supplementary figure 1 summary of overall study design and ...€¦ · supplementary figure 3....
TRANSCRIPT
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Supplementary Figure 1. Summary of overall study design and workflow for meta-analyses. All numbers providedrepresent the maximum number specific for that trait (BMI-red, WCadjBMI-blue, and WHRadjBMI-green) and strata (EUR-European descent participants, nonEUR-excluding European descent participants). Three studies provided GWAS data for EUR and nonEUR participants.
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Supplementary Figure 2. Summary plots of discovery meta-analysis for Approach 1 primary meta-analyses. (a)Manhattan plot showing the loci identified in Approach 1 in primary meta-analyses, used to identify significant main effects loci (SNPadjSMK), in the primary meta-analyses association –log10P-values for BMI-red, WCadjBMI-blue, and WHRadjBMI-green; (b) Manhattan plot showing the loci identified in Approach 1 excluding known regions +/- 500 kb andlabeled with the nearest gene to the index SNP; (c) QQ-plot showing the Approach 1 P-values as observed against thoseexpected under the null for each phenotypes separately (colored); (d) QQ-plot for Approach 1 after excluding knownassociation regions. *PSMB10 locus is >500 +/- kb from previously identified index SNPs, but is not independent of known GWAS signals.
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Supplementary Figure 3. Regional association plots for Approach 1 primary meta-analyses. Regional association plotsfor all novel loci identified in Approach 1 (SNPadjSMK) in primary meta-analyses for BMI: (a) rs10929925, (b) rs6794880; WCadjBMI: (c) rs17396340, (d) rs6743226, (e) rs4378999, (f) rs7697556, (g) rs10269774, (h) rs6470765, (i) rs9409082, (j) rs6012558; and WHRadjBMI: (k) rs1049281, and ordered as they appear in Table 1. LD has beencalculated using the combined ancestries from the 1000 Genomes Phase 1 reference panel. For comparison, each plot highlights the p-value for the tag SNP in Approach 1 (PadjSMK), Approach 2 (Pjoint), Approach 3 (Pint), current smokers (PSMK), and in nonsmokers (PnonSMK).
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a. BMI: rs10929925 −
0
2
4
6
8
10
−lo
g 10(
p−va
lue)
0
20
40
60
80
100
Recom
bination rate (cM/M
b)
●●●
LINC01248
SOX11
LINC01105
LOC400940
LINC01247
5.8 6 6.2 6.4 6.6Position on chr2 (Mb)
Coronary artery calcification
Chronic kidney disease
s disease
0.2
0.4
0.6
0.8
r2
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b. BMI: rs6794880 −
0
2
4
6
8
10
−lo
g 10(
p−va
lue)
0
20
40
60
80
100
Recom
bination rate (cM/M
b)
●●●
LINC00971
84 84.2 84.4 84.6 84.8Position on chr3 (Mb)
Obesity−related traits Brain structure
0.2
0.4
0.6
0.8
r2
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c. WCadjBMI: rs17396340 −
0
2
4
6
8
10
−lo
g 10(
p−va
lue)
0
20
40
60
80
100
Recom
bination rate (cM/M
b)
●●●
PIK3CD
CLSTN1
CTNNBIP1
LZIC
NMNAT1
RBP7
UBE4B KIF1B
PGD
APITD1
APITD1−CORT
CORT
DFFA
PEX14
CASZ1
9.8 10 10.2 10.4 10.6Position on chr1 (Mb)
Alcohol dependence (age at onset)
0.2
0.4
0.6
0.8
r2
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d. WCadjBMI: rs6743226 −
0
2
4
6
8
10
−lo
g 10(
p−va
lue)
0
20
40
60
80
100
Recom
bination rate (cM/M
b)
●●●
KIF1A
AGXT
C2orf54
LOC200772
SNED1
MTERFD2
PASK
PPP1R7
ANO7
HDLBP
SEPT2
FARP2
STK25
BOK−AS1
BOK
THAP4
ATG4B
DTYMK
ING5
D2HGDH
GAL3ST2
241.8 242 242.2 242.4 242.6Position on chr2 (Mb)
Height
Height
Height
Brain structure
HIPadjBMI
Height
0.2
0.4
0.6
0.8
r2
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e. WCadjBMI: rs4378999 −
0
2
4
6
8
10
−lo
g 10(
p−va
lue)
0
20
40
60
80
100
Recom
bination rate (cM/M
b)
●●●
MIR4787
DOCK3
MANF
RBM15B
VPRBP
RAD54L2
TEX264
50.8 51 51.2 51.4 51.6Position on chr3 (Mb)
Height
Height
0.2
0.4
