Supplementary Figure 1. Summary of Overall Study Design and Workflow for Meta-Analyses. All Numbers Provided Represent the Maxim

Supplementary Figure 1. Summary of overall study design and workflow for meta-analyses. All numbers provided represent 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. 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 and labeled with the nearest gene to the index SNP; (c) QQ-plot showing the Approach 1 P-values as observed against those expected under the null for each phenotypes separately (colored); (d) QQ-plot for Approach 1 after excluding known association regions. *PSMB10 locus is >500 +/- kb from previously identified index SNPs, but is not independent of known GWAS signals. Supplementary Figure 3. Regional association plots for Approach 1 primary meta-analyses. Regional association plots for 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 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). a. BMI: rs10929925 −Approach 1

2 10 r 100

0.8 0.6 0.4 8 0.2 80 ● R ecombination rate

6 60 (p − value) 10 ( log cM −

4 40 / Mb )

2 20

0 0

Coronary artery calcification Chronic kidney disease s disease

LINC01248 LINC01105 LINC01247

SOX11 LOC400940

5.8 6 6.2 6.4 6.6 Position on chr2 (Mb) b. BMI: rs6794880 −Approach 1

10 r2 100

0.8 0.6 0.4

8 0.2 80 R ecombination rate 6 60 ● (p − value) 10 ( log cM − /

4 40 Mb )

2 20

0 0

Obesity−related traits Brain structure

LINC00971

84 84.2 84.4 84.6 84.8 Position on chr3 (Mb) c. WCadjBMI: rs17396340 − Approach 1

r2 100 10 0.8 0.6 ● 0.4 80 8 0.2 R ecombination rate

60 6 (p − value) 10 ( log cM −

40 /

4 Mb )

2 20

0 0

Alcohol dependence (age at onset)

PIK3CD CTNNBIP1 NMNAT1 UBE4B KIF1B APITD1 PEX14

CLSTN1 LZIC RBP7 PGD DFFA CASZ1

APITD1−CORT

CORT

9.8 10 10.2 10.4 10.6 Position on chr1 (Mb) d. WCadjBMI: rs6743226 − Approach 1

r2 100

10 0.8 0.6 ● 0.4 80 0.2 8 R ecombination rate

60 6 (p − value) 10 ( log cM − 40 / 4 Mb )

20 2

0 0

Height Brain structure Height Height HIPadjBMI Height

KIF1A C2orf54 SNED1 PASK ANO7 SEPT2 STK25 BOK ATG4B ING5

AGXT LOC200772 MTERFD2 HDLBP FARP2 BOK−AS1 DTYMK GAL3ST2

PPP1R7 THAP4 D2HGDH

241.8 242 242.2 242.4 242.6 Position on chr2 (Mb) e. WCadjBMI: rs4378999 − Approach 1

10 r2 100

0.8 0.6 0.4 8 0.2 80 R

● ecombination rate 6 60 (p − value) 10 ( log cM −

4 40 / Mb )

2 20

0 0

Height Height

MIR4787 MANF RAD54L2

DOCK3 VPRBP TEX264

RBM15B

50.8 51 51.2 51.4 51.6 Position on chr3 (Mb) f. WCadjBMI: rs7697556 − Approach 1

r2 100

0.8 10 0.6

0.4 ● 80 0.2

8 R ecombination rate

6 (p − value) 10 ( log cM − 40 / Mb 4 )

20 2

0 0

Metabolite levels HIPadjBMI Height Height Lipid metabolism phenotypes

ADAMTS3 COX18

ANKRD17

73.2 73.4 73.6 73.8 74 Position on chr4 (Mb) g. WCadjBMI: rs10269774 − Approach 1

10 r2 100

0.8 0.6 8 0.4 80 0.2 R

● ecombination rate

6 60 (p − value) 10 ( log cM

− 4 40 / Mb )

2 20

0 0

Height Height Height 1 GWAS hit Height omitted Height HIPadjBMI

CYP51A1 ANKIB1 GATAD1 RBM48 CDK6 SAMD9

LRRD1 KRIT1 PEX1 LOC101927497

MGC16142

FAM133B

FAM133DP

91.8 92 92.2 92.4 92.6 Position on chr7 (Mb) h. WCadjBMI: rs6470765 − Approach 1

10 r2 100

0.8 0.6 0.4 8 80 0.2 R ecombination rate

6 ● 60 (p − value) 10 ( log cM − 4 40 / Mb )

2 20

0 0

HIPadjBMI Height Inflammatory bowel disease Height

LINC00977 GSDMC FAM49B ASAP1

MIR5194

ASAP1−IT2

130.4 130.6 130.8 131 131.2 Position on chr8 (Mb) i. WCadjBMI: rs9409082 − Approach 1

