A Variation in FGF14 Is Associated with Downbeat Nystagmus in a Genome-Wide Association Study
Downbeat nystagmus (DBN) is a frequent form of acquired persisting central fixation nystagmus, often associated with other cerebellar ocular signs, such as saccadic smooth pursuit or gaze-holding deficits. Despite its distinct clinical features, the underlying etiology of DBN often remains unclear....
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| Veröffentlicht in: | Cerebellum (London, England) England), 2020-06, Vol.19 (3), p.348-357 |
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| creator | Strupp, Michael Maul, Stephan Konte, Bettina Hartmann, Annette M. Giegling, Ina Wollenteit, Sophia Feil, Katharina Rujescu, Dan |
| description | Downbeat nystagmus (DBN) is a frequent form of acquired persisting central fixation nystagmus, often associated with other cerebellar ocular signs, such as saccadic smooth pursuit or gaze-holding deficits. Despite its distinct clinical features, the underlying etiology of DBN often remains unclear. Therefore, a genome-wide association study (GWAS) was conducted in 106 patients and 2609 healthy controls of European ancestry to identify genetic variants associated with DBN. A genome-wide significant association (
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p
< 5 × 10
−8
) with DBN was found for a variation on chromosome 13 located within the fibroblast growth factor 14 gene (FGF14). FGF14 is expressed in Purkinje cells (PCs) and a reduction leads to a decreased spontaneous firing rate and excitability of PCs, compatible with the pathophysiology of DBN. In addition, mutations in the FGF14 gene cause spinocerebellar ataxia type 27. Suggestive associations (
p
< 1 × 10
−05
) could be detected for 15 additional LD-independent loci, one of which is also located in the FGF14 gene. An association of a region containing the dihydrofolate reductase (DHFR) and MutS Homolog 3 (MSH3) genes on chromosome 5 was slightly below the genome-wide significance threshold. DHFR is relevant for neuronal regulation, and a dysfunction is known to induce cerebellar damage. Among the remaining twelve suggestive associations, four genes (MAST4, TPPP, FTMT, and IDS) seem to be involved in cerebral pathological processes. Thus, this GWAS analysis has identified a potential genetic contribution to idiopathic DBN, including suggestive associations to several genes involved in postulated pathological mechanisms of DBN (i.e., impaired function of cerebellar PCs).</description><identifier>ISSN: 1473-4222</identifier><identifier>EISSN: 1473-4230</identifier><identifier>DOI: 10.1007/s12311-020-01113-x</identifier><identifier>PMID: 32157568</identifier><language>eng</language><publisher>New York: Springer US</publisher><subject>Aged ; Aged, 80 and over ; Biomedical and Life Sciences ; Biomedicine ; Cerebellum ; Chromosome 13 ; Chromosome 5 ; Dihydrofolate reductase ; Etiology ; Excitability ; Female ; Fibroblast growth factors ; Fibroblast Growth Factors - genetics ; Firing rate ; Genes ; Genetic analysis ; Genetic diversity ; Genetic Variation - genetics ; Genome-wide association studies ; Genome-Wide Association Study - methods ; Genomes ; Germany - epidemiology ; Humans ; Male ; Middle Aged ; Neurobiology ; Neurology ; Neurosciences ; Nystagmus ; Nystagmus, Pathologic - diagnosis ; Nystagmus, Pathologic - epidemiology ; Nystagmus, Pathologic - genetics ; Original Paper ; Purkinje cells</subject><ispartof>Cerebellum (London, England), 2020-06, Vol.19 (3), p.348-357</ispartof><rights>The Author(s) 2020</rights><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><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c474t-9729aa6cae64f98cad230318d7cbe783412b2cbd779a043d2ee6f1481b44ea463</citedby><cites>FETCH-LOGICAL-c474t-9729aa6cae64f98cad230318d7cbe783412b2cbd779a043d2ee6f1481b44ea463</cites><orcidid>0000-0002-0668-797X</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1007/s12311-020-01113-x$$EPDF$$P50$$Gspringer$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1007/s12311-020-01113-x$$EHTML$$P50$$Gspringer$$Hfree_for_read</linktohtml><link.rule.ids>230,314,776,780,881,27903,27904,41467,42536,51297</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/32157568$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Strupp, Michael</creatorcontrib><creatorcontrib>Maul, Stephan</creatorcontrib><creatorcontrib>Konte, Bettina</creatorcontrib><creatorcontrib>Hartmann, Annette M.