0.6
0.8
r2
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f. WCadjBMI: rs7697556 −
0
2
4
6
8
10
−lo
g 10(
p−va
lue)
0
20
40
60
80
100
Recom
bination rate (cM/M
b)
●●●
ADAMTS3 COX18
ANKRD17
73.2 73.4 73.6 73.8 74Position on chr4 (Mb)
Metabolite levels
HIPadjBMI
Height
Height
Lipid metabolism phenotypes
0.2
0.4
0.6
0.8
r2
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g. WCadjBMI: rs10269774 −
0
2
4
6
8
10
−lo
g 10(
p−va
lue)
0
20
40
60
80
100
Recom
bination rate (cM/M
b)
●●●
CYP51A1
LRRD1 KRIT1
ANKIB1 GATAD1
PEX1
RBM48
MGC16142
FAM133B
FAM133DP
CDK6
LOC101927497
SAMD9
91.8 92 92.2 92.4 92.6Position on chr7 (Mb)
1 GWAS hitomitted
Height
Height
Height
Height
Height
HIPadjBMI
0.2
0.4
0.6
0.8
r2
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h. WCadjBMI: rs6470765 −
0
2
4
6
8
10
−lo
g 10(
p−va
lue)
0
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100
Recom
bination rate (cM/M
b)
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LINC00977 GSDMC FAM49B
MIR5194
ASAP1
ASAP1−IT2
130.4 130.6 130.8 131 131.2Position on chr8 (Mb)
HIPadjBMI
Height
Inflammatory bowel disease
Height
0.2
0.4
0.6
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r2
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i. WCadjBMI: rs9409082 −
0
2
4
6
8
10
−lo
g 10(
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lue)
0
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Recom
bination rate (cM/M
b)
●●●
●●
FKTN
TAL2 TMEM38B
MIR8081
LOC100996590
108.6 108.8 109 109.2 109.4Position on chr9 (Mb)
2 GWAS hitsomitted
Menarche (age at onset)
Menarche (age at onset)
Height
Menarche and menopause (age at onset)
Height
Menarche (age at onset)
Menarche (age at onset)
0.2
0.4
0.6
0.8
r2
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j. WCadjBMI: rs6012558 −
0
2
4
6
8
10
−lo
g 10(
p−va
lue)
0
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60
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100
Recom
bination rate (cM/M
b)
●●●
PREX1 ARFGEF2
LOC102723483
CSE1L
STAU1 DDX27
ZNFX1
ZFAS1
SNORD12C
SNORD12B
SNORD12
KCNB1
47.2 47.4 47.6 47.8 48Position on chr20 (Mb)
QT interval
Obesity−relat
Height
Height
0.2
0.4
0.6
0.8
r2
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k. WHRadjBMI: rs1049281 −
0
2
4
6
8
10
−lo
g 10(
p−va
lue)
0
20
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100
Recom
bination rate (cM/M
b)
●●●
8 genesomitted
DDR1
MIR4640
GTF2H4
VARS2
SFTA2
DPCR1
MUC21
MUC22
HCG22
C6orf15
PSORS1C1
CDSN
PSORS1C2
CCHCR1
TCF19
POU5F1
PSORS1C3
HCG27
HLA−C HLA−B
MIR6891
MICA
HCP5
HCG26
MICB
MCCD1
DDX39B
ATP6V1G2−DDX39B
SNORD117
SNORD84
ATP6V1G2
NFKBIL1
LTA
TNF
LTB
AIF1
PRRC2A
MIR6832
BAG6
APOM
C6orf47
GPANK1
CSNK2B
LY6G5B
LY6G5C
ABHD16A
LY6G6F
LY6G6E
LY6G6D
C6orf25
CLIC1
MSH5
VWA7
30.8 31 31.2 31.4 31.6Position on chr6 (Mb)
20 GWAS hitsomitted
Height
Renal function−related traits (eGRFcrea)
Height
Diastolic blood pressure
Systolic blood pressure
Pubertal anthropometrics
Renal function−related traits (sCR)
Height
Hematology traits Menopause (age at onset)
0.2
0.4
0.6
0.8
r2
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Supplementary Figure 4. Summary plots of discovery meta-analysis for Approach 2 primary meta-analyses. (a) Manhattan plot showing the loci identified in Approach 2 in primary meta-analyses, used to identify significant joint main+interaction effects loci (SNPjoint), in the primary meta-analyses association –log10P-values for BMI-red, WCadjBMI-blue, and WHRadjBMI-green; (b) Manhattan plot showing the loci identified in Approach 2 excluding known regions +/- 500 kb and labeled with the nearest gene to the index SNP; (c) QQ-plot showing the Approach 2 P-values as observed against those expected under the null for each phenotypes separately (colored); (d) QQ-plot for Approach 2 after excluding known association regions.
