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) 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.
Vyšlo v časopise:
Brain Expression Genome-Wide Association Study (eGWAS) Identifies Human Disease-Associated Variants. PLoS Genet 8(6): e32767. doi:10.1371/journal.pgen.1002707
Kategorie:
Research Article
prolekare.web.journal.doi_sk:
https://doi.org/10.1371/journal.pgen.1002707
Souhrn
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.
Zdroje
1. Ertekin-TanerN 2011 Gene expression endophenotypes: a novel approach for gene discovery in Alzheimer's disease. Mol Neurodegener 6 31
2. MurphyAChuJHXuMCareyVJLazarusR 2010 Mapping of numerous disease-associated expression polymorphisms in primary peripheral blood CD4+ lymphocytes. Hum Mol Genet 19 4745 4757
3. NicolaeDLGamazonEZhangWDuanSDolanME 2010 Trait-associated SNPs are more likely to be eQTLs: annotation to enhance discovery from GWAS. PLoS Genet 6 e1000888 doi:10.1371/journal.pgen.1000888
4. SchadtEEMonksSADrakeTALusisAJCheN 2003 Genetics of gene expression surveyed in maize, mouse and man. Nature 422 297 302
5. CheungVGConlinLKWeberTMArcaroMJenKY 2003 Natural variation in human gene expression assessed in lymphoblastoid cells. Nat Genet 33 422 425
6. MorleyMMolonyCMWeberTMDevlinJLEwensKG 2004 Genetic analysis of genome-wide variation in human gene expression. Nature 430 743 747
7. MonksSALeonardsonAZhuHCundiffPPietrusiakP 2004 Genetic inheritance of gene expression in human cell lines. Am J Hum Genet 75 1094 1105
8. CheungVGSpielmanRSEwensKGWeberTMMorleyM 2005 Mapping determinants of human gene expression by regional and genome-wide association. Nature 437 1365 1369
9. StrangerBEForrestMSClarkAGMinichielloMJDeutschS 2005 Genome-wide associations of gene expression variation in humans. PLoS Genet 1 e78 doi:10.1371/journal.pgen.0010078
10. StrangerBENicaACForrestMSDimasABirdCP 2007 Population genomics of human gene expression. Nat Genet 39 1217 1224
11. StrangerBEForrestMSDunningMIngleCEBeazleyC 2007 Relative impact of nucleotide and copy number variation on gene expression phenotypes. Science 315 848 853
12. DixonALLiangLMoffattMFChenWHeathS 2007 A genome-wide association study of global gene expression. Nat Genet 39 1202 1207
13. DaussetJCannHCohenDLathropMLalouelJM 1990 Centre d'etude du polymorphisme humain (CEPH): collaborative genetic mapping of the human genome. Genomics 6 575 577
14. 2005 A haplotype map of the human genome. Nature 437 1299 1320
15. StrangerBEForrestMSClarkAGMinichielloMJDeutschS 2005 Genome-wide associations of gene expression variation in humans. PLoS Genet 1 e78 doi:10.1371/journal.pgen.0010078
16. GoringHHCurranJEJohnsonMPDyerTDCharlesworthJ 2007 Discovery of expression QTLs using large-scale transcriptional profiling in human lymphocytes. Nat Genet 39 1208 1216
17. RotivalMZellerTWildPSMaoucheSSzymczakS 2011 Integrating genome-wide genetic variations and monocyte expression data reveals trans-regulated gene modules in humans. PLoS Genet 7 e1002367 doi:10.1371/journal.pgen.1002367
18. DimasASDeutschSStrangerBEMontgomerySBBorelC 2009 Common regulatory variation impacts gene expression in a cell type-dependent manner. Science 325 1246 1250
19. DingJGudjonssonJELiangLStuartPELiY 2010 Gene expression in skin and lymphoblastoid cells: Refined statistical method reveals extensive overlap in cis-eQTL signals. Am J Hum Genet 87 779 789
20. EmilssonVThorleifssonGZhangBLeonardsonASZinkF 2008 Genetics of gene expression and its effect on disease. Nature 452 423 428
