SUPPLEMENT This document includes the following Supplemental
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SUPPLEMENT This document includes the following Supplemental Online-only Material: eMethods eFigure 1: Overview of co-expression analysis workflow and associated data sets. eFigure 2: Micrographs of colorimetric in situ hybridization experiments from the Allen Brain Atlas (http://mouse.brain-map.org) illustrating some examples of ataxia genes that were found in gene expression modules associated with Purkinje cells (A) and granule cells (B). eFigure 3: Overview of the ubiquitin-proteasome system (UPS), which is enriched in the cerebellar tan gene co-expression module. eTable 1: Fold change in expression levels - CRBL vs other brain regions. eTable 2: SCA transcripts assigned to gene co-expression modules across 10 brain regions. eTable 3: List of genes in the cerebellar tan module with the respective module membership (MM). eTable 4: List of genes in the cerebellar light-yellow module with the respective module membership (MM). eTable 5: Genes in the tan and the light-yellow modules known to interact with SCA genes according to BIOGRID. eTable 6: Enrichment analysis (GO terms and KEGG pathways) for genes in the tan module. eTable 7: Enrichment analysis (GO terms and KEGG pathways) for genes in the light-yellow module. eReferences 1 eMethods Human brain samples and analysis of Affymetrix Human Exon 1.0 ST array Brain samples were collected by the Medical Research Council (MRC) Sudden Death Brain and Tissue Bank.1 All samples had fully informed consent for retrieval and were authorized for ethically approved scientific investigation (Research Ethics Committee number 10/H0716/3). Total RNA was isolated and processed for analysis using Affymetrix Exon 1.0 ST Arrays (Affymetrix UK Ltd, High Wycombe, UK) as previously described 2 (GSE46706). We expression profiled 788 brain samples sampled from 101 neuropathologically normal individuals (10 distinct brain regions each) as part of the UK Human Brain Expression Consortium (UKBEC). Samples were randomized for all experimental procedures from RNA extraction to array hybridization. Array data was investigated for technical quality using the Expression Console software version 1.1 (Affymetrix UK Ltd, High Wycombe, UK) to assess labelling, hybridization, scanning and background signal quality. All arrays were pre-processed using Robust Multichip Analysis quantile normalization with GC background correction. Normalized expression data were corrected for individual effects (within which are nested post-mortem interval, brain pH, sex, age at death, and cause of death) and experimental batch effects (date of hybridization). We restricted our analysis to probe sets that had gene annotation (based on re-mapping the Affymetrix probe sets onto human genome build 19 (GRCh37) as documented in the NetAffx annotation file HuEx-1_0-st-v2 Probeset Annotations, Release 31), contained at least 3 probes that hybridized uniquely to a genome position and passed the Detection Above Background (DABG) criteria (p < 0.001 in at least 50% of samples in at least 1 brain region). Since gene co-expression analyses are particularly sensitive to the presence of outlier samples, further rigorous quality control procedures were used to ensure the highest possible level of data quality. Outlier detection was performed by visual inspection after unsupervised hierarchical clustering of all samples using Euclidean distance as the measure. We also confirmed that the majority of the identified outliers had low interarray correlation, which is defined as the Pearson correlation coefficient of the expression levels for a given pair of transcripts using all available data (i.e. <3 standard deviations [SDs] of the average interarray correlation). After outlier removal, we repeated the process to check for additional outliers. The resulting expression data has been validated using qRT-PCR and a PCR-independent method, direct RNA quantification with branched DNA (QuantiGene 2.0 Assay), for a range of genes.2-5 In particular we have validated the expression of high, medium and low expressing genes in cerebellum, occipital cortex, putamen and white matter samples from 12 individuals using the QuantiGene platform to show a similar regional pattern of expression across the two platforms.2 Gene expression patterns throughout development and aging were assessed using data from the Human Brain Transcriptome project (http://hbatlas.org).6,7 Data from the Biological General Repository for Interaction Datasets (BioGRID) v3.2.106 (http://thebiogrid.org)8 was used for the analysis of SCA interactors. Weighted gene co-expression network analysis SCA genes/transcripts were assigned to modules (arbitrary color designations) identified through weighted gene co-expression analysis (WGCNA) on whole-transcriptome gene expression. A total of 15,409 transcripts (13,706 genes) passing QC were used to identify modules, as previously described,9 and 3,743 additional transcripts (3,541 genes) were assigned to modules based on their highest module membership. Briefly, the WGCNA network10,11 was constructed for each tissue separately using a signed network with power (Beta) of 12 to achieve a scale-free topology. A dissimilarity 2 matrix based on topological overlap measure (TOM), a pairwise measure of node similarity (i.e. how the neighbors of a gene are to the neighbors of another gene), was used to identify gene modules (i.e. densely interconnected and co-expressed genes) through a dynamic treecutting algorithm. Module preservation statistics12 were calculated to assess how well modules from one tissue are reproducible (or preserved) in another tissue. We calculated a Z summary statistic that aggregates different measures of preservation through permutation test procedures implemented in a WGCNA function. To assess preservation we used the thresholds previously proposed:12 Z summary < 2 implies no evidence for module preservation, 2 < Z summary < 10 implies weak to moderate evidence, and Z summary > 10 implies strong evidence for module preservation. The hypergeometric distribution, as determined by R statistical package, was used to evaluate SCA-transcript enriched modules (P-values < 0.05 were considered significant). Only modules with at least two SCA transcripts were considered. In order to assess the reliability of the gene co-expression networks constructed using the UKBEC data set we have previously investigated gene co-expression networks in the gene expression data set published by Colantuoni and colleagues,13 which used a custom Agilent array to measure gene expression in 175 individuals. Importantly we were able to demonstrate a highly significant overlap in module membership amongst genes contained within a microglia-related module (Fisher’s exact test P-value <7 x 10-142).9 Gene enrichment analysis The database for annotation, visualization and integrated discovery (DAVID) v6.7 (http://david.abcc.ncifcrf.gov/home.jsp)14,15 was used to evaluate the biological and functional relevance of common features among SCA genes and genes within SCA-enriched modules. Only genes with expression data (N=17,247) were used as background for this analysis. Overrepresentation of Gene Ontology (GO) categories (biological processes, cellular components, and molecular functions) and KEGG pathways was examined. Bonferroni corrected P-values below 0.05 were considered significant. The oPOSSUM Version 3.0 (http://opossum.cisreg.ca/oPOSSUM3)16-18 was used for enrichment analysis on conserved transcription factor binding sites (TFBS) in SCA genes, with cutoffs of 10 and 7 for the Z-score and the Fisher score, respectively. The oPOSSUM search was performed using default analysis parameters, including TFBS that are up to 5,000 bp around the transcription start sites for each gene. From all SCA genes (N=24), only the PPP2R2B gene was omitted from the analysis by oPOSSUM. An overview of the co-expression analysis workflow and associated data sets is shown in eFigure 1. 