- Email: [email protected]
GENOME-WIDE META-ANALYSIS OF TRANSCRIPTOME PROFILING IDENTIFIES NOVEL DYSREGULATED GENES IMPLICATED IN ALZHEIMER’S DISEASE
P238
Podium Presentations: Monday, July 25, 2016
drivers within our data, approximately half of which are novel targets. Conclusions: We present a novel pipeline for the analysis of our existing Human Brainome data. O2-06-02
GENOME-WIDE META-ANALYSIS OF TRANSCRIPTOME PROFILING IDENTIFIES NOVEL DYSREGULATED GENES IMPLICATED IN ALZHEIMER’S DISEASE
Kwangsik Nho1, Sungeun Kim1, Shannon L. Risacher1,2, Liana G. Apostolova1,2, Kuang Lin3, Aoife Keohane4, Katie Lunnon5, Angela Hodges3, Mariet Allen6, Xue Wang6, Jeremy D. Burgess6, Nilufer Ertekin-Taner6, Ronald C. Petersen7, Holly Soares8, Parul Singh8, Lisu Wang8, Zhenhao Qi8, Aiqing He8, Isaac Neuhaus8, Vishal Patel8, Tatiana M. Foroud1, Kelley Faber9, Simon Lovestone10, Andrew Simmons11,12, Michael W. Weiner13, Andrew J. Saykin1,2,14, 1 Indiana University School of Medicine, Indianapolis, IN, USA; 2Indiana Alzheimer Disease Center, Indianapolis, IN, USA; 3King’s College London, Institute of Psychiatry, Psychology & Neuroscience, London, United Kingdom; 4King’s College London, London, United Kingdom; 5University of Exeter Medical School, Exeter, United Kingdom; 6Mayo Clinic, Jacksonville, FL, USA; 7Mayo Clinic, Rochester, MN, USA; 8Bristol-Myers Squibb, Wallingford, CT, USA; 9Indiana University, Indianapolis, IN, USA; 10 University of Oxford, Oxford, United Kingdom; 11King’s College London, London, United Kingdom; 12NIHR Biomedical Research Centre for Mental Health, London, United Kingdom; 13University of California, San Francisco, San Francisco, CA, USA; 14Indiana University Network Science, Indianapolis, IN, USA. Contact e-mail: [email protected]
Figure 2. Association of CREB5 gene expression levels with brain structure using whole brain surface-based analysis using two independent cohorts: (a) ADNI (discovery sample) and (b) AddNeuroMed (replication sample). Whole-brain cortical thickness analysis demonstrated the identification and replication of brain regions, especially entorhinal cortex, significantly associated with expression of CREB5. Statistical maps computed using SurfStat were thresholded using random field theory (RFT) as a multiple testing correction at p-corrected < 0.05.
Background: Gene expression is a fundamental mechanism in
susceptibility to and manifestation of complex disease. Prior studies suggest that abnormal gene expression patterns may contribute to the onset and progression of late-onset Alzheimer’s disease (LOAD). We performed genome-wide transcriptome meta-analysis and whole-brain cortical thickness analysis in LOAD using blood-based microarray gene expression profiles. Methods: 1,440 non-Hispanic Caucasian participants (661 from the ADNI as a discovery sample and 674 and 105 from the AddNeuroMed and Mayo cohorts as
Figure 1. Volcano plot of transcriptome analysis results in the ADNI cohort (discovery sample). Red circles represent significantly differentially expressed genes in AD compared to CN.
Figure 3. Results of cis-eQTL mapping analysis of CREB5 using two independent cohorts: (a) ADNI (discovery sample) and (b) AddNeuroMed (replication sample). cis-eQTL mapping analyses of CREB5 detected 5 significant associations with p < 5310-8 in the ADNI. The most significant ciseQTL SNP (rs56388170) in the ADNI was replicated in the AddNeroMed. All SNPs are plotted based on their -log10 p-values, NCBI build 37 genomic position, and recombination rates calculated from the 1000 Genomes Project reference data.
