Mapping of gene expression reveals CYP27A1 as a susceptibility gene for sporadic ALS

Amyotrophic lateral sclerosis (ALS) is a progressive, neurodegenerative disease characterized by loss of upper and lower motor neurons. ALS is considered to be a complex trait and genome-wide association studies (GWAS) have implicated a few susceptibility loci. However, many more causal loci remain...

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Veröffentlicht in:PloS one 2012-04, Vol.7 (4), p.e35333-e35333
Hauptverfasser: Diekstra, Frank P, Saris, Christiaan G J, van Rheenen, Wouter, Franke, Lude, Jansen, Ritsert C, van Es, Michael A, van Vught, Paul W J, Blauw, Hylke M, Groen, Ewout J N, Horvath, Steve, Estrada, Karol, Rivadeneira, Fernando, Hofman, Albert, Uitterlinden, Andre G, Robberecht, Wim, Andersen, Peter M, Melki, Judith, Meininger, Vincent, Hardiman, Orla, Landers, John E, Brown, Jr, Robert H, Shatunov, Aleksey, Shaw, Christopher E, Leigh, P Nigel, Al-Chalabi, Ammar, Ophoff, Roel A, van den Berg, Leonard H, Veldink, Jan H
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container_issue 4
container_start_page e35333
container_title PloS one
container_volume 7
creator Diekstra, Frank P
Saris, Christiaan G J
van Rheenen, Wouter
Franke, Lude
Jansen, Ritsert C
van Es, Michael A
van Vught, Paul W J
Blauw, Hylke M
Groen, Ewout J N
Horvath, Steve
Estrada, Karol
Rivadeneira, Fernando
Hofman, Albert
Uitterlinden, Andre G
Robberecht, Wim
Andersen, Peter M
Melki, Judith
Meininger, Vincent
Hardiman, Orla
Landers, John E
Brown, Jr, Robert H
Shatunov, Aleksey
Shaw, Christopher E
Leigh, P Nigel
Al-Chalabi, Ammar
Ophoff, Roel A
van den Berg, Leonard H
Veldink, Jan H
description Amyotrophic lateral sclerosis (ALS) is a progressive, neurodegenerative disease characterized by loss of upper and lower motor neurons. ALS is considered to be a complex trait and genome-wide association studies (GWAS) have implicated a few susceptibility loci. However, many more causal loci remain to be discovered. Since it has been shown that genetic variants associated with complex traits are more likely to be eQTLs than frequency-matched variants from GWAS platforms, we conducted a two-stage genome-wide screening for eQTLs associated with ALS. In addition, we applied an eQTL analysis to finemap association loci. Expression profiles using peripheral blood of 323 sporadic ALS patients and 413 controls were mapped to genome-wide genotyping data. Subsequently, data from a two-stage GWAS (3,568 patients and 10,163 controls) were used to prioritize eQTLs identified in the first stage (162 ALS, 207 controls). These prioritized eQTLs were carried forward to the second sample with both gene-expression and genotyping data (161 ALS, 206 controls). Replicated eQTL SNPs were then tested for association in the second-stage GWAS data to find SNPs associated with disease, that survived correction for multiple testing. We thus identified twelve cis eQTLs with nominally significant associations in the second-stage GWAS data. Eight SNP-transcript pairs of highest significance (lowest p = 1.27 × 10(-51)) withstood multiple-testing correction in the second stage and modulated CYP27A1 gene expression. Additionally, we show that C9orf72 appears to be the only gene in the 9p21.2 locus that is regulated in cis, showing the potential of this approach in identifying causative genes in association loci in ALS. This study has identified candidate genes for sporadic ALS, most notably CYP27A1. Mutations in CYP27A1 are causal to cerebrotendinous xanthomatosis which can present as a clinical mimic of ALS with progressive upper motor neuron loss, making it a plausible susceptibility gene for ALS.
