Genome-wide association study identifies zonisamide responsive gene in Parkinson's disease patients
Long-term treatment of Parkinson's disease (PD) by levodopa leads to motor complication "wearing-off". Zonisamide is a nondopaminergic antiparkinsonian drug that can improve "wearing-off" although response to the treatment varies between individuals. To clarify the genetic b...
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| Veröffentlicht in: | Journal of human genetics 2020-08, Vol.65 (8), p.693-704 |
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| creator | Cha, Pei-Chieng Satake, Wataru Ando-Kanagawa, Yuko Yamamoto, Ken Murata, Miho Toda, Tatsushi |
| description | Long-term treatment of Parkinson's disease (PD) by levodopa leads to motor complication "wearing-off". Zonisamide is a nondopaminergic antiparkinsonian drug that can improve "wearing-off" although response to the treatment varies between individuals. To clarify the genetic basis of zonisamide responsiveness, we conducted a genome-wide association study (GWAS) on 200 PD patients from a placebo-controlled clinical trial, including 67 responders whose "off" time decreased >= 1.5 h after 12 weeks of zonisamide treatment and 133 poor responders. We genotyped and evaluated the association between 611,492 single nucleotide polymorphisms (SNPs) and "off" time reduction. We also performed whole-genome imputation, gene- and pathway-based analyses of GWAS data. For promising SNPs, we examined single-tissue expression quantitative trait loci (eQTL) data in the GTEx database. SNP rs16854023 (Mouse double minute 4, MDM4) showed genome-wide significant association with reduced "off" time (P-Adjusted = 4.85 x 10(-9)). Carriers of responsive genotype showed >7-fold decrease in mean "off" time compared to noncarriers (1.42 h vs 0.19 h; P = 2.71 x 10(-7)). In silico eQTL data indicated that zonisamide sensitivity is associated with higher MDM4 expression. Among the 37 pathways significantly influencing "off" time, calcium and glutamate signaling have also been associated with anti-epileptic effect of zonisamide. MDM4 encodes a negative regulator of p53. The association between improved motor fluctuation and MDM4 upregulation implies that p53 inhibition may prevent dopaminergic neuron loss and consequent motor symptoms. This is the first genome-wide pharmacogenetics study on antiparkinsonian drug. The findings provide a basis for improved management of "wearing-off" in PD by genotype-guided zonisamide treatment. |
| doi_str_mv | 10.1038/s10038-020-0760-8 |
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Zonisamide is a nondopaminergic antiparkinsonian drug that can improve "wearing-off" although response to the treatment varies between individuals. To clarify the genetic basis of zonisamide responsiveness, we conducted a genome-wide association study (GWAS) on 200 PD patients from a placebo-controlled clinical trial, including 67 responders whose "off" time decreased >= 1.5 h after 12 weeks of zonisamide treatment and 133 poor responders. We genotyped and evaluated the association between 611,492 single nucleotide polymorphisms (SNPs) and "off" time reduction. We also performed whole-genome imputation, gene- and pathway-based analyses of GWAS data. For promising SNPs, we examined single-tissue expression quantitative trait loci (eQTL) data in the GTEx database. SNP rs16854023 (Mouse double minute 4, MDM4) showed genome-wide significant association with reduced "off" time (P-Adjusted = 4.85 x 10(-9)). Carriers of responsive genotype showed >7-fold decrease in mean "off" time compared to noncarriers (1.42 h vs 0.19 h; P = 2.71 x 10(-7)). In silico eQTL data indicated that zonisamide sensitivity is associated with higher MDM4 expression. Among the 37 pathways significantly influencing "off" time, calcium and glutamate signaling have also been associated with anti-epileptic effect of zonisamide. MDM4 encodes a negative regulator of p53. The association between improved motor fluctuation and MDM4 upregulation implies that p53 inhibition may prevent dopaminergic neuron loss and consequent motor symptoms. This is the first genome-wide pharmacogenetics study on antiparkinsonian drug. The findings provide a basis for improved management of "wearing-off" in PD by genotype-guided zonisamide treatment.