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Supplementary Figure 5. Regional association plots for Approach 2 primary meta-analyses. Regional association plotfor all novel loci identified in Approach 2 (SNPjoint) in the primary meta-analyses for BMI: (a) rs10929925, (b) rs13069244; WCadjBMI: (c) rs17396340, (d) rs6743226, (e) rs7697556, (f) rs9408815, and WHRadjBMI: (g) rs1049281,and ordered as they appear in Table 1. LD has been calculated using the combined ancestries from the 1000 Genomes Phase 1 reference panel. For comparison, each plot highlights the p-value for the tag SNP in Approach 1 (PadjSMK), Approach 2 (Pjoint), Approach 3 (Pint), current smokers (PSMK), and in nonsmokers (PnonSMK).
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a. BMI: rs10929925 − Approach 2
0
2
4
6
8
10
−lo
g 10(
p−va
lue)
0
20
40
60
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100
Recom
bination rate (cM/M
b)
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LINC01248
SOX11
LINC01105
LOC400940
LINC01247
5.8 6 6.2 6.4 6.6Position on chr2 (Mb)
Coronary artery calcification
Chronic kidney disease
s disease
0.2
0.4
0.6
0.8
r2
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b. BMI: rs13069244 − Approach 2
0
2
4
6
8
10
−lo
g 10(
p−va
lue)
0
20
40
60
80
100
Recom
bination rate (cM/M
b)
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TTC14
CCDC39
LOC101928882 FXR1
DNAJC19
SOX2−OT
180 180.2 180.4 180.6 180.8Position on chr3 (Mb)
0.2
0.4
0.6
0.8
r2
-
c. WCadjBMI: rs17396340 − Approach 2
0
2
4
6
8
10
−lo
g 10(
p−va
lue)
0
20
40
60
80
100
Recom
bination rate (cM/M
b)
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PIK3CD
CLSTN1
CTNNBIP1
LZIC
NMNAT1
RBP7
UBE4B KIF1B
PGD
APITD1
APITD1−CORT
CORT
DFFA
PEX14
CASZ1
9.8 10 10.2 10.4 10.6Position on chr1 (Mb)
Alcohol dependence (age at onset)
0.2
0.4
0.6
0.8
r2
justanneTypewritten Text
justanneTypewritten Text
-
d. WCadjBMI: rs6743226 − Approach 2
0
2
4
6
8
10
−lo
g 10(
p−va
lue)
0
20
40
60
80
100
Recom
bination rate (cM/M
b)
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KIF1A
AGXT
C2orf54
LOC200772
SNED1
MTERFD2
PASK
PPP1R7
ANO7
HDLBP
SEPT2
FARP2
STK25
BOK−AS1
BOK
THAP4
ATG4B
DTYMK
ING5
D2HGDH
GAL3ST2
241.8 242 242.2 242.4 242.6Position on chr2 (Mb)
Height
Height
Height
Brain structure
HIPadjBMI
Height
-
e. WCadjBMI: rs7697556 − Approach 2
0
2
4
6
8
10
−lo
g 10(
p−va
lue)
0
20
40
60
80
100
Recom
bination rate (cM/M
b)
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ADAMTS3 COX18
ANKRD17
73.2 73.4 73.6 73.8 74Position on chr4 (Mb)
Metabolite levels
HIPadjBMI
Height
Height
Lipid metabolism phenotypes
0.2
0.4
0.6
0.8
r2
-
f. WCadjBMI: rs9408815 − Approach 2
0
2
4
6
8
10
−lo
g 10(
p−va
lue)
0
20
40
60
80
100
Recom
bination rate (cM/M
b)
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FKTN
TAL2
TMEM38B MIR8081
LOC100996590
108.4 108.6 108.8 109 109.2Position on chr9 (Mb)
2 GWAS hitsomitted
Menarche (age at onset)
Menarche (age at onset)
Height
Menarche and menopause (age at onset)
Height
Menarche (age at onset)
Menarche (age at onset)
0.2
0.4
0.6
0.8
r2
-
g. WHRadjBMI: rs1049281 − Approach 2
0
2
4
6
8
10
−lo
g 10(
p−va
lue)
0
20
40
60
80
100
Recom
bination rate (cM/M
b)
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8 genesomitted
DDR1
MIR4640
GTF2H4
VARS2
