Extended Data Table 1. Descriptive characteristics of meta-analyses.
T o t a l num be r
M e t a - a na lys is
o f s t udie s
E uro pe a n s e x- c o m bine d
GWA S
80
M etabo chip
34
Jo int GWA S+M etabo chip
114
E uro pe a n m e n
GWA S
72
M etabo chip
34
Jo int GWA S+M etabo chip
106
E uro pe a n wo m e n
GWA S
74
M etabo chip
33
Jo int GWA S+M etabo chip
107
E uro pe a n po pula t io n- ba s e d
GWA S
49
M etabo chip
20
Jo int GWA S+M etabo chip
69
A ll a nc e s t rie s
GWA S
82
M etabo chip
43
Jo int GWA S+M etabo chip
125
M a xim um num be r
o f s ubje c t s
N um be r o f
SN P s*
λG C
234,069
88,137
322,154
2,550,021
156,997
2,554,623
1.526
1.250
1.084
104,666
48,274
152,893
2,473,152
152,326
2,477,617
1.279
1.121
1.006
132,115
39,864
171,977
2,491,697
153,086
2,494,571
1.336
1.029
1.002
162,262
46,263
209,521
2,502,573
155,617
2,506,448
1.385
1.034
1.003
236,231
103,047
339,224
2,550,614
181,718
2,555,496
1.451
1.250
1.004
For the GWAS and joint GWAS+Metabochip analyses, SNP count reflects N≥50,000.
*
1
Extended Data Table 2. Association of the genome-wide significant SNPs for BMI with cis-gene
expression (cis-eQTLs)
P
SN P
N o v e l lo c i
rs11583200
rs492400
rs492400
rs492400
rs492400
rs492400
rs17001654
rs9400239
rs9400239
rs1167827
rs1167827
rs1167827
rs1167827
rs1167827
rs1167827
rs1167827
rs9641123
rs11191560
rs11191560
rs7164727
rs9925964
rs9925964
rs9925964
rs9914578
rs1808579
rs1808579
rs17724992
P re v io us ly
rs10182181
rs2176040
rs13107325
rs205262
rs205262
rs205262
rs3817334
rs3817334
rs3817334
rs3817334
rs12016871
rs12016871
rs12446632
rs12446632
rs3888190
rs3888190
rs3888190
rs3888190
rs3888190
rs3888190
rs3888190
rs1808579
rs3888190
rs3810291
B M Iinc re a s ing
C hr.
a lle le
1
2
2
2
2
2
4
6
6
7
7
7
7
7
7
7
7
10
10
15
16
16
16
17
18
18
19
re po rt e d
2
2
4
6
6
6
11
11
11
11
13
13
16
16
16
16
16
16
16
16
16
18
16
19
C
C
C
C
C
C
G
C
C
G
G
G
G
G
G
G
C
C
C
T
A
A
A
G
C
C
A
lo c i
G
A
T
G
G
G
T
T
T
T
T
T
G
G
A
A
A
A
A
A
A
C
A
A
T is s ue
G e ne
Subcutaneo us
ELA VL4
Liver
P LCD4
Lympho cyte
RQCD1
PBM C
RQCD1
Omental
TTLL4
Lympho cyte
TTLL4
Lympho cyte
SCA RB 2
Subcutaneo us HSS00296402
Omental
HSS00296402
B lo o d
P M S2P 3
Omental
P M S2P 3
Subcutaneo us
P M S2P 3
A dipo se
P M S2P 3
B lo o d
P M S2P 5
Subcutaneo us
WB SCR16
Omental
WB SCR16
A bdo minal SA T hsa-miR-653
Gluteal SA T
SFXN2
A bdo minal SA T
SFXN2
Lympho cyte
B B S4
Liver
VKORC1
Subcutaneo us
ZNF646
B lo o d
ZNF668
Subcutaneo us
C17o rf13
Skin
C18o rf8
Subcutaneo us
C18o rf8
B lo o d
P GP EP 1