</description><identifier>ISSN: 1434-5161</identifier><identifier>EISSN: 1435-232X</identifier><identifier>DOI: 10.1038/s10038-020-0760-8</identifier><identifier>PMID: 32355309</identifier><language>eng</language><publisher>LONDON: Springer Nature</publisher><subject>Aged ; Antiparkinson Agents - pharmacology ; Antiparkinson Agents - therapeutic use ; Asian Continental Ancestry Group - genetics ; Calcium signalling ; Cell Cycle Proteins - genetics ; Cell Cycle Proteins - metabolism ; Clinical trials ; DNA-Binding Proteins - genetics ; DNA-Binding Proteins - metabolism ; Dopamine ; Dopamine receptors ; Drug dosages ; Dyskinesia ; Epilepsy ; Female ; Genetics & Heredity ; Genome-wide association studies ; Genome-Wide Association Study ; Genomes ; Humans ; Levodopa ; Life Sciences & Biomedicine ; Male ; Middle Aged ; Movement disorders ; Neurodegenerative diseases ; Neurology ; Neurons ; p53 Protein ; Parkinson Disease - drug therapy ; Parkinson Disease - genetics ; Parkinson Disease - metabolism ; Parkinson's disease ; Patients ; Pharmacogenetics ; Polymorphism, Single Nucleotide ; Proto-Oncogene Proteins - genetics ; Proto-Oncogene Proteins - metabolism ; Quantitative Trait Loci ; Science & Technology ; Signal Transduction - genetics ; Single-nucleotide polymorphism ; Zonisamide ; Zonisamide - pharmacology ; Zonisamide - therapeutic use</subject><ispartof>Journal of human genetics, 2020-08, Vol.65 (8), p.693-704</ispartof><rights>The Author(s) 2020. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>The Author(s) 2020</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>true</woscitedreferencessubscribed><woscitedreferencescount>8</woscitedreferencescount><woscitedreferencesoriginalsourcerecordid>wos000529712600001</woscitedreferencesoriginalsourcerecordid><citedby>FETCH-LOGICAL-c565t-ef8aff64241e390769252811e79ad0f1ee47273801b9ff74f239c3618d30cb0a3</citedby><cites>FETCH-LOGICAL-c565t-ef8aff64241e390769252811e79ad0f1ee47273801b9ff74f239c3618d30cb0a3</cites><orcidid>0000-0002-5718-2824 ; 0000-0002-1531-9685</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,315,781,785,886,27929,27930,28253</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/32355309$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Cha, Pei-Chieng</creatorcontrib><creatorcontrib>Satake, Wataru</creatorcontrib><creatorcontrib>Ando-Kanagawa, Yuko</creatorcontrib><creatorcontrib>Yamamoto, Ken</creatorcontrib><creatorcontrib>Murata, Miho</creatorcontrib><creatorcontrib>Toda, Tatsushi</creatorcontrib><title>Genome-wide association study identifies zonisamide responsive gene in Parkinson's disease patients</title><title>Journal of human genetics</title><addtitle>J HUM GENET</addtitle><addtitle>J Hum Genet</addtitle><description>Long-term treatment of Parkinson's disease (PD) by levodopa leads to motor complication "wearing-off". Zonisamide is a nondopaminergic antiparkinsonian drug that can improve "wearing-off" although response to the treatment varies between individuals. To clarify the genetic basis of zonisamide responsiveness, we conducted a genome-wide association study (GWAS) on 200 PD patients from a placebo-controlled clinical trial, including 67 responders whose "off" time decreased >= 1.5 h after 12 weeks of zonisamide treatment and 133 poor responders. We genotyped and evaluated the association between 611,492 single nucleotide polymorphisms (SNPs) and "off" time reduction. We