SFTA2
DPCR1
MUC21
MUC22
HCG22
C6orf15
PSORS1C1
CDSN
PSORS1C2
CCHCR1
TCF19
POU5F1
PSORS1C3
HCG27
HLA−C HLA−B
MIR6891
MICA
HCP5
HCG26
MICB
MCCD1
DDX39B
ATP6V1G2−DDX39B
SNORD117
SNORD84
ATP6V1G2
NFKBIL1
LTA
TNF
LTB
AIF1
PRRC2A
MIR6832
BAG6
APOM
C6orf47
GPANK1
CSNK2B
LY6G5B
LY6G5C
ABHD16A
LY6G6F
LY6G6E
LY6G6D
C6orf25
CLIC1
MSH5
VWA7
30.8 31 31.2 31.4 31.6Position on chr6 (Mb)
20 GWAS hitsomitted
Height
Renal function−related traits (eGRFcrea)
Height
Diastolic blood pressure
Systolic blood pressure
Pubertal anthropometrics
Renal function−related traits (sCR)
Height
Hematology traits Menopause (age at onset)
0.2
0.4
0.6
0.8
r2
-
Supplementary Figure 6. Regional association plots for Approaches 1-3 secondary meta-analyses. Regional association plot for additional novel loci identified in Approaches 1 (SNPadjSMK), Approach 2 (SNPjoint), or Approach 3 (SNPint) secondary meta-analyses for BMI: (a) rs2481665, (b) rs2173039, (c) rs12629427; WCadjBMI: (d) rs1545348, (e) rs6076699 (Approach 2), (f) rs6076699 (Approach 3), (g) rs670752; and WHRadjBMI: (h) rs589428, (i) rs1856293, (j) rs2001945, (k) rs17065323. LD has been calculated using the combined ancestries from the 1000 Genomes Phase 1 reference panel. For comparison, each plot highlights the p-value for the tag SNP in Approach 1 (PadjSMK), Approach 2 (Pjoint), Approach 3 (Pint), current smokers (PSMK), and in nonsmokers (PnonSMK). P-values are shown from the strata in which the signal was identified (e.g. European-only women). EUR- European-only meta-analyses; ALL- all ancestries combined meta-analyses.
justanneTypewritten Text
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a.
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MGC34796
TM2D1
INADL L1TD1
KANK4
USP1
DOCK7
ANGPTL3
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EPHA3
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EPHA3
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TTC23L
RAD1
BRIX1
DNAJC21
AGXT2
PRLR
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LOC728228
ADRA1D
PRNP
PRND
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RASSF2 SLC23A2
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f.
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SMOX
LOC728228
ADRA1D
PRNP
PRND
PRNT
RASSF2 SLC23A2
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g. LL
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LINC00882
LINC00883
CCDC54
LOC101929607
BBX LINC00635
LINC00636
CD47
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h.
−
●●●
MICA
HCP5
HCG26
MICB
MCCD1
DDX39B
ATP6V1G2−DDX39B
SNORD117
SNORD84
ATP6V1G2
NFKBIL1
LTA
TNF
LTB
AIF1
PRRC2A
MIR6832
BAG6
APOM
C6orf47
GPANK1
CSNK2B
LY6G5B
LY6G5C
ABHD16A
LY6G6F
LY6G6E
LY6G6D
C6orf25
CLIC1
MSH5
SAPCD1
VWA7
VARS
LSM2
HSPA1L
HSPA1A
HSPA1B
C6orf48
SNORD48
SNORD52
NEU1
SLC44A4
EHMT2
C2
ZBTB12
LOC102060414
CFB
NELFE
MIR1236
SKIV2L
DXO
STK19
C4A
C4B
C4B_2
CYP21A2
TNXB
ATF6B
FKBPL
PRRT1
LOC100507547
PPT2
PPT2−EGFL8
EGFL8
AGPAT1
MIR6721
RNF5
PBX2
NOTCH4
C6orf10
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VNN1
VNN3
VNN2
SLC18B1
RPS12
SNORD101
SNORD100
SNORA33
LINC00326 EYA4
EYA4−AS1
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j. LL
−
●●●
ZNF572
SQLE
KIAA0196
NSMCE2 TRIB1 LINC00861
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k.