3 eFigure 1: Overview of co-expression analysis workflow and associated data sets. 4 eFigure 2: Micrographs of colorimetric in situ hybridization experiments from the Allen Brain Atlas (http://mouse.brain-map.org)19 illustrating some examples of ataxia genes that were found in gene expression modules associated with Purkinje cells (A) and granule cells (B). Each micrograph shows part of the mouse cerebellum on a sagittal section. p – Purkinje cell layer; g – Granular layer 5 eFigure 3: Overview of the ubiquitin-proteasome system (UPS), which is enriched in the cerebellar tan gene co-expression module. Ubiquitin activating enzymes (E1) transfer ubiquitin (Ub) to ubiquitin conjugating enzymes (E2), which associate with ubiquitin ligases (E3). E3 ligases catalyze the bond between Ub and the target protein. The E4 enzymes then promote the formation of polyubiquitin chains. Polyubiquitinated target proteins are subject to proteasome degradation, and deubiquitinating enzymes (DUB) promote the recycling of ubiquitin monomers for reactivation by E1. Examples of UPS components involved in ataxias are marked with an asterisk, and include ataxin-3 (ATXN3 mutated in SCA3), which functions as a DUB, as well as the proteins encoded by recently identified ataxia genes – STUB1, RNF216 and OTUD4 (two ubiquitin E3 ligases and a DUB, respectively).20-22 Sacsin (SACS mutated in spastic ataxia – ARSACS) is thought to interact with the proteasome through its ubiquitinlike domain.23 Other UPS components are also involved in neurodegenerative diseases, such as parkin (PARK2 mutated in Parkinson’s disease), which is a RING-finger type E3 ligase and is known to ubiquitinate ataxin-2 (ATXN2 mutated in SCA2). Adapted from the KEGG pathways for “Proteasome” and “Ubiquitin mediated proteolysis” as well as from a review by Lehman. 24 6 eTable 1: Fold change in expression levels - CRBL vs other brain regions. Gene Symbol Affymetrix ID FCTX TCTX OCTX HIPP PUTM MEDU THAL WHMT CACNA1A 3852133 4.49 4.22 3.36 6.46 5.81 SNIG 8.21 10.00 6.31 16.06 FGF14 3523499 3.47 3.37 3.06 5.43 3.59 11.06 8.24 5.04 14.14 ITPR1 2608469 1.38 1.49 1.24 3.12 1.71 4.49 10.53 3.75 14.81 TBP 2937984 1.34 1.33 1.20 1.47 1.41 1.37 1.36 1.34 1.24 ATXN7 2627390 1.46 1.37 1.21 1.46 1.19 1.47 1.55 1.43 1.46 KCND3 2428114 1.81 1.64 1.75 2.21 2.82 1.15 4.82 2.08 9.65 ATN1 3403045 1.20 1.23 1.12 1.32 1.39 1.65 1.70 1.36 1.63 KCNC3 3868378 1.62 1.65 1.11 2.15 2.70 4.19 3.12 2.53 4.74 SPTBN2 3378433 1.06 1.14 1.12 1.08 1.56 2.35 2.30 1.72 6.40 NOP56 3873874 1.17 1.14 1.12 1.06 1.32 1.18 1.16 1.25 1.11 KCND3 2428119 1.55 1.49 1.49 1.78 2.34 -1.02 4.05 1.79 7.14 ATXN3 3576889 1.04 1.05 1.06 1.46 1.32 -1.02 1.09 1.34 1.23 ATXN2 3471588 1.18 1.15 1.11 1.21 1.20 1.11 1.11 1.15 -1.03 ATXN8OS 3493047 1.23 1.29 1.24 1.18 1.06 -12.29 -1.33 1.06 1.05 ATXN8OS/KLHL1 3517051 2.04 1.97 2.13 2.10 1.40 -12.36 -1.13 1.85 1.96 AFG3L2 3799415 -1.02 1.01 -1.00 1.21 1.18 1.20 1.18 -1.09 1.55 TTBK2 3620799 -1.27 -1.15 -1.22 1.37 1.34 1.02 1.19 -1.12 1.36 IFRD1 3019519 1.10 1.07 1.08 -1.10 -1.03 -1.07 -1.07 1.11 -1.33 BEAN1 3664764 -1.42 -1.23 -2.44 -1.21 1.50 1.22 1.04 -1.03 1.35 PRKCG 3841102 -1.80 -1.24 1.98 -4.47 -1.74 3.60 5.98 -1.30 5.12 EEF2 3846538 -1.08 -1.04 -1.09 1.02 -1.04 -1.02 1.03 1.07 1.13 BEAN1 3664719 -1.10 -1.07 -1.49 -1.10 1.33 1.20 -1.03 -1.04 1.10 ATXN10 3948754 -1.17 -1.16 -1.06 -1.23 -1.06 -1.06 1.05 -1.06 1.16 ATXN1 2943434 -1.72 -1.64 -1.67 -1.21 -1.70 1.12 1.11 -1.34 -1.09 PPP2R2B 2880051 -4.41 -4.46 -5.27 -3.96 -4.89 -4.09 -4.00 -3.30 -3.76 PDYN 3894906 -1.29 -1.62 -1.54 -6.85 -15.87 1.01 1.00 1.02 -1.11 CRBL – cerebellum, FCTX – frontal cortex, HIPP – hippocampus, MEDU –medulla, OCTX – occipital cortex, PUTM – putamen, SNIG – substantia nigra, TCTX – temporal cortex, THAL – thalamus, and WHMT – white matter. *Pink indicates higher expression in cerebellum when compared to other regions 7 eTable 2: SCA transcripts assigned to gene co-expression modules across 10 brain regions. ID Gene SCA X3471588 ATXN2 SCA2 X3523499 FGF14 SCA27 X3493047 ATXN8OS SCA8 X3664764 BEAN1 SCA31 X3019519 IFRD1 SCA18 X2428114 KCND3 SCA19/22 X3378433 SPTBN2 SCA5 X3852133 CACNA1A SCA6 X3868378 KCNC3 X3403045 ATN1 X3846538 X2428119 X2608469 CRBL (P-value)* FCTX HIPP MEDU OCTX PUTM SNIG TCTX THAL WHMT black royalblue brown yellow midnightblue black greenyellow red tan lightyellow green yellow lightgreen brown magenta green pink blue blue turquoise brown blue turquoise brown turquoise blue yellow black brown brown green turquoise magenta pink yellow blue tan salmon blue white turquoise blue red brown red yellow tan green tan red brown magenta magenta blue pink purple greenyellow cyan purple yellow lightyellow pink blue green greenyellow magenta midnightblue brown green pink blue SCA13 greenyellow (0.129) salmon greenyellow red brown darkolivegreen purple magenta pink magenta blue DRPLA grey60 black paleturquoise lightyellow cyan black black lightcyan black grey60 EEF2 SCA26 lightcyan pink brown lightyellow cyan cyan black lightcyan black red KCND3 SCA19/22 darkgreen red green tan brown cyan magenta pink blue SCA15/16 cyan darkturquoise yellow violet brown brown black yellow blue blue turquoise brown turquoise yellow cyan blue brown turquoise X3841102 ITPR1 ATXN8OS /KLHL1 PRKCG pink salmon turquoise red yellow yellow tan cyan blue X2943434 ATXN1 SCA1 lightgreen orange green violet red red black pink blue X2627390 ATXN7 SCA7 royalblue white purple lightyellow royalblue greenyellow black black pink X2937984 TBP SCA17 darkgreen white black lightyellow midnightblue salmon black magenta tan X3873874 NOP56 SCA36 purple salmon midnightblue turquoise yellow midnightblue brown greenyellow greenyellow green X2880051 PPP2R2B SCA12 red yellow orange yellow white red green black brown blue X3576889 ATXN3 SCA3 magenta lightcyan midnightblue greenyellow brown yellow green greenyellow green X3620799 TTBK2 SCA11 greenyellow pink brown greenyellow brown yellow pink darkgreen blue X3799415 AFG3L2 SCA28 red cyan brown purple brown yellow green darkgreen blue X3948754 ATXN10 SCA10 magenta darkorange greenyellow purple brown brown purple lightgreen blue X3664719 BEAN1 SCA31 turquoise turquoise turquoise green turquoise turquoise turquoise turquoise turquoise X3894906 PDYN SCA23 blue midnightblue turquoise red yellow turquoise tan turquoise turquoise X3517051 SCA8 black (0.374) blue (0.570) darkgrey green (0.246) lightyellow (2.865x10-5)* SCA14 magenta pink (0.373) tan (0.021)* turquoise (0.009) ID – Affymetrix exon probe ID, CRBL – cerebellum, FCTX – frontal cortex, HIPP – hippocampus, MEDU –medulla, OCTX – occipital cortex, PUTM – putamen, SNIG – substantia nigra, TCTX – temporal cortex, THAL – thalamus, and WHMT – white matter. *P-value for the Fisher’s exact test <0.05 with an Odds ratio greater than 1 was considered significant. 