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188 2
1 78
351 2 365 2
1 288 3 116
65 3 100 2 116 7
1 42 3 25 4 51
39 10 38 6 26 33 59 2
4 27 5 13 10 38 0 18
35 9 30 3 50 8 34 3 25 3
2 54 14 26 9 34 5 10 3 10
OFC
vmPFC
aINS
NAc
vSUB
dlPFC OFC vmPFC aINS NAc
130 2
2 260
86 3 174 8
1 111 4 115
52 4 88 5 88 1
0 125 2 94 1 72
89 15 71 25 103 3 66 1
1 40 21 25 3 25 0 30
42 5 149 6 134 2 75 1 70 2
0 141 6 131 1 79 4 72 3 22
OFC
vmPFC
aINS
NAc
vSUB
dlPFC OFC vmPFC aINS NAc
Females
1.3
Males >25
20
15
10
5
0 -lo
g(co
rrec
ted
p-v
alu
e)
a b >25
20
15
10
5
0 -lo
g(co
rrec
ted
p-v
alu
e)
1.3
Supplementary Figure 1.
Nature Medicine: doi:10.1038/nm.4386
Supplementary Figure 2.
1321 1427
211
1058 2432
258
1131
3030
419
BA46
Hippocampus
Striatum
Fem
ale
Male
23
1
18
5
13
9
92
46
0
-log(p-value)
Nature Medicine: doi:10.1038/nm.4386
0
40
80
120
160
Female Male
# o
f M
odule
s
Conserved LOC GOC
Chartreuse Blue Cyan 2
Gold 2
Khaki Lightyellow
Navy
Purple
Wheat
a b c Rhodopsin-like rc act.
Cholesterol Biosynt.
Transcrip. fact bind.
Glucuronosyltransf act.
Inflammatory resp.
Reg. lymph act.
Axoneme
Reg. Catechol. met.
Amine rc act.
Nerve Ensheath.
Olfactory rc act.
Cell projection
Synaptic transm.
Chromatin
GTP metabolism 1 210 1
0
500
1000
1500
2000
2500
3000
3500
5000
10000
Module
siz
e
MDC 1
Fem
ale
MD
D M
odule
s
Male MDD Modules
Pi3k-Akt signal.
Ca2+ signal.
Neurotrans. rc act.
Neurotransmission
Neuron differentiation
Reg. of catechol. met.
Transcription factor
Inflammatory resp.
Amine rc. act.
Neuropeptide rc act.
Nerve ensheathment
0
400
800
1200
1600
0 5 10
Module
siz
e
MDC
d e
20 40 60
Fold Enrichment
Supplementary Figure 3.
Nature Medicine: doi:10.1038/nm.4386
GOC Conserved
Neuron (2.2E-18)
Neuron (2.2E-4)
Neuron (4.6E-8)
Neuron (5.1E-3)
Microglia (1.0E-110)
Endoth Cells (4.1E-14)
Astrocyte (5.2E-46)
Neuron (1.1E-8)
Neuron (1.3E-15)
Neuron (1.4E-5)
Astrocyte (5.1E-3)
Neuron (8.6E-4)
Neuron (9.5E-4)
LOC
Myel.Oligod (1.3E-56)
Neuron (1.0E-2) 5000
0
10000
15000
20000
25000
Male CTRL vs Male MDD Modules
Mo
du
le S
ize
Conserved GOC
Neuron (1.2E-2)
Neuron (8.0E-3)
Neuron (6.6E-4)
Neuron (1.5E-13)
Neuron (6.0E-2)
Neuron (6.0E-2)
Neuron (1.3E-3)
5000
0
10000
15000
20000
25000
Neuron (2.4E-5)
Neuron (1.9E-4)
Astrocyte (1.0E-4)
Neuron (4.6E-6)
Astrocyte (1.6E-81)
Neuron (2.2E-10)
Astrocyte (8.8E-6)
Neuron (8.6E-18)
Endo Cell (7.4E-4)
Myel. Oligo. (2.0E-71)
Neuron (3.9E-2)
Neuron (1.4E-2)
Neuron (2.0E-5)
Microglia (9.7E-38)
Neuron (1.1E-8)
Microglia (2.3E-3)
Microglia (3.8E-3)
Mo
du
le S
ize
Female CTRL vs Female MDD Modules a b
Supplementary Figure 4.
Nature Medicine: doi:10.1038/nm.4386
2.7e-11 4.1e-8
1.4e-5 5.3e-3
5.1e-6 4.4e-5
Female NAc
Female NAc
Male NAc
Male NAc
Female vmPFC
Female vmPFC
Male vmPFC
Male vmPFC
↑
↓
↓
↓
↓
↑
↑
↑
1 2 3 4
Odd Ratio
Supplementary Figure 5.
Nature Medicine: doi:10.1038/nm.4386
75
50
37
25
Phospho-Erk (Green line indicates lanes for mouse male in main figure)
75
50
37
25
Total Erk (Green line indicates lanes for mouse male in main figure)
50
37
Actin (Green line indicates lanes for mouse male in main figure)
75
50
37
25
Phospho-Erk (Green line indicates lanes for mouse female in main figure)
75
50
37
25
Toal Erk (Green line indicates lanes for mouse female in main figure)
Actin (Green line indicates lanes for mouse female in main figure)
50
37
Supplementary Figure 6.
Nature Medicine: doi:10.1038/nm.4386
100 75
50
37 50
37
Phospho-Erk (Green line indicates lanes for human male in main figure)
50
37
Toal Erk (Green line indicates lanes for human male in main figure)
100 75
50
37
Actin (Green line indicates lanes for human male in main figure)
50
37
Phospho-Erk (Green line indicates lanes for human female in main figure)
100 75
50
37
Toal Erk (Green line indicates lanes for human female in main figure)
Actin (Green line indicates lanes for human female in main figure)