Subcutaneo us
Omental
Liver
B lo o d
PBM C
Omental
Skin
Subcutaneo us
B rain
FA T
PBM C
Lympho cyte
Omental
Liver
B lo o d
PBM C
Skin
A dipo se
Omental
Subcutaneo us
PBM C
Subcutaneo us
Skin
A dipo se
A DCY3
IRS1
SLC39A 8
SNRP C
SNRP C
SNRP C
C1QTNF4
M TCH2
M TCH2
SP I1
GTF3A
GTF3A
IQCK
IQCK
A P OB 48R
A TXN2L
SB K1
SH2B 1
SH2B 1
SULT1A 2
TUFM
NP C1
TUFM
ZC3H4
P
a
β fo r
G IA N T
SN P
v a lue
fo r
G IA N T
SN P
-0.066
-0.054
0.392
-0.102
0.018
0.158
0.248
0.034
0.015
-0.595
-0.027
-0.030
-0.346
-0.367
0.025
0.017
-0.344
0.153
0.628
-0.163
0.122
0.017
-0.382
-0.010
-0.073
-0.014
-0.825
1.90E-12
4.64E-40
7.11E-22
2.43E-06
1.33E-10
9.02E-06
5.57E-09
9.51E-22
1.34E-13
4.20E-32
1.57E-11
1.30E-10
3.40E-09
1.20E-11
1.44E-10
1.75E-06
1.54E-04
1.72E-05
1.44E-04
3.14E-05
4.41E-37
2.55E-06
1.70E-12
3.01E-06
5.74E-10
8.41E-08
1.60E-40
0.44
0.98
0.94
0.98
0.82
1
0.59
0.97
0.50
0.66
0.95
0.71
1
0.47
1
1
0.23
0.20
0.02
1
0.84
1
0.48
0.99
0.86
1
1
rs6588374
rs10187066
rs526134
rs526134
rs12987009
rs492400
rs6835324
rs2153960
rs2153960
rs6963105
rs6963105
rs1167796
rs1167827
rs6963105
rs1167827
rs1167827
rs16868443
rs71496550
rs71496550
rs7164727
rs2303223
rs9925964
rs10871454
rs7225843
rs1788781
rs1808579
rs17724992
0.022
-0.036
-0.101
-0.462
-0.127
-0.012
-0.051
0.044
28.255
-0.090
-0.258
-0.375
0.028
0.031
0.303
0.084
-0.063
-0.407
-0.014
0.067
0.694
-0.027
0.074
-0.386
7.57E-06
3.74E-09
1.29E-17
9.60E-15
3.40E-09
6.64E-06
1.34E-09
7.64E-13
7.51E-08
9.90E-07
6.68E-34
3.89E-15
2.27E-10
5.39E-06
2.10E-08
1.04E-04
1.63E-06
4.10E-13
5.29E-07
3.36E-21
9.81E-198
2.52E-10
7.90E-10
3.70E-09
0.69
0.97
1
0.58
0.03
0.81
0.82
0.76
NA
0.90
0.90
0.32
0.83
0.74
0.68
0.99
0.41
0.67
0.87
0.52
0.94
0.83
0.46
1
rs11684619
rs908252
rs13107325
rs6457792
rs2744943
rs2814984
rs7124681
rs12794570
NA e
rs10769262
rs7988412
rs7988412
rs11865578
rs9921401
rs2411453
rs8049439
rs4788084
rs12928404
rs12928404
rs1074631
rs8049439
rs1805081
rs2411453
rs3810291
adj
fo r
G IA N T
SN P
P eak
SN P b
P fo r
pe a k
SN P
P adj d
f o r pe a k
SN P
R e f e re nc e
0.78
0.996
1
0.95
0.73
1
0.94
0.94
0.93
0.93
0.98
0.73
1.00
0.93
1
1
0.71
NA
NA
1
0.88
1
0.93
0.99
0.90
1
1
1.07E-12
4.49E-40
4.06E-22
2.21E-06
2.82E-13
9.02E-06
3.42E-09
1.93E-23
4.64E-17
3.00E-32
6.94E-12
1.04E-12
3.40E-09
5.00E-12
1.44E-10
1.75E-06
1.38E-04
4.42E-06
9.13E-05
3.14E-05
3.62E-44
2.55E-06
1.10E-12
2.86E-06
1.67E-10
8.41E-08
1.60E-40
0.36
0.98
0.21
0.96
0.07
1
0.25
0.48
0.22
0.39
0.86
0.10
1
0.14
1
1
0.20
0.41
0.94
1
0.05
1
0.26
0.97
0.13
1
1
Zho ng et al.
