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Large-scale data integration for systems- level understanding of complex diseases How do GWAS, NexGen sequencing, microRNAs and -OMICs relate? Sergio E. Baranzini, PhD Associate Professor, Department of Neurology University of
How do GWAS, NexGen sequencing, microRNAs and ‘-OMICs’ relate?
Associate Professor, Department of Neurology University of California, San Francisco B2PM Vancouver, BC March 8-9, 2011
Cell cycle Cell differentiation apoptosis
Cellular process proteins pathways
Physiological/pathological Process (health/disease)
autoimmunity cancer metabolic neurodegenerative infectious
genomic expression
Twins 041896
Affected Unaffected
Twins 230178
Affected Unaffected
Twins 041907
Affected Unaffected Reads (x109) >1 >1 n.d. n.d. n.d. n.d. Coverage (X) 21.7 22.5 n.d. n.d. n.d. n.d. Coverage of Reference (%) 99.6 99.5 n.d. n.d. n.d. n.d. Number of SNPs (x106) 3.55 3.66 n.d. n.d. n.d. n.d. SNP differences / total 3,241 / 1,089,550 n.d. n.d. n.d. n.d. Confirmed by Sanger Seq. 0 / 15 Number of indels (x106) 0.22 0.20 n.d. n.d. n.d. n.d. Indel differences / total 213 / 27,121 n.d. n.d. n.d. n.d. SNP differences / total 126 / 736,908 153 / 783,342 120 / 796,990 CNV differences / total 0 / 143 0 / 13 0 / 58 Number of CpG sites 2,146,620 2,033,078 1,636,285 1,917,131 1,779,140 1,642,200 CpG differences 2 10 176 mRNA reads (x106) 50/63 51/62 63 68 65 57 Number of differentially expressed genes / total 13,714 / 28,443 8,595 / 28,443 14,163 / 28,443 cSNP differences / total 322 / 51,523 1,017 / 40,833 380 / 18,503 Differential allelic expression 115 n.d. n.d. Number of differentially expressed genes / total 1,721 / 22,877 n.d. n.d.
Coverage GS1641 GS1679 GS1685 GS1687 GS1748 GS1768 GS1843 GS1881 GS1883 GS1884 GS1901 GS1922 GS2023 10X 0.963 0.960 0.966 0.960 0.963 0.966 0.963 0.967 0.965 0.961 0.966 0.968 0.963 20X 0.938 0.927 0.940 0.928 0.937 0.943 0.936 0.947 0.938 0.931 0.946 0.947 0.930 30X 0.897 0.872 0.898 0.874 0.896 0.905 0.892 0.918 0.892 0.884 0.915 0.916 0.870 40X 0.836 0.790 0.830 0.794 0.836 0.845 0.827 0.875 0.818 0.816 0.868 0.867 0.772 50X 0.756 0.685 0.737 0.693 0.756 0.760 0.742 0.817 0.716 0.730 0.805 0.800 0.640 60X 0.659 0.565 0.623 0.577 0.660 0.653 0.641 0.746 0.593 0.632 0.728 0.716 0.491 100X 0.242 0.145 0.184 0.165 0.252 0.213 0.233 0.395 0.157 0.247 0.355 0.318 0.085
Trait 0001 1203 1204 1302 1000 1102 2400 2500 2701 2702 3301 3302 Type 2 diabetes 0.000001 0.000001 0.000001 0.000001 0.000001 0.000001 0.000001 0.000001 0.000001 0.000001 0.000001 0.000001 Peripheral artery disease 0.000001 0.000001 0.000001 0.000001 0.000001 0.000001 0.000001 0.000001 0.000001 0.000001 0.000001 0.000001 Ulcerative colitis 0.000001 0.000001 0.000001 0.000001 0.000001 0.000001 0.000001 0.000001 0.000001 9.40E-05 0.000001 0.000001 AIDS progression 0.000001 0.014534 0.014374 0.014561 0.014487 0.287732 0.014317 0.014401 0.014312 0.287537 0.014472 0.014259 Schizophrenia 9.20E-05 0.037415 0.000123 0.03701 0.003334 0.037177 0.189105 0.003317 0.037359 8.80E-05 0.000104 0.003256 Obesity (extreme) 0.000112 0.052772 0.052282 0.001504 0.051855 9.70E-05 0.010984 0.000101 0.052342 0.052286 0.16968 0.05221 Type 1 diabetes 0.00037 0.207176 0.122182 0.122547 0.001419 0.319395 0.030425 0.318769 0.448956 0.00147 1.90E-05 9.40E-05 Colorectal cancer 0.001776 0.000001 0.000001 0.001773 0.001813 0.000001 0.00177 0.000001 0.000001 0.000001 0.000001 0.024097 Asthma (toluene diisocyanate-induced) 0.008473 0.008868 0.008661 0.237072 0.008621 0.008442 0.000001 0.008668 0.008515 0.000001 0.000001 0.000001 Attention deficit hyperactivity