10 r2 100

0.8 0.6 0.4 8 80 0.2 ● ●● R ecombination rate

6 60 (p − value) 10 ( log cM − 4 40 / Mb )

2 20

0 0

Menarche (age at onset) Height Menarche (age at onset) Height 2 GWAS hits Menarche and menopause (age at onset) omitted Menarche (age at onset) Menarche (age at onset)

FKTN MIR8081

TAL2 TMEM38B LOC100996590

108.6 108.8 109 109.2 109.4 Position on chr9 (Mb) j. WCadjBMI: rs6012558 − Approach 1

10 r2 100

0.8 0.6 8 0.4 80 0.2

● R ecombination rate

6 60 (p − value) 10 ( log cM

− 4 40 / Mb )

2 20

0 0

QT interval Obesity−relat Height Height

PREX1 ARFGEF2 STAU1 DDX27 KCNB1

LOC102723483 ZNFX1

CSE1L ZFAS1

SNORD12C

SNORD12B

SNORD12

47.2 47.4 47.6 47.8 48 Position on chr20 (Mb) k. WHRadjBMI: rs1049281 − Approach 1

10 100 r2

0.8 ● 8 0.6 80 R

0.4 ecombination rate 0.2 6 60 (p − value) 10 ( log

4 40 cM − / Mb )

2 20

0 0

Height Diastolic blood pressure Renal function−related traits (eGRFcrea) Height Systolic blood pressure 20 GWAS hits Pubertal anthropometrics Height omitted Renal function−related traits (sCR) Hematology traits Menopause (age at onset)

DDR1 MUC21 HCG22 PSORS1C2 HLA−C HLA−B HCP5 MCCD1 AIF1 LY6G5C

MIR4640 MUC22 C6orf15 HCG27 MIR6891 HCG26 NFKBIL1 MIR6832 LY6G6F

GTF2H4 PSORS1C1 MICA MICB LTA BAG6 LY6G6E

VARS2 CDSN DDX39B PRRC2A LY6G6D SFTA2 CCHCR1 ATP6V1G2−DDX39B APOM C6orf25 8 genes DPCR1 TCF19 SNORD117 C6orf47 CLIC1 omitted POU5F1 SNORD84 GPANK1 MSH5

PSORS1C3 ATP6V1G2 CSNK2B VWA7

TNF LY 6 G 5 B

LTB ABHD16A

30.8 31 31.2 31.4 31.6 Position on chr6 (Mb) 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. Supplementary Figure 5. Regional association plots for Approach 2 primary meta-analyses. Regional association plot for 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). a. BMI: rs10929925 − Approach 2