Zho ng et al.
Dixo n et al.
P B M C meta-analysis
Zho ng et al.
Dixo n et al.
Dixo n et al.
Zho ng et al.
Zho ng et al.
Emilsso n et al.
Zho ng et al.
Zho ng et al.
Emilsso n et al.
Emilsso n et al.
Zho ng et al.
Zho ng et al.
P arts et al.
M in et al.
M in et al.
Dixo n et al.
Zho ng et al.
Zho ng et al.
Emilsso n et al.
Zho ng et al.
Grundberg et al.
Zho ng et al.
Emilsso n et al.
0.72
0.87
1.00
0.96
0.73
0.75
1
0.76
NA
0.70
0.81
0.86
0.83
0.70
0.83
0.99
0.82
0.92
0.93
0.80
0.99
0.78
0.76
1
8.70E-09
3.98E-10
1.29E-17
9.40E-15
3.15E-11
8.03E-07
9.42E-10
2.54E-15
NA
1.15E-08
1.81E-36
1.32E-15
4.14E-13
3.82E-07
1.10E-08
8.59E-05
2.87E-07
2.40E-13
4.65E-07
3.93E-23
9.81E-198
7.86E-14
1.91E-10
3.70E-09
0.05
0.47
1
0.55
0.12
0.30
0.34
0.10
NA
1
0.29
0.06
0.14
0.20
0.25
0.88
0.10
0.30
0.83
0.14
0.12
0.06
0.09
1
Zho ng et al.
Zho ng et al.
Zho ng et al.
Emilsso n et al.
P B M C meta-analysis
Zho ng et al.
Grundberg et al.
Zho ng et al.
M yers et al.
Grundberg et al.
P B M C meta-analysis
Dixo n et al.
Zho ng et al.
Zho ng et al.
Emilsso n et al.
P B M C meta-analysis
Grundberg et al.
Emilsso n et al.
Zho ng et al.
Zho ng et al.
P B M C meta-analysis
Zho ng et al.
Grundberg et al.
Emilsso n et al.
r
2 c
a
P value for the GIANT SNP after adjusting for the peak SNP
Most significant SNP associated with the gene transcript
c 2
r between the GIANT SNP and the peak SNP
d
P value for the peak SNP after adjusting for the GIANT SNP
e
Peak SNPs were not determined for this data set
b
2
Extended Data Table 3. Putative coding variants in linkage disequilibrium (r2 > 0.7) with
genome-wide significant BMI loci
P ut a t iv e
SN P
C hr. S o urc e c o ding v a ria nt r 2
G e ne
N o v e l ge no m e - wide s ignif ic a nt lo c i
rs492400
2
1000G rs3770213
0.89 ZNF142
rs492400
2
1000G rs3770214
0.89 ZNF142
rs492400
2
1000G rs2230115
0.96 ZNF142
rs492400
2
1000G rs1344642
0.96
STK36
rs492400
2
1000G rs1863704
0.89
STK36
rs492400
2
1000G rs1863704
0.89
STK36
rs492400
2
1000G rs3731877
0.79
TTLL4
rs17001654
4
1000G rs61750814
1
NUP 54
rs4740619
9
1000G rs4741510
0.90 CCDC171
rs4740619
9
1000G rs1539172
0.74 CCDC171
rs2176598
11
1000G rs11555762
0.77 HSD17B 12
rs3849570
3
1000G rs2229519
0.77
GB E1
rs3736485
15
1000G rs12102203
0.97 DM XL2
rs7164727
15
1000G rs2277598
0.84
B B S4
rs9925964
16
1000G rs749670
0.87 ZNF646
P re v io us ly ide nt if ie d ge no m e - wide s ignif ic a nt lo c i
rs10182181
2
HapM ap rs11676272
