Impact of schizophrenia GWAS loci converge onto distinct pathways in cortical interneurons vs glutamatergic neurons during development
Remarkable advances have been made in schizophrenia (SCZ) GWAS, but gleaning biological insight from these loci is challenging. Genetic influences on gene expression (e.g., eQTLs) are cell type-specific, but most studies that attempt to clarify GWAS loci’s influence on gene expression have employed...
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Veröffentlicht in: | Molecular psychiatry 2022-10, Vol.27 (10), p.4218-4233 |
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creator | Liu, Dongxin Zinski, Amy Mishra, Akanksha Noh, Haneul Park, Gun-Hoo Qin, Yiren Olorife, Oshoname Park, James M. Abani, Chiderah P. Park, Joy S. Fung, Janice Sawaqed, Farah Coyle, Joseph T. Stahl, Eli Bendl, Jaroslav Fullard, John F. Roussos, Panos Zhang, Xiaolei Stanton, Patric K. Yin, Changhong Huang, Weihua Kim, Hae-Young Won, Hyejung Cho, Jun-Hyeong Chung, Sangmi |
description | Remarkable advances have been made in schizophrenia (SCZ) GWAS, but gleaning biological insight from these loci is challenging. Genetic influences on gene expression (e.g., eQTLs) are cell type-specific, but most studies that attempt to clarify GWAS loci’s influence on gene expression have employed tissues with mixed cell compositions that can obscure cell-specific effects. Furthermore, enriched SCZ heritability in the fetal brain underscores the need to study the impact of SCZ risk loci in specific developing neurons. MGE-derived cortical interneurons (cINs) are consistently affected in SCZ brains and show enriched SCZ heritability in human fetal brains. We identified SCZ GWAS risk genes that are dysregulated in iPSC-derived homogeneous populations of developing SCZ cINs. These SCZ GWAS loci differential expression (DE) genes converge on the PKC pathway. Their disruption results in PKC hyperactivity in developing cINs, leading to arborization deficits. We show that the fine-mapped GWAS locus in the ATP2A2 gene of the PKC pathway harbors enhancer marks by ATACseq and ChIPseq, and regulates ATP2A2 expression. We also generated developing glutamatergic neurons (GNs), another population with enriched SCZ heritability, and confirmed their functionality after transplantation into the mouse brain. Then, we identified SCZ GWAS risk genes that are dysregulated in developing SCZ GNs. GN-specific SCZ GWAS loci DE genes converge on the ion transporter pathway, distinct from those for cINs. Disruption of the pathway gene CACNA1D resulted in deficits of Ca
2+
currents in developing GNs, suggesting compromised neuronal function by GWAS loci pathway deficits during development. This study allows us to identify cell type-specific and developmental stage-specific mechanisms of SCZ risk gene function, and may aid in identifying mechanism-based novel therapeutic targets. |
doi_str_mv | 10.1038/s41380-022-01654-z |
format | Article |
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2+