2 10 r 100

0.8 0.6 0.4 8 0.2 80 ●● R ● ecombination rate

● ●● ●●●● ● ● 6 ● 60 ●● ● ● ● ●

● ● (p − value) ●

10 ● ● ( log ● ● cM −

4 ● 40 / Mb

● ● ● ) ● ● ● ●

● ● ● ● ● ● ● ● ● ● ●● ● ● ● ● ●●● ● ● ●● ● ● ● ● ● ● ●● ● ●● ●● ● ● ● ● ● ● 2 ● ● ● ● ● ● ●●● 20 ●● ●●● ● ●● ● ●● ● ● ● ● ● ●● ● ● ● ● ● ● ● ● ● ● ●● ● ● ● ● ● ●●● ● ●●● ● ● ●● ●●● ● ● ● ● ●● ● ● ● ● ●● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●● ● ● ● ● ● ● ● ●● ● ● ● ●● ● ● ● ●● ● ● ● ● ●● ●● ● ●● ● ●●● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●● ● ●● ● ●● ● ● ● ● ●● ● ●● ● ● ● ●● ● ● ● ● ● ● ● ●●●●● ● ● ● ● ● ●●●● ● ● ● ● ● ● ●● ● ● ● ● ● ● ● ● ●● ●● ● ● ●● ●●● ● ●●● ● ● ● ● ●● ● ● ● ● ●● ● ●●● ● ● ● ●● ● ● ●● ● ● ● ● ● ●●● ● ●● ●● ● ● ●●● ●● ●●●● ● ● ● ● ● ● ● ●●● ● ●● ● ● ● ● ●●●●● ● ● ● ●● ●● ● ● ● ● ● ● ●● ● ●●● ● ● ● ● ● ●●● ● ● ● ● ● ●●●● ●●●● ●● ●● ● ●● ● ● ●● ● ● ● ● ● ● ●●●● ●● ● ● ●● ●●● ● ● ●● ●●● ● ●●● ● ●● ● ●●●● ● ●●● ● ● ●● ● ● ● ● ● ●● ●●●●●●● ● ● ● ●● ● ●●●●● ●●●● ● ●●●●●●●●●●● ● ●●● ● ● ● ● ● ●●● ● ●● ●●● ● ● ● ● ● ●●● ● ● ● ● ●●●●●●● ●● ●●● ●● ● ● ●●● ●●● ● ● ● ● ● ● ●●●●●●●●● ●● ● ●●●● ● ●● ● ● ● ●●●●●● ●● ● ● ● ●●● ● ●● ●●●● ● ● ● ● ●● ● ● ● ●● ● ● ● ● ●●● ● ● ● ●● ●●● ●●●● ● ● ●● ●● ● ● ● ● ● ● ● ● ● ●● ● ●●●●●● ● ● ● ●●● ●● ●● ●● ● ● ●●●● ●● ● ●● ● ●● ● ● ●● ●●●● ● ● ● ● ● ●● ●●●●● ● ● ●●● ●●● ● ● ● ●●●●●●●● ● ● ● ● ● ● ●● ●● ●●● ●● ● ●● ●●● ● ● ●●●● ● ●● ● ● ● ● ● ●● ● ● ● ● ●●●● ●●●● ● ● ●●● ● ●●●●●●●●● ●●●● ● ● ●●● ● ● ● ●● ● ● ●● ● ● ● ●●● ●●●●● ●● ● ●●●● ●● ●●●●●● ● ●●● ● ● ● ● ● ● ● ●● ●●●● ● ●●● ● ●● ● ●● ●● ●●● ● ● ● ● ● ● ●● ●●●●●● ● ● ●● ● ● ● ●●● ●● ●●● ●●●● ●●● ● ●●● ● ●● ● ● ● ●● ●●● ●●●●● ●● ● ●● ●● ● ●● ● ●●●●●●●●● ●● ●●●●●● ●●● ● ●● ● ●●● ● ●● ● ●● ●●●●● ●● ● ●●●● ● ●●●● ●● ● ● ●●●● ●● ●●●●●●● ●● ●●● ● ● ●●● ●● ●●● ● ● ●● ●● ●●●●●●●●●● ●●●●●●●●● ● ●● ●● ●● 0 ● ● ● ● ●● ●● ●● ● ●●● ●●●●●●●●●●● ● ● ● ● ●●●●● ● ● ● ●●●● ●●● ● ● ● ● ● ● ● ● ●●●● ● ●●●●●●●●● ●●●●●●●●● ●● ●●●● ● ●●●●● 0

Coronary artery calcification Chronic kidney disease s disease

LINC01248 LINC01105 LINC01247

SOX11 LOC400940

5.8 6 6.2 6.4 6.6 Position on chr2 (Mb) b. BMI: rs13069244 − Approach 2

10 r2 100

0.8 0.6 0.4

8 0.2 80

●● R ecombination rate

6 ● 60 ● ●

● ● ● ●

(p − value) ● 10 ( log cM − ● ● /

4 40 Mb

● ●●

● )

● ●● ●● ● ●● ● ● ● ● ● ● ● ●● ● ●● ●● ● ● ● ● ● ● ● ● ● ● ●● ● ● ● ● ● ●● ● ● ● ● ● ●● ● ● ● ● ● ● ● ● ● ● ●● ● ● ● ● ● ● ● ●● ● ● ● ● ● ● ● ● ● ● 2 ● ● ● 20 ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●● ● ● ● ●● ● ● ● ● ● ● ●● ● ●● ● ● ● ● ● ● ● ●●● ● ● ● ●● ●● ● ● ● ● ● ● ● ● ● ● ● ● ● ●● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●● ●● ● ● ● ●● ●●●● ● ● ● ● ● ● ● ●●● ● ●● ● ● ● ● ● ● ● ● ● ● ● ●●● ●● ● ● ● ● ● ● ● ● ●● ●● ● ●●●● ●● ● ● ● ● ● ●● ● ● ●● ●● ●● ● ● ● ●● ● ● ● ● ● ● ● ● ●●●●●●●●● ●● ● ● ● ●● ●● ●● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●●● ●●● ● ● ● ●● ● ● ● ● ●●● ● ● ● ● ●● ● ●● ● ● ● ● ● ●● ● ●● ● ● ● ● ● ● ●●●● ● ● ●●● ●● ●● ●● ●● ● ● ● ● ● ● ● ● ●●● ● ● ● ●●● ●●● ● ●● ● ● ● ● ● ●● ● ● ●● ●●●● ●●● ● ●●●● ● ● ● ● ● ● ● ● ●● ● ●● ● ● ●●●●● ●●●●●● ● ●●● ● ●● ●● ● ● 0 ● ●●●●● ●●●●●● ●●● ● ● ● ● ● ● ● ● ● ● ● 0