8 eTable 3: List of genes in the cerebellar tan module with the respective module membership (MM). Affymetrix ID MM CRBL tan (1-quantiles) X3468009 0.00 ARL1 X3768103 0.00 PSMD12 X3874313 0.00 ATRN X3467637 0.00 UHRF1BP1L X3223646 0.01 PSMD5 X3410695 0.01 DNM1L X3729172 0.01 CLTC X3426215 0.01 MRPL42 X3420713 0.01 CAND1 X4012868 0.01 RLIM X3347234 0.01 AASDHPPT X3178416 0.01 SPIN1 X3692895 0.02 NUDT21 X3348852 0.02 DLAT X3535186 0.02 SAV1 X3284882 0.02 CUL2 X3690193 0.02 ITFG1 X3909395 0.02 DPM1 X4017810 0.02 ACSL4 X3537813 0.02 ACTR10 X3992354 0.03 SLC9A6 X3326540 0.03 PDHX X3947986 0.03 SAMM50 X3697799 0.03 AP1G1 X3142519 0.03 ZFAND1 X3888133 0.03 CSE1L X3371719 0.03 CKAP5 X3401878 0.03 NDUFA9 X3679564 0.04 USP7 X3261165 0.04 BTRC X3146661 0.04 ANKRD46 X3407926 0.04 CMAS X3759356 0.04 EFTUD2 X3139035 0.04 ARFGEF1 X3237088 0.04 STAM X4014251 0.04 CHM X3561952 0.05 SEC23A X3125819 0.05 MTMR7 X3452622 0.05 RPAP3 X3590422 0.05 RTF1 X3506153 0.05 LOC646482 X3580319 0.05 CINP Gene 9 eTable 3: List of genes in the cerebellar tan module with the respective module membership (MM) (Cont). X3721718 0.05 ATP6V0A1 X3214668 0.05 IARS X3669092 0.06 TERF2IP X3147726 0.06 LOC100131102 X3789442 0.06 WDR7 X3255220 0.06 GHITM X3974556 0.06 ATP6AP2 X4002809 0.06 APOO X3778823 0.06 NAPG X3706355 0.06 PAFAH1B1 X3828032 0.07 POP4 X3127878 0.07 ENTPD4 X3603408 0.07 PSMA4 X3386638 0.07 SLC36A4 X3363979 0.07 PSMA1 X3665161 0.07 C16orf70 X3760625 0.07 CDC27 X3560575 0.07 EAPP X3927949 0.08 RNF160 X3235461 0.08 CDC123 X3185063 0.08 UGCG X3136413 0.08 IMPAD1 X3475545 0.08 VPS33A X3578278 0.08 ATG2B X3740171 0.08 CRK X3652271 0.08 C16orf52 X3431553 0.09 C12orf24 X3757487 0.09 DNAJC7 X3419849 0.09 TBK1 X3421630 0.09 CCT2 X3877221 0.09 C20orf7 X3689922 0.09 VPS35 X3282213 0.09 YME1L1 X3132333 0.09 TM2D2 X3454662 0.10 CSRNP2 X3968512 0.10 CLCN4 X3765167 0.10 USP32 X3125775 0.10 CNOT7 X3202171 0.10 PLAA X3197869 0.10 RANBP6 X3513883 0.10 KPNA3 X3285614 0.10 ZNF25 X3419147 0.11 USP15 X3450775 0.11 KIF21A X3778601 0.11 VAPA 10 eTable 3: List of genes in the cerebellar tan module with the respective module membership (MM) (Cont). X3974708 0.11 USP9X X3740304 0.11 PITPNA X3541137 0.11 EIF2S1 X3428131 0.11 SCYL2 X3458614 0.11 DCTN2 X3559570 0.12 HECTD1 X3874900 0.12 CDS2 X3706000 0.12 RPA1 X3780287 0.12 RNMT X3653619 0.12 LCMT1 X3595909 0.12 RNF111 X3163136 0.12 SNAPC3 X3860208 0.12 ALKBH6 X3476130 0.13 SBNO1 X3140763 0.13 UBE2W X3591327 0.13 CCNDBP1 X3631794 0.13 MYO9A X3988874 0.13 UBE2A X3257559 0.13 RPP30 X3708366 0.13 C17orf81 X3629698 0.13 DPP8 X3399623 0.14 THYN1 X3537557 0.14 MUDENG X3757433 0.14 ACLY X3425134 0.14 TMTC3 X3569200 0.14 ATP6V1D X3431483 0.14 ATP2A2 X3229529 0.14 CAMSAP1 X3764471 0.14 MTMR4 X3988740 0.15 PGRMC1 X3322958 0.15 ZDHHC13 X3265432 0.15 FAM160B1 X3351531 0.15 ARCN1 X3872733 0.15 ZNF329 X3722152 0.15 PSME3 X3205108 0.15 GNE X3151401 0.15 DERL1 X3888055 0.16 ARFGEF2 X3600744 0.16 ARIH1 X3771297 0.16 SRP68 X3607183 0.16 MRPS11 X3420079 0.16 LEMD3 X3562003 0.16 TRAPPC6B X4016572 0.16 MORF4L2 X3383322 0.16 NARS2 11 eTable 3: List of genes in the cerebellar tan module with the respective module membership (MM) (Cont). X3269280 0.17 FAM175B X3729569 0.17 BCAS3 X3250204 0.17 SUPV3L1 X3613300 0.17 NIPA2 X3603199 0.17 IDH3A X4012204 0.17 HDAC8 X3719702 0.17 MRPL45 X3361116 0.18 MRPL17 X3747717 0.18 COPS3 X3995371 0.18 NSDHL X3638665 0.18 AP3S2 X3588069 0.18 TMEM85 X3538324 0.18 JKAMP X3951887 0.18 ATP6V1E1 X3599432 0.18 FEM1B X3447863 0.19 KRAS X3293998 0.19 CBARA1 X3441215 0.19 C12orf4 X3662750 0.19 POLR2C X3223872 0.19 RAB14 X3709685 0.19 NDEL1 X3363923 0.19 COPB1 X3203162 0.19 NDUFB6 X3247712 0.20 CISD1 X3662041 0.20 OGFOD1 X3218113 0.20 C9orf125 X3787031 0.20 C18orf25 X3564790 0.20 ERO1L X3743852 0.20 FXR2 X3212143 0.20 UBQLN1 X3896524 0.20 TRMT6 X3484768 0.21 PDS5B X3574207 0.21 SEL1L X3775686 0.21 USP14 X3513293 0.21 SUCLA2 X3636470 0.21 BTBD1 X3257268 0.21 IFIT5 X3537747 0.21 PSMA3 X3897431 0.21 MKKS X3453556 0.22 PRKAG1 X3495076 0.22 NDFIP2 X3726992 0.22 UTP18 X3894637 0.22 NSFL1C X3602723 0.22 RCN2 X3620799 0.22 TTBK2 12 eTable 3: List of genes in the cerebellar tan module with the respective module membership (MM) (Cont). X3620880 0.22 UBR1 X3366554 0.22 SVIP X3779756 0.23 SEH1L X3217807 0.23 TEX10 X3729014 0.23 GDPD1 X3629378 0.23 MTFMT X3905073 0.23 KIAA0406 X3160735 0.23 CDC37L1 X3219547 0.23 IKBKAP X3396916 0.23 SRPR X3145801 0.24 TSPYL5 X3466826 0.24 CDK17 X3842675 0.24 ZNF542 X3470037 0.24 PRDM4 X3895075 0.24 IDH3B X3255402 0.24 FAM190B X3532313 0.24 SRP54 X3482498 0.24 CDK8 X3717539 0.25 RHOT1 X3465791 0.25 UBE2N X3799415 0.25 AFG3L2 X3191695 0.25 EXOSC2 X3553607 0.25 EIF5 X3777886 0.25 RAB12 X3806689 0.25 HDHD2 X3572041 0.25 KIAA0317 X3224259 0.26 RBM18 X3823625 0.26 AP1M1 X3308864 0.26 RAB11FIP2 X3296512 0.26 POLR3A X3699707 0.26 ADAT1 X3726934 0.26 NME1 X3579546 0.26 WARS X3685306 0.26 NDUFAB1 X3531553 0.27 AKAP6 X3660213 0.27 CYLD X3797032 0.27 EPB41L3 X3418303 0.27 PIP4K2C X3308397 0.27 HSPA12A X3981609 0.27 CHIC1 X3972067 0.27 PDK3 X3535842 0.27 GPR137C X3611126 0.28 LYSMD4 X3256689 0.28 PTEN X3430552 0.28 PWP1 13 eTable 3: List of genes in the cerebellar tan module with the respective module membership (MM) (Cont). X3147286 0.28 RRM2B X3264004 0.28 SHOC2 X3589570 0.28 EIF2AK4 X3168415 0.28 CLTA X3309124 0.28 C10orf46 X3925439 0.29 HSPA13 X3349014 0.29 PTS X3920566 0.29 DYRK1A X3531032 0.29 SCFD1 X3245682 0.29 MAPK8 X3458033 0.29 ATP5B X3896078 0.29 SLC23A2 X3804195 0.29 SLC39A6 X3719161 0.30 GGNBP2 X3833093 0.30 TIMM50 X3517594 0.30 C13orf34 X3487220 0.30 AKAP11 X3261492 0.30 NOLC1 X3906942 0.30 SERINC3 X3134034 0.30 PRKDC X3598482 0.30 RAB11A X3390067 0.31 NPAT X3430129 0.31 POLR3B X3265494 0.31 TRUB1 X3833291 0.31 PSMC4 X3142554 0.31 SNX16 X3362342 0.31 TMEM41B X3146012 0.31 NIPAL2 X3471300 0.31 PPTC7 X3556386 0.32 RAB2B X3863060 0.32 EXOSC5 X3534128 0.32 FAM179B X3967689 0.32 STS X3860450 0.32 ZNF566 X3462949 0.32 OSBPL8 X3891643 0.32 C20orf177 X3140833 0.32 TCEB1 X3442282 0.33 MLF2 X3219682 0.33 C9orf5 X3527493 0.33 APEX1 X3301857 0.33 TM9SF3 X3513953 0.33 C13orf1 X3652218 0.33 UQCRC2 X3800070 0.33 C18orf19 X3351359 0.34 ATP5L 14 eTable 3: List of genes in the cerebellar tan module with the respective module membership (MM) (Cont). X3633522 0.34 SNUPN X3401099 0.34 FKBP4 X3718682 0.34 AP2B1 X3970130 0.34 SYAP1 X3214582 0.34 SPTLC1 X3534923 0.34 KLHDC2 X3303392 0.34 BLOC1S2 X3564872 0.35 GNPNAT1 X3489350 0.35 CDADC1 X3724698 0.35 NPEPPS X3294499 0.35 PPP3CB X3809324 0.35 TXNL1 X3153328 0.35 FAM49B X3415937 0.35 C12orf10 X3823613 0.35 FAM32A X3299255 0.36 ATAD1 X3224366 0.36 RC3H2 X3574074 0.36 GTF2A1 X3416522 0.36 COPZ1 X3659931 0.36 PAPD5 X3351775 0.36 TRAPPC4 X3978819 0.36 RRAGB X3273484 0.36 LARP4B X3423184 0.37 ZDHHC17 X3351315 0.37 UBE4A X3418872 0.37 SLC16A7 X3668898 0.37 ZFP1 X3656527 0.37 PHKG2 X3451264 0.37 YAF2 X3638048 0.37 MRPL46 X3649245 0.37 BFAR X3294438 0.38 ANXA7 X3563372 0.38 C14orf104 X3363645 0.38 BTBD10 X3497790 0.38 IPO5 X4003954 0.38 MAP3K7IP3 X3556924 0.38 PRMT5 X3928040 0.38 RWDD2B X3237548 0.38 ARL5B X3542063 0.39 SLC39A9 X3725481 0.39 UBE2Z X3462693 0.39 KRR1 X3948754 0.39 ATXN10 X3986585 0.39 MID2 X3591909 0.39 CTDSPL2 15 eTable 3: List of genes in the cerebellar tan module with the respective module membership (MM) (Cont). X3438027 0.39 RAN X3576889 0.39 ATXN3 X3890154 0.40 CSTF1 X3971329 0.40 MBTPS2 X3498502 0.40 TM9SF2 X3757423 0.40 KLHL11 X3903481 0.40 PIGU X3755649 0.40 FBXL20 X3847112 0.40 PTPRS X3592484 0.40 PLDN X3628650 0.41 HERC1 X3695268 0.41 NAE1 X3674840 0.41 POLR3K X3422703 0.41 ATXN7L3B X3466284 0.41 NDUFA12 X3368748 0.41 FBXO3 X3354174 0.41 TBRG1 X3929705 0.41 DNAJC28 X3591400 0.42 TUBGCP4 X3583577 0.42 TUBGCP5 X3307795 0.42 C10orf118 X3774029 0.42 NPLOC4 X3886639 0.42 YWHAB X3235414 0.42 SEC61A2 X3433843 0.42 SUDS3 X3254337 0.42 C10orf57 X3653042 0.43 DCTN5 X3904189 0.43 NFS1 X3561321 0.43 MBIP X3204404 0.43 VCP X3527418 0.43 PARP2 X3623424 0.43 COPS2 X3603675 0.43 ANKRD34C X3687789 0.43 DCTPP1 X3310725 0.44 C10orf88 X3552847 0.44 DYNC1H1 X3717737 0.44 PSMD11 X3180957 0.44 CDC14B X3417371 0.44 ESYT1 X3352904 0.44 SC5DL X3649492 0.44 PDXDC1 X3693533 0.44 CSNK2A2 X3325680 0.45 EIF3M X3814734 0.45 TXNL4A X3713093 0.45 ALKBH5 16 eTable 3: List of genes in the cerebellar tan module with the respective module membership (MM) (Cont). X3636522 0.45 HDGFRP3 X3730439 0.45 TANC2 X3322717 0.45 GTF2H1 X3537604 0.45 NAA30 X3387171 0.45 CWC15 X3500772 0.46 ABHD13 X3677612 0.46 ZNF597 X3327906 0.46 API5 X3449910 0.46 AMN1 X3225398 0.46 HSPA5 X3381607 0.46 RAB6A X3299408 0.46 RNLS X3452231 0.46 SLC38A1 X3894322 0.47 SRXN1 X3945877 0.47 SMCR7L X3807370 0.47 DYM X3489667 0.47 KCNRG X3537264 0.47 C14orf101 X3290368 0.47 IPMK X3550328 0.47 C14orf129 X3570454 0.47 COX16 X3405531 0.48 DDX47 X3184896 0.48 ZNF483 X3751830 0.48 BLMH X3883971 0.48 C20orf24 X3942954 0.48 DRG1 X3850576 0.48 YIPF2 X3755655 0.48 FBXL20 X3647632 0.48 C16orf72 