SUPPLEMENTARY APPENDIX - BMJ

1

SUPPLEMENTARY APPENDIX

Study Descriptions ............................................................................................................................................... 2

Supplementary Figures ....................................................................................................................................... 4

References ........................................................................................................................................................... 5

Supplementary material BMJ Open Diab Res Care

doi: 10.1136/bmjdrc-2019-001091:e001091. 8 2020;BMJ Open Diab Res Care, et al. Leong A

2

Study Descriptions

1. The Multi-Ethnic Cohort (MEC)1 is a closed cohort formed by combining two

existing population-based studies conducted between 2004 to 2007, the

Singapore Prospective Study Program (SP2) and the Singapore Cardiovascular

Cohort Study (SCCS2), with additional recruitment of participants between 2007 to

2010. A subset of Chinese participants from SP2 was selected as controls for a

type 2 diabetes case control association study. Details of the genotyping and

quality control (QC) has been described elsewhere.2

2. The Living Biobank study3 is designed for a phenotype-by-genotype-recall study,

and included non-diseased Chinese and Malay participants with consent for re-

contact selected from the Multi-Ethnic Cohort1 and Singapore Health Study 2012.4

3. The Singapore Epidemiology of Eye Diseases (SEED) studies aim to document

the prevalence, incidence, risk factors and complications of eye diseases in multi-

ethnic Singapore populations. The SEED studies include the Singapore Malay

Eye Study (SiMES),5 the Singapore Chinese Eye Study (SCES),6 and the

Singapore Indian Eye Study (SINDI).6 These studies were conducted in the

south-western part of Singapore and individuals aged 40-79 were eligible to

participate in these population-based studies. Details of genotyping performed in

the SEED studies have been described elsewhere.2,7,8

4. The Singapore Chinese Health Study (SCHS-MI)9,10 is a nested case control

study of myocardial infraction (MI), consisting of 744 cases and 644 controls aged

between 45 to 74. Cases were ascertained from Singapore Registry of Births and

Deaths and the Hospital Discharge Database and reviewed by a cardiologist.

5. The Beijing Eye Study (BES)8,11 is a population-based study conducted in 2001

to examine various ocular related measurements and risk factors in individuals



3

aged ≥40 from seven communities in both rural and urban regions of Greater

Beijing. In 2006, the participants were follow-up and biological specimens were

collected.



4

Supplementary Figures

Supplementary Figure 1. Chr X quality control (QC), imputation, association and

meta-analysis.

Supplementary Figure 2. Regional association plot centered on G6PD loci, for (A)

men, (B) women, and (C) sex-combined.

Supplementary Figure 3. Forest plot of association of G6PD-Canton (rs72554665)

with HbA1c by sex. (A) Men, assuming haploid; (B) Women.

Supplementary Figure 4. Regional association plot at G6PD locus for men.

Variants are colored based on LD with the lead variants, G6PD-Canton

(rs72554665) (blue) and G6PD-Kaiping (rs72554665) (red) based on Living Biobank

Chinese data.

Supplementary Figure 5. Forest plot of association at lead secondary signal

(rs190054725).



5

References

1. Tan KHX, Tan LWL, Sim X, et al. Cohort Profile: The Singapore Multi-Ethnic

Cohort (MEC) study. Int J Epidemiol 2018.

2. Sim X, Ong RT, Suo C, et al. Transferability of type 2 diabetes implicated loci

in multi-ethnic cohorts from Southeast Asia. PLoS Genet 2011; 7(4): e1001363.

3. Dou J, Sun B, Sim X, et al. Estimation of kinship coefficient in structured and

admixed populations using sparse sequencing data. PLoS Genet 2017; 13(9):

e1007021.

4. Win AM, Yen LW, Tan KH, Lim RB, Chia KS, Mueller-Riemenschneider F.

Patterns of physical activity and sedentary behavior in a representative sample of a

multi-ethnic South-East Asian population: a cross-sectional study. BMC Public

Health 2015; 15: 318.

5. Foong AW, Saw SM, Loo JL, et al. Rationale and methodology for a

population-based study of eye diseases in Malay people: The Singapore Malay eye

study (SiMES). Ophthalmic Epidemiol 2007; 14(1): 25-35.