also performed whole-genome imputation, gene- and pathway-based analyses of GWAS data. For promising SNPs, we examined single-tissue expression quantitative trait loci (eQTL) data in the GTEx database. SNP rs16854023 (Mouse double minute 4, MDM4) showed genome-wide significant association with reduced "off" time (P-Adjusted = 4.85 x 10(-9)). Carriers of responsive genotype showed >7-fold decrease in mean "off" time compared to noncarriers (1.42 h vs 0.19 h; P = 2.71 x 10(-7)). In silico eQTL data indicated that zonisamide sensitivity is associated with higher MDM4 expression. Among the 37 pathways significantly influencing "off" time, calcium and glutamate signaling have also been associated with anti-epileptic effect of zonisamide. MDM4 encodes a negative regulator of p53. The association between improved motor fluctuation and MDM4 upregulation implies that p53 inhibition may prevent dopaminergic neuron loss and consequent motor symptoms. This is the first genome-wide pharmacogenetics study on antiparkinsonian drug. The findings provide a basis for improved management of "wearing-off" in PD by genotype-guided zonisamide treatment.</description><subject>Aged</subject><subject>Antiparkinson Agents - pharmacology</subject><subject>Antiparkinson Agents - therapeutic use</subject><subject>Asian Continental Ancestry Group - genetics</subject><subject>Calcium signalling</subject><subject>Cell Cycle Proteins - genetics</subject><subject>Cell Cycle Proteins - metabolism</subject><subject>Clinical trials</subject><subject>DNA-Binding Proteins - genetics</subject><subject>DNA-Binding Proteins - metabolism</subject><subject>Dopamine</subject><subject>Dopamine receptors</subject><subject>Drug dosages</subject><subject>Dyskinesia</subject><subject>Epilepsy</subject><subject>Female</subject><subject>Genetics & Heredity</subject><subject>Genome-wide association studies</subject><subject>Genome-Wide Association Study</subject><subject>Genomes</subject><subject>Humans</subject><subject>Levodopa</subject><subject>Life Sciences & Biomedicine</subject><subject>Male</subject><subject>Middle Aged</subject><subject>Movement disorders</subject><subject>Neurodegenerative diseases</subject><subject>Neurology</subject><subject>Neurons</subject><subject>p53 Protein</subject><subject>Parkinson Disease - drug therapy</subject><subject>Parkinson Disease - genetics</subject><subject>Parkinson Disease - metabolism</subject><subject>Parkinson's disease</subject><subject>Patients</subject><subject>Pharmacogenetics</subject><subject>Polymorphism, Single Nucleotide</subject><subject>Proto-Oncogene Proteins - genetics</subject><subject>Proto-Oncogene Proteins - metabolism</subject><subject>Quantitative Trait Loci</subject><subject>Science & Technology</subject><subject>Signal Transduction - genetics</subject><subject>Single-nucleotide polymorphism</subject><subject>Zonisamide</subject><subject>Zonisamide - pharmacology</subject><subject>Zonisamide - therapeutic use</subject><issn>1434-5161</issn><issn>1435-232X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2020</creationdate><recordtype>article</recordtype><sourceid>AOWDO</sourceid><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><recordid>eNqNkU-LFDEQxRtR3HX1A3iRBg8KEs2fTid9EWTQVVjQg4K3kElX1qzTyZjq3mX99NbsrIN68pQi-b1XVXlN81jwl4Ir-woFp4NxyRk3PWf2TnMsOqWZVPLr3Zu6Y1r04qh5gHjBiZZG3m-OlFRaKz4cN-EUcpmAXaURWo9YQvJzKrnFeRmvW7rNc4oJsP1ZckI_7bgKuC0Z0yW055ChTbn95Ov3lLHkZ9iOCcEjtFtyIjk-bO5Fv0F4dHueNF_evf28es_OPp5-WL05Y0H3emYQrY-x72QnQA200CC1tEKAGfzIowDojDTKcrEeYjRdlGoIqhd2VDysuVcnzeu973ZZTzAG6l39xm1rmny9dsUn9_dLTt_cebl0lhs9dJoMnt8a1PJjAZzdlDDAZuMzlAUdNTS9kdz2hD79B70oS820nqP5baelFjtDsadCLYgV4mEYwd0uQreP0FGEbhehs6R58ucWB8XvzAiwe-AK1iVioD8OcMAoZC0HI2RPFRerNN_kuSpLnkn64v-l6hdCX7la</recordid><startdate>20200801</startdate><enddate>20200801</enddate><creator>Cha, Pei-Chieng</creator><creator>Satake, Wataru</creator><creator>Ando-Kanagawa, Yuko</creator><creator>Yamamoto, Ken</creator><creator>Murata, Miho</creator><creator>Toda, Tatsushi</creator><general>Springer