SCFD1 expression quantitative trait loci in amyotrophic lateral sclerosis are differentially expressed.
SCFD1 expression quantitative trait loci in amyotrophic lateral sclerosis are differentially expressed.
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DOI：
10.1093/braincomms/fcab236
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发表时间：
2021
影响因子：
4.8
通讯作者：
Jones AR
中科院分区：
文献类型：
--
作者：
Iacoangeli A;Fogh I;Selvackadunco S;Topp SD;Shatunov A;van Rheenen W;Al-Khleifat A;Opie-Martin S;Ratti A;Calvo A;UK Brain Expression Consortium;Van Damme P;Robberecht W;Chio A;Dobson RJ;Hardiman O;Shaw CE;van den Berg LH;Andersen PM;Smith BN;Silani V;Veldink JH;Breen G;Troakes C;Al-Chalabi A;Jones AR
有证据表明，在全基因组关联研究中发现的常见变异通过表达数量性状位点的基因调控增加疾病的风险。使用多个全基因组方法，我们检查了单核苷酸多态性是否通过表达定量性状基因座增加肌萎缩侧索硬化症的风险，以及表达定量性状基因座表达是否在患有肌萎缩侧索硬化症的人和那些没有的人之间一致。在将公开表达的数量性状基因座数据与肌萎缩侧索硬化症全基因组关联研究相结合时，我们使用基于汇总数据的孟德尔随机化来证实SCFD 1是唯一一个通过表达数量性状基因座在介导肌萎缩侧索硬化症风险中具有全基因组意义的基因。（基于汇总数据的孟德尔随机化β = 0.20，标准误= 0.04，P值= 4.29 × 10−6）。使用死后运动皮层，我们测试了表达数量性状基因座是否在肌萎缩侧索硬化症（n = 76）和对照（n = 25）之间的全基因组表达中显示出显著差异。在分析的20757个基因中，显示肌萎缩侧索硬化症和对照之间表达差异的两个最显著的表达数量性状位点涉及两个已知的肌萎缩侧索硬化症基因（SCFD 1和VCP）。顺式作用SCFD 1表达基因下游的定量性状基因座显示肌萎缩侧索硬化症和对照之间的表达存在显著差异（最高表达定量性状基因座β = 0. 34，标准误= 0. 063，P值= 4. 54 × 10−7）。这些SCFD 1表达的数量性状基因座也显著改变了肌萎缩侧索硬化症的生存率（样本数量= 4265，风险比= 1.11，95%置信区间= 1.05-1.17，P值= 2.06 × 10−4），并作为肌萎缩侧索硬化症反式-表达定量性状基因座热点，用于更广泛的SCFD 1功能和肌萎缩侧索硬化症途径富集基因网络。利用基因集分析，我们发现与这个反式表达的数量性状位点热点相关的基因显著增加了肌萎缩侧索硬化症的风险（β = 0.247，标准差= 0.017，P = 0.001）和精神分裂症（β = 0.263，标准差= 0.008，P值= 1.18 × 10−5），一种与肌萎缩侧索硬化症遗传相关的疾病。总之，SCFD 1表达数量性状位点是肌萎缩侧索硬化症的主要因素，不仅影响疾病风险，而且在死后肌萎缩侧索硬化症中差异表达。SCFD 1表达定量性状基因座在肌萎缩侧索硬化症中显示出不同的表达谱，其与更广泛的基因网络相关，这些基因网络也赋予疾病的风险并改变疾病的持续时间。先前的研究表明，增加肌萎缩侧索硬化症（ALS）风险的DNA变异与SCFD 1 RNA活性相关。Iacoangeli等人报告说，SCFD 1 RNA和DNA变体在ALS中具有不同的活性，这不仅增加了疾病的风险，而且改变了其持续时间，证实了它们与ALS有关。
Evidence indicates that common variants found in genome-wide association studies increase risk of disease through gene regulation via expression Quantitative Trait Loci. Using multiple genome-wide methods, we examined if Single Nucleotide Polymorphisms increase risk of Amyotrophic Lateral Sclerosis through expression Quantitative Trait Loci, and whether expression Quantitative Trait Loci expression is consistent across people who had Amyotrophic Lateral Sclerosis and those who did not. In combining public expression Quantitative Trait Loci data with Amyotrophic Lateral Sclerosis genome-wide association studies, we used Summary-data-based Mendelian Randomization to confirm that SCFD1 was the only gene that was genome-wide significant in mediating Amyotrophic Lateral Sclerosis risk via expression Quantitative Trait Loci (Summary-data-based Mendelian Randomization beta = 0.20, standard error = 0.04, P-value = 4.29 × 10−6). Using post-mortem motor cortex, we tested whether expression Quantitative Trait Loci showed significant differences in expression between Amyotrophic Lateral Sclerosis (n = 76) and controls (n = 25), genome-wide. Of 20 757 genes analysed, the two most significant expression Quantitative Trait Loci to show differential in expression between Amyotrophic Lateral Sclerosis and controls involve two known Amyotrophic Lateral Sclerosis genes (SCFD1 and VCP). Cis-acting SCFD1 expression Quantitative Trait Loci downstream of the gene showed significant differences in expression