currents in developing GNs, suggesting compromised neuronal function by GWAS loci pathway deficits during development. This study allows us to identify cell type-specific and developmental stage-specific mechanisms of SCZ risk gene function, and may aid in identifying mechanism-based novel therapeutic targets.</description><identifier>ISSN: 1359-4184</identifier><identifier>ISSN: 1476-5578</identifier><identifier>EISSN: 1476-5578</identifier><identifier>DOI: 10.1038/s41380-022-01654-z</identifier><identifier>PMID: 35701597</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>13/1 ; 13/100 ; 13/51 ; 14/19 ; 14/35 ; 38/22 ; 38/39 ; 38/43 ; 38/47 ; 38/77 ; 38/89 ; 45/44 ; 45/91 ; 631/378 ; 631/477 ; 631/532 ; 82/29 ; 82/51 ; 9/74 ; 96/44 ; Animals ; ATP2A2 gene ; Behavioral Sciences ; Biological Psychology ; Brain - metabolism ; Calcium currents ; Fetuses ; Gene expression ; Genetic Predisposition to Disease - genetics ; Genome-Wide Association Study - methods ; Glutamatergic transmission ; Heritability ; Humans ; Hyperactivity ; Interneurons ; Interneurons - metabolism ; Medicine ; Medicine & Public Health ; Mental disorders ; Mice ; Neurogenesis ; Neurons - metabolism ; Neurosciences ; Pharmacotherapy ; Psychiatry ; Schizophrenia ; Schizophrenia - genetics ; Schizophrenia - metabolism ; Therapeutic targets ; Transplantation</subject><ispartof>Molecular psychiatry, 2022-10, Vol.27 (10), p.4218-4233</ispartof><rights>The Author(s), under exclusive licence to Springer Nature Limited 2022</rights><rights>2022. The Author(s), under exclusive licence to Springer Nature Limited.</rights><rights>The Author(s), under exclusive licence to Springer Nature Limited 2022.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c375t-ce8c88884af743ad39616ef775e6a6c6cbdd8105e94967dc68f0fd8c41db2c553</citedby><cites>FETCH-LOGICAL-c375t-ce8c88884af743ad39616ef775e6a6c6cbdd8105e94967dc68f0fd8c41db2c553</cites><orcidid>0000-0002-6844-3583 ; 0000-0002-8737-9978 ; 0000-0001-9989-2720 ; 0000-0002-1718-5043 ; 0000-0002-4640-6239 ; 0000-0003-3651-0566 ; 0000-0001-9874-2907 ; 0000-0001-7916-6625 ; 0000-0001-7860-3459</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/35701597$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Liu, Dongxin</creatorcontrib><creatorcontrib>Zinski, Amy</creatorcontrib><creatorcontrib>Mishra, Akanksha</creatorcontrib><creatorcontrib>Noh, Haneul</creatorcontrib><creatorcontrib>Park, Gun-Hoo</creatorcontrib><creatorcontrib>Qin, Yiren</creatorcontrib><creatorcontrib>Olorife, Oshoname</creatorcontrib><creatorcontrib>Park, James M.</creatorcontrib><creatorcontrib>Abani, Chiderah P.</creatorcontrib><creatorcontrib>Park, Joy S.</creatorcontrib><creatorcontrib>Fung, Janice</creatorcontrib><creatorcontrib>Sawaqed, Farah</creatorcontrib><creatorcontrib>Coyle, Joseph T.</creatorcontrib><creatorcontrib>Stahl, Eli</creatorcontrib><creatorcontrib>Bendl, Jaroslav</creatorcontrib><creatorcontrib>Fullard, John F.</creatorcontrib><creatorcontrib>Roussos, Panos</creatorcontrib><creatorcontrib>Zhang, Xiaolei</creatorcontrib><creatorcontrib>Stanton, Patric K.</creatorcontrib><creatorcontrib>Yin, Changhong</creatorcontrib><creatorcontrib>Huang, Weihua</creatorcontrib><creatorcontrib>Kim, Hae-Young</creatorcontrib><creatorcontrib>Won, Hyejung</creatorcontrib><creatorcontrib>Cho, Jun-Hyeong</creatorcontrib><creatorcontrib>Chung, Sangmi</creatorcontrib><title>Impact of schizophrenia GWAS loci converge onto distinct pathways in cortical interneurons vs glutamatergic neurons during development</title><title>Molecular psychiatry</title><addtitle>Mol Psychiatry</addtitle><addtitle>Mol Psychiatry</addtitle><description>Remarkable advances have been made in schizophrenia (SCZ) GWAS, but gleaning biological insight from these loci is challenging. Genetic influences on gene expression (e.g., eQTLs) are cell type-specific, but most studies that attempt to clarify GWAS loci’s influence on gene expression have employed tissues with mixed cell compositions that can obscure cell-specific