadaoka Suita Osaka 5650871 Japan Niigata Univ Brain Res Inst Dept Mol Genet Niigata Japan Asahigawaso Res Inst Asahigawaso Med Welf Ctr Okayama Japan

Background Genome-wide association studies (GWASs) have identified single-nucleotide polymorphisms (SNPs) that may be genetic factors underlying Alzheimer's disease (AD). However, how these AD-associated SNPs (AD SNPs) contribute to the pathogenesis of this disease is poorly understood because most of them are located in non-coding regions, such as introns and intergenic regions. Previous studies reported that some disease-associated SNPs affect regulatory elements including enhancers. We hypothesized that non-coding AD SNPs are located in enhancers and affect gene expression levels via chromatin loops. Methods To characterize AD SNPs within non-coding regions, we extracted 406 AD SNPs with GWAS p-values of less than 1.00 x 10(- 6) from the GWAS catalog database. Of these, we selected 392 SNPs within non-coding regions. Next, we checked whether those non-coding AD SNPs were located in enhancers that typically regulate gene expression levels using publicly available data for enhancers that were predicted in 127 human tissues or cell types. We sought expression quantitative trait locus (eQTL) genes affected by non-coding AD SNPs within enhancers because enhancers are regulatory elements that influence the gene expression levels. To elucidate how the non-coding AD SNPs within enhancers affect the gene expression levels, we identified chromatin-chromatin interactions by Hi-C experiments. Results We report the following findings: (1) nearly 30% of non-coding AD SNPs are located in enhancers;(2) eQTL genes affected by non-coding AD SNPs within enhancers are associated with amyloid beta clearance, synaptic transmission, and immune responses;(3) 95% of the AD SNPs located in enhancers co-localize with their eQTL genes in topologically associating domains suggesting that regulation may occur through chromatin higher-order structures;(4) rs1476679 spatially contacts the promoters of eQTL genes via CTCF-CTCF interactions;(5) the effect of other AD SNPs such as rs7364180 is lik

关键词： Alzheimer's disease Genome-wide association study non-coding variants Chromatin higher-order structure

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Novel disease syndromes unveiled by integrative multiscale network analysis of diseases sharing molecular effectors and comorbidities

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BMC MEDICAL GENOMICS 2018年第6期11卷 1-15页

作者： Li, Haiquan Fan, Jungwei Vitali, Francesca Berghout, Joanne Aberasturi, Dillon Li, Jianrong Wilson, Liam Chiu, Wesley Pumarejo, Minsu Han, Jiali Kenost, Colleen Koripella, Pradeep C. Pouladi, Nima Billheimer, Dean Bedrick, Edward J. Lussier, Yves A. Univ Arizona Ctr Biomed Informat & Biostat Tucson AZ 85721 USA Univ Arizona Coll Med Tucson Dept Med Tucson AZ 85721 USA Univ Arizona Grad Interdisciplinary Program Stat Tucson AZ 85721 USA Univ Arizona Ctr Appl Genet & Genom Med Tucson AZ 85721 USA Univ Arizona Ctr Innovat Brain Sci Tucson AZ 85721 USA Univ Arizona UA Canc Ctr Tucson AZ 85721 USA Univ Arizona Univ Arizona Hlth Sci Tucson AZ 85721 USA Univ Arizona Coll Publ Hlth Epidemiol & Biostat Dept Tucson AZ 85721 USA Univ Arizona Dept Biosyst Engn Tucson AZ 85721 USA Univ Arizona Dept Syst & Ind Engn Tucson AZ 85721 USA

BackgroundForty-two percent of patients experience disease comorbidity, contributing substantially to mortality rates and increased healthcare costs. Yet, the possibility of underlying shared mechanisms for diseases remains not well established, and few studies have confirmed their molecular predictions with clinical *** this work, we integrated genome-wide association study (GWAS) associating diseases and single nucleotide polymorphisms (SNPs) with transcript regulatory activity from expression quantitative trait loci (eQTL). This allowed novel mechanistic insights for noncoding and intergenic regions. We then analyzed pairs of SNPs across diseases to identify shared molecular effectors robust to multiple test correction (False Discovery Rate FDReRNA<0.05). We hypothesized that disease pairs found to be molecularly convergent would also be significantly overrepresented among comorbidities in clinical datasets. To assess our hypothesis, we used clinical claims datasets from the Healthcare Cost and Utilization Project (HCUP) and calculated significant disease comorbidities (FDRcomorbidity<0.05). We finally verified if disease pairs resulting molecularly convergent were also statistically comorbid more than by chance using the Fisher's Exact *** approach integrates: (i) 6175 SNPs associated with 238 diseases from similar to 1000 GWAS, (ii) eQTL associations from 19 tissues, and (iii) claims data for 35 million patients from HCUP. Logistic regression (controlled for age, gender, and race) identified comorbidities in HCUP, while enrichment analyses identified cis- and trans-eQTL downstream effectors of GWAS-identified variants. Among similar to 16,000 combinations of diseases, 398 disease-pairs were prioritized by both convergent eQTL-genetics (RNA overlap enrichment, FDReRNA<0.05) and clinical comorbidities (OR>1.5, FDRcomorbidity<0.05). Case studies of comorbidities illustrate specific convergent noncoding regulatory elements. An intergenic

关键词： Disease comorbidities GWAS studies eQTL Genetic network non-coding variants RNA SNP Diseases Complex diseases Intergenic Common diseases

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Data integration for functional annotation of regulatory single nucleotide polymorphisms associated with Alzheimer's disease susceptibility

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GENE 2018年 672卷 115-125页

作者： Amber, Sanila Zahid, Saadia Natl Univ Sci & Technol Atta ur Rahman Sch Appl Biosci Dept Healthcare Biotechnol Neurobiol Res Lab Islamabad Pakistan

Background. Alzheimer's disease (AD), the most common form of dementia affects 24.3 million people worldwide. More than twenty genetic loci have been associated with AD and a significant number of genetic variants were mapped within these loci. A large proportion of genome wide significant variants lie outside the coding region. However, the plausible function of these variants is still unexplored. Objective: The present study aimed to unravel the regulatory role of proxy single nucleotide polymorphisms (SNPs), to determine their risk of developing AD. Methods: The RegulomeDB was employed to predict the regulatory role of proxy SNPs. Protein association network and functional enrichment analysis was performed using String10.5 and gene ontology, respectively. Results: A total of 451 SNPs were examined through SNAP web portal (r(2) <= 0.80) which returned 2186 proxy SNPs in linkage disequilibrium (LD) with genome wide significant SNPs for AD. Out of 2186 SNPs analyzed in RegulomeDB, 151 had the scores < 3 that indicates the high degree of their potential regulatory function. Further analysis revealed that out of these 151 SNPs, 37 were genome wide significant for AD, 17 were significantly associated with diseases other than AD, 89 were proxy SNPs (not genome wide significant) for various diseases including AD while 8 SNPs were novel proxy SNPs for AD. Conclusion: These findings support the notion that the non-coding variants can be strongly associated with disease risk. Further validation through genome wide association studies will be helpful for the elucidation of their regulatory potential.\

关键词： Alzheimer's disease Genome wide association studies RegulomeDB Single nucleotide polymorphisms non-coding variants Linkage disequilibrium

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