</creatorcontrib><creatorcontrib>Giegling, Ina</creatorcontrib><creatorcontrib>Wollenteit, Sophia</creatorcontrib><creatorcontrib>Feil, Katharina</creatorcontrib><creatorcontrib>Rujescu, Dan</creatorcontrib><title>A Variation in FGF14 Is Associated with Downbeat Nystagmus in a Genome-Wide Association Study</title><title>Cerebellum (London, England)</title><addtitle>Cerebellum</addtitle><addtitle>Cerebellum</addtitle><description>Downbeat nystagmus (DBN) is a frequent form of acquired persisting central fixation nystagmus, often associated with other cerebellar ocular signs, such as saccadic smooth pursuit or gaze-holding deficits. Despite its distinct clinical features, the underlying etiology of DBN often remains unclear. Therefore, a genome-wide association study (GWAS) was conducted in 106 patients and 2609 healthy controls of European ancestry to identify genetic variants associated with DBN. A genome-wide significant association (
p
< 5 × 10
−8
) with DBN was found for a variation on chromosome 13 located within the fibroblast growth factor 14 gene (FGF14). FGF14 is expressed in Purkinje cells (PCs) and a reduction leads to a decreased spontaneous firing rate and excitability of PCs, compatible with the pathophysiology of DBN. In addition, mutations in the FGF14 gene cause spinocerebellar ataxia type 27. Suggestive associations (
p
< 1 × 10
−05
) could be detected for 15 additional LD-independent loci, one of which is also located in the FGF14 gene. An association of a region containing the dihydrofolate reductase (DHFR) and MutS Homolog 3 (MSH3) genes on chromosome 5 was slightly below the genome-wide significance threshold. DHFR is relevant for neuronal regulation, and a dysfunction is known to induce cerebellar damage. Among the remaining twelve suggestive associations, four genes (MAST4, TPPP, FTMT, and IDS) seem to be involved in cerebral pathological processes. Thus, this GWAS analysis has identified a potential genetic contribution to idiopathic DBN, including suggestive associations to several genes involved in postulated pathological mechanisms of DBN (i.e., impaired function of cerebellar PCs).</description><subject>Aged</subject><subject>Aged, 80 and over</subject><subject>Biomedical and Life Sciences</subject><subject>Biomedicine</subject><subject>Cerebellum</subject><subject>Chromosome 13</subject><subject>Chromosome 5</subject><subject>Dihydrofolate reductase</subject><subject>Etiology</subject><subject>Excitability</subject><subject>Female</subject><subject>Fibroblast growth factors</subject><subject>Fibroblast Growth Factors - genetics</subject><subject>Firing rate</subject><subject>Genes</subject><subject>Genetic analysis</subject><subject>Genetic diversity</subject><subject>Genetic Variation - genetics</subject><subject>Genome-wide association studies</subject><subject>Genome-Wide Association Study - methods</subject><subject>Genomes</subject><subject>Germany - epidemiology</subject><subject>Humans</subject><subject>Male</subject><subject>Middle Aged</subject><subject>Neurobiology</subject><subject>Neurology</subject><subject>Neurosciences</subject><subject>Nystagmus</subject><subject>Nystagmus, Pathologic - diagnosis</subject><subject>Nystagmus, Pathologic - epidemiology</subject><subject>Nystagmus, Pathologic - genetics</subject><subject>Original Paper</subject><subject>Purkinje