Exome Array Analysis of Early-Onset Ischemic Stroke
BACKGROUND AND PURPOSE:The genetic contribution to ischemic stroke may include rare- or low-frequency variants of high-penetrance and large-effect sizes. Analyses focusing on early-onset disease, an extreme-phenotype, and on the exome, the protein-coding portion of genes, may increase the likelihood...
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| creator | Jaworek, Thomas Ryan, Kathleen A. Gaynor, Brady J. McArdle, Patrick F. Stine, Oscar C. OConnor, Timothy D. Lopez, Haley Aparicio, Hugo J. Gao, Yan Lin, Xiaochen Groves, Megan L. Flaherty, Matthew L. Liu, Simin Yang, Qiong Wilson, James Seshadri, Sudha Kittner, Steven J. Mitchell, Braxton D. Xu, Huichun Cole, John W. |
| description | BACKGROUND AND PURPOSE:The genetic contribution to ischemic stroke may include rare- or low-frequency variants of high-penetrance and large-effect sizes. Analyses focusing on early-onset disease, an extreme-phenotype, and on the exome, the protein-coding portion of genes, may increase the likelihood of identifying such rare functional variants. To evaluate this hypothesis, we implemented a 2-stage discovery and replication design, and then addressed whether the identified variants also associated with older-onset disease.
METHODS:Discovery was performed in UMD-GEOS Study (University of Maryland-Genetics of Early-Onset Stroke), a biracial population-based study of first-ever ischemic stroke cases 15 to 49 years of age (n=723) and nonstroke controls (n=726). All participants had prior GWAS (Genome Wide Association Study) and underwent Illumina exome-chip genotyping. Logistic-regression was performed to test single-variant associations with all-ischemic stroke and TOAST (Trial of ORG 10172 in Acute Stroke Treatment) subtypes in Whites and Blacks. Population level results were combined using meta-analysis. Gene-based aggregation testing and meta-analysis were performed using seqMeta. Covariates included age and gender, and principal-components for population structure. Pathway analyses were performed across all nominally associated genes for each stroke outcome. Replication was attempted through lookups in a previously reported meta-analysis of early-onset stroke and a large-scale stroke genetics study consisting of primarily older-onset cases.
RESULTS:Gene burden tests identified a significant association with NAT10 in small-vessel stroke (P=3.79×10). Pathway analysis of the top 517 genes (P |
| doi_str_mv | 10.1161/STROKEAHA.120.031357 |
| format | Article |
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METHODS:Discovery was performed in UMD-GEOS Study (University of Maryland-Genetics of Early-Onset Stroke), a biracial population-based study of first-ever ischemic stroke cases 15 to 49 years of age (n=723) and nonstroke controls (n=726). All participants had prior GWAS (Genome Wide Association Study) and underwent Illumina exome-chip genotyping. Logistic-regression was performed to test single-variant associations with all-ischemic stroke and TOAST (Trial of ORG 10172 in Acute Stroke Treatment) subtypes in Whites and Blacks. Population level results were combined using meta-analysis. Gene-based aggregation testing and meta-analysis were performed using seqMeta. Covariates included age and gender, and principal-components for population structure. Pathway analyses were performed across all nominally associated genes for each stroke outcome. Replication was attempted through lookups in a previously reported meta-analysis of early-onset stroke and a large-scale stroke genetics study consisting of primarily older-onset cases.
RESULTS:Gene burden tests identified a significant association with NAT10 in small-vessel stroke (P=3.79×10). Pathway analysis of the top 517 genes (P<0.05) from the gene-based analysis of small-vessel stroke identified several signaling and metabolism-related pathways related to neurotransmitter, neurodevelopmental notch-signaling, and lipid/glucose metabolism. While no individual SNPs reached chip-wide significance (P<2.05×10), several were near, including an intronic variant in LEXM (rs7549251; P=4.08×10) and an exonic variant in TRAPPC11 (rs67383011; P=5.19×10).