Nature</general><general>Nature Publishing Group</general><general>Springer Singapore</general><scope>AOWDO</scope><scope>BLEPL</scope><scope>DTL</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8FD</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>LK8</scope><scope>M0S</scope><scope>M1P</scope><scope>M7P</scope><scope>P64</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0002-5718-2824</orcidid><orcidid>https://orcid.org/0000-0002-1531-9685</orcidid></search><sort><creationdate>20200801</creationdate><title>Genome-wide association study identifies zonisamide responsive gene in Parkinson's disease patients</title><author>Cha, Pei-Chieng ; Satake, Wataru ; Ando-Kanagawa, Yuko ; Yamamoto, Ken ; Murata, Miho ; Toda, Tatsushi</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c565t-ef8aff64241e390769252811e79ad0f1ee47273801b9ff74f239c3618d30cb0a3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2020</creationdate><topic>Aged</topic><topic>Antiparkinson Agents - pharmacology</topic><topic>Antiparkinson Agents - therapeutic use</topic><topic>Asian Continental Ancestry Group - genetics</topic><topic>Calcium signalling</topic><topic>Cell Cycle Proteins - genetics</topic><topic>Cell Cycle Proteins - metabolism</topic><topic>Clinical trials</topic><topic>DNA-Binding Proteins - genetics</topic><topic>DNA-Binding Proteins - metabolism</topic><topic>Dopamine</topic><topic>Dopamine receptors</topic><topic>Drug dosages</topic><topic>Dyskinesia</topic><topic>Epilepsy</topic><topic>Female</topic><topic>Genetics & Heredity</topic><topic>Genome-wide association studies</topic><topic>Genome-Wide Association Study</topic><topic>Genomes</topic><topic>Humans</topic><topic>Levodopa</topic><topic>Life Sciences & Biomedicine</topic><topic>Male</topic><topic>Middle Aged</topic><topic>Movement disorders</topic><topic>Neurodegenerative diseases</topic><topic>Neurology</topic><topic>Neurons</topic><topic>p53 Protein</topic><topic>Parkinson Disease - drug therapy</topic><topic>Parkinson Disease - genetics</topic><topic>Parkinson Disease - metabolism</topic><topic>Parkinson's disease</topic><topic>Patients</topic><topic>Pharmacogenetics</topic><topic>Polymorphism, Single Nucleotide</topic><topic>Proto-Oncogene Proteins - genetics</topic><topic>Proto-Oncogene Proteins - metabolism</topic><topic>Quantitative Trait Loci</topic><topic>Science & Technology</topic><topic>Signal Transduction - genetics</topic><topic>Single-nucleotide polymorphism</topic><topic>Zonisamide</topic><topic>Zonisamide - pharmacology</topic><topic>Zonisamide - therapeutic use</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Cha, Pei-Chieng</creatorcontrib><creatorcontrib>Satake, Wataru</creatorcontrib><creatorcontrib>Ando-Kanagawa, Yuko</creatorcontrib><creatorcontrib>Yamamoto, Ken</creatorcontrib><creatorcontrib>Murata, Miho</creatorcontrib><creatorcontrib>Toda, Tatsushi</creatorcontrib><collection>Web of Science - Science Citation Index Expanded - 2020</collection><collection>Web of Science Core Collection</collection><collection>Science Citation Index Expanded</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>Technology Research Database</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Natural Science Collection</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Engineering Research Database</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>ProQuest Biological Science Collection</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Biological Science Database</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Journal of human