X3705641 0.49 TIMM22 X3184408 0.49 AKAP2 X3274758 0.49 AKR1C2 X3752611 0.49 C17orf75 X3796244 0.49 METTL4 X3593652 0.49 USP8 X3302572 0.49 CRTAC1 X3484005 0.49 USPL1 X3328389 0.50 EXT2 X3204243 0.50 SIGMAR1 X3304406 0.50 ACTR1A X3283378 0.50 MTPAP X3960782 0.50 JOSD1 X3956854 0.50 THOC5 X3365437 0.50 TSG101 X3408018 0.51 ETNK1 17 eTable 3: List of genes in the cerebellar tan module with the respective module membership (MM) (Cont). X3878025 0.51 DSTN X3414885 0.51 SLC4A8 X3758157 0.51 BECN1 X3234140 0.51 ATP5C1 X3594031 0.51 TMOD2 X3405396 0.51 CREBL2 X3970833 0.51 PDHA1 X3764384 0.52 SUPT4H1 X3734760 0.52 MRPS7 X3956290 0.52 PITPNB X3994999 0.52 VMA21 X3850832 0.52 TMEM205 X3994451 0.52 CXorf40A X3376235 0.52 WDR74 X3391234 0.52 TIMM8B X3770663 0.53 GGA3 X3754736 0.53 DDX52 X3668617 0.53 PSMD7 X3252170 0.53 ADK X3529156 0.53 NGDN X3354764 0.53 STT3A X3277662 0.53 UPF2 X3804358 0.53 C18orf10 X3972063 0.54 PDK3 X3229726 0.54 C9orf69 X3600621 0.54 SENP8 X3225348 0.54 PPP6C X3890913 0.54 VAPB X3577078 0.54 LGMN X3715535 0.54 TMEM199 X3490504 0.54 ALG11 X3422231 0.55 TMEM19 X3430389 0.55 C12orf23 X3223605 0.55 FBXW2 X3147591 0.55 AZIN1 X3470831 0.55 MMAB X3687308 0.55 KCTD13 X3809671 0.55 NARS X3376867 0.55 TRMT112 X3490655 0.56 CKAP2 X3738969 0.56 FOXK2 X3262509 0.56 GSTO1 X3432225 0.56 ERP29 X3267382 0.56 INPP5F X3851055 0.56 ELOF1 18 eTable 3: List of genes in the cerebellar tan module with the respective module membership (MM) (Cont). X3816380 0.56 OAZ1 X3624273 0.56 LYSMD2 X3402697 0.57 COPS7A X3374698 0.57 OSBP X3225003 0.57 PSMB7 X3279410 0.57 FAM188A X3617312 0.57 SLC12A6 X3407824 0.57 GOLT1B X3350749 0.57 PAFAH1B2 X3540007 0.57 MTHFD1 X3268669 0.58 BUB3 X3615556 0.58 NDNL2 X3573029 0.58 TMED8 X3505319 0.58 SACS X3687803 0.58 SEPHS2 X3443296 0.58 M6PR X3138811 0.58 VCPIP1 X3715489 0.58 TMEM97 X3961842 0.59 RANGAP1 X3945180 0.59 PICK1 X3978999 0.59 UBQLN2 X3743167 0.59 MED31 X3221646 0.59 POLE3 X3226493 0.59 TRUB2 X3985490 0.59 BEX4 X3388914 0.59 DCUN1D5 X3622436 0.60 SLC30A4 X3544029 0.60 LIN52 X3666773 0.60 CYB5B X3188993 0.60 ARPC5L X3334224 0.60 STIP1 X3375245 0.60 DDB1 X3468103 0.60 GNPTAB X3150283 0.60 SAMD12 X3294242 0.61 ECD X3580791 0.61 BAG5 X3728889 0.61 MIR21 X3480681 0.61 MRP63 X3247757 0.61 UBE2D1 X3318712 0.61 FXC1 X3141857 0.61 TPD52 X3430894 0.61 USP30 X3522225 0.62 STK24 X3707199 0.62 PSMB6 X3185558 0.62 PRPF4 19 eTable 3: List of genes in the cerebellar tan module with the respective module membership (MM) (Cont). X3669059 0.62 GABARAPL2 X3501661 0.62 ARHGEF7 X3562086 0.62 FBXO33 X3183238 0.62 FSD1L X3682135 0.62 C16orf63 X3602873 0.63 HMG20A X3617230 0.63 C15orf24 X3970214 0.63 REPS2 X3476265 0.63 EIF2B1 X3274173 0.63 PITRM1 X3549220 0.63 UBR7 X3226431 0.63 GOLGA2 X3227098 0.63 TOR1A X4013018 0.64 ZDHHC15 X3483348 0.64 POMP X3389566 0.64 KBTBD3 X3942805 0.64 RNF185 X3915087 0.64 USP25 X3887017 0.64 DNTTIP1 X3764002 0.64 MRPS23 X3506431 0.64 RNF6 X3662265 0.65 NUP93 X4021469 0.65 AIFM1 X3224587 0.65 STRBP X4002741 0.65 ACOT9 X3517569 0.65 C13orf37 X3838019 0.65 NUCB1 X3329904 0.65 NDUFS3 X3414512 0.65 LARP4 X3775906 0.66 ADCYAP1 X3941010 0.66 SRRD X4021508 0.66 ZNF280C X3510925 0.66 MRPS31 X3721886 0.66 MLX X3348608 0.66 SIK2 X3725456 0.66 ATP5G1 X3360941 0.66 ARFIP2 X3591044 0.67 HAUS2 X3348189 0.67 FDX1 X3598381 0.67 PTPLAD1 X3874751 0.67 PRNP X3876645 0.67 BTBD3 X3784670 0.67 C18orf21 X3646199 0.67 HMOX2 X3293244 0.68 SAR1A 20 eTable 3: List of genes in the cerebellar tan module with the respective module membership (MM) (Cont). X3681705 0.68 RRN3 X3848689 0.68 ELAVL1 X3129948 0.68 TMEM66 X3383164 0.68 ALG8 X3874947 0.68 LOC149832 X3696571 0.68 TERF2 X3146433 0.68 COX6C X3545466 0.69 AHSA1 X3258092 0.69 X3258092 X3535000 0.69 ARF6 X3666686 0.69 NIP7 X3985866 0.69 FAM199X X3902609 0.69 PDRG1 X3458587 0.69 DDIT3 X3893760 0.69 TPD52L2 X3887094 0.70 ZSWIM3 X3927105 0.70 MRPL39 X3907473 0.70 ACOT8 X3671873 0.70 USP10 X3563814 0.70 L2HGDH X3148796 0.70 NUDCD1 X3638242 0.70 LOC100129942 X3567984 0.70 PPP2R5E X3614901 0.71 HERC2 X3978760 0.71 MAGEH1 X3169094 0.71 DCAF10 X3781082 0.71 SNRPD1 X3168671 0.71 LOC401504 X3347615 0.71 ACAT1 X3843180 0.71 ZNF304 X3913712 0.71 YTHDF1 X3571634 0.72 FAM161B X3634852 0.72 RASGRF1 X3124180 0.72 PINX1 X3208995 0.72 KLF9 X3183219 0.72 FSD1L X3976797 0.72 SUV39H1 X3839142 0.72 ZNF473 X3372368 0.72 MTCH2 X4019900 0.73 CUL4B X3541383 0.73 ARG2 X3903708 0.73 TRPC4AP X3347831 0.73 DDX10 X3982103 0.73 UPRT X4002845 0.73 KLHL15 21 eTable 3: List of genes in the cerebellar tan module with the respective module membership (MM) (Cont). X3849752 0.73 ZNF426 X3476330 0.73 CCDC92 X3417574 0.74 SPRYD4 X3996721 0.74 FUNDC2 X3218067 0.74 MRPL50 X3325839 0.74 TCP11L1 X3528115 0.74 TOX4 X3529799 0.74 GMPR2 X3345415 0.74 SFRS2B X4025771 0.74 CD99L2 X3813604 0.75 ZADH2 X3421523 0.75 YEATS4 X3902860 0.75 COMMD7 X3903889 0.75 UQCC X3931329 0.75 DSCR3 X3770743 0.75 GRB2 X3340269 0.75 POLD3 X3139722 0.75 NCOA2 X3409432 0.76 CCDC91 X3185522 0.76 SLC31A1 X3562721 0.76 FKBP3 X3250093 0.76 KIAA1279 X2385121 0.76 LOC644006 X3750939 0.76 SDF2 X3303109 0.76 COX15 X3840759 0.76 ZNF525 X3624362 0.77 LEO1 X3569401 0.77 RDH11 X3890555 0.77 RAE1 X3260985 0.77 SFXN3 X3124537 0.77 CTSB X3435853 0.77 TMED2 X3678395 0.77 GLYR1 X3440017 0.77 FBXL14 X3697015 0.78 AARS X3704717 0.78 ANKRD11 X3844704 0.78 RNF126 X3233431 0.78 FBXO18 X3683783 0.78 THUMPD1 X3304718 0.78 PCGF6 X3168136 0.78 MSMP X3457201 0.78 DNAJC14 X3581249 0.79 AHNAK2 X3569374 0.79 ARG2 X3536663 0.79 MAPK1IP1L 22 eTable 3: List of genes in the cerebellar tan module with the respective module membership (MM) (Cont). X3445123 0.79 HEBP1 X3335517 0.79 KAT5 X3453214 0.79 LOC144438 X3379708 0.79 MRPL21 X3667281 0.79 SF3B3 X3680583 0.80 RSL1D1 X3567469 0.80 TRMT5 X3475511 0.80 DIABLO X3471704 0.80 BRAP X4023274 0.80 MMGT1 X3927226 0.80 APP X3306299 0.80 XPNPEP1 X3524999 0.80 LIG4 X3683037 0.81 ARL6IP1 X3445670 0.81 WBP11 X3734609 0.81 KCTD2 X3603727 0.81 KIAA1024 X3839276 0.81 NR1H2 X3303339 0.81 CWF19L1 X3511189 0.81 MTRF1 X3383209 0.81 KCTD21 X3183757 0.82 RAD23B X3962023 0.82 PPPDE2 X3486807 0.82 WBP4 X3762355 0.82 LRRC59 X3236538 0.82 RPP38 X4016396 0.82 TCEAL8 X3835490 0.82 ZNF234 X3956589 0.82 XBP1 X3203311 0.83 APTX X3308967 0.83 C10orf84 X3781734 0.83 C18orf8 X3829768 0.83 UBA2 X3962260 0.83 NDUFA6 X3773312 0.83 EIF4A3 X3371544 0.83 AMBRA1 X3153428 0.84 ASAP1 X3377826 0.84 RNASEH2C X3723348 0.84 HEXIM1 X3286393 0.84 ZNF32 X3490741 0.84 SUGT1 X3301556 0.84 TCTN3 X3921391 0.84 WRB X3383138 0.84 NDUFC2 X3870104 0.85 ZNF415 23 eTable 3: List of genes in the cerebellar tan module with the respective module membership (MM) (Cont). X3292792 0.85 TMEM14D X3488022 0.85 KIAA1704 X3535674 0.85 C14orf166 X3226709 0.85 C9orf114 X3303255 0.85 ERLIN1 X3962734 0.85 TTLL1 X3573261 0.85 SNW1 X3863323 0.86 RABAC1 X3985886 0.86 FAM199X X3631517 0.86 THAP10 X3392996 0.86 QSK X3675205 0.86 C16orf13 X3633550 0.86 IMP3 X3345774 0.86 JRKL X3638660 0.86 AP3S2 X3878533 0.87 DTD1 X3694657 0.87 CDH11 X3345413 0.87 SFRS2B X3912861 0.87 PSMA7 X3318009 0.87 RRM1 X3599709 0.87 GLCE X3155937 0.87 TRAPPC9 X3473727 0.87 WSB2 X3566302 0.88 EXOC5 X3275132 0.88 C10orf18 X3745504 0.88 SCO1 X3845909 0.88 LMNB2 X3473480 0.88 FBXO21 X3773239 0.88 TBC1D16 X3418436 0.88 OS9 X2494447 0.88 CIAO1 X3962587 0.89 ARFGAP3 X3248661 0.89 ZNF365 X3409006 0.89 MED21 X3329018 0.89 SLC35C1 X3676165 0.89 HAGH X3347118 0.89 GRIA4 X3426301 0.89 CRADD X3538789 0.89 SLC38A6 X3854066 0.90 C19orf42 X3996667 0.90 DKC1 X3693083 0.90 FAM192A X3649890 0.90 ABCC1 X3616216 0.90 LOC283713 X3256560 0.90 MINPP1 24 eTable 3: List of genes in the cerebellar tan module with the respective module membership (MM) (Cont). X3549205 0.90 C14orf109 X3345407 0.90 SFRS2B X3310413 0.91 ATE1 X3651955 0.91 METTL9 X3166844 0.91 CHMP5 X3759305 0.91 CCDC43 X3352070 0.91 CBL X3761959 0.91 SLC35B1 X3369762 0.91 COMMD9 X3577256 0.91 C14orf142 X3304355 0.92 CUEDC2 X3435946 0.92 GTF2H3 X3712949 0.92 DRG2 X3907650 0.92 