Supplementary Figure 1. a b - media.nature.com · 10 1 5 5 0-log(d p-a b >25 2 5 0 0-log(d-)...

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


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)


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



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



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



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



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)

100 75

50

37



a

b

c

d


20 m m

GAD67

pERK

GF P

*

Female GFP+/pERK

GAD+/pERK

% o

f C

ells

Male

% o

f C

ells

GFP+/pERK

GAD+/pERK

*

e


*

Peru

Habituation

1 week

D1 D2 D3 D7 D0 D4 D5 D6

Males

1217 2778

195

d

f

i

h

CVS 21 Days

Emx1 OE

CVS 21 Days

Emx1 OE

1 -1 Log FC


Hub/node

↑ DEG / ↓ DEG in

Emx1 OE/Dusp6 KD

16 13 10 7 3 0

-log(p value)

Male

Em

x1 O

E

Male CVS

Gray26

Females

Habituation

1 week

D1 D2 D3 D4 D0

c

g

b

e

a

1350 5364

781

Translation

Precursor metabolites…

Phosphate metabolic…

sGTPase mediated…

Ras protein signal…

Ribosome

Cytosol

Ribonucleoprotein…

Mitochondrial part

Mitochondrial…

0 2 4 6 8 10

Constituent of ribosome

Ribonucleotide binding

Cation transmemb.…

ATP binding

ATPase coupled activity

-log10(Benjamini pval)

Biological

processes

Cellular

components

Molecular

functions

CVS 21 Days

Dusp6 KD

CVS 21 Days

Dusp6 KD 1

-1

Log F

C

164 131 98 66 33 0

-log(p value)

Fem

ale

Dusp6 K

D

Female CVS


Supplementary Table 1. Postmortem sample demographics

* Prescribed for sleep disorders

Legend: PMI: postmortem interval; OFC: orbitofrontal cortex; dlPFC: dorsolateral prefrontal

cortex; vmPFC: ventromedial prefrontal cortex; aINS: anterior insula; Nac: nucleus accumbens;

vSUB: ventral subiculum.

Male CTRL Male MDD Female CTRL Female MDD

Age 41.2 ± 11.3 46.7 ± 15.7 58.1 ± 19.5 43.7 ± 11.6

pH 6.53 ± 0.28 6.68 ± 0.31 6.59 ± 0.32 6.65 ± 0.19

PMI 25.0 ± 14.4 31.8 ± 13.8 29.8 ± 31.9 22.5 ± 18.1

RIN OFC 7.02 ± 0.79 7.11 ± 1.20 7.31 ± 1.27 7.55 ± 0.72

RIN dlPFC 7.39 ± 0.54 7.34 ± 0.76 6.90 ± 0.63 7.29 ± 0.45

RIN vmPFC 6.88 ± 1.04 6.43 ± 0.89 6.41 ± 0.74 6.42 ± 0.95

RIN aINS 6.48 ± 0.92 6.18 ± 1.05 6.98 ± 1.27 6.62 ± 1.15

RIN Nac 7.08 ± 0.54 7.65 ± 0.92 7.74 ± 0.43 8.00 ± 0.51

RIN vSUB 6.79 ± 0.54 7.61 ± 0.93 7.00 ± 0.97 7.18 ± 0.60

Smoking

(NA/No/Moderate/Heavy) 6/4/0/3 5/3/0/5 1/4/0/4 3/3/1/6

Alcool 0 0 2 2

Drug of abuse 0 0 0 0

Antidepressant 0 4 2* 9

History of abuse 2 3 3 2

Cause of death

(Accident/Natural/Suicide) 3/3/7 0/0/13 1/3/5 0/0/13


Supplementary Table 5. Postmortem validation cohort sample socio-demographics

Male NanoString validation cohort

Male CTRL Male MDD

N 17 15

Age 41.8 ± 12.1 42.0 ± 17.3

pH 6.6±0.3 6.6±0.3

PMI 18.7 ± 4.0 21.6 ± 3.1

Smoking

(NA/ No/Moderate/Heavy) N/A N/A

Alcohol (NA/Yes) 1/4 1/6

Drug of abuse (NA/Yes) 0/2 1/6

Antidepressant 0 9

History of abuse (NA/Yes) 3/1 3/2

Cause of death

(NA/Accident/Natural/Suicide) 1/0/16/0 0/1/14/0

Legend: PMI: postmortem interval


Supplementary Table 6. Postmortem validation cohort sample socio-demographics

Female NanoString validation cohort

Legend: PMI: postmortem interval

Female

CTRL

Female

MDD

N 12 6

Age 61.6 ± 9.5 42.0 ± 11.6

pH 6.2 ± 0.4 6.6 ± 0.4

PMI 20.7 ± 5.4 23.7 ± 10.8

Smoking

(NA/No/Moderate/Heavy) 0/7/2/3 0/3/0/3

Alcohol (Yes/NA) 0/1 4/0

Drug of abuse 1 4

Antidepressant 0 4

History of abuse 1 4

Cause of death

(NA/Accident/Natural/Suicide) 0/0/11/1 0/1/1/4


Extended Table 12. Transcriptional overlap in DEG from male MDD and female MDD is

maintained for genes that are sexually dimorphic at baseline

Sexually dimorphic (Sex. Dimorp.) genes: DEG in male CTRL vs female CTRL

Male MDD: DEGs in male MDD vs male CTRL

Female MDD: DEGs in female MDD vs CTRL

Male and Female MDD: DEGs in males and females with MDD


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