Last updated: 2023-08-17

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Knit directory: m6A_in_disease_genetics/

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    Modified:   analysis/wbc_m6A_output.Rmd

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File Version Author Date Message
Rmd 06e2427 Jing Gu 2023-08-17 added lupus

Load ctwas results

# top 1 method
res <- impute_expr_z(z_snp, weight = weight, ld_R_dir = ld_R_dir,
                         method = NULL, outputdir = outputdir, outname = outname.e,
                         harmonize_z = T, harmonize_wgt = T, scale_by_ld_variance=F,
                         strand_ambig_action_z = "recover", 
                         recover_strand_ambig_wgt = T
# lasso/elastic-net method
res <- impute_expr_z(z_snp, weight = weight, ld_R_dir = ld_R_dir,
                         method = NULL, outputdir = outputdir, outname = outname.e,
                         harmonize_z = T, harmonize_wgt = T, scale_by_ld_variance=F,
                         strand_ambig_action_z = "none", 
                         recover_strand_ambig_wgt = F

GWAS: UK Biobank GWAS summary statistics - European individuals

Weights: FUSION weights using top1, lasso, or elastic-net models were converted into PredictDB format and were not needed to do scaling when running ctwas.

Check convergence of parameters

cTWAS analysis on m6A alone

[1] "Check convergence for the top1 model:"
[1] "Table of group size:"
    SNP    gene 
6731160     801 
                                SNP      gene
estimated_group_prior     0.0002642 0.0010266
estimated_group_prior_var 5.2751345 1.8792046
estimated_group_pve       0.6574782 0.0001083
attributable_group_pve    0.9998353 0.0001647
$top1

Joint analysis of expression, splicing and m6A

[1] "Check convergence for the lasso model when jointly analyzing expression, splicing and m6A:"
[1] "Table of group size before/after matching with UKBB SNPs:"
                          SNP      eQTL      sQTL   m6AQTL
prior_group_size    9.324e+06 2005.0000 2191.0000 918.0000
group_size          6.731e+06 1984.0000 2149.0000 902.0000
percent_of_overlaps 7.219e-01    0.9895    0.9808   0.9826
                                SNP     eQTL     sQTL    m6AQTL
estimated_group_prior     0.0002261 0.017777 0.002642  0.004184
estimated_group_prior_var 6.3614278 4.000501 3.878062 22.909135
estimated_group_pve       0.6787153 0.009889 0.001544  0.006061
attributable_group_pve    0.9748732 0.014205 0.002217  0.008705
$lasso

cTWAS results for individual analysis with m6A

top1 model

[1] genename   region_tag susie_pip  z         
<0 rows> (or 0-length row.names)

Summing up PIPs for m6A peaks located in the same gene

Top m6A PIPs by genes

# A tibble: 0 × 2
# ℹ 2 variables: genename <chr>, total_susie_pip <dbl>

cTWAS results for joint analysis using a lasso model

Top m6A modification pip

Top expression/splicing/m6A units

For m6A or splicing QTLs, they are assigned to the nearest genes (m6A needs to be confirmed with Kevin).

Top SNPs or genes with PIP > 0.6

$eQTL
     genename susie_pip group region_tag
1970    JADE2    0.6801  eQTL       5_80

$m6AQTL
     genename susie_pip  group region_tag
5032 MIR210HG     0.906 m6AQTL       11_1

$sQTL
[1] genename   susie_pip  group      region_tag
<0 rows> (or 0-length row.names)

Top m6A modification pip

   genename region_tag susie_pip       z
1  MIR210HG       11_1   0.90599  6.8092
2      IRF5       7_80   0.16925  0.6668
3    ICOSLG      21_23   0.09542 -3.1780
4    SH2D3C       9_66   0.09282  3.0549
5      IRF3      19_34   0.07407 -3.6731
6     SCIMP       17_5   0.07083  2.9299
7     PSMB1      6_112   0.06819 -2.8428
8     MKRN2        3_9   0.06440  2.8379
9   SNRNP25       16_1   0.06333 -2.8226
10   DENND3       8_92   0.06004  2.5839

