<i>SCFD1</i> expression quantitative trait loci in amyotrophic lateral sclerosis are differentially expressed.

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Iacoangeli, Alfredo ORCID: 0000-0002-5280-5017, Fogh, Isabella, Selvackadunco, Sashika, Topp, Simon D, Shatunov, Aleksey ORCID: 0000-0002-2671-8040, van Rheenen, Wouter, Al-Khleifat, Ahmad, Opie-Martin, Sarah, Ratti, Antonia, Calvo, Andrea ORCID: 0000-0002-5122-7243 et al (show 16 more authors) , UK Brain Expression Consortium, , Van Damme, Philip ORCID: 0000-0002-4010-2357, Robberecht, Wim, Chio, Adriano, Dobson, Richard J ORCID: 0000-0003-4224-9245, Hardiman, Orla, Shaw, Christopher E, van den Berg, Leonard H, Andersen, Peter M, Smith, Bradley N, Silani, Vincenzo, Veldink, Jan H, Breen, Gerome, Troakes, Claire, Al-Chalabi, Ammar ORCID: 0000-0002-4924-7712 and Jones, Ashley R (2021) <i>SCFD1</i> expression quantitative trait loci in amyotrophic lateral sclerosis are differentially expressed. Brain communications, 3 (4). fcab236-.

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Abstract

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 <i>SCFD1</i> 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, <i>P</i>-value = 4.29 × 10^-6). Using <i>post-mortem</i> motor cortex, we tested whether expression Quantitative Trait Loci showed significant differences in expression between Amyotrophic Lateral Sclerosis (<i>n</i> = 76) and controls (<i>n</i> = 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 (<i>SCFD1</i> and <i>VCP</i>). <i>Cis</i>-acting <i>SCFD1</i> 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, <i>P</i>-value = 4.54 × 10^-7). These <i>SCFD1</i> 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, <i>P</i>-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 <i>SCFD1</i> 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, <i>P</i> = 0.001) and schizophrenia (beta = 0.263, standard deviation = 0.008, <i>P</i>-value = 1.18 × 10^-5), a disease that genetically correlates with Amyotrophic Lateral Sclerosis. In summary, <i>SCFD1</i> expression Quantitative Trait Loci are a major factor in Amyotrophic Lateral Sclerosis, not only influencing disease risk but are differentially expressed in <i>post-mortem</i> Amyotrophic Lateral Sclerosis. <i>SCFD1</i> 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.

Item Type:	Article
Uncontrolled Keywords:	UK Brain Expression Consortium
Divisions:	Faculty of Health and Life Sciences Faculty of Health and Life Sciences > Institute of Systems, Molecular and Integrative Biology
Depositing User:	Symplectic Admin
Date Deposited:	27 Mar 2023 13:39
Last Modified:	18 Mar 2024 03:26
DOI:	10.1093/braincomms/fcab236
Open Access URL:	https://doi.org/10.1093/braincomms/fcab236
Related URLs:	Author Publisher
URI:	https://livrepository.liverpool.ac.uk/id/eprint/3169262