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Hunter et al.
Antidepressant Response Trajectory GWAS
1
A Genomewide Association Study of a Sustained Pattern of
Antidepressant Response
Hunter et al.
Supplemental Material
Contents
Supplemental Table 1 .................................................................................................... 2
Supplemental Table 2 .................................................................................................... 3
Supplemental Table 3 .................................................................................................... 4
Supplemental Table 4 .................................................................................................... 5
Supplemental Table 5.......................................................................................................8
Supplemental Figure 1 .................................................................................................... 9
Supplemental Figure 2.....................................................................................................10
Supplemental Figure 3.....................................................................................................11
Supplemental Figure 4.....................................................................................................12
Supplemental Figure 5.....................................................................................................13
Supplemental Figure 6.....................................................................................................14
Hunter et al.
Antidepressant Response Trajectory GWAS
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Supplemental Table 1: Summary of STAR*D models without distal outcomes and
their U shaped classes.
Model
MAR
Beuncken
Muthen-Roy
Roy
Sustained
(SUS)
Response
Class
55%
35%
32%
43%
Unsustained
Non(UNS)
response
Response
class
class
3%
15%
19%
25%
15%
14%
18%
28%
Hunter et al.
Antidepressant Response Trajectory GWAS
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Supplemental Table 2: Clinical and demographic characteristics of the STAR*D
sample.
Variable
N
Male (%)
Age (mean, years)
Baseline QIDS-SR (mean)
Intolerance (%)
MDS1 (mean)
MDS8 (mean)
Unsustained
247
113 (45.7)
41.3
14.2
66 (26.7)
-0.002
0.0009
Sustained
869
322 (37.1)
42.5
14.2
45 (5.2)
-0.004
-0.0001
p-value
0.01
NS
NS
<0.0001
NS
0.0007
Hunter et al.
Antidepressant Response Trajectory GWAS
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Supplemental Table 3: Clinical Outcome Trajectories in GENDEP.
Overall, statistical modeling provides evidence of U-shaped classes in the GENDEP data. However, compared to the STAR*D
model used for this study, the U-shape classes in GENDEP have either shallower or more extreme U shapes (reaching implausibly
high ratings in the later weeks due to all individuals dropping out and trajectory being extrapolated). Of the models considered
below, our preferred model is the Muthen-Roy without distal outcome being included. The choice between this model with two drop
out classes, and either two or three outcome classes (having very similar BIC scores), is driven by our hypothesis focusing on
sustained versus unsustained response. Whereas two outcome classes suggest comparing classes of non-responders and
responders (24% versus 74% of the sample), three outcome classes suggest looking at U-shape classes (unsustained responders)
versus sustained responders. We therefore, selected the Muthen-Roy model with three outcome classes ('Muthen Roy u2y3'
depicted below). Classes 2 and 3 were combined to constitute the U-shape (~21% unsustained responders), while classes 4 and 5
were combined to constitute sustained responders (~49%).
Summary of GENDEP models without distal outcomes and their U shaped classes
Model
Pattern Mixture Analysis
Roy latent dropout analysis
Muthen-Roy without distal outcome
Diggle-Kenward Mixture analysis without distal
outcome
Classes
1
2
3
4
5
6
u2y1
u2y2
u2y3
u2y4
2
3
4
BIC
50968.53
50856.9
50870.42
50932.47
50997.06
51063.54
50869.25
50797.27
50799.24
50813.44
58675.33
58133.49
57929.93
U shape
classes
1
1
2
2
2
2
1
2
2
4
1
1
2
Total
percentage
of individuals
100.0%
24.8%
34.1%
33.6%
18.0%
19.0%
27.2%
26.5%
21.1%
16.6%
35.5%
19.0%
30.9%
Hunter et al.
Antidepressant Response Trajectory GWAS
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Supplemental Table 4: Genes near SNPs with nominal association in the STAR*D GWAS.
Pathway/Gene
set name
HSA05010
ALZHEIMERS
DISEASE
Description
p-value
FDR
sig/selected/all Source
Sig Genes
Genes
involved in
Alzheimer's
disease
< 0.001
0
15/21/28
KEGG
APP, LPL, BACE2, C1QB, SNCA,
CASP3, C1QA, PSEN2, PSEN1,
CASP7, GSK3B, IL1B, MAPT,
NCSTN, MME
HSA04940 TYPE
I DIABETES
MELLITUS
Genes
involved in
type I diabetes
mellitus
< 0.001
0.004
26/40/45
KEGG
TUMOR
NECROSIS
FACTOR
PATHWAY
Tumor
necrosis factor
is a proinflammatory
cytokine that
activates NFkB and c-Jun.
Genes
involved in
antigen
processing
and
presentation
< 0.001
0.006
12/23/29
STKE
HLA-A, HLA-G, HLA-DQB1,
PTPRN2, HLA-DQA2, HLA-DQA1,
IL12B, HLA-C, PRF1, HLA-B,
HLA-F, HLA-DRB1, GAD2, ICA1,
GAD1, CD80, HLA-DOB, CPE,
FASLG, IL1A, HLA-DOA, IL1B,
CD28, CD86, HLA-DMB, HLADMA
NFKB1, TNFRSF1B, NFKBIA,
RALBP1, JUN, TRAF2, CASP8,
CASP3, TNFAIP3, BIRC2,
MAP3K7, MAP2K4
< 0.001
0.01
21/55/83
KEGG
HSA04612
ANTIGEN
PROCESSING
AND
PRESENTATION
HLA-A , HLA-G, HLA-DQB1,
IFNA5, HLA-DQA2, IFNA2, HLADQA1, HLA-C, KIR2DL3, HLA-B,
HLA-F, HLA-DRB1, CREB1, HLADOB, HLA-DOA, IFNA14, CTSB,
NFYC, PSME2, HLA-DMB, HLADMA
Hunter et al.
