A Genome-Wide Association Study Suggests Novel Loci Associated with a Schizophrenia-Related Brain-Based Phenotype
Patients with schizophrenia and their siblings typically show subtle changes of brain structures, such as a reduction of hippocampal volume. Hippocampal volume is heritable, may explain a variety of cognitive symptoms of schizophrenia and is thus considered an intermediate phenotype for this mental...
| Main Authors: | , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | en_US |
| Published: |
Public Library of Science
2013
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| Online Access: | http://hdl.handle.net/1721.1/81225 |
| _version_ | 1826207919144697856 |
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| author | Hass, Johanna Walton, Esther Kirsten, Holger Liu, Jingyu Priebe, Lutz Wolf, Christiane Karbalai, Nazanin White, Tonya Roessner, Veit Müller, Kathrin U. Paus, Tomas Smolka, Michael N. Schumann, Gunter Scholz, Markus Cichon, Sven Calhoun, Vince D. Ehrlich, Stefan Gollub, Randy Lyanne |
| author2 | Martinos Imaging Center (McGovern Institute for Brain Research at MIT) |
| author_facet | Martinos Imaging Center (McGovern Institute for Brain Research at MIT) Hass, Johanna Walton, Esther Kirsten, Holger Liu, Jingyu Priebe, Lutz Wolf, Christiane Karbalai, Nazanin White, Tonya Roessner, Veit Müller, Kathrin U. Paus, Tomas Smolka, Michael N. Schumann, Gunter Scholz, Markus Cichon, Sven Calhoun, Vince D. Ehrlich, Stefan Gollub, Randy Lyanne |
| author_sort | Hass, Johanna |
| collection | MIT |
| description | Patients with schizophrenia and their siblings typically show subtle changes of brain structures, such as a reduction of hippocampal volume. Hippocampal volume is heritable, may explain a variety of cognitive symptoms of schizophrenia and is thus considered an intermediate phenotype for this mental illness. The aim of our analyses was to identify single-nucleotide polymorphisms (SNP) related to hippocampal volume without making prior assumptions about possible candidate genes. In this study, we combined genetics, imaging and neuropsychological data obtained from the Mind Clinical Imaging Consortium study of schizophrenia (n = 328). A total of 743,591 SNPs were tested for association with hippocampal volume in a genome-wide association study. Gene expression profiles of human hippocampal tissue were investigated for gene regions of significantly associated SNPs. None of the genetic markers reached genome-wide significance. However, six highly correlated SNPs (rs4808611, rs35686037, rs12982178, rs1042178, rs10406920, rs8170) on chromosome 19p13.11, located within or in close proximity to the genes NR2F6, USHBP1, and BABAM1, as well as four SNPs in three other genomic regions (chromosome 1, 2 and 10) had p-values between 6.75×10[superscript −6] and 8.3×10[superscript −7]. Using existing data of a very recently published GWAS of hippocampal volume and additional data of a multicentre study in a large cohort of adolescents of European ancestry, we found supporting evidence for our results. Furthermore, allelic differences in rs4808611 and rs8170 were highly associated with differential mRNA expression in the cis-acting region. Associations with memory functioning indicate a possible functional importance of the identified risk variants. Our findings provide new insights into the genetic architecture of a brain structure closely linked to schizophrenia. In silico replication, mRNA expression and cognitive data provide additional support for the relevance of our findings. Identification of causal variants and their functional effects may unveil yet unknown players in the neurodevelopment and the pathogenesis of neuropsychiatric disorders. |
| first_indexed | 2024-09-23T13:57:01Z |
| format | Article |
| id | mit-1721.1/81225 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T13:57:01Z |
| publishDate | 2013 |
| publisher | Public Library of Science |
| record_format | dspace |
