SCFD1 expression Quantitative Trait Loci in Amyotrophic Lateral Sclerosis are differentially expressed Short title: SCFD1 expression quantitative loci in ALS

Alfredo Iacoangeli; Isabella Fogh; Sashika Selvackadunco; Simon Topp; Aleksey Shatunov; Wouter van Rheenen; Ahmad Al Khleifat; Sarah Martin; Antonia Ratti; Adriano Chio; Richard Dobson; Orla Hardiman; Christopher Shaw; Leonard H. van den Berg; Bradley Smith; Jan Veldink; Gerome Breen; Claire Troakes; Ammar Al-Chalabi; Ashley Jones

SCFD1 expression Quantitative Trait Loci in Amyotrophic Lateral Sclerosis are differentially expressed Short title: SCFD1 expression quantitative loci in ALS

Alfredo Iacoangeli, Isabella Fogh, Sashika Selvackadunco, Simon Topp, Aleksey Shatunov, Wouter van Rheenen, Ahmad Al Khleifat, Sarah Martin, Antonia Ratti, Adriano Chio, Richard Dobson, Orla Hardiman, Christopher Shaw, Leonard H. van den Berg, Bradley Smith, Jan Veldink, Gerome Breen, Claire Troakes, Ammar Al-Chalabi, Ashley Jones

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Abstract

Evidence indicates that common variants found in genome-wide association studies increase risk of disease through gene regulation via ex- pression 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 1⁄4 0.20, standard error 1⁄4 0.04, P-value 1⁄4 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 (n1⁄476) and controls (n1⁄425), genome-wide. Of 20757 genes analysed, the two most significant expression Quantitative Trait Loci to show differential in expression between Amyotrophic Lateral Sclerosis and controls in- volve two known Amyotrophic Lateral Sclerosis genes (SCFD1 and VCP). Cis-acting SCFD1 expression Quantitative Trait Loci down- stream of the gene showed significant differences in expression between Amyotrophic Lateral Sclerosis and controls (top expression Quantitative Trait Loci beta 1⁄4 0.34, standard error 1⁄4 0.063, P-value 1⁄4 4.54 􏰀 10􏰁7). These SCFD1 expression Quantitative Trait Loci also significantly modified Amyotrophic Lateral Sclerosis survival (number of samples 1⁄4 4265, hazard ratio 1⁄4 1.11, 95% confidence inter- val 1⁄4 1.05–1.17, P-value 1⁄4 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 1⁄4 0.247, standard deviation 1⁄4 0.017, P 1⁄4 0.001) and schizophrenia (beta 1⁄4 0.263, standard deviation 1⁄4 0.008, P-value 1⁄4 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.

Original language	English
Journal	Brain Communications
Publication status	Published - 7 Oct 2021

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Iacoangeli, A., Fogh, I., Selvackadunco, S., Topp, S., Shatunov, A., van Rheenen, W., Al Khleifat, A., Martin, S., Ratti, A., Chio, A., Dobson, R., Hardiman, O., Shaw, C., van den Berg, L. H., Smith, B., Veldink, J., Breen, G., Troakes, C., Al-Chalabi, A., & Jones, A. (2021). SCFD1 expression Quantitative Trait Loci in Amyotrophic Lateral Sclerosis are differentially expressed Short title: SCFD1 expression quantitative loci in ALS. Brain Communications.

@article{8820f1b0635944e2a03a7c0c67ea84be,

title = "SCFD1 expression Quantitative Trait Loci in Amyotrophic Lateral Sclerosis are differentially expressed Short title: SCFD1 expression quantitative loci in ALS",

abstract = "Evidence indicates that common variants found in genome-wide association studies increase risk of disease through gene regulation via ex- pression 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 1⁄4 0.20, standard error 1⁄4 0.04, P-value 1⁄4 4.29 ﰀ 10ﰁ6). Using post-mortem motor cortex, we tested whether expression Quantitative Trait Loci showed significant differences in expression between Amyotrophic Lateral Sclerosis (n1⁄476) and controls (n1⁄425), genome-wide. Of 20757 genes analysed, the two most significant expression Quantitative Trait Loci to show differential in expression between Amyotrophic Lateral Sclerosis and controls in- volve two known Amyotrophic Lateral Sclerosis genes (SCFD1 and VCP). Cis-acting SCFD1 expression Quantitative Trait Loci down- stream of the gene showed significant differences in expression between Amyotrophic Lateral Sclerosis and controls (top expression Quantitative Trait Loci beta 1⁄4 0.34, standard error 1⁄4 0.063, P-value 1⁄4 4.54 ﰀ 10ﰁ7). These SCFD1 expression Quantitative Trait Loci also significantly modified Amyotrophic Lateral Sclerosis survival (number of samples 1⁄4 4265, hazard ratio 1⁄4 1.11, 95% confidence inter- val 1⁄4 1.05–1.17, P-value 1⁄4 2.06 ﰀ 10ﰁ4) 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 1⁄4 0.247, standard deviation 1⁄4 0.017, P 1⁄4 0.001) and schizophrenia (beta 1⁄4 0.263, standard deviation 1⁄4 0.008, P-value 1⁄4 1.18 ﰀ 10ﰁ5), 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{\textquoteright}s duration.",