LOC100288047 X3975987 0.92 RBM10 X3856184 0.92 ZNF626 X3184218 0.92 C9orf6 X3722554 0.92 DHX8 X3702689 0.93 ZDHHC7 X3157660 0.93 TSTA3 X3227121 0.93 C9orf78 X3755839 0.93 C17orf37 X3796970 0.93 LOC339290 X3168938 0.93 POLR1E X3989678 0.93 XIAP X3821301 0.93 ZNF627 X3829313 0.94 CEBPG X3334484 0.94 ESRRA X3861832 0.94 FBXO27 X3597421 0.94 LACTB X3795501 0.94 ADNP2 X3686750 0.94 RABEP2 X3933399 0.94 ZNF295 X3687698 0.94 CD2BP2 X4054125 0.95 WDR47 X3354731 0.95 EI24 X3902489 0.95 BCL2L1 X3371928 0.95 ARFGAP2 X4016485 0.95 RAB40A X3845998 0.95 SLC39A3 X2436132 0.95 ILF2 X3740998 0.95 SRR X3186191 0.96 ATP6V1G1 X3869858 0.96 ZNF468 X3719150 0.96 PIGW 25 eTable 3: List of genes in the cerebellar tan module with the respective module membership (MM) (Cont). X3395416 0.96 HSPA8 X3408573 0.96 LYRM5 X3343546 0.96 TMEM135 X3346371 0.96 KIAA1377 X3961955 0.96 PHF5A X3824103 0.97 USE1 X3989089 0.97 ZBTB33 X3923312 0.97 RRP1 X3672455 0.97 COX4I1 X3418492 0.97 TSPAN31 X3273251 0.97 DIP2C X3835339 0.97 ZNF230 X3702497 0.97 KIAA1609 X3884324 0.98 CTNNBL1 X3651588 0.98 LYRM1 X3434374 0.98 GATC X3551677 0.98 YY1 X3995975 0.98 SSR4 X3294348 0.98 MRPS16 X4007216 0.98 UXT X3848408 0.98 PEX11G X2393816 0.99 C1orf174 X3913525 0.99 DIDO1 X3544387 0.99 EIF2B2 X3985534 0.99 NGFRAP1 X3226789 0.99 DOLK X3591365 0.99 ADAL X3732885 0.99 PRKAR1A X3372337 0.99 KBTBD4 X3180212 1.00 ZNF169 X3393944 1.00 DDX6 X3843321 1.00 ZNF773 26 eTable 4: List of genes in the cerebellar light-yellow module with the respective module membership (MM). Affymetrix ID MM CRBL light-yellow (1-quantiles) X3137120 0.00 CA8 X2348514 0.01 LPPR4 X3777470 0.02 PTPRM X3853036 0.02 SLC1A6 X3799542 0.03 CEP76 X2608469 0.04 ITPR1 X3675447 0.05 GNG13 X2447192 0.05 RGS8 X2995811 0.06 C7orf16 X3986087 0.07 NRK X3741800 0.08 ATP2A3 X2478064 0.08 ARHGEF33 X3755510 0.09 PLXDC1 X3333116 0.10 DAGLA X2327310 0.11 SMPDL3B X3757555 0.11 ZNF385C X3057955 0.12 FGL2 X3958658 0.13 LARGE X2875685 0.14 FSTL4 X2675315 0.14 CACNA2D2 X3429857 0.15 C12orf75 X3750767 0.16 ALDOC X3841102 0.17 PRKCG X3272205 0.17 INPP5A X2682913 0.18 CNTN3 X3296046 0.19 KCNMA1 X2646125 0.20 CHST2 X3037413 0.20 GRID2IP X3517051 0.21 ATXN8OS X2965653 0.22 GPR63 X3757538 0.23 ZNF385C X2602770 0.23 DNER X2429556 0.24 CASQ2 X3535628 0.25 GNG2 X3088486 0.26 LPL X2783596 0.27 PDE5A X2478050 0.27 ARHGEF33 X3710406 0.28 SHISA6 X2593159 0.29 STK17B X3590460 0.30 ITPKA X3384704 0.30 DLG2 X2478039 0.31 ARHGEF33 Gene 27 eTable 4: List of genes in the cerebellar light-yellow module with the respective module membership (MM) (Cont.). X3726618 0.32 CACNA1G X2716467 0.33 D4S234E X2831436 0.33 PSD2 X3391629 0.34 LOC100288346 X3144033 0.35 CALB1 X3384714 0.36 DLG2 X2478044 0.36 ARHGEF33 X2648991 0.37 KCNAB1 X2976041 0.38 IL20RA X3336074 0.39 RAB1B X3757557 0.39 ZNF385C X3265565 0.40 ATRNL1 X2478048 0.41 ARHGEF33 X3845844 0.42 LINGO3 X3338293 0.42 ANO1 X2784177 0.43 TRPC3 X3921599 0.44 PCP4 X3634656 0.45 CHRNA3 X2850071 0.45 MYO10 X3710505 0.46 SHISA6 X3922664 0.47 SLC37A1 X2826295 0.48 SNX2 X3917938 0.48 HUNK X3395464 0.49 ASAM X3928211 0.50 GRIK1 X3325968 0.51 C11orf41 X2411482 0.52 LOC284542 X2906824 0.52 FOXP4 X3416651 0.53 PDE1B X3757553 0.54 ZNF385C X3326062 0.55 C11orf41 X4002394 0.55 SMPX X3845848 0.56 LINGO3 X3334372 0.57 PLCB3 X3190514 0.58 GLE1 X3384718 0.58 DLG2 X3270270 0.59 PTPRE X2453881 0.60 IRF6 X3378072 0.61 GAL3ST3 X2924851 0.61 RSPO3 X3414351 0.62 ACCN2 X2468622 0.63 ID2 X3487095 0.64 DGKH X2457261 0.64 DUSP10 X3326067 0.65 C11orf41 28 eTable 4: List of genes in the cerebellar light-yellow module with the respective module membership (MM) (Cont.). X2583602 0.66 RBMS1 X3627422 0.67 RORA X2842194 0.67 CPLX2 X3246888 0.68 PRKG1 X3094157 0.69 ZNF703 X2400177 0.70 CAMK2N1 X3572461 0.70 C14orf1 X3168990 0.71 FRMPD1 X2603531 0.72 C2orf52 X3031880 0.73 AGAP3 X3994710 0.73 MAMLD1 X2842247 0.74 CPLX2 X3326060 0.75 C11orf41 X3018011 0.76 CDHR3 X3627418 0.77 RORA X3627420 0.77 RORA X2403707 0.78 EPB41 X3845899 0.79 TIMM13 X3091301 0.80 PTK2B X4000132 0.80 TRAPPC2 X3132782 0.81 SFRP1 X2334350 0.82 MMACHC X2428119 0.83 KCND3 X3033116 0.83 LOC202781 X2398894 0.84 RCC2 X3888383 0.85 SLC9A8 X2641032 0.86 SEC61A1 X2842253 0.86 CPLX2 X2899171 0.87 HIST1H1E X2324039 0.88 CAMK2N1 X3405297 0.89 LOH12CR1 X2453871 0.89 C1orf74 X3107724 0.90 C8orf38 X3957679 0.91 SELM X3708961 0.92 WRAP53 X3267273 0.92 LOC100131848 X2842255 0.93 CPLX2 X3078493 0.94 ZNF425 X2374126 0.95 NR5A2 X3743883 0.95 SAT2 X3870162 0.96 ZNF665 X3673921 0.97 LOC642533 X3442176 0.98 ING4 X3935232 0.98 C21orf56 X3345340 0.99 KDM4D 29 eTable 5: Genes in the tan and the light-yellow modules known to interact with SCA genes according to BIOGRID. SCA/gene Interactor gene Interactor gene name SCA PSME3 proteasome (prosome, macropain) activator subunit 3 (PA28 gamma; Ki) - RBM10 RNA binding motif protein 10 - TERF2 telomeric repeat binding factor 2 - C17orf81 elongator acetyltransferase complex subunit 5 - CRK v-crk sarcoma virus CT10 oncogene homolog (avian) - ESRRA estrogen-related receptor alpha - NARS asparaginyl-tRNA synthetase - NUDT21 nudix (nucleoside diphosphate linked moiety X)-type motif 21 - OAZ1 ornithine decarboxylase antizyme 1 - SAR1A SAR1 homolog A (S. cerevisiae) - TOX4 TOX high mobility group box family member 4 - USP7 ubiquitin specific peptidase 7 (herpes virus-associated) - CAND1 cullin-associated and neddylation-dissociated 1 - IDH3B isocitrate dehydrogenase 3 (NAD+) beta - KIAA1279 KIAA1279 - TSG101 tumor susceptibility gene 101 - APP amyloid beta (A4) precursor protein - ATXN3 ataxin 3 SCA3 BCL2L1 BCL2-like 1 - PICK1 protein interacting with PRKCA 1 - RAD23B RAD23 homolog B (S. cerevisiae) - UBE2N ubiquitin-conjugating enzyme E2N - UBQLN1 ubiquilin 1 - VCP valosin containing protein - ACTR1A ARP1 actin-related protein 1 homolog A, centractin alpha (yeast) - CKAP5 cytoskeleton associated protein 5 - UQCRC2 ubiquinol-cytochrome c reductase core protein II - GOLGA2 golgin A2 - PICK1 protein interacting with PRKCA 1 - PSMD7 proteasome (prosome, macropain) 26S subunit, non-ATPase, 7 - UBQLN2 ubiquilin 2 - MRPS16 mitochondrial ribosomal protein S16 - PTEN phosphatase and tensin homolog - CCT2 chaperonin containing TCP1, subunit 2 (beta) - KLHL15 kelch-like family member 15 - MYO9A myosin IXA - ZNF295 zinc finger and BTB domain containing 21 - ANXA7 annexin A7 - APP amyloid beta (A4) precursor protein - SCA-tan module interaction DRPLA/ATN1 SCA1/ATXN1 SCA2/ATXN2 SCA3/ATXN3 SCA5/SPTBN2 SCA6/CACNA1A SCA7/ATXN7 SCA10/ATXN10 SCA11/TTBK2 SCA12/PPP2R2B SCA14/PRKCG 30 eTable 5: Genes in the tan and the light-yellow modules known to interact with SCA genes according to BIOGRID (Cont.). SCA15/16/ITPR1 EXOC5 exocyst complex component 5 - GRIA4 glutamate receptor, ionotropic, AMPA 4 - PICK1 protein interacting with PRKCA 1 - ERLIN1 ER lipid raft associated 1 - VCP - GTF2A1 valosin containing protein ELAV (embryonic lethal, abnormal vision, Drosophila)-like 1 (Hu antigen R) general transcription factor IIA, 1, 19/37kDa RRN3 RRN3 RNA polymerase I transcription factor homolog (S. cerevisiae) - DDB1 damage-specific DNA binding protein 1, 127kDa - HSPA5 heat shock 70kDa protein 5 (glucose-regulated protein, 78kDa) - RCN2 reticulocalbin 2, EF-hand calcium binding domain - UQCRC2 ubiquinol-cytochrome c reductase core protein II - APP amyloid beta (A4) precursor protein - CAND1 cullin-associated and neddylation-dissociated 1 - CUL4B cullin 4B - PHKG2 phosphorylase kinase, gamma 2 (testis) - RRM1 ribonucleotide reductase M1 - APP amyloid beta (A4) precursor protein - BECN1 beclin 1, autophagy related - CAND1 cullin-associated and neddylation-dissociated 1 - CSNK2A2 casein kinase 2, alpha prime polypeptide - ILF2 interleukin enhancer binding factor 2 - NOLC1 nucleolar and coiled-body phosphoprotein 1 - PWP1 PWP1 homolog (S. cerevisiae) - RSL1D1 ribosomal L1 domain containing 1 - SCYL2 SCY1-like 2 (S. cerevisiae) - TRMT112 tRNA methyltransferase 11-2 homolog (S. cerevisiae) - UBQLN1 