6. Lavanya R, Jeganathan VS, Zheng Y, et al. Methodology of the Singapore

Indian Chinese Cohort (SICC) eye study: quantifying ethnic variations in the

epidemiology of eye diseases in Asians. Ophthalmic Epidemiol 2009; 16(6): 325-36.

7. Chen P, Ong RT, Tay WT, et al. A study assessing the association of glycated

hemoglobin A1C (HbA1C) associated variants with HbA1C, chronic kidney disease

and diabetic retinopathy in populations of Asian ancestry. PLoS One 2013; 8(11):

e79767.

8. Liao J, Su X, Chen P, et al. Meta-analysis of genome-wide association studies

in multiethnic Asians identifies two loci for age-related nuclear cataract. Hum Mol

Genet 2014; 23(22): 6119-28.



6

9. Hankin JH, Stram DO, Arakawa K, et al. Singapore Chinese Health Study:

development, validation, and calibration of the quantitative food frequency

questionnaire. Nutr Cancer 2001; 39(2): 187-95.

10. Dorajoo R, Sun Y, Han Y, et al. A genome-wide association study of n-3 and

n-6 plasma fatty acids in a Singaporean Chinese population. Genes Nutr 2015;

10(6): 53.

11. Jonas JB, Xu L, Wang YX. The Beijing Eye Study. Acta Ophthalmol 2009;

87(3): 247-61.













Men Women Men Women Men Women Men Women

Chinese Human610-Quadv1419

(142/277)

52.6

(8.6)

51.2

(8.3)

4.00

(0.39)

4.14

(0.41)- -

5.26

(0.64)

5.23

(0.56)

Chinese HumanOmniExpress-24v1-0_a309

(126/183)

55.5

(9.7)

53.2

(9.3)

3.98

(0.32)

4.17

(0.38)- -

5.24

(0.56)

5.19

(0.62)

Chinese232

(156/76)

49.5

(12.3)

49.6

(13.7)

5.43

(0.40)

5.38

(0.44)- -

4.74

(0.42)

4.66

(0.48)

Indian565

(229/336)

47.7

(8.2)

47.7

(7.7)

5.72

(0.31)

5.74

(0.34)- -

5.07

(0.49)

4.99

(0.45)


(791/780)

58.2

(9.6)

57.1

(9.1)

5.79

(0.31)

5.83

(0.27)

5.88

(1.20)

5.55

(1.08)- -

Chinese HumanOmniExpress-12v1-Multi_c507

(253/254)

60.1

(9.7)

58.5

(9.4)

5.63

(0.35)

5.52

(0.25)

5.71

(1.25)

5.37

(0.98)- -

cases Chinese452

(306/146)

65.6

(7.9)

68.9

(7.7)

5.73

(0.41)

5.77

(0.34)- - - -

controls Chinese999

(624/375)

65.4

(7.8)

68.0

(7.6)

5.67

(0.40)

5.73

(0.34)- - - -

Chinese Human1M-Duov3790

(511/279)

48.0

(10.6)

44.8

(9.1)

5.46

(0.40)

5.40

(0.42)- -

4.78

(0.45)

4.61

(0.45)


(163/662)

45.9

(11.2)

48.1

(10.5)

5.47

(0.41)

5.46

(0.41)- -

4.81

(0.49)

4.64

(0.48)

Chinese HumanOmniExpress-24v1-0_a1206

(612/594)

35.2

(11.7)

35.3

(8.9)

5.55

(0.32)

5.58

(0.30)- -

4.72

(0.41)

4.63

(0.38)

Malay HumanOmniExpress-24v1-0_a1003

(487/516)

37.5

(12.3)

34.9

(8.1)

5.58

(0.31)

5.57

(0.32)- -

4.86

(0.50)

4.72

(0.49)

SIMES Singapore Malay Eye Study cohort population-based Malay 17365815 21490949 Human610-Quadv11692

(835/857)

58.2

(11.5)

56.8

(10.9)

5.74

(0.37)

5.68

(0.38)

5.38

(1.20)

5.23

(1.02)- -

SINDI Singapore Indian Eye Study cohort population-based Indian 19995197 21490949 Human610-Quadv11486

(732/754)

56.9

(9.8)

56.0

(9.6)

5.69

(0.35)

5.68

(0.35)- - - -

Mean and standard deviation (in parentheses) were presented for HbA1c and age.