Podium Presentations: Monday, July 25, 2016
P239
replication samples) were included. Raw microarray expression values from peripheral blood samples (PaxGene RNA tubes) were pre-processed followed by standard quality control (QC) procedures on samples and probe sets. Statistical analysis of microarray data was performed using a linear regression model to evaluate differences in gene expression between LOAD and cognitively normal controls (CN). Meta-analysis was performed using a fixed-effect, inverse-variance-weighted model. Significant associations were determined using FDR adjustment and Bonferroni correction for multiple testing. Results: Of the 21,150 probe sets in ADNI represented on the array after QC, 18 probe sets (16 genes) were significantly up-regulated and 8 probe sets (7 genes) were significantly down-regulated in LOAD after controlling for multiple testing (FDR-corrected p<0.05) (Fig.1). Of the 23 differentially expressed genes, 6 genes were replicated in the meta-analysis (Table 1). The most significantly altered gene was CREB5 (up-regulated). Whole-brain cortical thickness analysis identified and replicated brain regions, especially entorhinal cortex, significantly associated with expression of CREB5 (Fig. 2). Individuals with lower expression showed greater cortical thickness (corrected p<0.05). cis-eQTL mapping analyses of CREB5 detected 5 significant associations with p < 5x10-8 (Fig. 3). cis-eQTL of rs56388170 (most significant) was replicated (Fig. 3) and was significantly associated with global cortical Ab load (measured by [18F]Florbetapir PET) and CSF Ab1-42 (Fig. 4). Conclusions: RNA from peripheral blood indicated a differential gene expression pattern between AD patients and controls. Genes identified in this study have been implicated in biological processes that may be relevant to AD. CREB is a key component of nervous system development, cell survival, plasticity and learning and memory (Sakamoto et al. 2011). O2-06-03
Figure 4. Association of the most significant cis-eQTL SNP (rs56388170) of CREB5 gene expression levels with (a) log transformed global cortical Ab levels measured by [18F]Florbetapir PET and (b) CSF Ab1-42 in the ADNI. rs56388170 was significantly associated with global cortical Ab load and CSF Ab1-42.
TISSUE-SPECIFIC GENOME-WIDE PREDICTIONS OF GENETICALLY REGULATED EXPRESSION IN ALZHEIMER’S DISEASE
Jennifer Below1, Lauren Petty1, Hao Hu2, Chad Huff2, Anita L. DeStefano3, Myriam Fornage4, Joshua C. Bis5, Johnathan L. Haines6, Margaret A. Pericak-Vance7, Richard Mayeux8, Gerard D. Schellenberg9, Cornelia M. van Duijn10, Ellen Wijsman5, Sudha Seshadri11, Eric Boerwinkle4,12, 1University of Texas Health Science Center at Houston School of Public Health, Houston, TX, USA; 2MD Anderson Cancer Center, Houston, TX, USA; 3The National Heart, Lung, and Blood Institute’s Framingham Heart Study, Framingham, MA, USA; 4 University of Texas Health Science Center at Houston, Houston, TX, USA;
Table 1 6 dysregulated genes replicated in the replication sample. Replication
Gene
Discovery ADNI
Direction
AddNeuoroMed
Mayo
Meta p-value (replication)
Direction
Meta p-value (all)
CREB5 FLOT1 CD46 DUSP5 CD63 PELO TMBIM6 IRAK3 FKBP5 IL1R2 RPAIN
5.03E-6 2.50E-5 2.93E-5 3.20E-5 3.68E-5 7.49E-5 9.80E-5 9.96E-5 1.16E-4 1.46E-4 3.28E-4
[ [ [ Y [ [ [ [ [ [ Y
1.96E-5 5.56E-2 7.62E-6 3.98E-1 5.68E-1 7.57E-2 1.06E-3 1.84E-4 3.71E-3 1.41E-1 1.55E-3
2.18E-2 1.98E-1 3.31E-1 5.07E-1 9.59E-1 3.97E-1 8.53E-1 3.93E-1 1.17E-2 6.08E-1 6.74E-1
1.29E-6 2.26E-2 8.19E-6 6.32E-1 5.91E-1 4.91E-2 4.00E-3 1.81E-4 1.24E-1 2.68E-1 2.37E-3