Summing up PIPs for m6A peaks located in the same gene

Top 10 m6A PIPs by genes

# A tibble: 809 × 2
   genename total_susie_pip
   <chr>              <dbl>
 1 MIR210HG          0.906 
 2 IRF5              0.169 
 3 SH2D3C            0.131 
 4 ICOSLG            0.101 
 5 IRF3              0.0741
 6 SCIMP             0.0708
 7 PSMB1             0.0682
 8 MKRN2             0.0644
 9 SNRNP25           0.0633
10 DENND3            0.0600
# ℹ 799 more rows

Top splicing PIPs

                    peak_id genename       pos region_tag susie_pip      z
1   chr22:42000157-42001876    DESI1  41914593      22_17   0.21438  3.351
2   chr20:44750537-44750690     CD40  44674743      20_28   0.15765 -3.713
3   chr14:24902238-24903306    KHNYN  24810413       14_4   0.14932  3.663
4  chr1:150240527-150241098    APH1A 150210120       1_75   0.14692 -3.263
5   chr19:50166515-50167931     IRF3  50093572      19_34   0.12050 -4.125
6      chr6:6589103-6625159     LY86   6521970        6_6   0.11113  3.131
7     chr12:6878840-6879010     PTMS   6870549       12_7   0.10886 -2.963
8   chr19:50168103-50168929     IRF3  50168871      19_34   0.09584  4.026
9    chr3:16305736-16306276     DPH3  16395668       3_12   0.09063 -2.866
10    chr20:5090091-5092142  TMEM230   5055138       20_4   0.08408 -3.286

Summing up PIPs for spliced introns located in the same gene

Top 10 splicing PIPs by genes

# A tibble: 10 × 2
   genename total_susie_pip
   <chr>              <dbl>
 1 CD40               0.309
 2 IFI44L             0.307
 3 WARS1              0.278
 4 IRF3               0.223
 5 DESI1              0.214
 6 TMEM230            0.206
 7 NADSYN1            0.177
 8 LBP                0.163
 9 PDCD2              0.163
10 MGST3              0.163