Antidepressant Response Trajectory GWAS
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HSA04720 LONG Genes
TERM
involved in
POTENTIATION
long-term
potentiation
< 0.001
0.02
32/54/69
KEGG
mPR PATHWAY
0.001
0.03
12/20/23
BioCarta
Progesterone
binding to its
intracellular
receptor
activates the
MAPK
pathway and
induces
oocyte
maturation;
binding to
membrane
receptor
inhibits
adenylyl
cyclase.
CACNA1C, CALM2, GRIN2A,
PLCB1, GRM5, CAMK2D, ITPR1,
RPS6KA2, GRM1, PPP3R2,
KRAS, ITPR2, PLCB4, RAP1A,
GRIA1, GRIN2B, ADCY1,
PPP1R12A, CAMK4, CREBBP,
RPS6KA1, PPP3CA, CALM1,
ADCY8, PRKACG, PRKCA,
RAPGEF3, GNAQ, GRIN2C,
BRAF, MAPK1, CALML3
GNB1, CDC2, ADCY1, MYT1,
RPS6KA1, PRKACG, GNAI1,
GNGT1, SRC, PRKAR2B,
MAPK1, ACTA1
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Antidepressant Response Trajectory GWAS
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WNT SIGNALING Wnt signaling
genes
GAQ PATHWAY
< 0.001
G-alpha-q
0.001
activates
phospholipase
C, resulting in
calcium influx
and increasing
protein kinase
C activity.
0.03
29/51/65
SuperArray CND2, APC, CTNNB1, FZD1,
FZD6, AXIN1, PRKCH, FZD10,
PRKCE, CCND3, JUN, SFRP4,
FZD2, TCF7, PRKCQ, PRKCA,
MAPK10, PRKCD, LDLR, GSK3B,
PRKD1, CSNK1E, FZD7, FZD8,
CCND1, WNT5B, MAPK9, WNT3,
MYC
0.04
10/22/28
STKE
PLD2, AKT3, NFKB1, ITPKB,
ITPR1, PDK1, NFKBIA, ITPR2,
PLD1, GNAQ
Hunter et al.
Antidepressant Response Trajectory GWAS
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Supplemental Table 5: Gene-based analyses of STAR*D using VEGAS.
CHR
GENE
START
STOP
SNPs
P
9
C9ORF16
129962359
129966028
5
0
9
LCN2
129951552
129955555
7
0
11
GPHA2
64458518
64459936
5
0
11
PPP2R5B
64448755
64458523
5
0
11
C11ORF85
64462504
64484185
5
1.00 x 10-6
17
B9D1
19187075
19206639
11
0
17
EPN2
19081282
19180621
11
0
CHR, chromosome; START/STOP, human genome build hg18 coordinates; SNPs, number of
SNPs within the gene and within 50kb of the 3’ and 5’ boundaries of the gene; P, p-value based
on 1 million permutations, therefore P = 0 is considered less than 1 x 10-6. P-value threshold for
significance is 2.86 x 10-6.
Hunter et al.
Antidepressant Response Trajectory GWAS
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Supplemental Figures 1 though 4 show MDS 1 plotted against MDS 2-5 for 1,116 STAR*D
samples. None of these vectors was independently associated with the sustained versus
unsustained response phenotype analyzed in the manuscript, suggesting that they (and by
extension, ancestry) are not genetic confounds in the analysis.
Supplemental Figure 1: MDS1 vs. MDS2.
0.12
Asian
0.1
Asian Hispanic
Black
Black Hispanic
White
0.08
White Hispanic
Other
MDS2
0.06
0.04
0.02
0
-0.02
-0.05
-0.03
-0.01
0.01
0.03
0.05
0.07
0.09
0.11
0.13
0.15
MDS1
Figure S1: MDS vector plot for 1,116 STAR*D samples. MDS1 separates those with
self-reported African ancestry from those without. MDS2 separates those with East
Asian and Native American ancestry from those without. Samples labeled “Other”
include unspecified, multi-racial, Native American, or Pacific Islander ancestry.
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Antidepressant Response Trajectory GWAS
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Supplemental Figure 2: Supplemental Figure 1: MDS1 vs. MDS3.
Figure S2: MDS vector plot for 1,116 STAR*D samples. MDS1 separates those with
self-reported African ancestry from those without. MDS3 likely separates Asian vs.
Native-American/Hispanic.
Hunter et al.
Antidepressant Response Trajectory GWAS
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Supplemental Figure 3: Supplemental Figure 1: MDS1 vs. MDS4.
Figure S3: MDS vector plot for 1,116 STAR*D samples. MDS1 separates those with
self-reported African ancestry from those without. MDS4 likely captures IntraEuropean stratification (Northern vs Southern).
Hunter et al.
Antidepressant Response Trajectory GWAS
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Supplemental Figure 4: Supplemental Figure 1: MDS1 vs. MDS5.
Figure S4: MDS vector plot for 1,116 STAR*D samples. MDS1 separates those with
self-reported African ancestry from those without. The basis of MDS5 stratification is
unclear; it may stratify by some variants common to all human populations.
Hunter et al.
Antidepressant Response Trajectory GWAS
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Supplemental Figure 5: Muthen-Roy u2y3 model
Hunter et al.
Antidepressant Response Trajectory GWAS
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Supplemental Figure 6: Regional association plot of genes significantly associated with
the response phenotype using the gene-based analysis in VEGAS.