0.97 A DCY3
rs13107325
4
1000G rs13107325
1 SLC39A 8
rs13107325
4
1000G rs13107325
1 SLC39A 8
rs2112347
5
1000G rs2307111
0.86
P OC5
rs2112347
5
1000G rs2307111
0.86
P OC5
rs4256980
11 HapM ap rs7935453
0.73 TRIM 66
rs4256980
11
1000G rs11042022
0.88 TRIM 66
rs4256980
11
1000G rs11042023
0.96 TRIM 66
rs11030104
11
1000G rs6265
0.82
B DNF
rs11030104
11
1000G rs6265
0.82
B DNF
rs11030104
11
1000G rs6265
0.82
B DNF
rs11030104
11
1000G rs6265
0.82
B DNF
rs11030104
11
1000G rs6265
0.82
B DNF
rs3817334
11
1000G rs1064608
0.81 M TCH2
rs3888190
16
1000G rs180743
0.79 A P OB R
rs3888190
16
1000G rs7498665
1
SH2B 1
rs16951275
15
1000G rs7170185
1 LB XCOR1
rs1808579
18
1000G rs1805082
0.94
NP C1
rs1808579
18
1000G rs1805081
0.91
NP C1
rs2287019
19
1000G rs1800437
0.71
GIP R
P ro t e in P ha s t C o n G E R P
a lt e ra t io n
s c o re
s c o re
G ra nt ha m
s c o re
P o lyP he n
pre dic t io n
S IF T
pre dic t io n
S IF T
s c o re
L956H
S751G
A 541S
R583Q
G1003D
G982D
E34Q
N250S
S121T
K1069R
S280L
R190G
S1288P
I182T
E327G
0
0.2
0.5
0
0
0
1
1
1
1
0
1
0.7
0
1
-1.6
1.4
5.1
2.4
2
2
5.5
5.5
2
4.1
0.4
4.8
1.7
-4.4
4.2
99
56
99
43
94
94
29
46
58
26
145
125
74
89
98
po ssibly-damaging
benign
benign
po ssibly-damaging
po ssibly-damaging
po ssibly-damaging
pro bably-damaging
benign
benign
benign
benign
benign
benign
benign
benign
Damaging
To lerated
To lerated
Damaging
To lerated
Unkno wn
Damaging
Damaging
To lerated
To lerated
Damaging
To lerated
To lerated
To lerated
0
0.08
0.044
0
0.41
No t sco red
0.05
0.05
1
0.74
0.04
0.32
0.47
0.44
S107P
A 324T
A 391T
H11R
H36R
L630V
H466R
H324R
V148M
V66M
V74M
V81M
V95M
P 290A
P 428A
T484A
W200R
I858V
H215R
E354Q
0
1
1
0.9
0.9
1
1
1
1
1
1
1
0.1
1
1
0
1
2.9
4.4
4.4
5.8
5.8
5.1
5.2
5.2
5.2
5.2
5.2
5.1
0.5
3.1
6.1
-1.1
3.1
74
5.8
5.8
29
29
29
21
21
21
21
21
27
27
58
29
29
29
benign
benign
benign
benign
benign
pro bably-damaging
pro bably-damaging
pro bably-damaging
pro bably-damaging
pro bably-damaging
pro bably-damaging
pro bably-damaging
benign
benign
benign
benign
pro bably-damaging
To lerated
To lerated
To lerated
Unkno wn
Unkno wn
To lerated
To lerated
Damaging
Damaging
Damaging
Damaging
Damaging
Damaging
To lerated
Unkno wn
To lerated
To lerated
To lerated
To lerated
0.28
0.09
0.09
No t sco red
No t sco red
1
0.38
0.03
0
0
0
0
0
0.12
No t sco red
0.25
0.24
0.59
0.09
r2 is the linkage disequilibrium (LD) between the BMI index SNP and the putative coding variant.
