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Brain expression genome-wide association study (eGWAS) identifies human disease-associated variants.

Zou F, Chai HS, Younkin CS, Allen M, Crook J, Pankratz VS, Carrasquillo MM, Rowley CN, Nair AA, Middha S, Maharjan S, Nguyen T, Ma L, Malphrus KG, Palusak R, Lincoln S, Bisceglio G, Georgescu C, Kouri N, Kolbert CP, Jen J, Haines JL, Mayeux R, Pericak-Vance MA, Farrer LA, Schellenberg GD, Alzheimer's Disease Genetics ConsortiumPetersen RC, Graff-Radford NR, Dickson DW, Younkin SG, Ertekin-Taner N - PLoS Genet. (2012)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, USA.

ABSTRACT
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.

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Summary of brain eGWAS and human disease associations.
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pgen-1002707-g001: Summary of brain eGWAS and human disease associations.

Mentions: To achieve internal replication, we first analyzed the ADs and non–ADs separately. In our cerebellar eGWAS, at q<0.05, there were 5,271 significant cisSNP/transcript associations (1,156 unique genes) in the AD, 4,450 (1,022 unique genes) in the non–AD and 10,281 (1,875 unique genes) in the combined datasets. Q-Q plots suggested a clear excess of significant results (Figure 1, Figure S1a–S1d). 2,980 cisSNP/transcript associations (2,596 unique cisSNPs, 686 unique genes) were significant at q<0.05 in both ADs and non–ADs (Table 1, Supplementary Table 3 in Dataset S1, Figure S2). The direction and magnitude of associations in both groups demonstrate remarkable similarities (Pearson's correlation coefficient = 0.98, p<0.0001). The box plots depicted for some of these top associations (Figure S3a–S3c) demonstrate this replication in ADs and non–ADs. Most associations have an additive or dominant pattern with respect to the minor allele.


Brain expression genome-wide association study (eGWAS) identifies human disease-associated variants.

Zou F, Chai HS, Younkin CS, Allen M, Crook J, Pankratz VS, Carrasquillo MM, Rowley CN, Nair AA, Middha S, Maharjan S, Nguyen T, Ma L, Malphrus KG, Palusak R, Lincoln S, Bisceglio G, Georgescu C, Kouri N, Kolbert CP, Jen J, Haines JL, Mayeux R, Pericak-Vance MA, Farrer LA, Schellenberg GD, Alzheimer's Disease Genetics ConsortiumPetersen RC, Graff-Radford NR, Dickson DW, Younkin SG, Ertekin-Taner N - PLoS Genet. (2012)

Summary of brain eGWAS and human disease associations.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3369937&req=5

pgen-1002707-g001: Summary of brain eGWAS and human disease associations.
Mentions: To achieve internal replication, we first analyzed the ADs and non–ADs separately. In our cerebellar eGWAS, at q<0.05, there were 5,271 significant cisSNP/transcript associations (1,156 unique genes) in the AD, 4,450 (1,022 unique genes) in the non–AD and 10,281 (1,875 unique genes) in the combined datasets. Q-Q plots suggested a clear excess of significant results (Figure 1, Figure S1a–S1d). 2,980 cisSNP/transcript associations (2,596 unique cisSNPs, 686 unique genes) were significant at q<0.05 in both ADs and non–ADs (Table 1, Supplementary Table 3 in Dataset S1, Figure S2). The direction and magnitude of associations in both groups demonstrate remarkable similarities (Pearson's correlation coefficient = 0.98, p<0.0001). The box plots depicted for some of these top associations (Figure S3a–S3c) demonstrate this replication in ADs and non–ADs. Most associations have an additive or dominant pattern with respect to the minor allele.

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, USA.

ABSTRACT
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.

Show MeSH
Related in: MedlinePlus