TTC14 LOC101928882 FXR1 SOX2−OT

CCDC39 DNAJC19

180 180.2 180.4 180.6 180.8 Position on chr3 (Mb) c. WCadjBMI: rs17396340 − Approach 2

r2 100 10 0.8 0.6 ●● 0.4 80 8 0.2

●

● R

● ecombination rate ● ●

● ● ● ● ● 60 6 ● ● ●

● (p − value) 10 ( log cM ● − ●

40 /

4 Mb

● ) ●

● ● ● ● ● ● ● ●● ● ●● ● ●● ●● ● ● ● ● ● ●● ● ● ●● ●● ● ● ●●● ● 20 2 ●●● ● ●● ● ● ● ●● ● ● ● ● ●● ● ● ● ● ● ● ● ● ● ● ● ● ●●● ● ● ● ● ● ● ● ● ● ● ●● ● ● ● ● ● ● ● ●● ● ● ●● ● ●● ● ●● ● ●● ● ●●● ●● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●●● ●●● ● ●● ● ● ● ● ●●● ●●● ● ● ● ●● ● ● ●●● ● ● ● ●● ● ● ● ● ● ● ● ●●● ●●●●●● ● ● ●●● ● ●● ● ● ● ● ● ● ●● ● ● ● ●● ●● ● ●● ● ●●● ● ●●● ● ● ●● ● ●● ● ● ● ● ● ● ● ● ● ● ● ● ● ●● ● ● ● ●● ● ● ● ● ● ● ● ● ● ● ● ●● ● ● ● ● ● ●● ● ●●● ●● ● ●● ● ●● ● ●●●● ●● ●● ● ● ● ● ●● ● ●●●●●● ● ● ● ●●● ● ● ●● ●●●● ●● ● 0 ● ● ●● ● ● ● ● ● ● ● ● ●●●● ● ● ●● ● ● ●● ● ●●● ●●●● ●●● ● 0

Alcohol dependence (age at onset)

PIK3CD CTNNBIP1 NMNAT1 UBE4B KIF1B APITD1 PEX14

CLSTN1 LZIC RBP7 PGD DFFA CASZ1

APITD1−CORT

CORT

9.8 10 10.2 10.4 10.6 Position on chr1 (Mb) d. WCadjBMI: rs6743226 − Approach 2

100

●● 80

8 ● R ecombination rate

● ● 60 ● 6 ●

● ● (p − value)

10 ● ● ● ( log ● ● cM − ● 40

● / ● ● Mb ●● 4 ● ) ● ● ● ● ● ● ● ● ● ● ● ● ● ●● ● ●●● ● ●●● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●● ● ● ● ● ● ● ● ● 20 ●● ● ● ● ● ● ● ● ● 2 ● ● ● ● ● ● ● ● ●● ● ● ● ● ● ●● ● ● ● ● ● ● ● ● ● ● ●● ● ● ● ● ● ●● ● ●● ●●● ● ● ● ● ● ● ● ● ● ● ● ● ●● ● ● ●● ● ● ● ● ● ● ●● ● ●● ● ● ● ● ● ● ● ● ● ● ●● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●●● ● ● ● ● ● ● ● ● ● ● ●● ● ●● ● ●●● ● ● ● ● ● ● ●● ●●●● ● ● ● ● ● ● ● ● ● ● ● ●●● ●●●● ● ● ●● ● ● ● ● ● ● ● ● ● ● ● ●● ●● ●● ● ● ● ● ●● ● ● ● ●● ●● ● ● ● ● ● ● ● ● ● ● ●● ● ● ● ● ● ● ● ● ●●● ● ● ● ● ● ● ● ● ● ● ●● ● ● ●● ● ● ● ● ● ● ● ●● ● ●●● ● ● ● ● ● ● ● ● ● ● ● ● ● ●● ●●●●●● ●●● ● ● ● ● ● ●●●● ● ● ● ● ● ● ●● ● ●● ●●●●●● ●●●●●●●● ● ● ●● ● ● ● ● ● ● ●● ●● ● ● ●●●●●● ●●● ● ● ●●● ● ● ●● ● ●● 0 ● ●●● ●● ● ●● ● ● ●●● ●●● ●●● ● ● ● ●● ● ●●● ●●● ●●●● ●● ● 0

Height Brain structure Height Height HIPadjBMI Height

KIF1A C2orf54 SNED1 PASK ANO7 SEPT2 STK25 BOK ATG4B ING5

AGXT LOC200772 MTERFD2 HDLBP FARP2 BOK−AS1 DTYMK GAL3ST2

PPP1R7 THAP4 D2HGDH

241.8 242 242.2 242.4 242.6 Position on chr2 (Mb) e. WCadjBMI: rs7697556 − Approach 2