doi_str_mv 10.1371/journal.pone.0035333
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ALS is considered to be a complex trait and genome-wide association studies (GWAS) have implicated a few susceptibility loci. However, many more causal loci remain to be discovered. Since it has been shown that genetic variants associated with complex traits are more likely to be eQTLs than frequency-matched variants from GWAS platforms, we conducted a two-stage genome-wide screening for eQTLs associated with ALS. In addition, we applied an eQTL analysis to finemap association loci. Expression profiles using peripheral blood of 323 sporadic ALS patients and 413 controls were mapped to genome-wide genotyping data. Subsequently, data from a two-stage GWAS (3,568 patients and 10,163 controls) were used to prioritize eQTLs identified in the first stage (162 ALS, 207 controls). These prioritized eQTLs were carried forward to the second sample with both gene-expression and genotyping data (161 ALS, 206 controls). Replicated eQTL SNPs were then tested for association in the second-stage GWAS data to find SNPs associated with disease, that survived correction for multiple testing. We thus identified twelve cis eQTLs with nominally significant associations in the second-stage GWAS data. Eight SNP-transcript pairs of highest significance (lowest p = 1.27 × 10(-51)) withstood multiple-testing correction in the second stage and modulated CYP27A1 gene expression. Additionally, we show that C9orf72 appears to be the only gene in the 9p21.2 locus that is regulated in cis, showing the potential of this approach in identifying causative genes in association loci in ALS. This study has identified candidate genes for sporadic ALS, most notably CYP27A1. Mutations in CYP27A1 are causal to cerebrotendinous xanthomatosis which can present as a clinical mimic of ALS with progressive upper motor neuron loss, making it a plausible susceptibility gene for ALS.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0035333</identifier><identifier>PMID: 22509407</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Amyotrophic lateral sclerosis ; Amyotrophic Lateral Sclerosis - genetics ; Analysis ; Arabidopsis ; Bioinformatics ; Biology ; Brain ; Cholestanetriol 26-Monooxygenase - genetics ; Councils ; Cytochrome P-450 ; Dementia ; Disease susceptibility ; DNA methylation ; Epidemiology ; Gene expression ; Gene Expression Profiling ; Gene mapping ; Genes ; Genetic aspects ; Genetic diversity ; Genetic Predisposition to Disease ; Genetic variance ; Genetics ; Genome-Wide Association Study ; Genomes ; Genomics ; Genotype ; Genotyping ; Haplotypes ; HapMap Project ; Hospitals ; Humans ; Linkage Disequilibrium ; Loci ; Medical research ; Medicine ; Metabolism ; Motor neurons ; Motor Neurons - pathology ; Mutation ; Nervous system diseases ; Neurodegeneration ; Neurology ; Neurosciences ; Patients ; Pedigree ; Peripheral blood ; Polymorphism, Single Nucleotide ; Psychiatry ; Quantitative Trait Loci - genetics ; Single-nucleotide polymorphism ; Stress response ; Transcription ; Xanthomatosis ; Xanthomatosis, Cerebrotendinous - genetics</subject><ispartof>PloS one, 2012-04, Vol.7 (4), p.e35333-e35333</ispartof><rights>COPYRIGHT 2012 Public Library of Science</rights><rights>2012 Diekstra et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License: https://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. 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ALS is considered to be a complex trait and genome-wide association studies (GWAS) have implicated a few susceptibility loci. However, many more causal loci remain to be discovered. Since it has been shown that genetic variants associated with complex traits are more likely to be eQTLs than frequency-matched variants from GWAS platforms, we conducted a two-stage genome-wide screening for eQTLs associated with ALS. In addition, we applied an eQTL analysis to finemap association loci. Expression profiles using peripheral blood of 323 sporadic ALS patients and 413 controls were mapped to genome-wide genotyping data. Subsequently, data from a two-stage GWAS (3,568 patients and 10,163 controls) were used to prioritize eQTLs identified in the first stage (162 ALS, 207 controls). These prioritized eQTLs were carried forward to the second sample with both gene-expression and genotyping data (161 ALS, 206 controls). Replicated eQTL SNPs were then tested for association in the second-stage GWAS data to find SNPs associated with disease, that survived correction for multiple testing. We thus identified twelve cis eQTLs with nominally significant associations in the second-stage GWAS data. Eight SNP-transcript pairs of highest significance (lowest p = 1.27 × 10(-51)) withstood multiple-testing correction in the second stage and modulated CYP27A1 gene expression. Additionally, we show that C9orf72 appears to be the only gene in the 9p21.2 locus that is regulated in cis, showing the potential of this approach in identifying causative genes in association loci in ALS. This study has identified candidate genes for sporadic ALS, most notably CYP27A1. Mutations in CYP27A1 are causal to cerebrotendinous xanthomatosis which can present as a clinical mimic of ALS with progressive upper motor neuron loss, making it a plausible susceptibility gene for ALS.