CONCLUSIONS:Exome-based analysis in the setting of early-onset stroke is a promising strategy for identifying novel genetic risk variants, loci, and pathways.</description><identifier>ISSN: 0039-2499</identifier><identifier>EISSN: 1524-4628</identifier><identifier>DOI: 10.1161/STROKEAHA.120.031357</identifier><identifier>PMID: 32912094</identifier><language>eng</language><publisher>United States: American Heart Association, Inc</publisher><subject>Adolescent ; Adult ; Age of Onset ; Black or African American ; Exome - genetics ; Female ; Gene Regulatory Networks ; Genome-Wide Association Study ; Humans ; Ischemic Stroke - genetics ; Male ; Middle Aged ; White People ; Young Adult</subject><ispartof>Stroke (1970), 2020-11, Vol.51 (11), p.3356-3360</ispartof><rights>American Heart Association, Inc.</rights><rights>2020 American Heart Association, Inc.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c5027-249a6b1d0e9bf8de0a86ca14af980fc63fe9c2217e642d9f2fb3d5fa48d055583</citedby><cites>FETCH-LOGICAL-c5027-249a6b1d0e9bf8de0a86ca14af980fc63fe9c2217e642d9f2fb3d5fa48d055583</cites><orcidid>0000-0001-9263-8930 ; 0000-0001-6649-0717 ; 0000-0002-4142-0613 ; 0000-0003-2098-3844</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,776,780,881,3674,27901,27902</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/32912094$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Jaworek, Thomas</creatorcontrib><creatorcontrib>Ryan, Kathleen A.</creatorcontrib><creatorcontrib>Gaynor, Brady J.</creatorcontrib><creatorcontrib>McArdle, Patrick F.</creatorcontrib><creatorcontrib>Stine, Oscar C.</creatorcontrib><creatorcontrib>OConnor, Timothy D.</creatorcontrib><creatorcontrib>Lopez, Haley</creatorcontrib><creatorcontrib>Aparicio, Hugo J.</creatorcontrib><creatorcontrib>Gao, Yan</creatorcontrib><creatorcontrib>Lin, Xiaochen</creatorcontrib><creatorcontrib>Groves, Megan L.</creatorcontrib><creatorcontrib>Flaherty, Matthew L.</creatorcontrib><creatorcontrib>Liu, Simin</creatorcontrib><creatorcontrib>Yang, Qiong</creatorcontrib><creatorcontrib>Wilson, James</creatorcontrib><creatorcontrib>Seshadri, Sudha</creatorcontrib><creatorcontrib>Kittner, Steven J.</creatorcontrib><creatorcontrib>Mitchell, Braxton D.</creatorcontrib><creatorcontrib>Xu, Huichun</creatorcontrib><creatorcontrib>Cole, John W.</creatorcontrib><title>Exome Array Analysis of Early-Onset Ischemic Stroke</title><title>Stroke (1970)</title><addtitle>Stroke</addtitle><description>BACKGROUND AND PURPOSE:The genetic contribution to ischemic stroke may include rare- or low-frequency variants of high-penetrance and large-effect sizes. Analyses focusing on early-onset disease, an extreme-phenotype, and on the exome, the protein-coding portion of genes, may increase the likelihood of identifying such rare functional variants. To evaluate this hypothesis, we implemented a 2-stage discovery and replication design, and then addressed whether the identified variants also associated with older-onset disease.
METHODS:Discovery was performed in UMD-GEOS Study (University of Maryland-Genetics of Early-Onset Stroke), a biracial population-based study of first-ever ischemic stroke cases 15 to 49 years of age (n=723) and nonstroke controls (n=726). All participants had prior GWAS (Genome Wide Association Study) and underwent Illumina exome-chip genotyping. Logistic-regression was performed to test single-variant associations with all-ischemic stroke and TOAST (Trial of ORG 10172 in Acute Stroke Treatment) subtypes in Whites and Blacks. Population level results were combined using meta-analysis. Gene-based aggregation testing and meta-analysis were performed using seqMeta. Covariates included age and gender, and principal-components for population structure. Pathway analyses were performed across all nominally associated genes for each stroke outcome. Replication was attempted through lookups in a previously reported meta-analysis of early-onset stroke and a large-scale stroke genetics study consisting of primarily older-onset cases.
RESULTS:Gene burden tests identified a significant association with NAT10 in small-vessel stroke (P=3.79×10). Pathway analysis of the top 517 genes (P<0.05) from the gene-based analysis of small-vessel stroke identified several signaling and metabolism-related pathways related to neurotransmitter, neurodevelopmental notch-signaling, and lipid/glucose metabolism. While no individual SNPs reached chip-wide significance (P<2.05×10), several were near, including an intronic variant in LEXM (rs7549251; P=4.08×10) and an exonic variant in TRAPPC11 (rs67383011; P=5.19×10).