genetics</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Cha, Pei-Chieng</au><au>Satake, Wataru</au><au>Ando-Kanagawa, Yuko</au><au>Yamamoto, Ken</au><au>Murata, Miho</au><au>Toda, Tatsushi</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Genome-wide association study identifies zonisamide responsive gene in Parkinson's disease patients</atitle><jtitle>Journal of human genetics</jtitle><stitle>J HUM GENET</stitle><addtitle>J Hum Genet</addtitle><date>2020-08-01</date><risdate>2020</risdate><volume>65</volume><issue>8</issue><spage>693</spage><epage>704</epage><pages>693-704</pages><issn>1434-5161</issn><eissn>1435-232X</eissn><abstract>Long-term treatment of Parkinson's disease (PD) by levodopa leads to motor complication "wearing-off". Zonisamide is a nondopaminergic antiparkinsonian drug that can improve "wearing-off" although response to the treatment varies between individuals. To clarify the genetic basis of zonisamide responsiveness, we conducted a genome-wide association study (GWAS) on 200 PD patients from a placebo-controlled clinical trial, including 67 responders whose "off" time decreased >= 1.5 h after 12 weeks of zonisamide treatment and 133 poor responders. We genotyped and evaluated the association between 611,492 single nucleotide polymorphisms (SNPs) and "off" time reduction. We also performed whole-genome imputation, gene- and pathway-based analyses of GWAS data. For promising SNPs, we examined single-tissue expression quantitative trait loci (eQTL) data in the GTEx database. SNP rs16854023 (Mouse double minute 4, MDM4) showed genome-wide significant association with reduced "off" time (P-Adjusted = 4.85 x 10(-9)). Carriers of responsive genotype showed >7-fold decrease in mean "off" time compared to noncarriers (1.42 h vs 0.19 h; P = 2.71 x 10(-7)). In silico eQTL data indicated that zonisamide sensitivity is associated with higher MDM4 expression. Among the 37 pathways significantly influencing "off" time, calcium and glutamate signaling have also been associated with anti-epileptic effect of zonisamide. MDM4 encodes a negative regulator of p53. The association between improved motor fluctuation and MDM4 upregulation implies that p53 inhibition may prevent dopaminergic neuron loss and consequent motor symptoms. This is the first genome-wide pharmacogenetics study on antiparkinsonian drug. The findings provide a basis for improved management of "wearing-off" in PD by genotype-guided zonisamide treatment.</abstract><cop>LONDON</cop><pub>Springer Nature</pub><pmid>32355309</pmid><doi>10.1038/s10038-020-0760-8</doi><tpages>12</tpages><orcidid>https://orcid.org/0000-0002-5718-2824</orcidid><orcidid>https://orcid.org/0000-0002-1531-9685</orcidid><oa>free_for_read</oa></addata></record> |
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| subjects | Aged Antiparkinson Agents - pharmacology Antiparkinson Agents - therapeutic use Asian Continental Ancestry Group - genetics Calcium signalling Cell Cycle Proteins - genetics Cell Cycle Proteins - metabolism Clinical trials DNA-Binding Proteins - genetics DNA-Binding Proteins - metabolism Dopamine Dopamine receptors Drug dosages Dyskinesia Epilepsy Female Genetics & Heredity Genome-wide association studies Genome-Wide Association Study Genomes Humans Levodopa Life Sciences & Biomedicine Male Middle Aged Movement disorders Neurodegenerative diseases Neurology Neurons p53 Protein Parkinson Disease - drug therapy Parkinson Disease - genetics Parkinson Disease - metabolism Parkinson's disease Patients Pharmacogenetics Polymorphism, Single Nucleotide Proto-Oncogene Proteins - genetics Proto-Oncogene Proteins - metabolism Quantitative Trait Loci Science & Technology Signal Transduction - genetics Single-nucleotide polymorphism Zonisamide Zonisamide - pharmacology Zonisamide - therapeutic use |
| title | Genome-wide association study identifies zonisamide responsive gene in Parkinson's disease patients |
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