effects. Furthermore, enriched SCZ heritability in the fetal brain underscores the need to study the impact of SCZ risk loci in specific developing neurons. MGE-derived cortical interneurons (cINs) are consistently affected in SCZ brains and show enriched SCZ heritability in human fetal brains. We identified SCZ GWAS risk genes that are dysregulated in iPSC-derived homogeneous populations of developing SCZ cINs. These SCZ GWAS loci differential expression (DE) genes converge on the PKC pathway. Their disruption results in PKC hyperactivity in developing cINs, leading to arborization deficits. We show that the fine-mapped GWAS locus in the ATP2A2 gene of the PKC pathway harbors enhancer marks by ATACseq and ChIPseq, and regulates ATP2A2 expression. We also generated developing glutamatergic neurons (GNs), another population with enriched SCZ heritability, and confirmed their functionality after transplantation into the mouse brain. Then, we identified SCZ GWAS risk genes that are dysregulated in developing SCZ GNs. GN-specific SCZ GWAS loci DE genes converge on the ion transporter pathway, distinct from those for cINs. Disruption of the pathway gene CACNA1D resulted in deficits of Ca
2+
currents in developing GNs, suggesting compromised neuronal function by GWAS loci pathway deficits during development. This study allows us to identify cell type-specific and developmental stage-specific mechanisms of SCZ risk gene function, and may aid in identifying mechanism-based novel therapeutic targets.</description><subject>13/1</subject><subject>13/100</subject><subject>13/51</subject><subject>14/19</subject><subject>14/35</subject><subject>38/22</subject><subject>38/39</subject><subject>38/43</subject><subject>38/47</subject><subject>38/77</subject><subject>38/89</subject><subject>45/44</subject><subject>45/91</subject><subject>631/378</subject><subject>631/477</subject><subject>631/532</subject><subject>82/29</subject><subject>82/51</subject><subject>9/74</subject><subject>96/44</subject><subject>Animals</subject><subject>ATP2A2 gene</subject><subject>Behavioral Sciences</subject><subject>Biological Psychology</subject><subject>Brain - metabolism</subject><subject>Calcium currents</subject><subject>Fetuses</subject><subject>Gene expression</subject><subject>Genetic Predisposition to Disease - genetics</subject><subject>Genome-Wide Association Study - methods</subject><subject>Glutamatergic transmission</subject><subject>Heritability</subject><subject>Humans</subject><subject>Hyperactivity</subject><subject>Interneurons</subject><subject>Interneurons - metabolism</subject><subject>Medicine</subject><subject>Medicine & Public Health</subject><subject>Mental disorders</subject><subject>Mice</subject><subject>Neurogenesis</subject><subject>Neurons - metabolism</subject><subject>Neurosciences</subject><subject>Pharmacotherapy</subject><subject>Psychiatry</subject><subject>Schizophrenia</subject><subject>Schizophrenia - genetics</subject><subject>Schizophrenia - metabolism</subject><subject>Therapeutic targets</subject><subject>Transplantation</subject><issn>1359-4184</issn><issn>1476-5578</issn><issn>1476-5578</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2022</creationdate><recordtype>article</recordtype><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>eNp9kc1u1DAUhS0EomXgBVggS2y6CbXjv2RZVbRUqsSiIJaWx76ZcZXYwXYGdR6A58bDtCCxwBtf-X7nXOsehN5S8oES1p1nTllHGtK2DaFS8Gb_DJ1SrmQjhOqe15qJvuG04yfoVc73hBya4iU6YUIRKnp1in7eTLOxBccBZ7v1-zhvEwRv8PW3izs8RuuxjWEHaQM4hhKx87n4UBWzKdsf5iFjHyqSirdmrHWBFGBJMWS8y3gzLsVMpj5uvMVPDbckHzbYwQ7GOE8Qymv0YjBjhjeP9wp9vfr45fJTc_v5-uby4raxTInSWOhsVw83g-LMONZLKmFQSoA00kq7dq6jREDPe6mcld1ABtdZTt26tUKwFTo7-s4pfl8gFz35bGEcTYC4ZN1KJfuWEc4q-v4f9D4uKdTf6VZxUbdKKrlC7ZGyKeacYNBz8pNJD5oSfUhJH1PSNSX9OyW9r6J3j9bLegL3R_IUSwXYEcjzYVOQ_s7-j-0vR7WhJg</recordid><startdate>20221001</startdate><enddate>20221001</enddate><creator>Liu, 