cells</subject><issn>1473-4222</issn><issn>1473-4230</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2020</creationdate><recordtype>article</recordtype><sourceid>C6C</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>eNp9kU9PGzEQxa2qFX9SvgCHylIvXLb12M5691IpgiZFQuVAoafK8nonwShrg71byLfHIZDSHnqy5fm9NzN-hBwC-wSMqc8JuAAoGGcFAwBRPLwheyCVKCQX7O32zvku2U_phjHOmVQ7ZFdwGKtxWe2RXxN6ZaIzvQueOk-nsylIeproJKVg8zu29N711_Qk3PsGTU-_r1JvFt2Q1rihM_Shw-Kna3GrWXtd9EO7ek_ezc0y4cHzOSKX068_jr8VZ-ez0-PJWWGlkn1RK14bU1qDpZzXlTVtnl9A1SrboKqEBN5w27RK1YZJ0XLEcg6ygkZKNLIUI_Jl43s7NB22Fn0fzVLfRteZuNLBOP13xbtrvQi_tYK6KkWVDY6eDWK4GzD1unPJ4nJpPIYhaS5UmT-bjSGjH_9Bb8IQfV4vU7Wqa2AZHRG-oWwMKUWcb4cBptfp6U16Oqenn9LTD1n04fUaW8lLXBkQGyDlkl9g_NP7P7aPU_ClKw</recordid><startdate>20200601</startdate><enddate>20200601</enddate><creator>Strupp, Michael</creator><creator>Maul, Stephan</creator><creator>Konte, Bettina</creator><creator>Hartmann, Annette M.</creator><creator>Giegling, Ina</creator><creator>Wollenteit, Sophia</creator><creator>Feil, Katharina</creator><creator>Rujescu, Dan</creator><general>Springer US</general><general>Springer Nature B.V</general><scope>C6C</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>7RV</scope><scope>7TK</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>88G</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BENPR</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>K9.</scope><scope>KB0</scope><scope>M0S</scope><scope>M1P</scope><scope>M2M</scope><scope>NAPCQ</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>PSYQQ</scope><scope>Q9U</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0002-0668-797X</orcidid></search><sort><creationdate>20200601</creationdate><title>A Variation in FGF14 Is Associated with Downbeat Nystagmus in a Genome-Wide Association Study</title><author>Strupp, Michael ; Maul, Stephan ; Konte, Bettina ; Hartmann, Annette M. ; Giegling, Ina ; Wollenteit, Sophia ; Feil, Katharina ; Rujescu, Dan</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c474t-9729aa6cae64f98cad230318d7cbe783412b2cbd779a043d2ee6f1481b44ea463</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2020</creationdate><topic>Aged</topic><topic>Aged, 80 and over</topic><topic>Biomedical and Life Sciences</topic><topic>Biomedicine</topic><topic>Cerebellum</topic><topic>Chromosome 13</topic><topic>Chromosome 5</topic><topic>Dihydrofolate reductase</topic><topic>Etiology</topic><topic>Excitability</topic><topic>Female</topic><topic>Fibroblast growth factors</topic><topic>Fibroblast Growth Factors - genetics</topic><topic>Firing rate</topic><topic>Genes</topic><topic>Genetic analysis</topic><topic>Genetic diversity</topic><topic>Genetic Variation - genetics</topic><topic>Genome-wide association studies</topic><topic>Genome-Wide Association Study - methods</topic><topic>Genomes</topic><topic>Germany - epidemiology</topic><topic>Humans</topic><topic>Male</topic><topic>Middle Aged</topic><topic>Neurobiology</topic><topic>Neurology</topic><topic>Neurosciences</topic><topic>Nystagmus</topic><topic>Nystagmus, Pathologic - diagnosis</topic><topic>Nystagmus, Pathologic - epidemiology</topic><topic>Nystagmus, Pathologic - genetics</topic><topic>Original Paper</topic><topic>Purkinje cells</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Strupp, Michael</creatorcontrib><creatorcontrib>Maul, Stephan</creatorcontrib><creatorcontrib>Konte, Bettina</creatorcontrib><creatorcontrib>Hartmann, Annette M.