| spelling | mit-1721.1/812252022-09-28T17:19:00Z A Genome-Wide Association Study Suggests Novel Loci Associated with a Schizophrenia-Related Brain-Based Phenotype Hass, Johanna Walton, Esther Kirsten, Holger Liu, Jingyu Priebe, Lutz Wolf, Christiane Karbalai, Nazanin White, Tonya Roessner, Veit Müller, Kathrin U. Paus, Tomas Smolka, Michael N. Schumann, Gunter Scholz, Markus Cichon, Sven Calhoun, Vince D. Ehrlich, Stefan Gollub, Randy Lyanne Martinos Imaging Center (McGovern Institute for Brain Research at MIT) Harvard University--MIT Division of Health Sciences and Technology McGovern Institute for Brain Research at MIT Gollub, Randy Lyanne Patients with schizophrenia and their siblings typically show subtle changes of brain structures, such as a reduction of hippocampal volume. Hippocampal volume is heritable, may explain a variety of cognitive symptoms of schizophrenia and is thus considered an intermediate phenotype for this mental illness. The aim of our analyses was to identify single-nucleotide polymorphisms (SNP) related to hippocampal volume without making prior assumptions about possible candidate genes. In this study, we combined genetics, imaging and neuropsychological data obtained from the Mind Clinical Imaging Consortium study of schizophrenia (n = 328). A total of 743,591 SNPs were tested for association with hippocampal volume in a genome-wide association study. Gene expression profiles of human hippocampal tissue were investigated for gene regions of significantly associated SNPs. None of the genetic markers reached genome-wide significance. However, six highly correlated SNPs (rs4808611, rs35686037, rs12982178, rs1042178, rs10406920, rs8170) on chromosome 19p13.11, located within or in close proximity to the genes NR2F6, USHBP1, and BABAM1, as well as four SNPs in three other genomic regions (chromosome 1, 2 and 10) had p-values between 6.75×10[superscript −6] and 8.3×10[superscript −7]. Using existing data of a very recently published GWAS of hippocampal volume and additional data of a multicentre study in a large cohort of adolescents of European ancestry, we found supporting evidence for our results. Furthermore, allelic differences in rs4808611 and rs8170 were highly associated with differential mRNA expression in the cis-acting region. Associations with memory functioning indicate a possible functional importance of the identified risk variants. Our findings provide new insights into the genetic architecture of a brain structure closely linked to schizophrenia. In silico replication, mRNA expression and cognitive data provide additional support for the relevance of our findings. Identification of causal variants and their functional effects may unveil yet unknown players in the neurodevelopment and the pathogenesis of neuropsychiatric disorders. National Center for Research Resources (U.S.) (P41RR14075) United States. Dept. of Energy (DE-FG02-99ER62764) Mind Research Network Biomedical Informatics Research Network (1U24) Biomedical Informatics Research Network (RR021382A) Biomedical Informatics Research Network (U24RR021992-01) Biomedical Informatics Research Network (NIH.NCRR M01 RR025758-01) 2013-09-30T12:08:53Z 2013-09-30T12:08:53Z 2013-06 2012-10 Article http://purl.org/eprint/type/JournalArticle 1932-6203 http://hdl.handle.net/1721.1/81225 Hass, Johanna, Esther Walton, Holger Kirsten, Jingyu Liu, Lutz Priebe, Christiane Wolf, Nazanin Karbalai, et al. “A Genome-Wide Association Study Suggests Novel Loci Associated with a Schizophrenia-Related Brain-Based Phenotype.” Edited by Huiping Zhang. PLoS ONE 8, no. 6 (June 21, 2013): e64872. en_US http://dx.doi.org/10.1371/journal.pone.0064872 PLoS ONE Creative Commons Attribution http://creativecommons.org/licenses/by/2.5/ application/pdf Public Library of Science PLoS |
| spellingShingle | Hass, Johanna Walton, Esther Kirsten, Holger Liu, Jingyu Priebe, Lutz Wolf, Christiane Karbalai, Nazanin White, Tonya Roessner, Veit Müller, Kathrin U. Paus, Tomas Smolka, Michael N. Schumann, Gunter Scholz, Markus Cichon, Sven Calhoun, Vince D. Ehrlich, Stefan Gollub, Randy Lyanne A Genome-Wide Association Study Suggests Novel Loci Associated with a Schizophrenia-Related Brain-Based Phenotype |
| title | A Genome-Wide Association Study Suggests Novel Loci Associated with a Schizophrenia-Related Brain-Based Phenotype |
| title_full | A Genome-Wide Association Study Suggests Novel Loci Associated with a Schizophrenia-Related Brain-Based Phenotype |
| title_fullStr | A Genome-Wide Association Study Suggests Novel Loci Associated with a Schizophrenia-Related Brain-Based Phenotype |
| title_full_unstemmed | A Genome-Wide Association Study Suggests Novel Loci Associated with a Schizophrenia-Related Brain-Based Phenotype |
| title_short | A Genome-Wide Association Study Suggests Novel Loci Associated with a Schizophrenia-Related Brain-Based Phenotype |
| title_sort | genome wide association study suggests novel loci associated with a schizophrenia related brain based phenotype |
| url | http://hdl.handle.net/1721.1/81225 |
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