r2 100

0.8 10 0.6

0.4 ●● 80 0.2 ●

8 ●

● R ● ● ●

● ecombination rate

● ● ● ● ● ● 60 ● ● ●● ● ● ● ● 6 ● ●● ●

● (p − value) ●● 10

● ( log cM − ● 40 / Mb ● ● 4 ● ● ) ● ●

● ● ● ● ● ● ●●● ● ●● ● ●● ● ● ● ●● ●●● 20 ● ●● ● ●● ● ● ● ●●● ● 2 ● ● ● ●● ● ● ● ● ● ● ● ● ● ● ● ●● ● ● ● ● ● ● ● ● ● ● ● ●● ● ● ● ● ● ● ● ● ●●● ●● ●● ● ●●● ● ● ● ●● ●● ● ● ● ● ●● ● ● ● ● ● ● ● ●● ● ● ●● ● ● ● ● ● ● ● ●● ●●● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●● ● ●●● ● ● ● ● ● ● ●● ● ● ●● ● ● ● ●● ● ● ● ● ● ●● ● ● ● ●● ● ● ● ●●● ● ● ● ●●●● ● ● ● ● ● ● ● ● ● ● ●● ● ● ●● ● ●●●● ● ● ●● ● ● ● ● ● ●● ● ●●●● ●●●● ● ●● ●● ● ● ● ●●● ● ● ● ● ●●● ● ●● ●● ● ●●● ●● ● ● ● ● ● ●●● ●●●●●●●●●● ● ● ● ● ● ● ●● ● ●● ● ● ● ● ● ●●●●● ● ● ●● ● ● ● ● ● ● ●● ● ● ● ● ● ● ● ● ● ● ● ●●●● ● ● ● ●●●● ● ●● ● ● ● ●● ●●●● ●● ● ●●●●● ● ● ● ●● ● ● ● ●●● ●● ●●●●● ●● ● ● ● ● ●●● ● ● ●● ● ● ● 0 ●● ● ●●●●●●●●●●●●●●●●●●●●●● ●● ● ●●●● ● ● ● ●●●●●● ●●● ● ●●●●●● ● ● ●●●●●●●●● ●●● ●●●●●●●● ●●●● ● ● ● ● ●● ●●●● 0

Metabolite levels HIPadjBMI Height Height Lipid metabolism phenotypes

ADAMTS3 COX18

ANKRD17

73.2 73.4 73.6 73.8 74 Position on chr4 (Mb) f. WCadjBMI: rs9408815 − Approach 2

10 r2 100

0.8 0.6 0.4 8 80 0.2 ●● ● ●●

●● ● R ecombination rate

● ●

●● ● ●● 6 ● ● 60 ● ● ● ● ●● ● ●● ● ● ●● ● ● ● ● ● ● ● ● (p − value) ● 10 ● ● ● ● ● ● ( log ● ● ●●● cM ●● − ●● ● ● ● 4 ● ● 40 ● / ● Mb ● ● ● ● ●

● ) ● ● ● ● ● ● ● ● ● ●● ● ●● ● ● ● ● ● ● ●● ● ● ● ● ●● ● ● ● ● ●● ● ●● ● ● ● ●● ●● ● ● ● ● ● ● ● ● ● ●●● ●●● ● ● ● ● ● ●● ● ● ● ● ●●● ● ● ● ●● 2 ● ● 20 ● ●● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●● ● ● ● ●● ● ● ●●● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●● ● ● ● ●● ● ● ● ● ● ● ● ● ●●● ● ● ● ● ● ●● ● ● ● ● ●● ● ● ● ● ● ● ● ● ●● ● ● ● ● ●● ● ● ● ● ● ● ● ●●●● ● ● ● ● ● ● ● ●● ● ● ● ● ● ● ● ● ●●●●● ● ●● ● ●●● ● ● ● ● ●● ● ● ● ● ● ● ●●●● ● ●● ● ● ●● ● ●●● ● ● ● ● ●●● ● ● ● ● ● ● ● ● ● ● ● ● ● ●●● ●● ●●● ●●● ● ● ● ● ● ●● ● ● ● ●● ● ● ● ● ●● ● ● ● ● ● ●●● ● ●●● ● ● ● ● ● ● ● ● ● ● ●● ● ●● ● ● ● ● ●● ●● ● ●●● ●● ● ● ● ● ● ●● ●● ● ● ● ●● ●● ● ● ●● ●● ●● ●● ● ●● ● ● ● ● ● ● ● ● ● ● ●● ● ● ● ● ●● ●● ● ● ● ● ●●● ● ● ● ●● ● ●● ● ● ● ● ● ● ● ● ● ●● ● ● ● ● ●● ● ● ● ●●●● ● ● ● ● ●●●● ● ● ●● ● ● ● ● ● ● ● ●● ●● ● ●●● ●● ● ●● ●● ● ●● ● ●● ● ● ● ● ●● ● ●● ● ● ● ●●●● ● ● ● ● ●●● ● ● ●● ● ● ● ● ● ● ● ●● ● ● ● ● ●●●● ●● ● ● ● ● ● ● ● ●● ● ● ● ● ● ●●● ●● ●● ● ● ● ●● ● ●●●● ●● ●● ● ●● ● ● ●●● ●●●●●● ●●●● ● ●● ●●●● ● ● ● ●● ●● ●●●●● ● ●● ●● ● ● ●●●● ● ●● ● ● ● ●●● ●●● ● ●● ●●●● ●●●● ●●● ●● ● ● ● ● ● ●●●●●●●●●●●●●●●● ● ●●● ●● ● ●●●● ● ● ● ●●● ● ●● ●●● ●● ● ●●●●●●●●●● ● ●●● ●●●●● 0 ● ● ●●●●● ● ● ● ●●●●●●● ●●● ● ● ●●●●●●● ● ● ● ●● ●● ●● ● ● ●●●●●●●● ●●● ●● ● ●●●● ● ●●●● ●●● 0