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of schizophrenia GWAS loci converge onto distinct pathways in cortical interneurons vs glutamatergic neurons during development</title><author>Liu, Dongxin ; Zinski, Amy ; Mishra, Akanksha ; Noh, Haneul ; Park, Gun-Hoo ; Qin, Yiren ; Olorife, Oshoname ; Park, James M. ; Abani, Chiderah P. ; Park, Joy S. ; Fung, Janice ; Sawaqed, Farah ; Coyle, Joseph T. ; Stahl, Eli ; Bendl, Jaroslav ; Fullard, John F. ; Roussos, Panos ; Zhang, Xiaolei ; Stanton, Patric K. ; Yin, Changhong ; Huang, Weihua ; Kim, Hae-Young ; Won, Hyejung ; Cho, Jun-Hyeong ; Chung, Sangmi</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c375t-ce8c88884af743ad39616ef775e6a6c6cbdd8105e94967dc68f0fd8c41db2c553</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2022</creationdate><topic>13/1</topic><topic>13/100</topic><topic>13/51</topic><topic>14/19</topic><topic>14/35</topic><topic>38/22</topic><topic>38/39</topic><topic>38/43</topic><topic>38/47</topic><topic>38/77</topic><topic>38/89</topic><topic>45/44</topic><topic>45/91</topic><topic>631/378</topic><topic>631/477</topic><topic>631/532</topic><topic>82/29</topic><topic>82/51</topic><topic>9/74</topic><topic>96/44</topic><topic>Animals</topic><topic>ATP2A2 gene</topic><topic>Behavioral Sciences</topic><topic>Biological Psychology</topic><topic>Brain - metabolism</topic><topic>Calcium currents</topic><topic>Fetuses</topic><topic>Gene expression</topic><topic>Genetic Predisposition to Disease - genetics</topic><topic>Genome-Wide Association Study - methods</topic><topic>Glutamatergic transmission</topic><topic>Heritability</topic><topic>Humans</topic><topic>Hyperactivity</topic><topic>Interneurons</topic><topic>Interneurons - metabolism</topic><topic>Medicine</topic><topic>Medicine & Public Health</topic><topic>Mental disorders</topic><topic>Mice</topic><topic>Neurogenesis</topic><topic>Neurons - metabolism</topic><topic>Neurosciences</topic><topic>Pharmacotherapy</topic><topic>Psychiatry</topic><topic>Schizophrenia</topic><topic>Schizophrenia - genetics</topic><topic>Schizophrenia - metabolism</topic><topic>Therapeutic targets</topic><topic>Transplantation</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Liu, Dongxin</creatorcontrib><creatorcontrib>Zinski, Amy</creatorcontrib><creatorcontrib>Mishra, Akanksha</creatorcontrib><creatorcontrib>Noh, Haneul</creatorcontrib><creatorcontrib>Park, 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Jun-Hyeong</au><au>Chung, Sangmi</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Impact of schizophrenia GWAS loci converge onto distinct pathways in cortical interneurons vs glutamatergic neurons during development</atitle><jtitle>Molecular psychiatry</jtitle><stitle>Mol Psychiatry</stitle><addtitle>Mol Psychiatry</addtitle><date>2022-10-01</date><risdate>2022</risdate><volume>27</volume><issue>10</issue><spage>4218</spage><epage>4233</epage><pages>4218-4233</pages><issn>1359-4184</issn><issn>1476-5578</issn><eissn>1476-5578</eissn><abstract>Remarkable advances have been made in schizophrenia (SCZ) GWAS, but gleaning biological insight from these loci is