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Supplementary information:
MOLECULAR PATHWAYS INVOLVED IN NEURONAL EVIDENCE FOR OVERLAPPING MOLECULAR SUSCEPTIBILITY
PATHWAYS IN SCHIZOPHRENIA AND BIPOLAR DISORDER
CONTENTS:
SRT Pathway significance versus SNP and gene summary statistics
2
SRT results for ISC and GAIN datasets
3
KEGG Cell Adhesion Molecules Pathway (CAM) (hsa04514)
5
KEGG Tight Junction Pathway (hsa04530)
6
KEGG Cell Cycle Pathway (hsa04110)
7
KEGG SNARE Interactions in Vesicular Transport Pathway (hsa04130)
8
KEGG Glycan structures - biosynthesis 1 Pathway (hsa01030)
9
Risk alleles replicated across the 5 significant pathways in ISC and GAIN WGA datasets
11
Gene/SNP summary for 5 significant pathways in ISC and GAIN datasets
12
1
SRT Pathway significance versus SNP and gene summary statistics
Supplementary Figure 1: ISC SRT p-value versus the number of (a) significant SNPs for each
of 212 KEGG pathways, (b) average length of all KEGG pathway genes, (c) total length of all
KEGG pathway genes, (d) number of pathway genes. The p=0.05 cut-off is highlighted by a
vertical red line. Similar weaker patterns are seen for the GAIN dataset
2
SRT results for ISC and GAIN datasets
ISC
Pathway
ID
sig
GAIN
non- sig
p-value
hsa00061
16
95
0.048
hsa00310
36
328
hsa00350
55
547
hsa00360
38
hsa00510
sig
non-sig
p-value
Pathway name
10
102
0.173
Fatty acid biosynthesis
0.021
6
358
0.967
Lysine degradation
0.03
41
558
0.184
Tyrosine metabolism
206
0.011
22
213
0.151
Phenylalanine metabolism
69
533
0.003
35
555
0.317
N-Glycan biosynthesis
hsa00561
92
1003
0.01
55
1011
0.458
Glycerolipid metabolism
hsa00562
107
1345
0.045
50
1367
0.859
Inositol phosphate metabolism
hsa00564
102
1045
0.007
63
1050
0.335
Glycerophospholipid metabolism
hsa00565
48
473
0.033
27
485
0.414
hsa00602
24
226
0.04
15
225
0.296
hsa00624
27
109
0.013
5
129
0.508
hsa00632
30
160
0.019
6
177
0.602
Ether lipid metabolism
Glycosphingolipid biosynthesis neo-lactoseries
1- and 2-Methylnaphthalene
degradation
Benzoate degradation via CoA
ligation
hsa00730
27
188
0.011
13
202
0.338
Thiamine metabolism
hsa00740
28
198
0.007
14
207
0.314
Riboflavin metabolism
hsa00903
34
175
0.003
7
195
0.663
Limonene and pinene degradation
hsa00920
31
216
0.016
12
236
0.473
Sulfur metabolism
hsa00960
27
141
0.012
10
156
0.356
Alkaloid biosynthesis II
246
3151
0.007
231
3111
0.033
Glycan structures - biosynthesis 1
hsa03022
29
238
0.03
12
251
0.518
Basal transcription factors
hsa03410
27
203
0.022
12
217
0.414
Base excision repair
hsa01030
hsa03420
34
307
0.035
14
319
0.604
Nucleotide excision repair
hsa04010
395
5335
0.006
303
5297
0.254
hsa04070
191
2612
0.032
146
2597
0.342
MAPK signaling pathway
Phosphatidylinositol signaling
system
hsa04110
70
831
0.027
77
799
0.015
hsa04130
47
417
0.017
51
409
0.016
Cell cycle
SNARE interactions in vesicular
transport
hsa04350
101
1221
0.027
98
1197
0.063
TGF-beta signaling pathway
hsa04510
350
5251
0.021
243
5257
0.809
Focal adhesion
hsa04514
270
3613
0.022
319
3469
0.001
Cell adhesion molecules (CAMs)
hsa04530
332
4375
0.003
310
4315
0.034
Tight junction
hsa04612
37
292
0.002
24
293
0.13
Antigen processing and presentation
hsa04620
65
676
0.01
32
707
0.655
Toll-like receptor signaling pathway
hsa04630
96
1284
0.05
56
1288
0.745
Jak-STAT signaling pathway
hsa04662
80
983
0.032
40
998
0.786
B cell receptor signaling pathway
hsa04664
121
1634
0.049
50
1676
0.979
Fc epsilon RI signaling pathway
hsa04910
157
1772
0.005
97
1800
0.422
Insulin signaling pathway
hsa04920
89
903
0.008
45
932
0.604
Adipocytokine signaling pathway
hsa05010
43
358
0.05
13
389
0.769
Alzheimer's disease
3
hsa05050
104
969
0.004
43
1021
0.702
Dentatorubropallidoluysian atrophy
(DRPLA)
hsa05211
103
1028
0.004
58
1046
0.418
Renal cell carcinoma
hsa05212
89
1025
0.012
62
1028
0.296
Pancreatic cancer
hsa05222
186
2447
0.019
137
2445
0.369
Small cell lung cancer
hsa05223
137
1791
0.033
90
1805
0.557
Non-small cell lung cancer
hsa05310
17
117
0.017
11
113
0.141
Asthma
hsa05322
84
926
0.039
68
933
0.164
Systemic lupus erythematosus
hsa05330
28
203
0.006
13
207
0.34
hsa05332
26
203
0.008
12
207
0.399
Graft-versus-host disease
hsa05340
22
226
0.048
17
227
0.205
Primary immunodeficiency
Allograft rejection
Supplementary Table 1: SRT results for ISC and GAIN. “sig”=number of significant SNPs in
pathway, “non-sig”=number of non-significant SNPs in pathway, “p-value” = empirical pvalue from comparing ratio of significant to non-significant SNPs to ratios in simulated
datasets. Pathways significant in the ISC dataset that were also significant in the GAIN dataset
are highlighted in bold
4