Top genes by combined PIP

            genename combined_pip expression_pip splicing_pip  m6A_pip
1838        MIR210HG        0.906        0.00000      0.00000 0.905991
1602           JADE2        0.704        0.68005      0.02365 0.000000
1098 ENSG00000257073        0.488        0.48833      0.00000 0.000000
304              BIK        0.481        0.48108      0.00000 0.000000
3215           WARS1        0.468        0.19047      0.27791 0.000000
1315           FCRLA        0.419        0.37282      0.04602 0.000000
269             AZI2        0.378        0.37755      0.00000 0.000000
2960           TMA16        0.371        0.37074      0.00000 0.000000
760            DRAM2        0.360        0.24891      0.11092 0.000000
2763           SNX11        0.351        0.34579      0.00000 0.004929
1030 ENSG00000244625        0.348        0.34797      0.00000 0.000000
1954         NADSYN1        0.342        0.16519      0.17699 0.000000
694             DEF6        0.332        0.33198      0.00000 0.000000
1542          IFI44L        0.320        0.00000      0.30674 0.013162
467             CD40        0.309        0.00000      0.30888 0.000000
640        CTTNBP2NL        0.305        0.30490      0.00000 0.000000
2215         PITPNC1        0.303        0.30273      0.00000 0.000000
181            AP5B1        0.298        0.29767      0.00000 0.000000
2262          POLR1E        0.298        0.25222      0.01010 0.035767
1584            IRF3        0.297        0.00000      0.22294 0.074067
2554        RPS19BP1        0.297        0.29678      0.00000 0.000000
2965           TMCO4        0.296        0.29551      0.00000 0.000000
2006           NFRKB        0.288        0.28830      0.00000 0.000000
705            DESI1        0.285        0.07062      0.21438 0.000000
491           CDK11A        0.279        0.27856      0.00000 0.000000
151          ANKDD1A        0.265        0.26522      0.00000 0.000000
187             APIP        0.265        0.22475      0.04049 0.000000
1585            IRF5        0.265        0.01898      0.07662 0.169246
1830            MIB2        0.262        0.26245      0.00000 0.000000
719           DHTKD1        0.261        0.26086      0.00000 0.000000
2999          TMEM44        0.261        0.26106      0.00000 0.000000
2863            SWI5        0.259        0.25876      0.00000 0.000000
1428           GSDMD        0.255        0.19767      0.00000 0.057483
1827           MGST3        0.255        0.09258      0.16291 0.000000
824             ELL2        0.253        0.25318      0.00000 0.000000
3204           VPS16        0.253        0.25326      0.00000 0.000000
1682            LHPP        0.248        0.24766      0.00000 0.000000
210            ARL5B        0.247        0.24684      0.00000 0.000000
903  ENSG00000211891        0.247        0.24720      0.00000 0.000000
2370           PTPRA        0.242        0.20415      0.02904 0.008818
     region_tag
1838       11_1
1602       5_80
1098      17_42
304       22_18
3215      14_52
1315       1_81
269        3_21
2960      4_105
760        1_69
2763      17_28
1030       22_8
1954      11_40
694        6_28
1542       1_48
467       20_28
640        1_69
2215      17_39
181       11_36
2262       9_28
1584      19_34
2554      22_16
2965       1_13
2006      11_80
705       22_17
491         1_1
151       15_30
187       11_23
1585       7_80
1830        1_1
719       10_10
2999      3_119
2863       9_66
1428       8_94
1827       1_83
824        5_56
3204       20_3
1682      10_78
210       10_15
903       14_55
2370       20_3
Loading required package: grid
Warning: replacing previous import 'utils::download.file' by
'restfulr::download.file' when loading 'rtracklayer'

Locus plots for specific examples

Some literature that relates MIR210HG to m6A modification

     genename combined_pip expression_pip splicing_pip m6A_pip region_tag
1838 MIR210HG        0.906              0            0   0.906       11_1


R version 4.2.0 (2022-04-22)
Platform: x86_64-pc-linux-gnu (64-bit)
Running under: CentOS Linux 7 (Core)

Matrix products: default
BLAS/LAPACK: /software/openblas-0.3.13-el7-x86_64/lib/libopenblas_haswellp-r0.3.13.so

locale:
 [1] LC_CTYPE=en_US.UTF-8 LC_NUMERIC=C         LC_TIME=C           
 [4] LC_COLLATE=C         LC_MONETARY=C        LC_MESSAGES=C       
 [7] LC_PAPER=C           LC_NAME=C            LC_ADDRESS=C        
[10] LC_TELEPHONE=C       LC_MEASUREMENT=C     LC_IDENTIFICATION=C 

attached base packages:
[1] grid      stats4    stats     graphics  grDevices utils     datasets 
[8] methods   base     

other attached packages:
 [1] biomaRt_2.52.0       Gviz_1.40.1          cowplot_1.1.1       
 [4] ggplot2_3.4.3        GenomicRanges_1.48.0 GenomeInfoDb_1.32.2 
 [7] IRanges_2.30.1       S4Vectors_0.34.0     BiocGenerics_0.42.0 
[10] ctwas_0.1.38         dplyr_1.1.2          workflowr_1.7.0     