</description><subject>Amyotrophic lateral sclerosis</subject><subject>Amyotrophic Lateral Sclerosis - genetics</subject><subject>Analysis</subject><subject>Arabidopsis</subject><subject>Bioinformatics</subject><subject>Biology</subject><subject>Brain</subject><subject>Cholestanetriol 26-Monooxygenase - genetics</subject><subject>Councils</subject><subject>Cytochrome P-450</subject><subject>Dementia</subject><subject>Disease susceptibility</subject><subject>DNA methylation</subject><subject>Epidemiology</subject><subject>Gene expression</subject><subject>Gene Expression Profiling</subject><subject>Gene mapping</subject><subject>Genes</subject><subject>Genetic aspects</subject><subject>Genetic diversity</subject><subject>Genetic Predisposition to Disease</subject><subject>Genetic variance</subject><subject>Genetics</subject><subject>Genome-Wide Association Study</subject><subject>Genomes</subject><subject>Genomics</subject><subject>Genotype</subject><subject>Genotyping</subject><subject>Haplotypes</subject><subject>HapMap Project</subject><subject>Hospitals</subject><subject>Humans</subject><subject>Linkage Disequilibrium</subject><subject>Loci</subject><subject>Medical research</subject><subject>Medicine</subject><subject>Metabolism</subject><subject>Motor neurons</subject><subject>Motor Neurons - pathology</subject><subject>Mutation</subject><subject>Nervous system diseases</subject><subject>Neurodegeneration</subject><subject>Neurology</subject><subject>Neurosciences</subject><subject>Patients</subject><subject>Pedigree</subject><subject>Peripheral blood</subject><subject>Polymorphism, Single Nucleotide</subject><subject>Psychiatry</subject><subject>Quantitative Trait Loci - genetics</subject><subject>Single-nucleotide polymorphism</subject><subject>Stress response</subject><subject>Transcription</subject><subject>Xanthomatosis</subject><subject>Xanthomatosis, Cerebrotendinous - 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genetics</topic><topic>Analysis</topic><topic>Arabidopsis</topic><topic>Bioinformatics</topic><topic>Biology</topic><topic>Brain</topic><topic>Cholestanetriol 26-Monooxygenase - genetics</topic><topic>Councils</topic><topic>Cytochrome P-450</topic><topic>Dementia</topic><topic>Disease susceptibility</topic><topic>DNA methylation</topic><topic>Epidemiology</topic><topic>Gene expression</topic><topic>Gene Expression Profiling</topic><topic>Gene mapping</topic><topic>Genes</topic><topic>Genetic aspects</topic><topic>Genetic diversity</topic><topic>Genetic Predisposition to Disease</topic><topic>Genetic variance</topic><topic>Genetics</topic><topic>Genome-Wide Association Study</topic><topic>Genomes</topic><topic>Genomics</topic><topic>Genotype</topic><topic>Genotyping</topic><topic>Haplotypes</topic><topic>HapMap Project</topic><topic>Hospitals</topic><topic>Humans</topic><topic>Linkage Disequilibrium</topic><topic>Loci</topic><topic>Medical research</topic><topic>Medicine</topic><topic>Metabolism</topic><topic>Motor neurons</topic><topic>Motor Neurons - pathology</topic><topic>Mutation</topic><topic>Nervous system diseases</topic><topic>Neurodegeneration</topic><topic>Neurology</topic><topic>Neurosciences</topic><topic>Patients</topic><topic>Pedigree</topic><topic>Peripheral blood</topic><topic>Polymorphism, Single Nucleotide</topic><topic>Psychiatry</topic><topic>Quantitative Trait Loci - genetics</topic><topic>Single-nucleotide polymorphism</topic><topic>Stress response</topic><topic>Transcription</topic><topic>Xanthomatosis</topic><topic>Xanthomatosis, Cerebrotendinous - genetics</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Diekstra, Frank P</creatorcontrib><creatorcontrib>Saris, Christiaan G J</creatorcontrib><creatorcontrib>van Rheenen, Wouter</creatorcontrib><creatorcontrib>Franke, Lude</creatorcontrib><creatorcontrib>Jansen, Ritsert 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Ammar</creatorcontrib><creatorcontrib>Ophoff, Roel A</creatorcontrib><creatorcontrib>van den Berg, Leonard H</creatorcontrib><creatorcontrib>Veldink, Jan H</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Gale In Context: Opposing Viewpoints</collection><collection>Gale In Context: Science</collection><collection>ProQuest Central (Corporate)</collection><collection>Animal Behavior Abstracts</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Biotechnology Research Abstracts</collection><collection>Nursing &amp; Allied Health Database</collection><collection>Ecology