ubiquilin 1 - ELAVL1 SCA17/TBP SCA19/22/KCND3 SCA23/PDYN SCA26/EEF2 SCA28/AFG3L2 SCA36/NOP56 - SCA-light-yellow module interaction SCA1/ATXN1 C11orf41 KIAA1549-like - SCA3/ATXN3 ACCN2 acid-sensing (proton-gated) ion channel 1 - SCA6/CACNA1A KLHL1 kelch-like family member 1 - SCA14/PRKCG PRKCG protein kinase C, gamma SCA14 CA8 carbonic anhydrase VIII - PRKG1 protein kinase, cGMP-dependent, type I - TRPC3 transient receptor potential cation channel, subfamily C, member 3 - GRK5 G protein-coupled receptor kinase 5 - SCA15/16/ITPR1 SCA26/EEF2 31 eTable 6: Enrichment analysis (GO terms and KEGG pathways) for genes in the tan module. Category Term Count % P-Value GOTERM _BP_FAT GO:0019941~mo dificationdependent protein catabolic process 77 10 1.57E-17 GOTERM _BP_FAT GO:0043632~mo dificationdependent macromolecule catabolic process 77 10 1.57E-17 GOTERM _BP_FAT GO:0030163~prot ein catabolic process 80 11 3.98E-17 Genes USPL1, TSG101, BTRC, SENP8, RLIM, OS9, CUL2, BTBD1, FBXO27, USP10, FBXL14, PSMD5, FBXO21, USP15, PSMD7, USP14, VCPIP1, UBE2A, FBXL20, DDB1, ERLIN1, UBR1, HERC2, HERC1, UBE2N, PSMA1, UBR7, KLHL15, PSMA4, FBXO18, UBE2W, PSME3, CAND1, USP25, USP7, CUEDC2, RAD23B, USP30, DERL1, UBE2Z, USP8, XIAP, USP9X, PSMA7, FEM1B, RAB40A, CYLD, ARIH1, PSMB7, PSMB6, OTUD7A, FBXW2, FBXO3, UBE2D1, USP32, BUB3, HECTD1, NPLOC4, UBE4A, CBL, SUGT1, CDC27, MARCH5, NAE1, ATE1, RNF6, VCP, PSMD12, KIAA0317, PSMC4, PSMD11, UBA2, WSB2, FBXO33, CUL4B, TCEB1, RNF111 USPL1, TSG101, BTRC, SENP8, RLIM, OS9, CUL2, BTBD1, FBXO27, USP10, FBXL14, PSMD5, FBXO21, USP15, PSMD7, USP14, VCPIP1, UBE2A, FBXL20, DDB1, ERLIN1, UBR1, HERC2, HERC1, UBE2N, PSMA1, UBR7, KLHL15, PSMA4, FBXO18, UBE2W, PSME3, CAND1, USP25, USP7, CUEDC2, RAD23B, USP30, DERL1, UBE2Z, USP8, XIAP, USP9X, PSMA7, FEM1B, RAB40A, CYLD, ARIH1, PSMB7, PSMB6, OTUD7A, FBXW2, FBXO3, UBE2D1, USP32, BUB3, HECTD1, NPLOC4, UBE4A, CBL, SUGT1, CDC27, MARCH5, NAE1, ATE1, RNF6, VCP, PSMD12, KIAA0317, PSMC4, PSMD11, UBA2, WSB2, FBXO33, CUL4B, TCEB1, RNF111 USPL1, TSG101, BTRC, USE1, SENP8, RLIM, OS9, CUL2, BTBD1, FBXO27, USP10, FBXL14, PSMD5, FBXO21, USP15, PSMD7, USP14, VCPIP1, UBE2A, FBXL20, DDB1, ERLIN1, UBR1, HERC2, HERC1, UBE2N, PSMA1, UBR7, KLHL15, PSMA4, FBXO18, UBE2W, PSME3, YME1L1, CAND1, USP25, USP7, CUEDC2, RAD23B, USP30, DERL1, UBE2Z, USP8, XIAP, USP9X, PSMA7, FEM1B, RAB40A, CYLD, ARIH1, PSMB7, PSMB6, OTUD7A, FBXW2, FBXO3, UBE2D1, USP32, BUB3, HECTD1, NPLOC4, UBE4A, CBL, SUGT1, AFG3L2, CDC27, MARCH5, NAE1, ATE1, RNF6, VCP, PSMD12, KIAA0317, PSMC4, PSMD11, UBA2, WSB2, FBXO33, CUL4B, TCEB1, RNF111 List Total Pop Hits Pop Total Fold Enrichment Bonferroni 567 514 11001 2.9 3.15E-14 567 514 11001 2.9 3.15E-14 567 557 11001 2.8 7.97E-14 32 eTable 6: Enrichment analysis (GO terms and KEGG pathways) for genes in the tan module (Cont.). GOTERM _BP_FAT GO:0051603~prot eolysis involved in cellular protein catabolic process 77 10 3.00E-16 GOTERM _BP_FAT GO:0044257~cell ular protein catabolic process 77 10 3.70E-16 GOTERM _BP_FAT GOTERM _BP_FAT GO:0044265~cell ular macromolecule catabolic process GO:0006511~ubi quitin-dependent 84 11 6.07E-15 44 6 7.69E-15 USPL1, TSG101, BTRC, SENP8, RLIM, OS9, CUL2, BTBD1, FBXO27, USP10, FBXL14, PSMD5, FBXO21, USP15, PSMD7, USP14, VCPIP1, UBE2A, FBXL20, DDB1, ERLIN1, UBR1, HERC2, HERC1, UBE2N, PSMA1, UBR7, KLHL15, PSMA4, FBXO18, UBE2W, PSME3, CAND1, USP25, USP7, CUEDC2, RAD23B, USP30, DERL1, UBE2Z, USP8, XIAP, USP9X, PSMA7, FEM1B, RAB40A, CYLD, ARIH1, PSMB7, PSMB6, OTUD7A, FBXW2, FBXO3, UBE2D1, USP32, BUB3, HECTD1, NPLOC4, UBE4A, CBL, SUGT1, CDC27, MARCH5, NAE1, ATE1, RNF6, VCP, PSMD12, KIAA0317, PSMC4, PSMD11, UBA2, WSB2, FBXO33, CUL4B, TCEB1, RNF111 USPL1, TSG101, BTRC, SENP8, RLIM, OS9, CUL2, BTBD1, FBXO27, USP10, FBXL14, PSMD5, FBXO21, USP15, PSMD7, USP14, VCPIP1, UBE2A, FBXL20, DDB1, ERLIN1, UBR1, HERC2, HERC1, UBE2N, PSMA1, UBR7, KLHL15, PSMA4, FBXO18, UBE2W, PSME3, CAND1, USP25, USP7, CUEDC2, RAD23B, USP30, DERL1, UBE2Z, USP8, XIAP, USP9X, PSMA7, FEM1B, RAB40A, CYLD, ARIH1, PSMB7, PSMB6, OTUD7A, FBXW2, FBXO3, UBE2D1, USP32, BUB3, HECTD1, NPLOC4, UBE4A, CBL, SUGT1, CDC27, MARCH5, NAE1, ATE1, RNF6, VCP, PSMD12, KIAA0317, PSMC4, PSMD11, UBA2, WSB2, FBXO33, CUL4B, TCEB1, RNF111 USPL1, TSG101, BTRC, SENP8, RLIM, OS9, CUL2, BTBD1, FBXO27, USP10, FBXL14, PSMD5, FBXO21, USP15, PSMD7, USP14, VCPIP1, UBE2A, AIFM1, FBXL20, DFFB, DDB1, GTF2H3, ERLIN1, UBR1, HERC2, HERC1, GTF2H1, UBE2N, PSMA1, EIF4A3, UBR7, KLHL15, PSMA4, FBXO18, UBE2W, PSME3, CAND1, USP25, USP7, CUEDC2, RAD23B, USP30, DERL1, UBE2Z, USP8, XIAP, USP9X, PSMA7, FEM1B, RAB40A, RPA1, CYLD, ARIH1, PSMB7, PSMB6, OTUD7A, FBXW2, FBXO3, UBE2D1, USP32, BUB3, HECTD1, UPF2, NPLOC4, UBE4A, CBL, SUGT1, CDC27, MARCH5, ATE1, NAE1, RNF6, VCP, PSMD12, KIAA0317, PSMC4, PSMD11, UBA2, WSB2, FBXO33, CUL4B, TCEB1, RNF111 USP7, RAD23B, USP30, USPL1, USP8, DERL1, TSG101, USP9X, BTRC, PSMA7, OS9, ARIH1, CYLD, CUL2, PSMB7, 567 537 11001 2.8 6.67E-13 567 540 11001 2.8 6.67E-13 567 653 11001 2.5 1.22E-11 567 215 11001 4.0 1.53E-11 33 eTable 6: Enrichment analysis (GO terms and KEGG pathways) for genes in the tan module (Cont.). protein catabolic process GOTERM _BP_FAT GOTERM _BP_FAT GOTERM _BP_FAT GOTERM _BP_FAT GO:0009057~ma cromolecule catabolic process GO:0006508~prot eolysis GO:0043161~prot easomal ubiquitindependent protein catabolic process GO:0010498~prot easomal protein catabolic process 87 11 1.24E-14 89 12 9.12E-10 20 3 1.97E-07 20 3 1.97E-07 PSMB6, USP10, PSMD5, UBE2D1, FBXO21, PSMD7, USP15, USP32, USP14, BUB3, UBE2A, NPLOC4, UBE4A, DDB1, ERLIN1, UBR1, CDC27, ATE1, PSMA1, RNF6, PSMD12, VCP, PSMC4, PSMD11, PSMA4, PSME3, TCEB1, CUL4B, USP25 USPL1, TSG101, BTRC, USE1, SENP8, RLIM, OS9, CUL2, BTBD1, FBXO27, USP10, FBXL14, PSMD5, FBXO21, USP15, PSMD7, USP14, VCPIP1, UBE2A, AIFM1, FBXL20, DFFB, DDB1, GTF2H3, ERLIN1, UBR1, HERC2, HERC1, GTF2H1, UBE2N, PSMA1, EIF4A3, UBR7, KLHL15, PSMA4, FBXO18, UBE2W, PSME3, YME1L1, CAND1, USP25, USP7, CUEDC2, RAD23B, USP30, DERL1, UBE2Z, USP8, XIAP, USP9X, PSMA7, FEM1B, RAB40A, RPA1, CYLD, ARIH1, PSMB7, PSMB6, OTUD7A, FBXW2, FBXO3, UBE2D1, USP32, BUB3, HECTD1, UPF2, NPLOC4, UBE4A, CBL, SUGT1, AFG3L2, CDC27, MARCH5, ATE1, NAE1, RNF6, VCP, PSMD12, KIAA0317, PSMC4, PSMD11, UBA2, WSB2, FBXO33, CUL4B, TCEB1, RNF111 USPL1, ATP6AP2, TSG101, BTRC, LGMN, SENP8, RLIM, CRADD, OS9, CUL2, BTBD1, FBXO27, DPP8, USP10, FBXL14, PSMD5, FBXO21, USP15, PSMD7, USP14, VCPIP1, UBE2A, FBXL20, DDB1, ERLIN1, UBR1, HERC2, NPEPPS, HERC1, UBE2N, PSMA1, BLMH, UBR7, KLHL15, PSMA4, FBXO18, UBE2W, PSME3, YME1L1, CAND1, CTSB, USP25, USP7, CUEDC2, RAD23B, USP30, DERL1, UBE2Z, USP8, XIAP, USP9X, PSMA7, FEM1B, RAB40A, CYLD, ARIH1, PSMB7, PSMB6, PITRM1, OTUD7A, FBXW2, FBXO3, UBE2D1, USP32, BUB3, HECTD1, NPLOC4, WDR7, UBE4A, CBL, SUGT1, AFG3L2, CDC27, MARCH5, XPNPEP1, ATE1, NAE1, RNF6, VCP, PSMC4, PSMD12, KIAA0317, PSMD11, UBA2, WSB2, FBXO33, CUL4B, TCEB1, RNF111 RAD23B, NPLOC4, DERL1, ERLIN1, PSMA7, CDC27, OS9, PSMA1, PSMB7, PSMB6, PSMD12, PSMC4, VCP, PSMD11, PSMA4, PSME3, PSMD5, UBE2D1, PSMD7, BUB3 RAD23B, NPLOC4, DERL1, ERLIN1, PSMA7, CDC27, OS9, PSMA1, PSMB7, PSMB6, PSMD12, PSMC4, VCP, PSMD11, PSMA4, PSME3, PSMD5, UBE2D1, PSMD7, 567 699 11001 2.4 2.49E-11 567 887 11001 1.9 1.83E-06 567 93 11001 4.2 3.94E-04 567 93 11001 4.2 3.94E-04 34 eTable 6: Enrichment analysis (GO terms and KEGG pathways) for genes in the tan module (Cont.). BUB3 GOTERM _BP_FAT GO:0051438~reg ulation of ubiquitin-protein ligase activity 17 2 2.94E-07 GOTERM _BP_FAT GO:0045184~est ablishment of protein localization 69 9 4.33E-07 62 8 5.25E-07 17 2 5.47E-07 68 9 6.36E-07 GOTERM _BP_FAT GOTERM _BP_FAT GO:0046907~intr acellular transport GO:0051340~reg ulation of ligase activity GOTERM _BP_FAT GO:0015031~prot ein transport BTRC, FEM1B, PSMA7, CDC27, UBE2N, PSMA1, PSMB7, PSMB6, PSMC4, PSMD12, PSMD11, PSMA4, PSME3, PSMD5, UBE2D1, PSMD7, BUB3 