[[ [[ [[ [Y [[ [[ [Y [[ [Y [Y YY
3.90E-11 1.39E-5 1.26E-9 3.59E-2 3.80E-3 8.07E-5 3.58E-6 9.96E-8 4.06E-4 1.60E-3 4.58E-6
Podium Presentations: Monday, July 25, 2016
drivers within our data, approximately half of which are novel targets. Conclusions: We present a novel pipeline for the analysis of our existing Human Brainome data. O2-06-02
GENOME-WIDE META-ANALYSIS OF TRANSCRIPTOME PROFILING IDENTIFIES NOVEL DYSREGULATED GENES IMPLICATED IN ALZHEIMER’S DISEASE
Kwangsik Nho1, Sungeun Kim1, Shannon L. Risacher1,2, Liana G. Apostolova1,2, Kuang Lin3, Aoife Keohane4, Katie Lunnon5, Angela Hodges3, Mariet Allen6, Xue Wang6, Jeremy D. Burgess6, Nilufer Ertekin-Taner6, Ronald C. Petersen7, Holly Soares8, Parul Singh8, Lisu Wang8, Zhenhao Qi8, Aiqing He8, Isaac Neuhaus8, Vishal Patel8, Tatiana M. Foroud1, Kelley Faber9, Simon Lovestone10, Andrew Simmons11,12, Michael W. Weiner13, Andrew J. Saykin1,2,14, 1 Indiana University School of Medicine, Indianapolis, IN, USA; 2Indiana Alzheimer Disease Center, Indianapolis, IN, USA; 3King’s College London, Institute of Psychiatry, Psychology & Neuroscience, London, United Kingdom; 4King’s College London, London, United Kingdom; 5University of Exeter Medical School, Exeter, United Kingdom; 6Mayo Clinic, Jacksonville, FL, USA; 7Mayo Clinic, Rochester, MN, USA; 8Bristol-Myers Squibb, Wallingford, CT, USA; 9Indiana University, Indianapolis, IN, USA; 10 University of Oxford, Oxford, United Kingdom; 11King’s College London, London, United Kingdom; 12NIHR Biomedical Research Centre for Mental Health, London, United Kingdom; 13University of California, San Francisco, San Francisco, CA, USA; 14Indiana University Network Science, Indianapolis, IN, USA. Contact e-mail: [email protected]
Figure 2. Association of CREB5 gene expression levels with brain structure using whole brain surface-based analysis using two independent cohorts: (a) ADNI (discovery sample) and (b) AddNeuroMed (replication sample). Whole-brain cortical thickness analysis demonstrated the identification and replication of brain regions, especially entorhinal cortex, significantly associated with expression of CREB5. Statistical maps computed using SurfStat were thresholded using random field theory (RFT) as a multiple testing correction at p-corrected < 0.05.
Background: Gene expression is a fundamental mechanism in
susceptibility to and manifestation of complex disease. Prior studies suggest that abnormal gene expression patterns may contribute to the onset and progression of late-onset Alzheimer’s disease (LOAD). We performed genome-wide transcriptome meta-analysis and whole-brain cortical thickness analysis in LOAD using blood-based microarray gene expression profiles. Methods: 1,440 non-Hispanic Caucasian participants (661 from the ADNI as a discovery sample and 674 and 105 from the AddNeuroMed and Mayo cohorts as
Figure 1. Volcano plot of transcriptome analysis results in the ADNI cohort (discovery sample). Red circles represent significantly differentially expressed genes in AD compared to CN.
Figure 3. Results of cis-eQTL mapping analysis of CREB5 using two independent cohorts: (a) ADNI (discovery sample) and (b) AddNeuroMed (replication sample). cis-eQTL mapping analyses of CREB5 detected 5 significant associations with p < 5310-8 in the ADNI. The most significant ciseQTL SNP (rs56388170) in the ADNI was replicated in the AddNeroMed. All SNPs are plotted based on their -log10 p-values, NCBI build 37 genomic position, and recombination rates calculated from the 1000 Genomes Project reference data.