challenging. Genetic influences on gene expression (e.g., eQTLs) are cell type-specific, but most studies that attempt to clarify GWAS loci’s influence on gene expression have employed tissues with mixed cell compositions that can obscure cell-specific effects. Furthermore, enriched SCZ heritability in the fetal brain underscores the need to study the impact of SCZ risk loci in specific developing neurons. MGE-derived cortical interneurons (cINs) are consistently affected in SCZ brains and show enriched SCZ heritability in human fetal brains. We identified SCZ GWAS risk genes that are dysregulated in iPSC-derived homogeneous populations of developing SCZ cINs. These SCZ GWAS loci differential expression (DE) genes converge on the PKC pathway. Their disruption results in PKC hyperactivity in developing cINs, leading to arborization deficits. We show that the fine-mapped GWAS locus in the ATP2A2 gene of the PKC pathway harbors enhancer marks by ATACseq and ChIPseq, and regulates ATP2A2 expression. We also generated developing glutamatergic neurons (GNs), another population with enriched SCZ heritability, and confirmed their functionality after transplantation into the mouse brain. Then, we identified SCZ GWAS risk genes that are dysregulated in developing SCZ GNs. GN-specific SCZ GWAS loci DE genes converge on the ion transporter pathway, distinct from those for cINs. Disruption of the pathway gene CACNA1D resulted in deficits of Ca
2+
currents in developing GNs, suggesting compromised neuronal function by GWAS loci pathway deficits during development. This study allows us to identify cell type-specific and developmental stage-specific mechanisms of SCZ risk gene function, and may aid in identifying mechanism-based novel therapeutic targets.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>35701597</pmid><doi>10.1038/s41380-022-01654-z</doi><tpages>16</tpages><orcidid>https://orcid.org/0000-0002-6844-3583</orcidid><orcidid>https://orcid.org/0000-0002-8737-9978</orcidid><orcidid>https://orcid.org/0000-0001-9989-2720</orcidid><orcidid>https://orcid.org/0000-0002-1718-5043</orcidid><orcidid>https://orcid.org/0000-0002-4640-6239</orcidid><orcidid>https://orcid.org/0000-0003-3651-0566</orcidid><orcidid>https://orcid.org/0000-0001-9874-2907</orcidid><orcidid>https://orcid.org/0000-0001-7916-6625</orcidid><orcidid>https://orcid.org/0000-0001-7860-3459</orcidid></addata></record> |
fulltext | fulltext |
identifier | ISSN: 1359-4184 |
ispartof | Molecular psychiatry, 2022-10, Vol.27 (10), p.4218-4233 |
issn | 1359-4184 1476-5578 1476-5578 |
language | eng |
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subjects | 13/1 13/100 13/51 14/19 14/35 38/22 38/39 38/43 38/47 38/77 38/89 45/44 45/91 631/378 631/477 631/532 82/29 82/51 9/74 96/44 Animals ATP2A2 gene Behavioral Sciences Biological Psychology Brain - metabolism Calcium currents Fetuses Gene expression Genetic Predisposition to Disease - genetics Genome-Wide Association Study - methods Glutamatergic transmission Heritability Humans Hyperactivity Interneurons Interneurons - metabolism Medicine Medicine & Public Health Mental disorders Mice Neurogenesis Neurons - metabolism Neurosciences Pharmacotherapy Psychiatry Schizophrenia Schizophrenia - genetics Schizophrenia - metabolism Therapeutic targets Transplantation |
title | Impact of schizophrenia GWAS loci converge onto distinct pathways in cortical interneurons vs glutamatergic neurons during development |
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