SCFD1 expression quantitative trait loci in amyotrophic lateral sclerosis are differentially expressed Article Swipe

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Alfredo Iacoangeli , Isabella Fogh , Sashika Selvackadunco , Simon Topp , Aleksey Shatunov , Wouter van Rheenen , Ahmad Al Khleifat , Sarah Opie-Martin , Antonia Ratti , Andrea Calvo , John Wim Hardy , Michael E. Weale , Mina Ryten , Daniah Orla Trabzuni , Adaikalavan Ramasamy , Colin Smith , Manuel Sebastian Guelfi , Karishma D’Sa , Paola Forabosco , Philip Van Damme , Wim Robberecht , Adriano Chiò , Richard Dobson , Orla Hardiman , Christopher E. Shaw , Leonard H. van den Berg , Peter M. Andersen , Bradley Smith , Vincenzo Silani , Jan H. Veldink , Gerome Breen , Claire Troakes , Ammar Al‐Chalabi , Ashley Jones ·

YOU? · · 2021 · Open Access · · DOI: https://doi.org/10.1093/braincomms/fcab236

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.

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Genome-Wide Association Study

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Amyotrophic lateral sclerosis Expression quantitative trait loci Quantitative trait locus Genome-wide association study Biology Mendelian randomization Genetics Genetic architecture Single-nucleotide polymorphism Genetic association Trait Gene Disease Medicine Genotype Internal medicine Computer science Programming language Genetic variants

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Language: en
Landing Page: https://doi.org/10.1093/braincomms/fcab236
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Cited By: 27
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DOI: https://doi.org/10.1093/braincomms/fcab236

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Title: SCFD1 expression quantitative trait loci in amyotrophic lateral sclerosis are differentially expressed

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Publication year: 2021

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Authors: Alfredo Iacoangeli, Isabella Fogh, Sashika Selvackadunco, Simon Topp, Aleksey Shatunov, Wouter van Rheenen, Ahmad Al Khleifat, Sarah Opie-Martin, Antonia Ratti, Andrea Calvo, John Wim Hardy, Michael E. Weale, Mina Ryten, Daniah Orla Trabzuni, Adaikalavan Ramasamy, Colin Smith, Manuel Sebastian Guelfi, Karishma D’Sa, Paola Forabosco, Philip Van Damme, Wim Robberecht, Adriano Chiò, Richard Dobson, Orla Hardiman, Christopher E. Shaw, Leonard H. van den Berg, Peter M. Andersen, Bradley Smith, Vincenzo Silani, Jan H. Veldink, Gerome Breen, Claire Troakes, Ammar Al‐Chalabi, Ashley Jones

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Concepts: Amyotrophic lateral sclerosis, Expression quantitative trait loci, Quantitative trait locus, Genome-wide association study, Biology, Mendelian randomization, Genetics, Genetic architecture, Single-nucleotide polymorphism, Genetic association, Trait, Gene, Disease, Medicine, Genotype, Internal medicine, Computer science, Programming language, Genetic variants

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abstract_inverted_index.the	90, 157, 194, 288, 394, 398
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abstract_inverted_index.4.54	221
abstract_inverted_index.Loci	49, 71, 107, 133, 164, 191, 211, 229, 266, 297, 345, 372
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abstract_inverted_index.gene	16, 92, 195
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abstract_inverted_index.0.04,	117
abstract_inverted_index.0.20,	113
abstract_inverted_index.0.34,	214
abstract_inverted_index.1.11,	245
abstract_inverted_index.4265,	241
abstract_inverted_index.Loci,	43
abstract_inverted_index.Loci.	22
abstract_inverted_index.SCFD1	88, 187, 225, 276, 341, 368
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abstract_inverted_index.Trait	21, 42, 48, 70, 106, 132, 163, 190, 210, 228, 265, 296, 344, 371
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abstract_inverted_index.error	115, 216
abstract_inverted_index.found	6, 287
abstract_inverted_index.genes	155, 182, 273, 289, 388
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abstract_inverted_index.major	348
abstract_inverted_index.motor	125
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abstract_inverted_index.those	61
abstract_inverted_index.wider	270, 385
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abstract_inverted_index.0.001)	315
abstract_inverted_index.0.008,	324
abstract_inverted_index.0.017,	312
abstract_inverted_index.0.063,	218
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abstract_inverted_index.public	67
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abstract_inverted_index.tested	128
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abstract_inverted_index.10−4)	255
abstract_inverted_index.Lateral	37, 58, 75, 100, 141, 172, 180, 203, 234, 261, 280, 304, 337, 352, 366, 379
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abstract_inverted_index.between	139, 170, 201
abstract_inverted_index.confirm	86
abstract_inverted_index.cortex,	126
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abstract_inverted_index.Nucleotide	31
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