KEGG Cell Adhesion Molecules Pathway (CAM) (hsa04514)
Supplementary Figure 2: Genes involved in KEGG Cell Adhesion Molecules pathway (http://www.genome.jp/dbgetbin/www_bget?pathway+hsa04514) Colour scheme: RED= Significant SNPs in gene in both ISC and GAIN datasets, RED with
emboldened border and gene name= Replication of significant SNPs* in gene in ISC and GAIN datasets, Orange= Significant SNPs in gene
in ISC dataset only, Yellow= Significant SNPs in gene in GAIN dataset only, Grey=No significantly associated SNPs in gene for either
dataset/No SNPs in gene tested/Gene not included in SRT *Replication=same risk allele associated with SZ in the 2 datasets
5
KEGG Tight Junction Pathway (hsa04530)
Supplementary Figure 3: Genes involved in Tight Junction Pathway
(http://www.genome.jp/dbget-bin/show_pathway?hsa04530) Colour scheme:
RED= Significant SNPs in gene in both ISC and GAIN datasets, RED with
emboldened border and gene name= Replication of significant SNPs* in gene in
ISC and GAIN datasets, Orange= Significant SNPs in gene in ISC dataset, Yellow=
Significant SNPs in gene in GAIN dataset, Grey=No significantly associated SNPs
in gene/No SNPs in gene tested/Gene not included in SRT *Replication=same
risk allele associated with SZ in the 2 datasets
6
KEGG Cell Cycle Pathway (hsa04110)
Supplementary Figure 4: Genes involved in Cell Cycle Pathway
(http://www.genome.jp/dbget-bin/show_pathway?hsa04110) Colour scheme:
RED= Significant SNPs in gene in both ISC and GAIN datasets, RED with
emboldened border and gene name= Replication of significant SNPs* in gene in
ISC and GAIN datasets, Orange= Significant SNPs in gene in ISC dataset, Yellow=
Significant SNPs in gene in GAIN dataset, Grey=No significantly associated SNPs
in gene/No SNPs in gene tested/Gene not included in SRT *Replication=same
risk allele associated with SZ in the 2 datasets
7
KEGG SNARE Interactions in Vesicular Transport Pathway
(hsa04130)
Supplementary Figure 5: Genes involved in SNARE Interactions in Vesicular
Transport Pathway
(http://www.genome.jp/dbget-bin/show_pathway?hsa04130) Colour scheme:
RED = significant SNPs in gene in both ISC and GAIN datasets, RED with
emboldened border and gene name = replication of significant SNPs in gene in
ISC and GAIN datasets, Orange = significant SNPs in gene in ISC dataset, Yellow =
significant SNPs in gene in GAIN dataset, Grey = no significantly associated SNPs
in gene/No SNPs in gene tested/Gene not included in SRT, * = same risk allele
associated with SZ in the 2 datasets
8
KEGG Glycan structures - biosynthesis 1 Pathway (hsa01030)
A
B
9
C
Supplementary Figure 6 A, B & C: Genes involved in Glycan structures –
biosynthesis 1 Pathway (excluding High-mannose type N-glycan biosynthesis)
(http://www.genome.jp/dbget-bin/show_pathway?hsa01030) Colour scheme:
Gene name in bold and red interaction line = significant SNPs in gene in both ISC
and GAIN datasets, Gene name in bold with asterisk = replication of significant
SNPs in gene in ISC and GAIN datasets, Orange gene interaction line = significant
SNPs in gene in ISC dataset, Yellow gene interaction line = significant SNPs in
gene in GAIN dataset, Grey gene interaction line = no significantly associated
SNPs in gene/No SNPs in gene tested/Gene not included in SRT, * = same risk
allele associated with SZ in the 2 datasets. Note: As this pathway is complex, only
gene names for significantly associated genes were labelled on this pathway, for
full interactive gene information associated with this pathway, please visit
hyperlink
10
Risk alleles replicated across the 5 significant pathways in
ISC and GAIN WGA datasets
Supplementary Table 2: SNPs with replicating risk alleles in the 5 pathways
identified by the SRT as significant in both ISC and GAIN WGA studies.
11
Gene/SNP summary for 5 significant pathways in ISC and
GAIN datasets
#Genes with
same SNPs sig
in ISC and GAIN
and with
replicated risk
alleles
# Genes sig
in GAIN
only
# Genes in
Pathway
on Chip
#Genes
sig in
ISC
# Genes
sig in ISC
and GAIN
#Genes with
same SNPs
sig in ISC
and GAIN
KEGG cell adhesion
molecules pathway (cam) hsa04514
110
49
23
8
6
14
KEGG tight junction
pathway- hsa04530
128
47
27
16
8
17
KEGG cell cycle pathway hsa04110
107
22
5
1
1
17
36
16
6
2
2
5
111
50
30
8
4
7
Pathway
KEGG snare interactions in
vesicular transport
pathway - hsa04130
KEGG glycan structures biosynthesis 1 pathway hsa01030
Supplementary Table 3: Summary statistics for significantly associated SNPs in
the 5 KEGG pathways that were identified as significantly overrepresented in
both ISC and GAIN SZ datasets by the SRT
12
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