Brain expression genome-wide association study (eGWAS) identifies human disease-associated variants.
Genetic variants that modify brain gene expression may also influence risk for human diseases. We measured expression levels of 24,526 transcripts in brain samples from the cerebellum and temporal cortex of autopsied subjects with Alzheimer's disease (AD, cerebellar n=197, temporal cortex n=202...
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Public Library of Science (PLoS)
2012-01-01
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| Series: | PLoS Genetics |
| Online Access: | https://journals.plos.org/plosgenetics/article/file?id=10.1371/journal.pgen.1002707&type=printable |
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| author | Fanggeng Zou High Seng Chai Curtis S Younkin Mariet Allen Julia Crook V Shane Pankratz Minerva M Carrasquillo Christopher N Rowley Asha A Nair Sumit Middha Sooraj Maharjan Thuy Nguyen Li Ma Kimberly G Malphrus Ryan Palusak Sarah Lincoln Gina Bisceglio Constantin Georgescu Naomi Kouri Christopher P Kolbert Jin Jen Jonathan L Haines Richard Mayeux Margaret A Pericak-Vance Lindsay A Farrer Gerard D Schellenberg Alzheimer's Disease Genetics Consortium Ronald C Petersen Neill R Graff-Radford Dennis W Dickson Steven G Younkin Nilüfer Ertekin-Taner |
| author_facet | Fanggeng Zou High Seng Chai Curtis S Younkin Mariet Allen Julia Crook V Shane Pankratz Minerva M Carrasquillo Christopher N Rowley Asha A Nair Sumit Middha Sooraj Maharjan Thuy Nguyen Li Ma Kimberly G Malphrus Ryan Palusak Sarah Lincoln Gina Bisceglio Constantin Georgescu Naomi Kouri Christopher P Kolbert Jin Jen Jonathan L Haines Richard Mayeux Margaret A Pericak-Vance Lindsay A Farrer Gerard D Schellenberg Alzheimer's Disease Genetics Consortium Ronald C Petersen Neill R Graff-Radford Dennis W Dickson Steven G Younkin Nilüfer Ertekin-Taner |
| author_sort | Fanggeng Zou |
| collection | DOAJ |
| description | Genetic variants that modify brain gene expression may also influence risk for human diseases. We measured expression levels of 24,526 transcripts in brain samples from the cerebellum and temporal cortex of autopsied subjects with Alzheimer's disease (AD, cerebellar n=197, temporal cortex n=202) and with other brain pathologies (non-AD, cerebellar n=177, temporal cortex n=197). We conducted an expression genome-wide association study (eGWAS) using 213,528 cisSNPs within ± 100 kb of the tested transcripts. We identified 2,980 cerebellar cisSNP/transcript level associations (2,596 unique cisSNPs) significant in both ADs and non-ADs (q<0.05, p=7.70 × 10(-5)-1.67 × 10(-82)). Of these, 2,089 were also significant in the temporal cortex (p=1.85 × 10(-5)-1.70 × 10(-141)). The top cerebellar cisSNPs had 2.4-fold enrichment for human disease-associated variants (p<10(-6)). We identified novel cisSNP/transcript associations for human disease-associated variants, including progressive supranuclear palsy SLCO1A2/rs11568563, Parkinson's disease (PD) MMRN1/rs6532197, Paget's disease OPTN/rs1561570; and we confirmed others, including PD MAPT/rs242557, systemic lupus erythematosus and ulcerative colitis IRF5/rs4728142, and type 1 diabetes mellitus RPS26/rs1701704. In our eGWAS, there was 2.9-3.3 fold enrichment (p<10(-6)) of significant cisSNPs with suggestive AD-risk association (p<10(-3)) in the Alzheimer's Disease Genetics Consortium GWAS. These results demonstrate the significant contributions of genetic factors to human brain gene expression, which are reliably detected across different brain regions and pathologies. The significant enrichment of brain cisSNPs among disease-associated variants advocates gene expression changes as a mechanism for many central nervous system (CNS) and non-CNS diseases. Combined assessment of expression and disease GWAS may provide complementary information in discovery of human disease variants with functional implications. Our findings have implications for the design and interpretation of eGWAS in general and the use of brain expression quantitative trait loci in the study of human disease genetics. |
| format | Article |
| id | doaj-art-a148bd6289944186a3a7dd01c3a33cac |
| institution | Kabale University |
| issn | 1553-7390 1553-7404 |
| language | English |
| publishDate | 2012-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Genetics |