Samples included in association analyses are non-diabetic: no self-reported diabetes and not on diabetes medication use and (fasting glucose <7mmol/l or random glucose <11.1mmol/l where available) and HbA1c<6.5%.

Random glucose Fasting glucoseSupplementary Table 1. Study sample characteristics.

Beijing Eye Study

Singapore Prospective Study Program

Singapore Chinese Eye Study

Singapore Chinese Health Study

Living Biobank

Multi-Ethnic Cohort

population-based

cohort

myocardial infraction

case control

cohort population-based

HumanOmniZhongHua-8v1_a

19426355

19995197

SCHS

HbA1c (%)Study design PMID

cohort 24951543

24244560

26584805

Living Biobank

Age (Years)Sample size

(Men/Women)Genotyping array / Sequencing platformEthnic groupSample ascertainmentStudy designStudy nameStudy acroymn

SP2

SCES

BES

Illumina HiSeq 4000 and

Illumia Rapid Capture Exome enrichment kitMEC

GWAS

PMID

cohort21490949,

24244560

population-based

28961250

31118516

cohort

population-based

population-based

29452397, 25884916

29452397

2348145, 9328546,

10333940, 11693972,

19406920, 29452397

11759279, 20227258



Study acroymn Ethnic group Genotyping arrayMapped to

hg19Call rate <0.95

HWE P-value <10-6

in females

Not present

in 1000GIndels

ΔAF >0.2 or

0.3

Palindromic

variants MAF >0.4

Allele

mismatchDuplicates

Final QC+

variants

Chinese Human610-Quadv1 18190 3186 3 467 0 1 16 1250 0 13267

Chinese HumanOmniExpress-24v1-0_a 18363 689 71 663 0 3 11 2410 0 14516


Chinese HumanOmniExpress-12v1-Multi_c 18788 419 2 680 0 3 13 3080 0 14591

SCHS Chinese HumanOmniZhongHua-8v1_a 23799 662 16 580 0 12 51 662 1364 20452

Chinese Human1M-Duov3 46639 5568 5 4592 4 4 92 8533 2 27839


Chinese HumanOmniExpress-24v1-0_a 6 12 1541 0 15677

Malay HumanOmniExpress-24v1-0_a 7 12 1541 0 15676

SIMES Malay Human610-Quadv1 18027 3072 2 458 0 1 16 771 0 13707

SINDI Indian Human610-Quadv1 18027 3078 8 456 0 1 21 523 0 13940

Supplementary Table 2. Study-level chromosome X variant array quality control.

BES

SCES

SP2

ΔAF >0.2 or 0.3 refers to allele frequency difference threshold with 1000G comparisons (EAS for Chinese at 0.2; SAS for Indian at 0.3; EAS for Malay at 0.3).

Final QC+ SNPs were used for imputation.

18363 389 3 735 0Living Biobank



Sensitivity Concordance Sensitivity ConcordanceMale 632 2459 0.992 4/4 (1.0) 0.995 5/5 (1.0) 1.000

Female 629 2496 0.977 8/8 (1.0) 0.986 11/11 (1.0) 1.000Male 596 2683 0.993 - - - -

Female 591 2683 0.978 - - - -Male 267 2123 0.990 - - - -

Female 742 2211 0.979 15/17 (0.882) 0.982 - -Male 574 2582 0.994 11/11 (1.0) 0.990 - -

Female 313 2561 0.986 9/10 (0.9) 0.981 - -Male 599 2984 0.993 - - - -

Female 518 2914 0.981 - - - -

Sensitivity refers to proportion of effect allele imputed correctly against the whole exome as gold standard. Concordance metrics are shown for all overlapping variants with hard genotype calls in both exome sequencing and imputed data.

Supplementary Table 3. Concordance between exome sequenced and imputed genotypes for variants on chromosome X.Overlapping variants

(Rsq>0.3)

Overall

concordance

G6PD -Canton G6PD -Kaiping

Samples include both individuals with and without diabetes.