loaded via a namespace (and not attached):
  [1] colorspace_2.1-0            deldir_1.0-6               
  [3] rjson_0.2.21                rprojroot_2.0.3            
  [5] biovizBase_1.44.0           htmlTable_2.4.0            
  [7] XVector_0.36.0              base64enc_0.1-3            
  [9] fs_1.6.3                    dichromat_2.0-0.1          
 [11] rstudioapi_0.15.0           farver_2.1.1               
 [13] bit64_4.0.5                 AnnotationDbi_1.58.0       
 [15] fansi_1.0.4                 xml2_1.3.3                 
 [17] codetools_0.2-18            logging_0.10-108           
 [19] cachem_1.0.8                knitr_1.39                 
 [21] Formula_1.2-4               jsonlite_1.8.7             
 [23] Rsamtools_2.12.0            cluster_2.1.3              
 [25] dbplyr_2.3.3                png_0.1-7                  
 [27] compiler_4.2.0              httr_1.4.6                 
 [29] backports_1.4.1             lazyeval_0.2.2             
 [31] Matrix_1.6-1                fastmap_1.1.1              
 [33] cli_3.6.1                   later_1.3.0                
 [35] htmltools_0.5.2             prettyunits_1.1.1          
 [37] tools_4.2.0                 gtable_0.3.3               
 [39] glue_1.6.2                  GenomeInfoDbData_1.2.8     
 [41] rappdirs_0.3.3              Rcpp_1.0.11                
 [43] Biobase_2.56.0              jquerylib_0.1.4            
 [45] vctrs_0.6.3                 Biostrings_2.64.0          
 [47] rtracklayer_1.56.0          iterators_1.0.14           
 [49] xfun_0.30                   stringr_1.5.0              
 [51] ps_1.7.0                    lifecycle_1.0.3            
 [53] ensembldb_2.20.2            restfulr_0.0.14            
 [55] XML_3.99-0.14               getPass_0.2-2              
 [57] zlibbioc_1.42.0             scales_1.2.1               
 [59] BSgenome_1.64.0             VariantAnnotation_1.42.1   
 [61] ProtGenerics_1.28.0         hms_1.1.3                  
 [63] promises_1.2.0.1            MatrixGenerics_1.8.0       
 [65] parallel_4.2.0              SummarizedExperiment_1.26.1
 [67] AnnotationFilter_1.20.0     RColorBrewer_1.1-3         
 [69] yaml_2.3.5                  curl_5.0.2                 
 [71] memoise_2.0.1               gridExtra_2.3              
 [73] sass_0.4.1                  rpart_4.1.16               
 [75] latticeExtra_0.6-30         stringi_1.7.12             
 [77] RSQLite_2.3.1               highr_0.9                  
 [79] BiocIO_1.6.0                foreach_1.5.2              
 [81] checkmate_2.1.0             GenomicFeatures_1.48.4     
 [83] filelock_1.0.2              BiocParallel_1.30.3        
 [85] rlang_1.1.1                 pkgconfig_2.0.3            
 [87] matrixStats_0.62.0          bitops_1.0-7               
 [89] evaluate_0.15               lattice_0.20-45            
 [91] htmlwidgets_1.5.4           GenomicAlignments_1.32.0   
 [93] labeling_0.4.2              bit_4.0.5                  
 [95] processx_3.8.0              tidyselect_1.2.0           
 [97] magrittr_2.0.3              R6_2.5.1                   
 [99] generics_0.1.3              Hmisc_5.1-0                
[101] DelayedArray_0.22.0         DBI_1.1.3                  
[103] pgenlibr_0.3.6              pillar_1.9.0               
[105] whisker_0.4                 foreign_0.8-82             
[107] withr_2.5.0                 KEGGREST_1.36.2            
[109] RCurl_1.98-1.7              nnet_7.3-17                
[111] tibble_3.2.1                crayon_1.5.2               
[113] interp_1.1-4                utf8_1.2.3                 
[115] BiocFileCache_2.4.0         rmarkdown_2.14             
[117] jpeg_0.1-10                 progress_1.2.2             
[119] data.table_1.14.8           blob_1.2.4                 
[121] callr_3.7.3                 git2r_0.30.1               
[123] digest_0.6.33               httpuv_1.6.5               
[125] munsell_0.5.0               bslib_0.3.1