Podium Presentations: Monday, July 25, 2016
P239
replication samples) were included. Raw microarray expression values from peripheral blood samples (PaxGene RNA tubes) were pre-processed followed by standard quality control (QC) procedures on samples and probe sets. Statistical analysis of microarray data was performed using a linear regression model to evaluate differences in gene expression between LOAD and cognitively normal controls (CN). Meta-analysis was performed using a fixed-effect, inverse-variance-weighted model. Significant associations were determined using FDR adjustment and Bonferroni correction for multiple testing. Results: Of the 21,150 probe sets in ADNI represented on the array after QC, 18 probe sets (16 genes) were significantly up-regulated and 8 probe sets (7 genes) were significantly down-regulated in LOAD after controlling for multiple testing (FDR-corrected p<0.05) (Fig.1). Of the 23 differentially expressed genes, 6 genes were replicated in the meta-analysis (Table 1). The most significantly altered gene was CREB5 (up-regulated). Whole-brain cortical thickness analysis identified and replicated brain regions, especially entorhinal cortex, significantly associated with expression of CREB5 (Fig. 2). Individuals with lower expression showed greater cortical thickness (corrected p<0.05). cis-eQTL mapping analyses of CREB5 detected 5 significant associations with p < 5x10-8 (Fig. 3). cis-eQTL of rs56388170 (most significant) was replicated (Fig. 3) and was significantly associated with global cortical Ab load (measured by [18F]Florbetapir PET) and CSF Ab1-42 (Fig. 4). Conclusions: RNA from peripheral blood indicated a differential gene expression pattern between AD patients and controls. Genes identified in this study have been implicated in biological processes that may be relevant to AD. CREB is a key component of nervous system development, cell survival, plasticity and learning and memory (Sakamoto et al. 2011). O2-06-03
Figure 4. Association of the most significant cis-eQTL SNP (rs56388170) of CREB5 gene expression levels with (a) log transformed global cortical Ab levels measured by [18F]Florbetapir PET and (b) CSF Ab1-42 in the ADNI. rs56388170 was significantly associated with global cortical Ab load and CSF Ab1-42.
TISSUE-SPECIFIC GENOME-WIDE PREDICTIONS OF GENETICALLY REGULATED EXPRESSION IN ALZHEIMER’S DISEASE
Jennifer Below1, Lauren Petty1, Hao Hu2, Chad Huff2, Anita L. DeStefano3, Myriam Fornage4, Joshua C. Bis5, Johnathan L. Haines6, Margaret A. Pericak-Vance7, Richard Mayeux8, Gerard D. Schellenberg9, Cornelia M. van Duijn10, Ellen Wijsman5, Sudha Seshadri11, Eric Boerwinkle4,12, 1University of Texas Health Science Center at Houston School of Public Health, Houston, TX, USA; 2MD Anderson Cancer Center, Houston, TX, USA; 3The National Heart, Lung, and Blood Institute’s Framingham Heart Study, Framingham, MA, USA; 4 University of Texas Health Science Center at Houston, Houston, TX, USA;
Table 1 6 dysregulated genes replicated in the replication sample. Replication
Gene
Discovery ADNI
Direction
AddNeuoroMed
Mayo
Meta p-value (replication)
Direction
Meta p-value (all)
CREB5 FLOT1 CD46 DUSP5 CD63 PELO TMBIM6 IRAK3 FKBP5 IL1R2 RPAIN
5.03E-6 2.50E-5 2.93E-5 3.20E-5 3.68E-5 7.49E-5 9.80E-5 9.96E-5 1.16E-4 1.46E-4 3.28E-4
[ [ [ Y [ [ [ [ [ [ Y
1.96E-5 5.56E-2 7.62E-6 3.98E-1 5.68E-1 7.57E-2 1.06E-3 1.84E-4 3.71E-3 1.41E-1 1.55E-3
2.18E-2 1.98E-1 3.31E-1 5.07E-1 9.59E-1 3.97E-1 8.53E-1 3.93E-1 1.17E-2 6.08E-1 6.74E-1
1.29E-6 2.26E-2 8.19E-6 6.32E-1 5.91E-1 4.91E-2 4.00E-3 1.81E-4 1.24E-1 2.68E-1 2.37E-3
[[ [[ [[ [Y [[ [[ [Y [[ [Y [Y YY
3.90E-11 1.39E-5 1.26E-9 3.59E-2 3.80E-3 8.07E-5 3.58E-6 9.96E-8 4.06E-4 1.60E-3 4.58E-6