author = "Alfredo Iacoangeli and Isabella Fogh and Sashika Selvackadunco and Simon Topp and Aleksey Shatunov and {van Rheenen}, Wouter and {Al Khleifat}, Ahmad and Sarah Martin and Antonia Ratti and Adriano Chio and Richard Dobson and Orla Hardiman and Christopher Shaw and {van den Berg}, {Leonard H.} and Bradley Smith and Jan Veldink and Gerome Breen and Claire Troakes and Ammar Al-Chalabi and Ashley Jones",

year = "2021",

month = oct,

day = "7",

language = "English",

journal = "Brain Communications",

issn = "2632-1297",

publisher = "Oxford University Press",

}

Iacoangeli, A , Fogh, I , Selvackadunco, S , Topp, S , Shatunov, A, van Rheenen, W, Al Khleifat, A , Martin, S, Ratti, A, Chio, A, Dobson, R, Hardiman, O, Shaw, C, van den Berg, LH, Smith, B, Veldink, J, Breen, G , Troakes, C , Al-Chalabi, A & Jones, A 2021, 'SCFD1 expression Quantitative Trait Loci in Amyotrophic Lateral Sclerosis are differentially expressed Short title: SCFD1 expression quantitative loci in ALS', Brain Communications.

TY - JOUR

T1 - SCFD1 expression Quantitative Trait Loci in Amyotrophic Lateral Sclerosis are differentially expressed Short title: SCFD1 expression quantitative loci in ALS

AU - Iacoangeli, Alfredo

AU - Fogh, Isabella

AU - Selvackadunco, Sashika

AU - Topp, Simon

AU - Shatunov, Aleksey

AU - van Rheenen, Wouter

AU - Al Khleifat, Ahmad

AU - Martin, Sarah

AU - Ratti, Antonia

AU - Chio, Adriano

AU - Dobson, Richard

AU - Hardiman, Orla

AU - Shaw, Christopher

AU - van den Berg, Leonard H.

AU - Smith, Bradley

AU - Veldink, Jan

AU - Breen, Gerome

AU - Troakes, Claire

AU - Al-Chalabi, Ammar

AU - Jones, Ashley

PY - 2021/10/7

Y1 - 2021/10/7

N2 - Evidence indicates that common variants found in genome-wide association studies increase risk of disease through gene regulation via ex- pression 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 1⁄4 0.20, standard error 1⁄4 0.04, P-value 1⁄4 4.29 ﰀ 10ﰁ6). Using post-mortem motor cortex, we tested whether expression Quantitative Trait Loci showed significant differences in expression between Amyotrophic Lateral Sclerosis (n1⁄476) and controls (n1⁄425), genome-wide. Of 20757 genes analysed, the two most significant expression Quantitative Trait Loci to show differential in expression between Amyotrophic Lateral Sclerosis and controls in- volve two known Amyotrophic Lateral Sclerosis genes (SCFD1 and VCP). Cis-acting SCFD1 expression Quantitative Trait Loci down- stream of the gene showed significant differences in expression between Amyotrophic Lateral Sclerosis and controls (top expression Quantitative Trait Loci beta 1⁄4 0.34, standard error 1⁄4 0.063, P-value 1⁄4 4.54 ﰀ 10ﰁ7). These SCFD1 expression Quantitative Trait Loci also significantly modified Amyotrophic Lateral Sclerosis survival (number of samples 1⁄4 4265, hazard ratio 1⁄4 1.11, 95% confidence inter- val 1⁄4 1.05–1.17, P-value 1⁄4 2.06 ﰀ 10ﰁ4) 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 1⁄4 0.247, standard deviation 1⁄4 0.017, P 1⁄4 0.001) and schizophrenia (beta 1⁄4 0.263, standard deviation 1⁄4 0.008, P-value 1⁄4 1.18 ﰀ 10ﰁ5), 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.

AB - Evidence indicates that common variants found in genome-wide association studies increase risk of disease through gene regulation via ex- pression 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 1⁄4 0.20, standard error 1⁄4 0.04, P-value 1⁄4 4.29 ﰀ 10ﰁ6). Using post-mortem motor cortex, we tested whether expression Quantitative Trait Loci showed significant differences in expression between Amyotrophic Lateral Sclerosis (n1⁄476) and controls (n1⁄425), genome-wide. Of 20757 genes analysed, the two most significant expression Quantitative Trait Loci to show differential in expression between Amyotrophic Lateral Sclerosis and controls in- volve two known Amyotrophic Lateral Sclerosis genes (SCFD1 and VCP). Cis-acting SCFD1 expression Quantitative Trait Loci down- stream of the gene showed significant differences in expression between Amyotrophic Lateral Sclerosis and controls (top expression Quantitative Trait Loci beta 1⁄4 0.34, standard error 1⁄4 0.063, P-value 1⁄4 4.54 ﰀ 10ﰁ7). These SCFD1 expression Quantitative Trait Loci also significantly modified Amyotrophic Lateral Sclerosis survival (number of samples 1⁄4 4265, hazard ratio 1⁄4 1.11, 95% confidence inter- val 1⁄4 1.05–1.17, P-value 1⁄4 2.06 ﰀ 10ﰁ4) 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 1⁄4 0.247, standard deviation 1⁄4 0.017, P 1⁄4 0.001) and schizophrenia (beta 1⁄4 0.263, standard deviation 1⁄4 0.008, P-value 1⁄4 1.18 ﰀ 10ﰁ5), 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.

M3 - Article

SN - 2632-1297

JO - Brain Communications

JF - Brain Communications

ER -

SCFD1 expression Quantitative Trait Loci in Amyotrophic Lateral Sclerosis are differentially expressed Short title: SCFD1 expression quantitative loci in ALS

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