disorder 0.017266 0.100153 0.001357 0.099332 0.016994 0.017151 0.099884 0.016951 0.100288 0.001455 0.017173 0.326867 Amyotrophic lateral sclerosis 0.019272 3.00E-06 0.000001 0.000001 0.000171 0.000178 0.00254 5.00E-06 0.087161 0.019426 0.000163 0.002512 Atrial fibrillation 0.029814 0.029646 0.179826 0.029545 0.179883 0.02987 0.029732 0.524261 0.029591 0.001688 0.524766 0.000001 Myocardial infarction (early onset) 0.035081 0.266216 0.712875 0.71342 0.26627 0.265822 0.266261 0.265314 0.266124 0.265864 0.266063 0.266212 Acute lymphoblastic leukemia (childhood) 0.042253 0.042782 0.001936 0.042598 0.712726 0.010849 0.010715 0.042835 0.001903 0.125269 0.001882 0.001894 Keloid 0.044053 0.000001 0.043806 0.000001 0.361922 0.000001 0.361714 0.000001 0.819742 0.043597 0.043498 0.043816 Kawasaki disease 0.048653 0.001374 0.048328 0.001387 0.048714 0.048347 0.001364 0.001334 0.000001 0.416528 0.001359 0.048823 Breast cancer 0.050822 0.104303 0.050123 0.007545 0.449744 0.450463 0.83778 0.189975 0.449709 3.60E-05 0.007711 0.838287
Multiple sclerosis
0.056872 0.020052 0.251476 0.129937 0.251946 0.019965 0.412769 0.020126 0.131014 0.589653 0.748581 0.056495 Psoriatic arthritis 0.081057 0.080526 0.445941 0.446259 0.446188 0.080928 0.081233 0.080512 0.080687 0.446934 0.080998 0.080953 Bipolar disorder 0.092613 0.092863 0.093143 0.322859 0.186321 0.014068 0.092627 0.6591 0.039247 0.004364 0.489711 0.039925 Age-related macular degeneration 0.115189 0.000001 0.023511 0.000001 0.002276 0.000001 0.002231 0.002275 0.000001 0.000001 0.002212 0.00224 Pancreatic cancer 0.115401 0.041925 0.011498 0.042178 0.011565 0.247828 0.247818 0.115835 0.04177 0.115491 0.115725 0.011601 Crohn's disease 0.119803 0.006783 0.013696 0.001343 0.251092 0.076135 0.178648 0.433503 0.338574 0.338703 0.719126 0.7191 Cardiovascular disease risk factors 0.137933 0.137515 0.137767 0.137395 0.137307 0.137993 0.138245 0.137499 0.138243 0.009344 0.009543 0.137879 N-glycan levels 0.146315 0.921644 0.146171 0.990956 0.922011 0.146013 0.032687 0.000192 0.712703 0.399174 0.712904 0.712869 Eosinophilic esophagitis (pediatric) 0.154239 0.404076 0.034309 0.404565 0.910855 0.034097 0.03442 0.003415 0.034261 0.154162 0.033862 0.153977 Parkinson's disease 0.163851 0.623571 0.164265 0.046531 0.62313 0.37479 0.164067 0.046769 0.000452 0.37482 0.375487 0.007243 Alopecia areata 0.17219 0.447022 0.030466 0.030439 0.172127 0.446345 0.030139 0.030335 0.000001 0.446861 0.172201 0.446838 Psoriasis 0.18249 0.082024 0.516329 0.333612 0.692406 0.082256 0.182276 0.18267 0.333428 0.922543 0.333901 0.182297 Hodgkin's lymphoma 0.205565 0.549786 0.032125 0.204856 0.548238 0.205056 0.982817 0.000001 0.204989 0.000001 0.032116 0.204542 Asthma 0.242964 0.084451 0.084421 0.477816 0.083828 0.998569 0.998556 0.7153 0.999847 0.961938 0.991209 0.998511 Lung adenocarcinoma 0.244914 0.567103 0.244654 0.566462 0.567338 0.244672 0.565752 0.244892 0.2451 0.244789 0.566523 0.245027 Chronic lymphocytic leukemia 0.245324 0.015564 0.015563 0.015431 0.001339 0.080243 0.079964 0.080589 0.015874 0.245427 0.001348 0.000001 Nasopharyngeal carcinoma 0.262375 0.261718 0.654263 0.654668 0.262437 0.654685 0.654547 0.033095 0.262524 0.261445 0.262888 0.654282 Esophageal cancer and gastric cancer 0.290537 0.290029 0.290109 0.732189 0.291227 0.732572 0.28995 0.044063 0.043845 0.000001 0.000001 0.290807 Cardiac structure and function 0.326248 0.017586 0.326518 0.017542 0.017804 0.326946 0.325954 0.326347 0.327106 0.017585 0.000267 0.326845 Alzheimer's disease (late onset) 0.379263 0.821454 0.379552 0.822727 0.822432 0.379674 0.379094 0.379062 0.073262 0.378776 0.822412 0.379416 