Study acroymn Genotyping array Ethnic group Sex Overlapping samples

SINDI Human610-Quadv1

Chinese

SP2

Living Biobank

Human1M-Duov3

Malay

Indian

HumanOmniExpress-24v1-0_a

ChineseHuman610-Quadv1



N # of studies EAF Effect SE P -value N # of studies EAF Effect SE P -value N EAF Effect SE P -value P -het

rs782517039 X 152548691 G C intergenic 2538 4 0.009 -0.31 0.04 7.91E-09 2411 4 0.008 -0.09 0.06 1.50E-01 4949 0.008 -0.24 0.03 2.78E-07 1.12E-03

rs199621559 X 152653880 ACCCTGAG A intergenic 3860 6 0.020 -0.20 0.03 2.50E-07 3630 8 0.019 -0.13 0.04 3.21E-03 7490 0.020 -0.18 0.02 8.72E-09 2.35E-01

rs782333428 X 152654882 CCA C intergenic 2538 4 0.013 -0.35 0.04 6.48E-11 2944 6 0.011 -0.15 0.05 1.53E-02 5482 0.012 -0.28 0.03 4.94E-10 3.12E-03

. X 152656962 C T intergenic 2538 4 0.013 -0.33 0.04 4.45E-10 3824 7 0.010 -0.18 0.05 4.36E-03 6362 0.011 -0.27 0.03 7.75E-10 2.19E-02

. X 152666564 C A upstream_gene U82695.5 1135 2 0.013 -0.27 0.06 2.76E-04 3090 7 0.008 -0.22 0.05 1.34E-05 4225 0.009 -0.24 0.04 2.05E-08 5.52E-01

rs192820967 X 152707771 A G regulatory 2538 4 0.018 -0.22 0.03 1.31E-09 2944 6 0.015 -0.07 0.04 5.29E-02 5482 0.016 -0.17 0.02 2.91E-08 1.49E-03

rs373841096 X 152795192 C A intron ATP2B3 1403 2 0.010 -0.39 0.05 8.49E-10 2036 3 0.008 -0.14 0.07 6.34E-02 3439 0.009 -0.32 0.04 8.93E-08 3.52E-03

rs781851814 X 152996405 C T regulatory_region 2844 5 0.016 -0.35 0.03 1.44E-19 2836 6 0.014 -0.20 0.04 8.67E-06 5680 0.015 -0.30 0.02 1.35E-21 2.85E-03

. X 153104014 C T upstream_gene CYCSP45 2844 5 0.020 -0.32 0.03 7.30E-22 3947 8 0.014 -0.18 0.04 4.58E-04 6791 0.017 -0.27 0.02 6.10E-19 7.80E-04

rs371161739 X 153122712 AAGAG AAG downstream_gene L1CAM 2538 4 0.012 -0.29 0.04 1.05E-07 2690 5 0.009 -0.25 0.06 2.88E-04 5228 0.010 -0.28 0.03 2.87E-10 5.46E-01

rs781895939 X 153330135 A G intron MECP2 2844 5 0.020 -0.34 0.03 1.30E-23 3090 7 0.017 -0.21 0.04 1.22E-07 5934 0.018 -0.30 0.02 5.86E-27 3.23E-03

rs782552292 X 153332795 C T regulatory_region 2844 5 0.021 -0.32 0.03 5.12E-22 3090 7 0.018 -0.20 0.04 5.38E-07 5934 0.020 -0.28 0.02 7.46E-25 3.99E-03

rs782435838 X 153381469 C T intergenic 2232 4 0.019 -0.36 0.04 1.33E-12 2836 6 0.017 -0.21 0.05 4.33E-06 5068 0.018 -0.30 0.03 3.84E-16 1.57E-02

rs149897670 X 153418524 T C missense OPN1LW 1597 4 0.095 -0.23 0.03 1.02E-10 876 4 0.103 -0.19 0.05 3.31E-04 2473 0.098 -0.22 0.02 2.27E-13 4.66E-01

rs782130010 X 153421043 T G intron OPN1LW 1123 2 0.019 -0.46 0.06 3.44E-06 800 3 0.017 -0.41 0.13 2.27E-03 1923 0.018 -0.45 0.05 3.45E-08 7.38E-01

rs190709425 X 153534488 A G intron TKTL1 3747 8 0.073 -0.14 0.02 2.10E-11 3090 7 0.072 -0.08 0.02 1.06E-03 6837 0.072 -0.12 0.01 8.03E-13 4.06E-02