21. ZhongHBeaulaurierJLumPYMolonyCYangX 2010 Liver and adipose expression associated SNPs are enriched for association to type 2 diabetes. PLoS Genet 6 e1000932 doi:10.1371/journal.pgen.1000932
22. GrundbergEAdoueVKwanTGeBDuanQL 2011 Global analysis of the impact of environmental perturbation on cis-regulation of gene expression. PLoS Genet 7 e1001279 doi:10.1371/journal.ppat.1001279
23. SchadtEEMolonyCChudinEHaoKYangX 2008 Mapping the genetic architecture of gene expression in human liver. PLoS Biol 6 e107 doi:10.1371/journal.pbio.0060107
24. MyersAJGibbsJRWebsterJARohrerKZhaoA 2007 A survey of genetic human cortical gene expression. Nat Genet 39 1494 1499
25. WebsterJAGibbsJRClarkeJRayMZhangW 2009 Genetic control of human brain transcript expression in Alzheimer disease. Am J Hum Genet 84 445 458
26. HindorffLASethupathyPJunkinsHARamosEMMehtaJP 2009 Potential etiologic and functional implications of genome-wide association loci for human diseases and traits. Proc Natl Acad Sci U S A 106 9362 9367
27. HoglingerGUMelhemNMDicksonDWSleimanPMWangLS 2011 Identification of common variants influencing risk of the tauopathy progressive supranuclear palsy. Nat Genet 43 699 705
28. NajACJunGBeechamGWWangLSVardarajanBN 2011 Common variants at MS4A4/MS4A6E, CD2AP, CD33 and EPHA1 are associated with late-onset Alzheimer's disease. Nat Genet 43 436 441
29. CarrasquilloMMZouFPankratzVSWilcoxSLMaL 2009 Genetic variation in PCDH11X is associated with susceptibility to late-onset Alzheimer's disease. Nat Genet 41 192 198
30. StoreyJDTibshiraniR 2003 Statistical significance for genomewide studies. Proc Natl Acad Sci U S A 100 9440 9445
31. BarryWTKernagisDNDressmanHKGriffisRJHunterJD 2010 Intratumor heterogeneity and precision of microarray-based predictors of breast cancer biology and clinical outcome. J Clin Oncol 28 2198 2206
32. Simon-SanchezJSchulteCBrasJMSharmaMGibbsJR 2009 Genome-wide association study reveals genetic risk underlying Parkinson's disease. Nat Genet 41 1308 1312
33. FuchsJNilssonCKachergusJMunzMLarssonEM 2007 Phenotypic variation in a large Swedish pedigree due to SNCA duplication and triplication. Neurology 68 916 922
34. EdwardsTLScottWKAlmonteCBurtAPowellEH 2010 Genome-wide association study confirms SNPs in SNCA and the MAPT region as common risk factors for Parkinson disease. Ann Hum Genet 74 97 109
35. HanJWZhengHFCuiYSunLDYeDQ 2009 Genome-wide association study in a Chinese Han population identifies nine new susceptibility loci for systemic lupus erythematosus. Nat Genet 41 1234 1237
36. GrahamRRKozyrevSVBaechlerECReddyMVPlengeRM 2006 A common haplotype of interferon regulatory factor 5 (IRF5) regulates splicing and expression and is associated with increased risk of systemic lupus erythematosus. Nat Genet 38 550 555
37. GrahamRRKyogokuCSigurdssonSVlasovaIADaviesLR 2007 Three functional variants of IFN regulatory factor 5 (IRF5) define risk and protective haplotypes for human lupus. Proc Natl Acad Sci U S A 104 6758 6763
38. AndersonCABoucherGLeesCWFrankeAD'AmatoM 2011 Meta-analysis identifies 29 additional ulcerative colitis risk loci, increasing the number of confirmed associations to 47. Nat Genet 43 246 252
39. HaroldDAbrahamRHollingworthPSimsRGerrishA 2009 Genome-wide association study identifies variants at CLU and PICALM associated with Alzheimer's disease. Nat Genet
40. LambertJCHeathSEvenGCampionDSleegersK 2009 Genome-wide association study identifies variants at CLU and CR1 associated with Alzheimer's disease. Nat Genet 41 1094 1099