−
●●●
ENOX1 CCDC122
LACC1
LINC00284 SMIM2−AS1
SMIM2
SMIM2−IT1
MIR8079
SERP2
TUSC8
TSC22D1
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Supplementary Figure 7. Simulation-based estimation of type 1 error using QQ plots. Shown are the QQ plots of simulation results for Approach 1 (adjusted effect), Approach 2 (joint effect),
Approach 3 and 4 (interaction effects). The simulation was based on MAF=0.05, 50,000 smokers and
180,000 nonsmokers.
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Supplementary Fig. 8. Heatmap of –log10P-values for SNPadjSMK, SNPjoint, and SNPint models. We have included each variant identified in the
all ancestries analysis which was significant for Approaches 1-3. Strength of color represents the –log10 P-value from the all ancestries,
combined sexes meta-analysis for (a) BMI in red, (b) WCadjBMI in blue, and (c) WHRadjBMI in green.
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Supplementary Figure . Summary plots of discovery meta-analysis for Approach 3 primary meta-analyses. (a) Manhattan plot showing the loci identified in Approach 3 in primary meta-analyses, used to identify significant interaction effects loci (SNPint), in the primary meta-analyses association –log10P-values for BMI-red, WCadjBMI-blue, and WHRadjBMI-green; (b) Manhattan plot showing the loci identified in Approach 3 excluding known regions +/- 500 kb and labeled with the nearest gene to the index SNP; (c) QQ-plot showing the Approach 3 P-values as observed against those expected under the null for each phenotypes separately (colored); (d) QQ-plot for Approach 3 after excluding known association regions.
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Supplementary Figure . Regional association plots for Approach 3 primary meta-analyses. Regional association plot for all loci identified in Approach 3 in primary meta-analyses, used to identify significant interaction (SNPint), in the primary meta-analyses for BMI: (a) rs336396, (b) rs12902602; and WCadjBMI: (c) rs4141488, and ordered as they appear in Table 3. LD has been calculated using the combined ancestries from the 1000 Genomes Phase 1 reference panel. For comparison, each plot highlights the p-value for the tag SNP in Approach 1 (PadjSMK), Approach 2 (Pjoint), Approach 3 (Pint), current smokers (PSMK), and in nonsmokers (PnonSMK).
justanneTypewritten Text
-
a. Approach 3
−
●●●
IL15 INPP4B
0.2
0.4
0.6
0.8
r2
justanneTypewritten Text
justanneTypewritten Text
-
b. Approach 3
−
●●●
ACSBG1
DNAJA4
WDR61
CRABP1
IREB2
HYKK
PSMA4
CHRNA5
CHRNA3
CHRNB4 LOC646938
ADAMTS7
MORF4L1
CTSH
RASGRF1
0.2
0.4
0.6
0.8
r2
-
c. Approach 3
−
●●●
C16orf72 MIR548X MIR7641−2 GRIN2A
0.2
0.4
0.6
0.8
r2
justanneTypewritten Text
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Supplementary Figure . Forest plot for significant loci stratified by smoking status. Estimated effects (β ± 95% CI) for smokers (N upto 51,080) and nonsmokers (N up to 190,178) per risk allele for (a) BMI, (b) WCadjBMI, and (c) WHRadjBMI for the most significant variant for each locus identified in the primary meta-analyses (combined ancestries and combined sexes) for Approaches 1 (SNPadjSMK), 2 (SNPjoint) and 3 (SNPint). Loci are grouped by those with greater effect in nonsmokers, then smokers and then ordered by magnitude of effect in smokers and labeled with the nearest gene.
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Supplementary Figure 1 . Estimated effects (β ± 95% CI) in smokers (N up to 51,080) and nonsmokers (N up to 190,178) per risk allele for (a) BMI, (b) WCadjBMI, and (c) WHRadjBMI for the most significant variant for each locus identified in the secondary meta-analyses (sex-stratified and European-only analyses) for Approaches 1 (SNPadjSMK), 2 (SNPjoint) and 3 (SNPint).
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Supplemen