Abstracts</collection><collection>Entomology Abstracts (Full archive)</collection><collection>Immunology Abstracts</collection><collection>Meteorological &amp; Geoastrophysical 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universitet</collection><collection>SwePub Articles full text</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>PloS one</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Diekstra, Frank P</au><au>Saris, Christiaan G J</au><au>van Rheenen, Wouter</au><au>Franke, Lude</au><au>Jansen, Ritsert C</au><au>van Es, Michael A</au><au>van Vught, Paul W J</au><au>Blauw, Hylke M</au><au>Groen, Ewout J N</au><au>Horvath, Steve</au><au>Estrada, Karol</au><au>Rivadeneira, Fernando</au><au>Hofman, Albert</au><au>Uitterlinden, Andre G</au><au>Robberecht, Wim</au><au>Andersen, Peter M</au><au>Melki, Judith</au><au>Meininger, Vincent</au><au>Hardiman, Orla</au><au>Landers, John E</au><au>Brown, Jr, Robert H</au><au>Shatunov, Aleksey</au><au>Shaw, Christopher E</au><au>Leigh, P Nigel</au><au>Al-Chalabi, Ammar</au><au>Ophoff, Roel A</au><au>van den Berg, Leonard H</au><au>Veldink, Jan H</au><au>van der Brug, Marcel P.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Mapping of gene expression reveals CYP27A1 as a susceptibility gene for sporadic ALS</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2012-04-11</date><risdate>2012</risdate><volume>7</volume><issue>4</issue><spage>e35333</spage><epage>e35333</epage><pages>e35333-e35333</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>Amyotrophic lateral sclerosis (ALS) is a progressive, neurodegenerative disease characterized by loss of upper and lower motor neurons. ALS is considered to be a complex trait and genome-wide association studies (GWAS) have implicated a few susceptibility loci. However, many more causal loci remain to be discovered. Since it has been shown that genetic variants associated with complex traits are more likely to be eQTLs than frequency-matched variants from GWAS platforms, we conducted a two-stage genome-wide screening for eQTLs associated with ALS. In addition, we applied an eQTL analysis to finemap association loci. Expression profiles using peripheral blood of 323 sporadic ALS patients and 413 controls were mapped to genome-wide genotyping data. Subsequently, data from a two-stage GWAS (3,568 patients and 10,163 controls) were used to prioritize eQTLs identified in the first stage (162 ALS, 207 controls). These prioritized eQTLs were carried forward to the second sample with both gene-expression and genotyping data (161 ALS, 206 controls). Replicated eQTL SNPs were then tested for association in the second-stage GWAS data to find SNPs associated with disease, that survived correction for multiple testing. We thus identified twelve cis eQTLs with nominally significant associations in the second-stage GWAS data. Eight SNP-transcript pairs of highest significance (lowest p = 1.27 × 10(-51)) withstood multiple-testing correction in the second stage and modulated CYP27A1 gene expression. Additionally, we show that C9orf72 appears to be the only gene in the 9p21.2 locus that is regulated in cis, showing the potential of this approach in identifying causative genes in association loci in ALS. This study has identified candidate genes for sporadic ALS, most notably CYP27A1. Mutations in CYP27A1 are causal to cerebrotendinous xanthomatosis which can present as a clinical mimic of ALS with progressive upper motor neuron loss, making it a plausible susceptibility gene for ALS.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>22509407</pmid><doi>10.1371/journal.pone.0035333</doi><tpages>e35333</tpages><oa>free_for_read</oa></addata></record>
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1932-6203
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subjects Amyotrophic lateral sclerosis
Amyotrophic Lateral Sclerosis - genetics
Analysis
Arabidopsis
Bioinformatics
Biology
Brain
Cholestanetriol 26-Monooxygenase - genetics
Councils
Cytochrome P-450
Dementia
Disease susceptibility
DNA methylation
Epidemiology
Gene expression
Gene Expression Profiling
Gene mapping
Genes
Genetic aspects
Genetic diversity
Genetic Predisposition to Disease
Genetic variance
Genetics
Genome-Wide Association Study
Genomes
Genomics
Genotype
Genotyping
Haplotypes
HapMap Project
Hospitals
Humans
Linkage Disequilibrium
Loci
Medical research
Medicine
Metabolism
Motor neurons
Motor Neurons - pathology
Mutation
Nervous system diseases
Neurodegeneration
Neurology
Neurosciences
Patients
Pedigree
Peripheral blood
Polymorphism, Single Nucleotide
Psychiatry
Quantitative Trait Loci - genetics
Single-nucleotide polymorphism
Stress response
Transcription
Xanthomatosis
Xanthomatosis, Cerebrotendinous - genetics
title Mapping of gene expression reveals CYP27A1 as a susceptibility gene for sporadic ALS
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