</creatorcontrib><creatorcontrib>Giegling, Ina</creatorcontrib><creatorcontrib>Wollenteit, Sophia</creatorcontrib><creatorcontrib>Feil, Katharina</creatorcontrib><creatorcontrib>Rujescu, Dan</creatorcontrib><collection>Springer Nature OA Free Journals</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>Nursing & Allied Health Database</collection><collection>Neurosciences Abstracts</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>Psychology Database (Alumni)</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>ProQuest Central</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Nursing & Allied Health Database (Alumni Edition)</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>ProQuest Psychology</collection><collection>Nursing & Allied Health Premium</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>ProQuest One Psychology</collection><collection>ProQuest Central Basic</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Cerebellum (London, England)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Strupp, Michael</au><au>Maul, Stephan</au><au>Konte, Bettina</au><au>Hartmann, Annette M.</au><au>Giegling, Ina</au><au>Wollenteit, Sophia</au><au>Feil, Katharina</au><au>Rujescu, Dan</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>A Variation in FGF14 Is Associated with Downbeat Nystagmus in a Genome-Wide Association Study</atitle><jtitle>Cerebellum (London, England)</jtitle><stitle>Cerebellum</stitle><addtitle>Cerebellum</addtitle><date>2020-06-01</date><risdate>2020</risdate><volume>19</volume><issue>3</issue><spage>348</spage><epage>357</epage><pages>348-357</pages><issn>1473-4222</issn><eissn>1473-4230</eissn><abstract>Downbeat nystagmus (DBN) is a frequent form of acquired persisting central fixation nystagmus, often associated with other cerebellar ocular signs, such as saccadic smooth pursuit or gaze-holding deficits. Despite its distinct clinical features, the underlying etiology of DBN often remains unclear. Therefore, a genome-wide association study (GWAS) was conducted in 106 patients and 2609 healthy controls of European ancestry to identify genetic variants associated with DBN. A genome-wide significant association (
p
< 5 × 10
−8
) with DBN was found for a variation on chromosome 13 located within the fibroblast growth factor 14 gene (FGF14). FGF14 is expressed in Purkinje cells (PCs) and a reduction leads to a decreased spontaneous firing rate and excitability of PCs, compatible with the pathophysiology of DBN. In addition, mutations in the FGF14 gene cause spinocerebellar ataxia type 27. Suggestive associations (
p
< 1 × 10
−05
) could be detected for 15 additional LD-independent loci, one of which is also located in the FGF14 gene. An association of a region containing the dihydrofolate reductase (DHFR) and MutS Homolog 3 (MSH3) genes on chromosome 5 was slightly below the genome-wide significance threshold. DHFR is relevant for neuronal regulation, and a dysfunction is known to induce cerebellar damage. Among the remaining twelve suggestive associations, four genes (MAST4, TPPP, FTMT, and IDS) seem to be involved in cerebral pathological processes. Thus, this GWAS analysis has identified a potential genetic contribution to idiopathic DBN, including suggestive associations to several genes involved in postulated pathological mechanisms of DBN (i.e., impaired function of cerebellar PCs).</abstract><cop>New York</cop><pub>Springer US</pub><pmid>32157568</pmid><doi>10.1007/s12311-020-01113-x</doi><tpages>10</tpages><orcidid>https://orcid.org/0000-0002-0668-797X</orcidid><oa>free_for_read</oa></addata></record> |
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| subjects | Aged Aged, 80 and over Biomedical and Life Sciences Biomedicine Cerebellum Chromosome 13 Chromosome 5 Dihydrofolate reductase Etiology Excitability Female Fibroblast growth factors Fibroblast Growth Factors - genetics Firing rate Genes Genetic analysis Genetic diversity Genetic Variation - genetics Genome-wide association studies Genome-Wide Association Study - methods Genomes Germany - epidemiology Humans Male Middle Aged Neurobiology Neurology Neurosciences Nystagmus Nystagmus, Pathologic - diagnosis Nystagmus, Pathologic - epidemiology Nystagmus, Pathologic - genetics Original Paper Purkinje cells |
| title | A Variation in FGF14 Is Associated with Downbeat Nystagmus in a Genome-Wide Association Study |
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