Annotating Transcriptional Effects of Genetic Variants in Disease-Relevant Tissue: Transcriptome-Wide Allelic Imbalance in Osteoarthritic Cartilage.
Annotating Transcriptional Effects of Genetic Variants in Disease-Relevant Tissue: Transcriptome-Wide Allelic Imbalance in Osteoarthritic Cartilage.
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DOI：
10.1002/art.40748
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发表时间：
2019-04
期刊：
影响因子：
--
通讯作者：
Meulenbelt I
中科院分区：
文献类型：
--
作者：
den Hollander W;Pulyakhina I;Boer C;Bomer N;van der Breggen R;Arindrarto W;Couthino de Almeida R;Lakenberg N;Sentner T;Laros JFJ;'t Hoen PAC;Slagboom EPE;Nelissen RGHH;van Meurs J;Ramos YFM;Meulenbelt I
Multiple single‐nucleotide polymorphisms (SNPs) conferring susceptibility to osteoarthritis (OA) mark imbalanced expression of positional genes in articular cartilage, reflected by unequally expressed alleles among heterozygotes (allelic imbalance [AI]). We undertook this study to explore the articular cartilage transcriptome from OA patients for AI events to identify putative disease‐driving genetic variation. AI was assessed in 42 preserved and 5 lesioned OA cartilage samples (from the Research Arthritis and Articular Cartilage study) for which RNA sequencing data were available. The count fraction of the alternative alleles among the alternative and reference alleles together (φ) was determined for heterozygous individuals. A meta‐analysis was performed to generate a meta‐φ and P value for each SNP with a false discovery rate (FDR) correction for multiple comparisons. To further validate AI events, we explored them as a function of multiple additional OA features. We observed a total of 2,070 SNPs that consistently marked AI of 1,031 unique genes in articular cartilage. Of these genes, 49 were found to be significantly differentially expressed (fold change <0.5 or >2, FDR <0.05) between preserved and paired lesioned cartilage, and 18 had previously been reported to confer susceptibility to OA and/or related phenotypes. Moreover, we identified notable highly significant AI SNPs in the CRLF1,WWP2, and RPS3 genes that were related to multiple OA features. We present a framework and resulting data set for researchers in the OA research field to probe for disease‐relevant genetic variation that affects gene expression in pivotal disease‐affected tissue. This likely includes putative novel compelling OA risk genes such as CRLF1,WWP2, and RPS3.
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影响因子：
12.3
作者：
Castel SE;Levy-Moonshine A;Mohammadi P;Banks E;Lappalainen T
通讯作者：
Lappalainen T
影响因子：
27.4
作者：
Raine, E. V. A.;Wreglesworth, N.;Loughlin, J.
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Loughlin, J.
影响因子：
3.5
作者：
Meulenbelt, Ingrid;Min, Josine L.;Slagboom, P. Eline
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Slagboom, P. Eline
全基因组的关联和功能研究确定了基质gla蛋白在手的骨关节炎中的作用。
影响因子：
27.4
作者：
den Hollander W;Boer CG;Hart DJ;Yau MS;Ramos YFM;Metrustry S;Broer L;Deelen J;Cupples LA;Rivadeneira F;Kloppenburg M;Peters M;Spector TD;Hofman A;Slagboom PE;Nelissen RGHH;Uitterlinden AG;Felson DT;Valdes AM;Meulenbelt I;van Meurs JJB
通讯作者：
van Meurs JJB
影响因子：
27.4
作者：
Panoutsopoulou K;Thiagarajah S;Zengini E;Day-Williams AG;Ramos YF;Meessen JM;Huetink K;Nelissen RG;Southam L;Rayner NW;arcOGEN Consortium;Doherty M;Meulenbelt I;Zeggini E;Wilkinson JM
通讯作者：
Wilkinson JM