Personality dimensions 0.406577 0.407177 0.006241 0.680685 0.043655 0.406434 0.044021 0.406241 0.043883 0.0061 0.16883 0.006192 Coronary heart disease 0.409575 0.675388 0.870101 0.870239 0.67489 0.869972 0.674831 0.172016 0.409767 0.172256 0.172824 0.172126 Chronic kidney disease 0.419755 0.928033 0.419071 0.85174 0.417929 0.583883 0.418556 0.149138 0.851369 0.928263 0.970283 0.735006 Major depressive disorder 0.493356 1.10E-05 0.021469 0.086761 0.08764 7.00E-06 0.749683 0.003388 0.997952 0.492413 0.916334 0.749359 HDL cholesterol 0.508191 0.060012 0.00231 0.508354 0.00232 0.030627 0.271379 0.832622 0.832652 0.01445 0.632142 0.998095 Pulmonary function 0.524955 0.00776 0.007837 0.007928 0.234896 0.52453 0.058549 0.000516 0.058675 0.52548 0.78942 0.058563 Restless legs syndrome 0.561935 0.90779 0.561707 0.562287 0.561757 0.5619 0.90729 0.563406 0.177318 0.177458 0.561701 0.562341 Major depressive disorder (broad) 0.599228 0.599146 0.249557 0.249708 0.599356 0.877517 0.877136 0.600048 0.982528 0.250056 0.87767 0.877654 Intracranial aneurysm 0.625893 0.872057 0.08553 0.305452 0.305894 0.305443 0.085392 0.624877 0.62546 0.305878 0.306459 0.627453 Melanoma 0.727557 0.72717 0.335863 0.727508 0.335628 0.72699 0.33533 0.335145 0.727395 0.957903 0.727463 0.957744 Prostate cancer 0.767835 0.010631 1.60E-05 0.025156 0.010679 0.004071 0.003908 0.001325 0.003942 0.025211 0.053743 0.053813 Vitiligo 0.784661 0.557413 0.305815 0.118288 0.305625 0.556976 0.30597 0.78444 0.924027 0.028812 0.556995 0.557298 Celiac disease 0.796046 0.51147 0.511247 0.219958 0.355173 0.949191 0.511352 0.979598 0.949541 0.057983 0.79645 0.510921 Primary biliary cirrhosis 0.799249 0.557377 0.10041 0.099627 0.558253 0.288145 0.100083 0.020313 0.100569 0.000001 0.001809 0.798228 LDL cholesterol 0.833519 0.518604 0.943973 0.518375 0.119285 0.98665 0.745667 0.017724 0.191193 0.833472 0.971481 0.518548 Ankylosing spondylitis 0.855362 0.855378 0.854828 0.855567 0.855823 0.855991 0.856044 0.52648 0.856214 0.162314 0.526387 0.527102 Bladder cancer 0.857056 0.257342 0.857444 0.970903 0.593613 0.59271 0.593345 0.257723 0.59296 0.258903 0.857502 0.257623 Systemic lupus erythematosus 0.89818 0.799851 0.800991 0.662998 0.800747 0.898462 0.8003 0.203139 0.955922 0.019467 0.049086 0.500122 Rheumatoid arthritis 0.98299 0.982942 0.982788 0.691608 0.794659 0.96378 0.439166 0.438109 0.874702 0.015027 0.034317 0.207514 Narcolepsy 0.986749 0.616676 0.986978 0.617403 0.986576 0.986928 0.98662 0.986648 0.617347 0.616556 0.615274 0.616367
Cell cycle Cell differentiation apoptosis
Cellular process proteins pathways
Physiological/pathological Process (health/disease)
autoimmunity cancer metabolic neurodegenerative infectious
genomic expression drugs
Published Genome-Wide Associations through 6/2010, 904 published GWA at p<5x10-8 for 165 traits
NHGRI GWA Catalog www.genome.gov/GWAStudies Hindorff LA, Junkins HA, Hall PN, Mehta JP, and Manolio TA. A Catalog of Published Genome-Wide Association Studies.
PPI TF GWAS Gex Drugs
prioritization algorithms
Diseases Genes Drugs
(p<10-7) gene disease
GWAS Fisher meta p-value (right click for Pubmed record)
(p<10-7)
immune neurologic metabolic pulmonary cancer unclassified cardiovascular
1 50
Number of shared genes
Expressed in relevant tissue (TRUE) Expressed in non-relevant tissue (FALSE)
Different Tissue Matching Tissue Good pval (<10-7) 565 764 Low Pval 3943 4676 P-value=0.029 Different Tissue Matching Tissue Good pval (<10-7) 130 228 Low Pval 326 382 P-value=0.003 Autoimmune diseases All diseases
gene disease drug tissue PPI Drug-target
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