41. ReimanEMWebsterJAMyersAJHardyJDunckleyT 2007 GAB2 alleles modify Alzheimer's risk in APOE epsilon4 carriers. Neuron 54 713 720
42. van EsMAVeldinkJHSarisCGBlauwHMvan VughtPW 2009 Genome-wide association study identifies 19p13.3 (UNC13A) and 9p21.2 as susceptibility loci for sporadic amyotrophic lateral sclerosis. Nat Genet 41 1083 1087
43. LaaksovirtaHPeuralinnaTSchymickJCScholzSWLaiSL 2010 Chromosome 9p21 in amyotrophic lateral sclerosis in Finland: a genome-wide association study. Lancet Neurol 9 978 985
44. Dejesus-HernandezMMackenzieIRBoeveBFBoxerALBakerM 2011 Expanded GGGGCC Hexanucleotide Repeat in Noncoding Region of C9ORF72 Causes Chromosome 9p-Linked FTD and ALS. Neuron 72 245 256
45. RentonAEMajounieEWaiteASimon-SanchezJRollinsonS 2011 A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS-FTD. Neuron 72 257 268
46. LeeWGlaeserHSmithLHRobertsRLMoeckelGW 2005 Polymorphisms in human organic anion-transporting polypeptide 1A2 (OATP1A2): implications for altered drug disposition and central nervous system drug entry. J Biol Chem 280 9610 9617
47. HollingworthPHaroldDSimsRGerrishALambertJC 2011 Common variants at ABCA7, MS4A6A/MS4A4E, EPHA1, CD33 and CD2AP are associated with Alzheimer's disease. Nat Genet 43 429 435
48. SeshadriSFitzpatrickALIkramMADeStefanoALGudnasonV 2010 Genome-wide analysis of genetic loci associated with Alzheimer disease. JAMA 303 1832 1840
49. AllenMZouFChaiHSYounkinCSCrookJ 2012 Novel late-onset Alzheimer's disease loci variants associate with brain gene expression. Neurology in-press
50. AtzMWalshDCartagenaPLiJEvansS 2007 Methodological considerations for gene expression profiling of human brain. J Neurosci Methods 163 295 309
51. BraakHBraakE 1991 Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol (Berl) 82 239 259
52. CaffreyTMJoachimCParacchiniSEsiriMMWade-MartinsR 2006 Haplotype-specific expression of exon 10 at the human MAPT locus. Hum Mol Genet 15 3529 3537
53. CaffreyTMJoachimCWade-MartinsR 2008 Haplotype-specific expression of the N-terminal exons 2 and 3 at the human MAPT locus. Neurobiol Aging 29 1923 1929
54. MyersAJPittmanAMZhaoASRohrerKKaleemM 2007 The MAPT H1c risk haplotype is associated with increased expression of tau and especially of 4 repeat containing transcripts. Neurobiol Dis 25 561 570
55. McKhannGDrachmanDFolsteinMKatzmanRPriceD 1984 Clinical diagnosis of Alzheimer's disease: report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer's Disease. Neurology 34 939 944
56. DuPKibbeWALinSM 2008 lumi: a pipeline for processing Illumina microarray. Bioinformatics 24 1547 1548
57. LinSMDuPHuberWKibbeWA 2008 Model-based variance-stabilizing transformation for Illumina microarray data. Nucleic Acids Res 36 e11
58. PurcellSNealeBTodd-BrownKThomasLFerreiraMA 2007 PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet 81 559 575
59. PriceALPattersonNJPlengeRMWeinblattMEShadickNA 2006 Principal components analysis corrects for stratification in genome-wide association studies. Nat Genet 38 904 909
60. WestfallPHZaykinDVYoungSS 2002 Multiple tests for genetic effects in association studies. Methods Mol Biol 184 143 168
61. WillerCJLiYAbecasisGR 2010 METAL: fast and efficient meta-analysis of genomewide association scans. Bioinformatics 26 2190 2191
Štítky
Genetika Reprodukčná medicínaČlánok vyšiel v časopise
PLOS Genetics
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