between Amyotrophic Lateral Sclerosis and controls (top expression Quantitative Trait Loci beta = 0.34, standard error = 0.063, P-value = 4.54 × 10−7). These SCFD1 expression Quantitative Trait Loci also significantly modified Amyotrophic Lateral Sclerosis survival (number of samples = 4265, hazard ratio = 1.11, 95% confidence interval = 1.05–1.17, P-value = 2.06 × 10−4) and act as an Amyotrophic Lateral Sclerosis trans-expression Quantitative Trait Loci hotspot for a wider network of genes enriched for SCFD1 function and Amyotrophic Lateral Sclerosis pathways. Using gene-set analyses, we found the genes that correlate with this trans-expression Quantitative Trait Loci hotspot significantly increase risk of Amyotrophic Lateral Sclerosis (beta = 0.247, standard deviation = 0.017, P = 0.001) and schizophrenia (beta = 0.263, standard deviation = 0.008, P-value = 1.18 × 10−5), a disease that genetically correlates with Amyotrophic Lateral Sclerosis. In summary, SCFD1 expression Quantitative Trait Loci are a major factor in Amyotrophic Lateral Sclerosis, not only influencing disease risk but are differentially expressed in post-mortem Amyotrophic Lateral Sclerosis. SCFD1 expression Quantitative Trait Loci show distinct expression profiles in Amyotrophic Lateral Sclerosis that correlate with a wider network of genes that also confer risk of the disease and modify the disease’s duration. Previous research indicates DNA variants that increase risk of Amyotrophic Lateral Sclerosis (ALS) correlate with SCFD1 RNA activity. Iacoangeli et al. report that SCFD1 RNA and DNA variants are differentially active in ALS, which not only increases risk of the disease but modifies its duration, confirming their involvement in ALS.
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全基因组荟萃分析发现ACSL5-ZDHHC6基因座与ALS相关，并将减肥与疾病遗传学联系起来。
影响因子：
8.8
作者：
Iacoangeli A;Lin T;Al Khleifat A;Jones AR;Opie-Martin S;Coleman JRI;Shatunov A;Sproviero W;Williams KL;Garton F;Restuadi R;Henders AK;Mather KA;Needham M;Mathers S;Nicholson GA;Rowe DB;Henderson R;McCombe PA;Pamphlett R;Blair IP;Schultz D;Sachdev PS;Newhouse SJ;Proitsi P;Fogh I;Ngo ST;Dobson RJB;Wray NR;Steyn FJ;Al-Chalabi A
通讯作者：
Al-Chalabi A
遗传对人体组织基因表达的影响。
影响因子：
64.8
作者：
GTEx Consortium;Laboratory, Data Analysis &Coordinating Center (LDACC)—Analysis Working Group;Statistical Methods groups—Analysis Working Group;Enhancing GTEx (eGTEx) groups;NIH Common Fund;NIH/NCI;NIH/NHGRI;NIH/NIMH;NIH/NIDA;Biospecimen Collection Source Site—NDRI;Biospecimen Collection Source Site—RPCI;Biospecimen Core Resource—VARI;Brain Bank Repository—University of Miami Brain Endowment Bank;Leidos Biomedical—Project Management;ELSI Study;Genome Browser Data Integration &Visualization—EBI;Genome Browser Data Integration &Visualization—UCSC Genomics Institute, University of California Santa Cruz;Lead analysts:;Laboratory, Data Analysis &Coordinating Center (LDACC):;NIH program management:;Biospecimen collection:;Pathology:;eQTL manuscript working group:;Battle A;Brown CD;Engelhardt BE;Montgomery SB
通讯作者：
Montgomery SB
影响因子：
56.9
作者：
Kwiatkowski, T. J., Jr.;Bosco, D. A.;Brown, R. H., Jr.
通讯作者：
Brown, R. H., Jr.
影响因子：
5.3
作者：
DASCHER, C;OSSIG, R;SCHMITT, HD
通讯作者：
SCHMITT, HD
通过替代变量分析捕获基因表达研究中的异质性。
影响因子：
4.5
作者：
Leek, Jeffrey T.;Storey, John D.
通讯作者：
Storey, John D.