Menarche (age at onset) Height Menarche (age at onset) Height 2 GWAS hits Menarche and menopause (age at onset) omitted Menarche (age at onset) Menarche (age at onset)

FKTN TMEM38B MIR8081

TAL2 LOC100996590

108.4 108.6 108.8 109 109.2 Position on chr9 (Mb) g. WHRadjBMI: rs1049281 − Approach 2

10 100 r2

0.8 ●● 8 0.6 80 R

0.4 ecombination rate 0.2

6 ● 60 ● ● ● ● ● ●

(p − value) ● ● ● ● ● 10 ● ● ● ● ● ● ● ● ● ●

● ● ( log ● 4 ● ● ● ● ● ● ● 40 cM ● ● ● ● − ● ● ● ● ● ● ● ● ● ● ●● ● ● ● ● ● ● ● ● ●● ● ● ● ● / ● ● ● ● ● ● ● ● ● ● Mb ● ● ● ● ● ● ● ● ● ● ● ● ●● ●● ● ● ● ● ● ●● ● ● ● ● ● ● ●● ● ● ●● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ) ● ● ●● ● ●● ● ● ● ● ● ● ● ● ● ●● ●● ● ● ●● ●● ● ● ● ● ● ● ● ● ● ● ● ● ●● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●● ● ● ● ● ● ● ●●● ●●● ● ● ●●● ● ● ● ●●●● ●● ● ● ● ●● ●●● ● ● ●● ● ● ● ● ● ●● ● ●● ● ● ● ● ●●●● ● ● ●●●●● ● ● ● ●●● ● ● 2 ● ● ● ● ● ● ●● ● ●● ● ● ●● ● ●● ● ●● ● ●● ●● ● ● ● 20 ● ● ● ● ● ● ● ●● ● ● ●● ●● ●●●● ● ●● ●●●● ● ● ● ● ● ●●●● ● ● ● ● ● ●● ●● ● ●●● ● ● ● ●● ● ● ● ● ● ● ● ●● ●● ● ● ● ● ● ● ●● ●● ●●●●●● ● ● ● ● ● ● ●● ● ●● ●● ● ● ● ● ● ● ● ● ● ● ● ●●●●●●● ●●●● ● ● ●● ● ● ●● ● ●● ● ● ●● ● ● ●●●● ●●● ● ● ● ● ● ●● ● ● ●●●● ●●●●●●●●●● ● ●● ● ● ● ● ● ● ● ● ● ● ● ● ● ●●● ● ● ●● ● ● ● ●● ● ● ● ● ● ● ● ●● ●●● ●● ●●● ●●●●● ●●●● ● ●● ● ●● ● ● ●● ● ● ● ● ● ● ●● ● ● ●● ●● ●●● ● ●● ●● ● ●● ● ●●●●●●● ●● ●●● ● ● ●● ● ● ●● ● ● ● ● ● ● ● ● ●● ● ●●●●●● ● ●● ● ● ● ● ● ● ● ● ●● ●●●●●●●● ●● ● ●●●●●●●● ● ●● ● ●●●●● ● ● ●●●● ● ● ● ●●● ● ● ●●●●● ● ● ● ●●●● ● ● ●● ● ● ●● ● ● ● ●●●●●● ●●●● ● ●●●