CLTA, TSG101, AP1G1, USE1, AP3S2, TIMM50, CLTC, VPS33A, AP2B1, SEH1L, DNAJC14, SRPR, FXC1, RANBP6, STAM, RAB6A, SAR1A, SEC23A, RAN, GOLT1B, SNUPN, ERP29, PICK1, VTI1B, HERC2, TIMM8B, TIMM22, ZDHHC15, ZDHHC17, RAB11FIP2, IPO5, ARCN1, RAB14, AKAP6, RAB12, KPNA3, MRPL45, ARL6IP1, ARFGAP2, PLDN, AP1M1, DERL1, SNX16, COPZ1, NUP93, CCDC91, ARF6, RAB40A, TMED2, GNPTAB, CSE1L, SNX21, PPP3CB, CHM, RAB11A, VPS35, EXOC5, SEC61A2, GABARAPL2, RAB2B, SRP54, GDI2, YWHAB, SCFD1, RABEP2, VCP, TRPC4AP, SSR4, GGA3 CLTA, AP1G1, USE1, AP3S2, CLTC, AP2B1, APP, SRPR, RAE1, FXC1, MKKS, STAM, SAR1A, SEC23A, ARL1, RAN, SNUPN, PICK1, ERP29, VTI1B, HERC2, M6PR, TIMM8B, UXT, NDEL1, TBRG1, IPO5, ARCN1, RAB14, TRAPPC4, AKAP6, THOC5, KPNA3, MRPL45, ARL6IP1, PLDN, AP1M1, DERL1, COPZ1, DSCR3, BCL2L1, CSE1L, PPP3CB, CHM, RAB11A, VPS35, PAFAH1B1, EXOC5, SEC61A2, GABARAPL2, UPF2, SRP54, YWHAB, SCFD1, KIAA1279, VCP, ATP2A2, MLX, RHOT1, TRPC4AP, SSR4, GGA3 BTRC, FEM1B, PSMA7, CDC27, UBE2N, PSMA1, PSMB7, PSMB6, PSMC4, PSMD12, PSMD11, PSMA4, PSME3, PSMD5, UBE2D1, PSMD7, BUB3 CLTA, TSG101, AP1G1, USE1, AP3S2, TIMM50, CLTC, VPS33A, AP2B1, SEH1L, DNAJC14, SRPR, FXC1, RANBP6, STAM, RAB6A, SAR1A, SEC23A, RAN, GOLT1B, SNUPN, ERP29, PICK1, VTI1B, HERC2, TIMM8B, TIMM22, ZDHHC17, RAB11FIP2, IPO5, ARCN1, RAB14, AKAP6, RAB12, KPNA3, MRPL45, ARL6IP1, ARFGAP2, PLDN, AP1M1, DERL1, SNX16, COPZ1, NUP93, CCDC91, ARF6, RAB40A, TMED2, GNPTAB, CSE1L, SNX21, PPP3CB, CHM, RAB11A, VPS35, EXOC5, SEC61A2, GABARAPL2, 567 69 11001 4.8 5.88E-04 567 713 11001 1.9 8.67E-04 567 617 11001 1.9 1.05E-03 567 72 11001 4.6 1.09E-03 567 706 11001 1.9 1.27E-03 35 eTable 6: Enrichment analysis (GO terms and KEGG pathways) for genes in the tan module (Cont.). RAB2B, SRP54, GDI2, YWHAB, SCFD1, RABEP2, VCP, TRPC4AP, SSR4, GGA3 GOTERM _BP_FAT GOTERM _BP_FAT GOTERM _BP_FAT GOTERM _BP_FAT GOTERM _BP_FAT GOTERM _BP_FAT GOTERM _BP_FAT GOTERM _BP_FAT GO:0051439~reg ulation of ubiquitin-protein ligase activity during mitotic cell cycle GO:0051443~pos itive regulation of ubiquitin-protein ligase activity GO:0031396~reg ulation of protein ubiquitination GO:0031145~ana phase-promoting complexdependent proteasomal ubiquitindependent protein catabolic process GO:0051436~neg ative regulation of ubiquitin-protein ligase activity during mitotic cell cycle GO:0051351~pos itive regulation of ligase activity GO:0051444~neg ative regulation of ubiquitin-protein ligase activity GO:0051352~neg ative regulation of ligase activity 15 2 2.28E-06 BTRC, PSMA7, CDC27, PSMA1, PSMB7, PSMB6, PSMC4, PSMD12, PSMD11, PSMA4, PSME3, PSMD5, UBE2D1, PSMD7, BUB3 15 2 2.28E-06 18 2 3.20E-06 BTRC, PSMA7, CDC27, UBE2N, PSMA1, PSMB7, PSMB6, PSMC4, PSMD12, PSMD11, PSMA4, PSME3, PSMD5, UBE2D1, PSMD7 BTRC, NDFIP2, FEM1B, PSMA7, CDC27, UBE2N, PSMA1, PSMB7, PSMB6, PSMC4, PSMD12, PSMD11, PSMA4, PSME3, PSMD5, UBE2D1, PSMD7, BUB3 3.78E-06 PSMA7, CDC27, PSMA1, PSMB7, PSMB6, PSMC4, PSMD12, PSMD11, PSMA4, PSME3, PSMD5, UBE2D1, PSMD7, BUB3 14 2 14 2 3.78E-06 15 2 4.15E-06 14 2 5.74E-06 14 2 5.74E-06 PSMA7, CDC27, PSMA1, PSMB7, PSMB6, PSMC4, PSMD12, PSMD11, PSMA4, PSME3, PSMD5, UBE2D1, PSMD7, BUB3 BTRC, PSMA7, CDC27, UBE2N, PSMA1, PSMB7, PSMB6, PSMC4, PSMD12, PSMD11, PSMA4, PSME3, PSMD5, UBE2D1, PSMD7 PSMA7, CDC27, PSMA1, PSMB7, PSMB6, PSMC4, PSMD12, PSMD11, PSMA4, PSME3, PSMD5, UBE2D1, PSMD7, BUB3 PSMA7, CDC27, PSMA1, PSMB7, PSMB6, PSMC4, PSMD12, PSMD11, PSMA4, PSME3, PSMD5, UBE2D1, PSMD7, BUB3 567 62 11001 4.7 4.56E-03 567 62 11001 4.7 4.56E-03 567 91 11001 3.8 6.39E-03 567 56 11001 4.9 7.54E-03 567 56 11001 4.9 7.54E-03 567 65 11001 4.5 8.28E-03 567 58 11001 4.7 1.14E-02 567 58 11001 4.7 1.14E-02 36 eTable 6: Enrichment analysis (GO terms and KEGG pathways) for genes in the tan module (Cont.). GOTERM _BP_FAT GOTERM _BP_FAT GOTERM _BP_FAT GOTERM _BP_FAT GO:0031398~pos itive regulation of protein ubiquitination GO:0008104~prot ein localization GO:0051437~pos itive regulation of ubiquitin-protein ligase activity during mitotic cell cycle GOTERM _BP_FAT GO:0000278~mit otic cell cycle GO:0031397~neg ative regulation of protein ubiquitination GOTERM _CC_FAT GO:0070013~intr acellular organelle lumen 16 2 5.97E-06 72 9 6.73E-06 14 2 8.54E-06 37 5 1.35E-05 14 2 2.14E-05 128 17 2.44E-08 BTRC, NDFIP2, PSMA7, CDC27, UBE2N, PSMA1, PSMB7, PSMB6, PSMC4, PSMD12, PSMD11, PSMA4, PSME3, PSMD5, UBE2D1, PSMD7 CLTA, TSG101, AP1G1, USE1, AP3S2, TIMM50, TERF2IP, CLTC, VPS33A, OS9, AP2B1, SEH1L, DNAJC14, SRPR, FXC1, RANBP6, STAM, RAB6A, SAR1A, SEC23A, RAN, GOLT1B, SNUPN, ERP29, PICK1, VTI1B, HERC2, TIMM8B, TIMM22, ZDHHC15, ZDHHC17, RAB11FIP2, IPO5, ARCN1, RAB14, AKAP6, RAB12, KPNA3, MRPL45, ARL6IP1, ARFGAP2, PLDN, AP1M1, DERL1, SNX16, COPZ1, NUP93, CCDC91, ARF6, RAB40A, TMED2, GNPTAB, CSE1L, SNX21, PPP3CB, CHM, RAB11A, VPS35, EXOC5, TERF2, SEC61A2, GABARAPL2, RAB2B, SRP54, GDI2, YWHAB, SCFD1, RABEP2, VCP, TRPC4AP, SSR4, GGA3 BTRC, PSMA7, CDC27, PSMA1, PSMB7, PSMB6, PSMC4, PSMD12, PSMD11, PSMA4, PSME3, PSMD5, UBE2D1, PSMD7 PPP6C, BTRC, USP9X, HAUS2, PSMA7, CUL2, APP, PSMB7, PSMB6, SEH1L, CDC123, NPAT, PPP3CB, PAFAH1B1, PSMD5, UBE2D1, DYNC1H1, PSMD7, BUB3, PINX1, VCPIP1, YEATS4, PDS5B, CKAP5, RAN, PAPD5, SUGT1, CDC27, DCTN2, PSMA1, NOLC1, PSMD12, PSMC4, PSMD11, PSMA4, PSME3, TXNL4A PSMA7, CDC27, PSMA1, PSMB7, PSMB6, PSMC4, PSMD12, PSMD11, PSMA4, PSME3, PSMD5, UBE2D1, PSMD7, BUB3 RPP38, MRPL42, RNMT, SRP68, MORF4L2, NDUFAB1, SNRPD1, CCT2, MBIP, CNOT7, MED21, CTNNBL1, WDR74, IMP3, PGRMC1, LRRC59, RPP30, MRPL39, PDHA1, IKBKAP, KRR1, RRP1, STK24, RAN, DFFB, YY1, ERP29, HMG20A, TOX4, RSL1D1, ATP5C1, MAPK8, SUDS3, RAD23B, MRPS16, FDX1, LMNB2, MRPS11, DTD1, DDX47, ZNF597, LEO1, SUPV3L1, UBE2D1, YEATS4, SRP54, TSR1, IDH3B, SNW1, DLAT, KAT5, 567 76 11001 4.1 1.19E-02 567 816 11001 1.7 1.34E-02 567 60 11001 4.5 1.70E-02 567 328 11001 2.2 2.67E-02 567 65 11001 4.2 4.20E-02 508 1618 10237 1.6 1.06E-05 37 eTable 6: Enrichment analysis (GO terms and KEGG pathways) for genes in the tan module (Cont.). GOTERM _CC_FAT GO:0005739~mit ochondrion 87 11 4.30E-08 GOTERM _CC_FAT GO:0043233~org anelle lumen 129 17 4.70E-08 CDC27, IDH3A, POLD3, RNF6, VCP, NOLC1, DYRK1A, POP4, HDAC8, PARP2, WRB, DDX52, MRP63, COPS2, ZBTB33, CDC14B, TSG101, UTP18, ATP5B, TIMM50, TERF2IP, RLIM, WBP4, OS9, RRN3, GTF2A1, NARS2, RTF1, MINPP1, POLR1E, AIFM1, NIP7, DDB1, EXOSC5, CDK8, EXOSC2, GTF2H3, APTX, PRPF4, GTF2H1, HAGH, EIF4A3, IPO5, UBE2Z, FKBP4, NFS1, PRKDC, WBP11, POLR2C, RPA1, NUDT21, PITRM1, TOR1A, NPAT, SUPT4H1, HSPA5, FAM32A, PDHX, APEX1, BUB3, TERF2, PINX1, POLR3K, NDUFA9, CEBPG, PDK3, YWHAB, POLR3A, MED31, DIS3, ATXN3, ILF2, TRPC4AP, PHF5A, TCEB1, TEX10, RCN2 MRPL42, SLC9A6, ATP5B, NDUFAB1, TIMM50, CLTC, PTEN, MRPS31, CDS2, ACOT9, MTHFD1, CISD1, NARS2, FXC1, LRRC59, PDHA1, MRPL39, NDUFS3, SUCLA2, COX16, COX15, FUNDC2, MRPL50, AIFM1, PICK1, CYB5B, HERC2, MRPS7, NDUFA12, TIMM8B, TIMM22, COX6C, HAGH, RALGAPA1, MTRF1, ATP5C1, YME1L1, CTSB, MRPL45, MTFMT, MRPL46, USP30, MRPS16, SAMM50, FDX1, MRPS11, SFXN3, NFS1, BCL2L1, ATP5G1, DTD1, MTCH2, C12ORF10, ARG2, MRPL17, PITRM1, PPP3CB, DIABLO, SUPV3L1, ACSL4, PTS, LACTB, PDHX, ATP5L2, SCO1, DNM1L, MRPS23, NDUFA9, NDUFA6, PDK3, IDH3B, NDFIP2, C20ORF7, DLAT, AFG3L2, MARCH5, MMAB, IDH3A, MRPL21, KIAA1279, PSMC4, L2HGDH, ATP6V1E1, HEBP1, RHOT1, SMCR7L, MRP63 RPP38, MRPL42, RNMT, SRP68, MORF4L2, NDUFAB1, SNRPD1, CCT2, MBIP, CNOT7, MED21, CTNNBL1, WDR74, IMP3, APP, PGRMC1, LRRC59, RPP30, MRPL39, PDHA1, IKBKAP, KRR1, RRP1, STK24, RAN, DFFB, YY1, ERP29, HMG20A, TOX4, RSL1D1, ATP5C1, MAPK8, SUDS3, RAD23B, MRPS16, FDX1, LMNB2, MRPS11, DTD1, DDX47, ZNF597, LEO1, SUPV3L1, UBE2D1, YEATS4, SRP54, TSR1, IDH3B, SNW1, DLAT, KAT5, CDC27, IDH3A, POLD3, RNF6, VCP, NOLC1, DYRK1A, POP4, HDAC8, PARP2, WRB, DDX52, MRP63, COPS2, ZBTB33, CDC14B, TSG101, UTP18, ATP5B, TIMM50, TERF2IP, RLIM, WBP4, OS9, RRN3, GTF2A1, NARS2, 508 970 10237 1.8 1.87E-05 508 1653 10237 1.6 2.05E-05 38 eTable 6: Enrichment analysis (GO terms and KEGG pathways) for genes in the tan module (Cont.). GOTERM _CC_FAT GO:0031974~me mbrane-enclosed lumen 131 17 4.74E-08 GOTERM _CC_FAT GO:0031090~org anelle membrane 87 11 1.18E-07 