| spelling | doaj-art-a148bd6289944186a3a7dd01c3a33cac2025-08-20T03:26:42ZengPublic Library of Science (PLoS)PLoS Genetics1553-73901553-74042012-01-0186e100270710.1371/journal.pgen.1002707Brain expression genome-wide association study (eGWAS) identifies human disease-associated variants.Fanggeng ZouHigh Seng ChaiCurtis S YounkinMariet AllenJulia CrookV Shane PankratzMinerva M CarrasquilloChristopher N RowleyAsha A NairSumit MiddhaSooraj MaharjanThuy NguyenLi MaKimberly G MalphrusRyan PalusakSarah LincolnGina BisceglioConstantin GeorgescuNaomi KouriChristopher P KolbertJin JenJonathan L HainesRichard MayeuxMargaret A Pericak-VanceLindsay A FarrerGerard D SchellenbergAlzheimer's Disease Genetics ConsortiumRonald C PetersenNeill R Graff-RadfordDennis W DicksonSteven G YounkinNilüfer Ertekin-TanerGenetic variants that modify brain gene expression may also influence risk for human diseases. We measured expression levels of 24,526 transcripts in brain samples from the cerebellum and temporal cortex of autopsied subjects with Alzheimer's disease (AD, cerebellar n=197, temporal cortex n=202) and with other brain pathologies (non-AD, cerebellar n=177, temporal cortex n=197). We conducted an expression genome-wide association study (eGWAS) using 213,528 cisSNPs within ± 100 kb of the tested transcripts. We identified 2,980 cerebellar cisSNP/transcript level associations (2,596 unique cisSNPs) significant in both ADs and non-ADs (q<0.05, p=7.70 × 10(-5)-1.67 × 10(-82)). Of these, 2,089 were also significant in the temporal cortex (p=1.85 × 10(-5)-1.70 × 10(-141)). The top cerebellar cisSNPs had 2.4-fold enrichment for human disease-associated variants (p<10(-6)). We identified novel cisSNP/transcript associations for human disease-associated variants, including progressive supranuclear palsy SLCO1A2/rs11568563, Parkinson's disease (PD) MMRN1/rs6532197, Paget's disease OPTN/rs1561570; and we confirmed others, including PD MAPT/rs242557, systemic lupus erythematosus and ulcerative colitis IRF5/rs4728142, and type 1 diabetes mellitus RPS26/rs1701704. In our eGWAS, there was 2.9-3.3 fold enrichment (p<10(-6)) of significant cisSNPs with suggestive AD-risk association (p<10(-3)) in the Alzheimer's Disease Genetics Consortium GWAS. These results demonstrate the significant contributions of genetic factors to human brain gene expression, which are reliably detected across different brain regions and pathologies. The significant enrichment of brain cisSNPs among disease-associated variants advocates gene expression changes as a mechanism for many central nervous system (CNS) and non-CNS diseases. Combined assessment of expression and disease GWAS may provide complementary information in discovery of human disease variants with functional implications. Our findings have implications for the design and interpretation of eGWAS in general and the use of brain expression quantitative trait loci in the study of human disease genetics.https://journals.plos.org/plosgenetics/article/file?id=10.1371/journal.pgen.1002707&type=printable |
| spellingShingle | Fanggeng Zou High Seng Chai Curtis S Younkin Mariet Allen Julia Crook V Shane Pankratz Minerva M Carrasquillo Christopher N Rowley Asha A Nair Sumit Middha Sooraj Maharjan Thuy Nguyen Li Ma Kimberly G Malphrus Ryan Palusak Sarah Lincoln Gina Bisceglio Constantin Georgescu Naomi Kouri Christopher P Kolbert Jin Jen Jonathan L Haines Richard Mayeux Margaret A Pericak-Vance Lindsay A Farrer Gerard D Schellenberg Alzheimer's Disease Genetics Consortium Ronald C Petersen Neill R Graff-Radford Dennis W Dickson Steven G Younkin Nilüfer Ertekin-Taner Brain expression genome-wide association study (eGWAS) identifies human disease-associated variants. PLoS Genetics |
| title | Brain expression genome-wide association study (eGWAS) identifies human disease-associated variants. |
| title_full | Brain expression genome-wide association study (eGWAS) identifies human disease-associated variants. |
| title_fullStr | Brain expression genome-wide association study (eGWAS) identifies human disease-associated variants. |
| title_full_unstemmed | Brain expression genome-wide association study (eGWAS) identifies human disease-associated variants. |
| title_short | Brain expression genome-wide association study (eGWAS) identifies human disease-associated variants. |
| title_sort | brain expression genome wide association study egwas identifies human disease associated variants |
| url | https://journals.plos.org/plosgenetics/article/file?id=10.1371/journal.pgen.1002707&type=printable |
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