●●● ●● ●● ●● ● ●●● ● ● ● ● ● ● ●● ● ● ● ● ●●●●● ● ● ● ●●● ●● ●●● ●●● ● ● ● ● ●● ● ● ● ●●●●●● ●● ●● ●●●●●●●●●● ●● ●● ● ● ● ● ● ● ●● ● ● ●●●●●●● ● ● ●●●●● ●● ●● ●●●● ● ●●● ●● ● ●●● ● ●●● ● ●●● ●●● ●● ● ●● ●●● ●● ●● ● ●●●● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●● ● ● ● ● ● ● ● ●●● ●●● ●●● ● ●● ● ● ●● ● ●● ● ● ●● ●●● ● ●●● ●●●●●●● ● ● ● ● ●● ● ●●● ●● ●● ●●●●●● ●●●● ●● ● ● ● ●●● ● ● ●●●● ●●●●● ● ●●●●● ● ●● ● ● ●●●● ● ●● ● ● ● ● ● ● ● ● ● ●● ●● ● ●●● ● ● ● ● ●●● ● ● ● ● ●●● ●●● ● ● ●●● ●●● ●●● ●● ●●● ●●● ● ● ● ● ● ● ●● ●● ●●● ●●●●●● ● ● ●● ● ●●●● ●●●●●● ● ●● ● ●●●● ●● ● ●●● ●● ●●● ●●●●● ●●●● ● ● ●●●● ●● ●● ●● ● ●●●●●●●●● ● ● ● ● ● ● ● ●●●● ●●●● ● ● ● ●●● ● ●● ● ●●● ●●●●●●●●● ●● ●●●●●●●●●● ●●● ●● ●● ●●●● ●● ●● ●●● ● ●●●●●●●●●● ●● ●●● ●● ●●●●●●●● ● ●● ● ● ● ●● ●●●● ●●● ●● ● ● ● ● ● ● ●●●● ● ●●● ●●● ●●●● ●●●● ● ●●● ●●●●● ● ●●● ● ●●● ●●●●● ● ●●●●●● ●● ●●●●●●●●● ●●● ● ● ● ●● ●●● ●●●● ●●●● ● ● ● ● ● ● ●●● ● ● ●●●●●● ● ●●● ●●●● ●●● ● ●● ●● ●● ●●● ●● ●●●● ●●●●●●●●●●●●●●● ●●●● ●●●● ● ●● ●●●● ●●● ● ● ● ●●●●●●●●●● ● ●●●● ●●●● ●●●●●●●●●●● ● ● ● ● ● ●●●● ● ● ● ●● ●●●●●● ●● ● ● ●●● ●●●●● ●●● ●● ●●●●● ●●● ●●●●●●●●●●●● ●●●●●●●●●●●●●●●● ●● ● ●● ● ●●● ●●●●●●●●●●●● ●●● ●●●●●●●●●● ●● ●●● ●●●●●●●●●●● ●●●●● ● ● ● ● ●● ● ●●● ●●●●● ●●●●●● ●●●● ●● ●●● ●●●● ●●●● ●●●● ●● ●● ●●●●●●●●● ●●●●●●●●●●●● ●● ●●●●●●● ●●●●●●● ●● ●● ●● ● ●●●●●●●●●●●●●●●● ●●● ●●●●●● ●● ●● ●●●● ● ● ● ● ● ● ●● ● ● ● ●● 0 ●●●● ●●●●● ●● ●●● ● ●●●●● ●●●●●● ●● ● ●●●● ●●●●●●●●●● ●●●●●●●●●●●●●●●●●●●●●●●●●●●●●● ● ● ●● ●●●● ● ●●●●● ●● ●●●●●●●●●● ● ●●●● ●●●●●●●●●●●●●● ●● ● ●●● ● ●●●●● ●● ●●● ● ● ● 0