CONCLUSIONS:Exome-based analysis in the setting of early-onset stroke is a promising strategy for identifying novel genetic risk variants, loci, and pathways.</description><subject>Adolescent</subject><subject>Adult</subject><subject>Age of Onset</subject><subject>Black or African American</subject><subject>Exome - genetics</subject><subject>Female</subject><subject>Gene Regulatory Networks</subject><subject>Genome-Wide Association Study</subject><subject>Humans</subject><subject>Ischemic Stroke - genetics</subject><subject>Male</subject><subject>Middle Aged</subject><subject>White People</subject><subject>Young Adult</subject><issn>0039-2499</issn><issn>1524-4628</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2020</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkU9vEzEQxS0EoqHwDRDaI5cN479rX5BWVaAVlSLRcrYc75gs9e4We0PJt8dRSgQXOI1G896b0W8IeU1hSami725uP68_rdrLdkkZLIFTLpsnZEElE7VQTD8lCwBuaiaMOSMvcv4GAIxr-ZyccWaKyYgF4auf04BVm5LbV-3o4j73uZpCtXIp7uv1mHGurrLf4tD76mZO0x2-JM-CixlfPdZz8uXD6vbisr5ef7y6aK9rL4E1h8VObWgHaDZBdwhOK--ocMFoCF7xgMYzRhtUgnUmsLDhnQxO6A6klJqfk_fH3PvdZsDO4zgnF-196geX9nZyvf17MvZb-3X6YRsFigtRAt4-BqTp-w7zbIc-e4zRjTjtsmVCFJJgJC9ScZT6NOWcMJzWULAH3vbE2xZ09si72N78eeLJ9BtwEeij4GGKM6Z8F3cPmOwWXZy3_8sW_7CWZ0KjGqgZMKC0dPXhv5r_AnISng0</recordid><startdate>202011</startdate><enddate>202011</enddate><creator>Jaworek, Thomas</creator><creator>Ryan, Kathleen A.</creator><creator>Gaynor, Brady J.</creator><creator>McArdle, Patrick F.</creator><creator>Stine, Oscar C.</creator><creator>OConnor, Timothy D.</creator><creator>Lopez, Haley</creator><creator>Aparicio, Hugo J.</creator><creator>Gao, Yan</creator><creator>Lin, Xiaochen</creator><creator>Groves, Megan L.</creator><creator>Flaherty, Matthew L.</creator><creator>Liu, Simin</creator><creator>Yang, Qiong</creator><creator>Wilson, James</creator><creator>Seshadri, Sudha</creator><creator>Kittner, Steven J.</creator><creator>Mitchell, Braxton D.</creator><creator>Xu, Huichun</creator><creator>Cole, John W.</creator><general>American Heart Association, Inc</general><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>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0001-9263-8930</orcidid><orcidid>https://orcid.org/0000-0001-6649-0717</orcidid><orcidid>https://orcid.org/0000-0002-4142-0613</orcidid><orcidid>https://orcid.org/0000-0003-2098-3844</orcidid></search><sort><creationdate>202011</creationdate><title>Exome Array Analysis of Early-Onset Ischemic Stroke</title><author>Jaworek, Thomas ; Ryan, Kathleen A. ; Gaynor, Brady J. ; McArdle, Patrick F. ; Stine, Oscar C. ; OConnor, Timothy D. ; Lopez, Haley ; Aparicio, Hugo J. ; Gao, Yan ; Lin, Xiaochen ; Groves, Megan L. ; Flaherty, Matthew L. ; Liu, Simin ; Yang, Qiong ; Wilson, James ; Seshadri, Sudha ; Kittner, Steven J. ; Mitchell, Braxton D. ; Xu, Huichun ; Cole, John W.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c5027-249a6b1d0e9bf8de0a86ca14af980fc63fe9c2217e642d9f2fb3d5fa48d055583</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2020</creationdate><topic>Adolescent</topic><topic>Adult</topic><topic>Age of Onset</topic><topic>Black or African American</topic><topic>Exome - genetics</topic><topic>Female</topic><topic>Gene Regulatory Networks</topic><topic>Genome-Wide Association Study</topic><topic>Humans</topic><topic>Ischemic Stroke - genetics</topic><topic>Male</topic><topic>Middle Aged</topic><topic>White People</topic><topic>Young Adult</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Jaworek, Thomas</creatorcontrib><creatorcontrib>Ryan, Kathleen A.</creatorcontrib><creatorcontrib>Gaynor, Brady J.</creatorcontrib><creatorcontrib>McArdle, Patrick F.</creatorcontrib><creatorcontrib>Stine, Oscar C.</creatorcontrib><creatorcontrib>OConnor, Timothy D.</creatorcontrib><creatorcontrib>Lopez, Haley</creatorcontrib><creatorcontrib>Aparicio, Hugo J.</creatorcontrib><creatorcontrib>Gao, Yan</creatorcontrib><creatorcontrib>Lin, Xiaochen</creatorcontrib><creatorcontrib>Groves, Megan L.</creatorcontrib><creatorcontrib>Flaherty, Matthew L.</creatorcontrib><creatorcontrib>Liu, Simin</creatorcontrib><creatorcontrib>Yang, Qiong</creatorcontrib><creatorcontrib>Wilson, James</creatorcontrib><creatorcontrib>Seshadri, Sudha</creatorcontrib><creatorcontrib>Kittner, Steven J.</creatorcontrib><creatorcontrib>Mitchell, Braxton D.