3
Extended Data Fig. 1
4
Extended Data Fig. 2
Variance & Covariance
12%
10%
A. TwinGene
Vg
Ve
8%
Cg + Ce
6%
4%
2%
0%
5.0E-08 5.0E-07 5.0E-06 5.0E-05 5.0E-04 5.0E-03
Variance & Covariance
Threshold p-value
12%
B. QIMR
10%
Vg
Ve
Cg + Ce
8%
6%
4%
2%
0%
5.0E-08 5.0E-07 5.0E-06 5.0E-05 5.0E-04 5.0E-03
Threshold p-value
5
Extended Data Fig. 3
7%
QIMR
TwinGene
6%
Weighted average
Predicted
2.5M
2.5M
4%
320
336
187
182
1%
121
122
2346
2325
2%
726
743
3%
78
79
Predic on R2
5%
0%
5.0E-08
5.0E-07
5.0E-06
5.0E-05
5.0E-04
5.0E-03
All
Threshold p-value
6
Extended Data Fig. 4
7
Extended Data Fig. 5
8
Extended Data Figure Legends
Extended Date Fig. 1. Study Design.
Extended Data Fig. 2. Partitioning the variance in SNP-derived predictor using withinfamily analyses. The analyses were performed using 2,758 full sibling pair from the TwinGene
cohort (panel A) and 1,622 pairs from the QIMR cohort (panel B). The SNP-based predictor was
adjusted for the first 20 principal components (PCs). The variance of the SNP-based predictor
can be partitioned into four components (Vg, Ve, Cg and Ce) using the within-family prediction
analysis, where Vg is the variance explained by real SNP effects, Cg is the covariance between
predictors attributed to the real effects of SNPs that are not in LD but correlated due to
population stratification, Ve is the accumulated variance due to the errors in estimating SNP
effects, and Ce is the covariance between predictors attributed to errors in estimating the effects
of SNPs that are correlated due to population stratification (details of the method can be found
in the supplemental methods of the GIANT height paper (A.R. Wood et al., in preparation).
Extended Data Fig. 3. SNP-based Risk Prediction Accuracy. Accuracy of predicting
phenotype by the SNP-based genetic predictor in unrelated individuals from the TwinGene (N =
5,668) and QIMR (N = 3,953) studies. The prediction R2 shown on the y-axis is the squared
correlation between phenotype and predictor. The number shown in each column is the number
of SNPs selected from the GCTA joint and conditional analysis at a range of P values
thresholds. In each case, the predictor was adjusted by the first 20 principal components. The
column in orange is the average prediction R2 weighted by sample size over the two cohorts.
The dashed gray line is the value inferred from the within-family prediction analyses
(Supplementary Fig. 11) using this equation R2 = (Vg + Cg)2 / (Vg + Ve + Cg + Ce). Details of the
within-family prediction analysis approach can be found at supplementary methods of the
GIANT height paper (A.R. Wood et al., in preparation).
Extended Data Fig. 4. Comparison of BMI-associated index SNPs across ethnicities. BMI
effects observed in European ancestry individuals (x-axes) compared to A. African ancestry or
B. Asian ancestry individuals (y-axes). Similarly, C. and D. compare allele frequencies between
9
ancestry groups, and E. and F. compare the estimates of explained variance. In all plots, novel
loci are in red and previously identified loci are in blue.
Extended Data Fig. 5. Bubble chart representing the genetic overlap across traits at BMI
susceptibility loci. Each bubble represents a trait for which association results were requested
for the 97 GW-significant BMI loci. The size of the bubble is proportional to the number of BMIincreasing loci with a significant association. A line connects each pair of bubbles with thickness
proportional to the number of significant loci shared between the traits. Traits tested include the
current study BMI SNPs, African American BMI (AA BMI), hip circumference (HIP), HIP
adjusted for BMI (HIPadjBMI), waist circumference (WC), waist circumference adjusted for BMI
(WCadjBMI), waist-to-hip ratio (WHR), waist-to-hip ratio adjusted for BMI (WHRadjBMI), height,
adiponectin, coronary artery disease (CAD), diastolic blood pressure (DBP), systolic blood
pressure (SBP), high-density lipoprotein (HDL), low-density lipoprotein (LDL), total cholesterol
(TC), triglycerides (TG), type 2 diabetes (T2D), fasting glucose (FG), fasting insulin (FI), fasting
insulin adjusted for BMI (FIadjBMI), two-hour glucose (Glu2hr), diabetic nephropathy
(Diab_Neph), age at menopause (AgeMenopause), and age at menarche (ageMenarche).
10