DDR1 MUC21 HCG22 PSORS1C2 HLA−C HLA−B HCP5 MCCD1 AIF1 LY6G5C

MIR4640 MUC22 C6orf15 HCG27 MIR6891 HCG26 NFKBIL1 MIR6832 LY6G6F

GTF2H4 PSORS1C1 MICA MICB LTA BAG6 LY6G6E

VARS2 CDSN DDX39B PRRC2A LY6G6D SFTA2 CCHCR1 ATP6V1G2−DDX39B APOM C6orf25 8 genes DPCR1 TCF19 SNORD117 C6orf47 CLIC1 omitted POU5F1 SNORD84 GPANK1 MSH5

PSORS1C3 ATP6V1G2 CSNK2B VWA7

TNF LY 6 G 5 B

LTB ABHD16A

30.8 31 31.2 31.4 31.6 Position on chr6 (Mb) 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. a. %0,UVí$SSURDFK(85&RPELQHG6H[HV

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MGC34796 INADL L1TD1 USP1 ANGPTL3

TM2D1 KANK4 DOCK7

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RAI14 RAD1 AGXT2

TTC23L PRLR

BRIX1

DNAJC21

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● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●● ● ● ●● ● ● ● ● ● ● ●● ● ● ● ● ●● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●●●●● ● ● ● ● ● ● ● ● ● ● ● ● ●● ● ● ● ● ● ● ●● ●● ● ● ● ●●● ● ●●● ● ● ●● ● ● ● ● ● ● ● ● ● ● ● ●● ● ● ●●●● ● ● ●● ● ● ● ● ● ●●●●● ●●● ●● ●● ● ● ●● ● ● ● ● ● ● ● ● ●● ● ●● ●● ● ● ●● ●●● ● ● ● ●● ●● ● ● ● ● ● ● ●● ● ● ● ●● ●●●●● ● ●● ● ● ● ● ● ● ● ●● ● ● ●● ●●●●●● ● ●●●● ● ● ●● ● ● ● ●● ● ● ●● ● ● ● ● ● ●●●●●●● ● ● ●●● ● ● ● ●●● ● ● ●●●● ● ●●●●● ●●●●● ● ● ● ● ● ●● ●●● ● ● ● ● ●● ●●● ● ●●●●● ●●● ● ● ●● ●●● ●●●● ● ●● ●●●● ●●●● ● ●● ● ●●● ● ● ● ●● ●● ●●● ● ● ●●●● ● ● ●● ● ●●● ● ● ●● ●●●●● ●●● ●●●● ●●● ● ●●●●● ●●●● ● ● ● ●●● ● ●●●●●● ● ● ● ● ●●●●●●● ● ● ● ● ●● ● ●●● ● ●●●●●●● ●●●●●●●●●●●● ●● ● ●●● ● ●● ● ●● ●●●● ● ● ●● ● ●● ●● ●●● ●●●●●●●● ●●●●●●●●●● ● ●●● ● ● ●● ● ●● ●●● ●● ●● ●●●●● ●● ●●●● ● ● ●●●●●●● ● ● ● ● ●●●●● ●● ●●●●● ●●●●● ● ●●●●● ●●● ●●●●●●●● ●●● ●● ●● ● ●● ●●●●● ● ●● ●●●● ●●●● ●●●●●●●●●●●●●●●●● ●●●●●●●●●● ●● ● ●● ●● ●●●●● ●●●● ●●●●●●●●●●●●●●● ●●●●●● ●●●●●●●●●●● ●●●● ●●●●●●●● ● ● ●●● ●●● ●●●●● ●●●● ●●●●●●●●●●●●●●● ●●●● ● ●●●●● ●● ● ●● ● ●●●●●●●● ●● ● ●●● ●● ● ●●● ●●●●●●●●●●●●●●●●●●●● ●●● ●●●●● ●● ● ●●●● ●●● ●● ●●●●● ●● ● ●●●● ● ● ●●

+HLJKW 3UHHFODPSVLD +HLJKW

SMOX PRNP RASSF2 SLC23A2

LOC728228 PRND

ADRA1D PRNT

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MICA HCG26 NFKBIL1 MIR6832 LY 6 G 6 F VARS NEU1 C2 STK19 ATF6B PBX2 C6orf10

HCP5 MCCD1 AIF1 LY6G5C MSH5 HSPA1B LOC102060414 TNXB PRRT1

MICB LTA BAG6 LY6G6E LSM2 EHMT2 CFB C4A FKBPL NOTCH4

DDX39B PRRC2A LY6G6D HSPA1L ZBTB12 DXO LOC100507547 ATP6V1G2−DDX39B APOM C6orf25 HSPA1A NELFE PPT2 JHQHV SNORD117 C6orf47 CLIC1 C6orf48 MIR1236 PPT2−EGFL8 RPLWWHG SNORD84 GPANK1 SAPCD1 SLC44A4 SKIV2L EGFL8

ATP6V1G2 CSNK2B VWA7 C4B AGPAT1

TNF LY 6 G 5 B SNORD48 C4B_2 MIR6721

LTB ABHD16A SNORD52 CYP21A2 RNF5

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3RVLWLRQRQFKU 0E 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. 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. Supplementary Figure 9. 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. Supplementary Figure 10. 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). a. %0,UVíApproach 3

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3RVLWLRQRQFKU 0E Supplementary Figure 11. 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. Supplementary Figure 12. 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). Supplementary Figure 13. Comparison of estimated effect estimates (+/-SE) for smokers (GIANT N up to 51,080; UKBB N up to 13,416) and nonsmokers (GIANT N up to 190,178; UKBB N up to 105,218) per risk allele in GIANT only and UKBiobank validation analysis for (a) BMI stratified by smoking status, (b) BMI adjusted for smoking status, (c) WCadjBMI stratified by smoking status, (d) WCadjBMI adjusted for smoking status,(e) WHRadjBMI stratified by smoking status, and (f) WHRadjBMI adjusted for smoking status for each novel and GxSMK SNP in Tables 1-4. All loci are ordered by chromosome and position. Supplementary Table 1. Study design, sample size, and data quality control for contributing genome‐wide association study and Metabochip cohorts.

GWAS DATA Study Sample QC Anthropometric assessment method Total WHR and BMI were Study References Study design Ancestry Region genotyped Short name Full name Call rate* sample exclusion criteria BMI WHR assessed at the (PMID) sample size (N) same t