</creatorcontrib><creatorcontrib>Xu, Huichun</creatorcontrib><creatorcontrib>Cole, John W.</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Stroke (1970)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Jaworek, Thomas</au><au>Ryan, Kathleen A.</au><au>Gaynor, Brady J.</au><au>McArdle, Patrick F.</au><au>Stine, Oscar C.</au><au>OConnor, Timothy D.</au><au>Lopez, Haley</au><au>Aparicio, Hugo J.</au><au>Gao, Yan</au><au>Lin, Xiaochen</au><au>Groves, Megan L.</au><au>Flaherty, Matthew L.</au><au>Liu, Simin</au><au>Yang, Qiong</au><au>Wilson, James</au><au>Seshadri, Sudha</au><au>Kittner, Steven J.</au><au>Mitchell, Braxton D.</au><au>Xu, Huichun</au><au>Cole, John W.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Exome Array Analysis of Early-Onset Ischemic Stroke</atitle><jtitle>Stroke (1970)</jtitle><addtitle>Stroke</addtitle><date>2020-11</date><risdate>2020</risdate><volume>51</volume><issue>11</issue><spage>3356</spage><epage>3360</epage><pages>3356-3360</pages><issn>0039-2499</issn><eissn>1524-4628</eissn><abstract>BACKGROUND AND PURPOSE:The genetic contribution to ischemic stroke may include rare- or low-frequency variants of high-penetrance and large-effect sizes. Analyses focusing on early-onset disease, an extreme-phenotype, and on the exome, the protein-coding portion of genes, may increase the likelihood of identifying such rare functional variants. To evaluate this hypothesis, we implemented a 2-stage discovery and replication design, and then addressed whether the identified variants also associated with older-onset disease.
METHODS:Discovery was performed in UMD-GEOS Study (University of Maryland-Genetics of Early-Onset Stroke), a biracial population-based study of first-ever ischemic stroke cases 15 to 49 years of age (n=723) and nonstroke controls (n=726). All participants had prior GWAS (Genome Wide Association Study) and underwent Illumina exome-chip genotyping. Logistic-regression was performed to test single-variant associations with all-ischemic stroke and TOAST (Trial of ORG 10172 in Acute Stroke Treatment) subtypes in Whites and Blacks. Population level results were combined using meta-analysis. Gene-based aggregation testing and meta-analysis were performed using seqMeta. Covariates included age and gender, and principal-components for population structure. Pathway analyses were performed across all nominally associated genes for each stroke outcome. Replication was attempted through lookups in a previously reported meta-analysis of early-onset stroke and a large-scale stroke genetics study consisting of primarily older-onset cases.
RESULTS:Gene burden tests identified a significant association with NAT10 in small-vessel stroke (P=3.79×10). Pathway analysis of the top 517 genes (P<0.05) from the gene-based analysis of small-vessel stroke identified several signaling and metabolism-related pathways related to neurotransmitter, neurodevelopmental notch-signaling, and lipid/glucose metabolism. While no individual SNPs reached chip-wide significance (P<2.05×10), several were near, including an intronic variant in LEXM (rs7549251; P=4.08×10) and an exonic variant in TRAPPC11 (rs67383011; P=5.19×10).
CONCLUSIONS:Exome-based analysis in the setting of early-onset stroke is a promising strategy for identifying novel genetic risk variants, loci, and pathways.</abstract><cop>United States</cop><pub>American Heart Association, Inc</pub><pmid>32912094</pmid><doi>10.1161/STROKEAHA.120.031357</doi><tpages>5</tpages><orcidid>https://orcid.org/0000-0001-9263-8930</orcidid><orcidid>https://orcid.org/0000-0001-6649-0717</orcidid><orcidid>https://orcid.org/0000-0002-4142-0613</orcidid><orcidid>https://orcid.org/0000-0003-2098-3844</orcidid><oa>free_for_read</oa></addata></record> |
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| source | Journals@Ovid Ovid Autoload; MEDLINE; American Heart Association Journals; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; Alma/SFX Local Collection |
| subjects | Adolescent Adult Age of Onset Black or African American Exome - genetics Female Gene Regulatory Networks Genome-Wide Association Study Humans Ischemic Stroke - genetics Male Middle Aged White People Young Adult |
| title | Exome Array Analysis of Early-Onset Ischemic Stroke |
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