RTF1, MINPP1, POLR1E, AIFM1, NIP7, DDB1, EXOSC5, CDK8, EXOSC2, GTF2H3, APTX, PRPF4, GTF2H1, HAGH, EIF4A3, IPO5, UBE2Z, FKBP4, NFS1, PRKDC, WBP11, POLR2C, RPA1, NUDT21, PITRM1, TOR1A, NPAT, SUPT4H1, HSPA5, FAM32A, PDHX, APEX1, BUB3, TERF2, PINX1, POLR3K, NDUFA9, CEBPG, PDK3, YWHAB, POLR3A, MED31, DIS3, ATXN3, ILF2, TRPC4AP, PHF5A, TCEB1, TEX10, RCN2 RPP38, MRPL42, RNMT, SRP68, MORF4L2, NDUFAB1, SNRPD1, CCT2, MBIP, CNOT7, MED21, CTNNBL1, WDR74, IMP3, APP, PGRMC1, LRRC59, RPP30, MRPL39, PDHA1, IKBKAP, KRR1, RRP1, STK24, RAN, DFFB, YY1, ERP29, HMG20A, TOX4, TIMM8B, RSL1D1, ATP5C1, MAPK8, SUDS3, RAD23B, MRPS16, FDX1, LMNB2, MRPS11, DTD1, DDX47, LEO1, ZNF597, SUPV3L1, UBE2D1, YEATS4, SRP54, TSR1, IDH3B, SNW1, DLAT, KAT5, CDC27, IDH3A, POLD3, RNF6, VCP, NOLC1, DYRK1A, POP4, HDAC8, PARP2, WRB, DDX52, MRP63, COPS2, ZBTB33, CDC14B, TSG101, UTP18, ATP5B, TIMM50, TERF2IP, RLIM, WBP4, OS9, RRN3, GTF2A1, FXC1, NARS2, RTF1, MINPP1, POLR1E, AIFM1, NIP7, DDB1, EXOSC5, CDK8, EXOSC2, GTF2H3, APTX, PRPF4, GTF2H1, HAGH, EIF4A3, IPO5, UBE2Z, FKBP4, NFS1, PRKDC, WBP11, POLR2C, RPA1, NUDT21, PITRM1, TOR1A, NPAT, SUPT4H1, HSPA5, FAM32A, PDHX, APEX1, BUB3, TERF2, PINX1, POLR3K, NDUFA9, CEBPG, PDK3, YWHAB, POLR3A, MED31, DIS3, ATXN3, ILF2, TRPC4AP, PHF5A, TCEB1, TEX10, RCN2 CLTA, SLC9A6, VAPA, VAPB, AP1G1, ATP5B, NDUFAB1, LEMD3, TIMM50, ALG8, CLTC, PEX11G, VPS33A, OS9, CDS2, AP2B1, CISD1, SRPR, RAE1, FXC1, VMA21, NDUFS3, COX16, COX15, SEC23A, STS, SPTLC1, PIGW, PICK1, PIGU, VTI1B, ERLIN1, CYB5B, HERC2, SIGMAR1, ATP6V1D, NDUFA12, TIMM8B, TIMM22, COX6C, SCYL2, ARCN1, ATP5C1, AKAP6, MRPL45, EXT2, ARL6IP1, USP30, AP1M1, DERL1, SAMM50, LMNB2, GRB2, COPZ1, BCL2L1, ATP5G1, ATP6V1G1, ARFGEF2, STT3A, TMED2, MTCH2, MRPL17, TOR1A, PAFAH1B1, ENTPD4, ERO1L, HSPA5, ACSL4, SEC61A2, ATP5L2, NSDHL, SCO1, 508 1687 10237 1.6 2.06E-05 508 992 10237 1.8 5.13E-05 39 eTable 6: Enrichment analysis (GO terms and KEGG pathways) for genes in the tan module (Cont.). GOTERM _CC_FAT GO:0000502~prot easome complex 15 2 2.98E-07 GOTERM _CC_FAT GO:0044429~mit ochondrial part 54 7 6.89E-07 GOTERM _CC_FAT GO:0031967~org anelle envelope 54 7 2.80E-06 GOTERM _CC_FAT GO:0031975~env elope 54 7 3.06E-06 GOTERM _CC_FAT GO:0012505~end omembrane system 63 8 9.57E-06 GABARAPL2, RAB2B, DNM1L, NDUFA9, NDUFA6, C20ORF7, GRIA4, AFG3L2, MARCH5, DOLK, ATP2A2, L2HGDH, RHOT1, DPM1, SSR4 RAD23B, UBR1, PSMA7, UBQLN1, PSMA1, PSMB7, PSMB6, PSMC4, PSMD12, PSMD11, PSMA4, POMP, PSME3, PSMD5, PSMD7 MRPL42, ATP5B, NDUFAB1, TIMM50, CDS2, CISD1, FXC1, NARS2, LRRC59, MRPL39, PDHA1, NDUFS3, COX16, COX15, AIFM1, HERC2, CYB5B, TIMM8B, NDUFA12, COX6C, TIMM22, HAGH, ATP5C1, MRPL45, USP30, MRPS16, SAMM50, FDX1, MRPS11, NFS1, BCL2L1, ATP5G1, DTD1, MTCH2, MRPL17, PITRM1, SUPV3L1, ACSL4, PDHX, SCO1, ATP5L2, DNM1L, NDUFA9, PDK3, NDUFA6, IDH3B, C20ORF7, DLAT, AFG3L2, MARCH5, IDH3A, L2HGDH, RHOT1, MRP63 ATP5B, NDUFAB1, LEMD3, TIMM50, RANGAP1, CDS2, CISD1, RAE1, SEH1L, FXC1, NDUFS3, COX16, COX15, STS, AIFM1, RAN, SNUPN, HERC2, CYB5B, SIGMAR1, TIMM8B, NDUFA12, TIMM22, COX6C, NDEL1, IPO5, ATP5C1, AKAP6, MRPL45, KPNA3, USP30, SAMM50, LMNB2, NUP93, ATP5G1, BCL2L1, ANXA7, CSE1L, MTCH2, MRPL17, TOR1A, PAFAH1B1, ACSL4, MTMR6, SCO1, ATP5L2, DNM1L, NDUFA9, NDUFA6, C20ORF7, AFG3L2, MARCH5, L2HGDH, RHOT1 ATP5B, NDUFAB1, LEMD3, TIMM50, RANGAP1, CDS2, CISD1, RAE1, SEH1L, FXC1, NDUFS3, COX16, COX15, STS, AIFM1, RAN, SNUPN, HERC2, CYB5B, SIGMAR1, TIMM8B, NDUFA12, TIMM22, COX6C, NDEL1, IPO5, ATP5C1, AKAP6, MRPL45, KPNA3, USP30, SAMM50, LMNB2, NUP93, ATP5G1, BCL2L1, ANXA7, CSE1L, MTCH2, MRPL17, TOR1A, PAFAH1B1, ACSL4, MTMR6, SCO1, ATP5L2, DNM1L, NDUFA9, NDUFA6, C20ORF7, AFG3L2, MARCH5, L2HGDH, RHOT1 CLTA, SLC9A6, VAPA, AP1G1, VAPB, LEMD3, RANGAP1, ALG8, CLTC, OS9, AP2B1, APP, SEH1L, SRPR, RAE1, VMA21, RC3H2, SEC23A, STS, SPTLC1, RAN, SNUPN, PIGW, PICK1, PIGU, ERLIN1, SIGMAR1, NDEL1, IPO5, ARCN1, RAB14, AKAP6, KPNA3, EXT2, ARL6IP1, AP1M1, DERL1, LMNB2, GRB2, COPZ1, NUP93, DSCR3, 508 55 10237 5.5 1.30E-04 508 531 10237 2.0 3.00E-04 508 556 10237 2.0 1.22E-03 508 558 10237 2.0 1.33E-03 508 717 10237 1.8 4.16E-03 40 eTable 6: Enrichment analysis (GO terms and KEGG pathways) for genes in the tan module (Cont.). GOTERM _CC_FAT GO:0030529~ribo nucleoprotein complex 45 6 1.29E-05 GOTERM _CC_FAT GO:0005794~Gol gi apparatus 67 9 3.11E-05 GOTERM _CC_FAT GOTERM _CC_FAT GO:0031981~nuc lear lumen GO:0042175~nuc lear envelope- 97 13 4.34E-05 29 4 5.36E-05 ARFGEF2, ANXA7, STT3A, TMED2, CSE1L, TOR1A, PAFAH1B1, ERO1L, ENTPD4, HSPA5, MTMR6, NSDHL, SEC61A2, GABARAPL2, RAB2B, NPLOC4, GRIA4, DOLK, ATP2A2, DPM1, SSR4 RPP38, MRPL42, MRPS16, UTP18, SRP68, MRPS11, CWC15, SNRPD1, MRPS31, WBP4, SF3B3, CYLD, IMP3, BTBD1, MRPL17, RPP30, MRPL39, APEX1, API5, DHX8, KRR1, SRP54, MRPL50, RRP1, MRPS23, EFTUD2, SNW1, MRPS7, FXR2, LARP4B, PRPF4, DDX6, RSL1D1, EIF4A3, PSMA1, MRPL21, ILF2, EIF2S1, POP4, PHF5A, MRPL45, MRPL46, EIF2AK4, TXNL4A, MRP63 CLTA, OSBP, AP1G1, VAPB, GNPNAT1, PITPNB, AP3S2, CLTC, RABAC1, APP, TRAPPC6B, VMA21, RAB6A, DYNC1H1, SIK2, SAR1A, GOLGA2, VCPIP1, SEC23A, ARL1, STS, GOLT1B, PICK1, VTI1B, HERC1, TOX4, GLCE, NUCB1, EAPP, ZDHHC17, TRAPPC9, SCYL2, ARCN1, RAB14, TRAPPC4, RAB12, PRNP, EXT2, ARFGAP2, AP1M1, MMGT1, GRB2, COPZ1, CCDC91, STIP1, ARF6, ARFGEF2, RRAGB, SERINC3, B3GNT9, TMED2, GNPTAB, RAB11A, ENTPD4, TERF2, GABARAPL2, RAB2B, GDI2, DNM1L, BECN1, NSFL1C, NDFIP2, SLC35C1, SCFD1, DYM, SVIP, GGA3 RPP38, RNMT, MORF4L2, SRP68, SNRPD1, CCT2, MBIP, MED21, CNOT7, CTNNBL1, WDR74, IMP3, PGRMC1, RPP30, IKBKAP, KRR1, RRP1, RAN, STK24, YY1, DFFB, HMG20A, TOX4, RSL1D1, MAPK8, SUDS3, RAD23B, LMNB2, DDX47, ZNF597, LEO1, UBE2D1, YEATS4, SRP54, TSR1, SNW1, KAT5, CDC27, POLD3, RNF6, NOLC1, VCP, DYRK1A, POP4, PARP2, HDAC8, DDX52, WRB, COPS2, ZBTB33, UTP18, TSG101, CDC14B, TIMM50, TERF2IP, RLIM, WBP4, GTF2A1, RRN3, RTF1, POLR1E, NIP7, DDB1, EXOSC5, CDK8, EXOSC2, APTX, GTF2H3, PRPF4, GTF2H1, EIF4A3, IPO5, UBE2Z, FKBP4, PRKDC, WBP11, POLR2C, RPA1, NUDT21, NPAT, SUPT4H1, FAM32A, APEX1, BUB3, TERF2, PINX1, POLR3K, CEBPG, YWHAB, POLR3A, DIS3, MED31, ATXN3, ILF2, TCEB1, PHF5A, TEX10 ARL6IP1, SLC9A6, DERL1, VAPA, VAPB, ALG8, OS9, STT3A, RAE1, SRPR, VMA21, HSPA5, ERO1L, NSDHL, 508 453 10237 2.0 5.60E-03 508 808 10237 1.7 1.35E-02 508 1316 10237 1.5 1.87E-02 508 253 10237 2.3 2.31E-02 41 eTable 6: Enrichment analysis (GO terms and KEGG pathways) for genes in the tan module (Cont.). endoplasmic reticulum network KEGG PATHW. KEGG PATHW. hsa03050:Proteas ome hsa04120:Ubiquiti n mediated proteolysis 11 1 1.23E-05 17 2 2.93E-04 SEC61A2, RAB2B, NPLOC4, STS, SPTLC1, PIGW, PIGU, ERLIN1, SIGMAR1, DOLK, ATP2A2, DPM1, RAB14, SSR4, EXT2 PSMA1, PSMB7, PSMB6, PSMD12, PSMC4, PSMD11, PSMA4, POMP, PSME3, PSMA7, PSMD7 UBE2A, UBE2Z, UBE4A, XIAP, DDB1, BTRC, CBL, HERC2, HERC1, CDC27, UBE2N, CUL2, UBA2, UBE2W, TCEB1, CUL4B, UBE2D1 203 39 4097 5.7 1.54E-03 203 123 4097 2.8 3.60E-02 42 eTable 7: Enrichment analysis (GO terms and KEGG pathways) for genes in the light-yellow module. Category GOTERM _CC_FAT GOTERM _MF_FAT KEGG_ PATHW. KEGG_ PATHW. Term GO:0043005~neuro n projection GO:0022836~gated channel activity hsa04020:Calcium signaling pathway hsa04730:Longterm depression Count % PValue 11 10 1.18E-04 10 9 1.62E-04 7 6 8.34E-04 5 5 0.001 Genes KCNMA1, KCND3, GRIK1, PTK2B, DNER, ALDOC, CACNA1G, PRKCG, CAMK2N1, CHRNA3, KLHL1 KCNMA1, ACCN2, KCND3, TRPC3, GRIK1, KCNAB1, CACNA1G, CACNA2D2, ITPR1, CHRNA3 PLCB3, ATP2A3, PTK2B, CACNA1G, PRKCG, ITPKA, ITPR1 PLCB3, C7ORF16, PRKCG, PRKG1, ITPR1 List Total Pop Hits Pop Total Fold Enrichment Bonferroni 77 320 10237 4.570 0.020 79 270 10540 4.941 0.039 32 153 4097 5.858 0.041 32 61 4097 10.494 0.051 43 eReferences 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. Millar T, Walker R, Arango JC, et al. Tissue and organ donation for research in forensic pathology: the MRC Sudden Death Brain and Tissue Bank. The Journal of pathology. Dec 2007;213(4):369-375. Trabzuni D, Ryten M, Walker R, et al. 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