. X 153597853 A G regulatory_region 2232 4 0.016 -0.40 0.03 3.69E-19 2836 6 0.013 -0.25 0.05 2.11E-07 5068 0.014 -0.35 0.03 9.32E-23 8.36E-03

rs781841740 X 153646539 A G intron TAZ 2844 5 0.019 -0.39 0.03 4.50E-26 2836 6 0.016 -0.24 0.04 7.36E-08 5680 0.018 -0.34 0.02 1.72E-29 2.69E-03

rs145693545 X 153687009 T C regulatory_region 4582 9 0.060 -0.11 0.02 4.17E-08 4740 10 0.059 -0.05 0.02 8.36E-03 9322 0.060 -0.09 0.01 1.04E-08 3.55E-02

rs782462814 X 153734352 A G regulatory_region 2844 5 0.022 -0.39 0.03 1.35E-27 2836 6 0.018 -0.23 0.04 9.16E-08 5680 0.020 -0.34 0.02 1.71E-30 6.70E-04

rs72554664 X 153760472 T C missense G6PD 768 2 0.016 -0.56 0.05 3.12E-15 969 2 0.008 -0.39 0.08 7.51E-05 1737 0.012 -0.52 0.04 2.38E-16 7.12E-02

rs72554665 X 153760484 A C missense G6PD 2844 5 0.022 -0.38 0.03 1.25E-27 2836 6 0.018 -0.22 0.04 1.40E-07 5680 0.020 -0.33 0.02 3.00E-30 5.13E-04

rs141157031 X 153893477 G T intergenic 2844 5 0.023 -0.37 0.03 1.50E-27 2836 6 0.019 -0.22 0.04 1.96E-07 5680 0.021 -0.32 0.02 5.73E-30 5.46E-04

rs781989359 X 153893654 A G intergenic 2844 5 0.023 -0.37 0.03 1.51E-27 2836 6 0.019 -0.22 0.04 1.97E-07 5680 0.021 -0.32 0.02 5.82E-30 5.45E-04

rs782121509 X 154010689 T TCTACAA regulatory_region 3331 6 0.021 -0.34 0.03 4.32E-19 3460 7 0.020 -0.14 0.04 6.37E-03 6791 0.020 -0.27 0.02 2.40E-16 1.29E-04

rs3795233 X 154019671 A G intron MPP1 4582 9 0.089 -0.06 0.01 3.57E-08 4923 11 0.086 -0.03 0.01 1.03E-02 9505 0.087 -0.05 0.01 1.40E-08 6.06E-02

rs5945243 X 154027171 A G regulatory_region 4724 10 0.122 -0.06 0.01 2.91E-08 4923 11 0.125 -0.03 0.01 2.64E-02 9647 0.124 -0.05 0.01 4.54E-08 3.30E-02

rs190054725 X 154039603 G A intron MPP1 1236 2 0.009 -0.66 0.06 7.29E-13 969 2 0.009 -0.44 0.10 7.51E-05 2205 0.009 -0.60 0.05 1.29E-15 5.95E-02

rs144356084 X 154059605 G A downstream_gene F8 4582 9 0.089 -0.06 0.01 2.96E-08 4923 11 0.086 -0.03 0.01 1.26E-02 9505 0.087 -0.05 0.01 1.65E-08 5.26E-02

rs201920434 X 154062475 GAGCCC G upstream_gene SMIM9 4582 9 0.061 -0.11 0.01 5.38E-12 4923 11 0.058 -0.06 0.02 7.34E-04 9505 0.060 -0.09 0.01 5.30E-13 2.10E-02

rs34700571 X 154064658 T C 3_prime_UTR F8 1236 2 0.011 -0.56 0.06 4.07E-11 1115 3 0.013 -0.22 0.07 2.15E-03 2351 0.012 -0.42 0.04 5.21E-12 1.94E-04

rs370772371 X 154167861 T C regulatory_region 2844 5 0.023 -0.34 0.02 2.85E-27 3090 7 0.018 -0.20 0.03 1.10E-07 5934 0.020 -0.29 0.02 1.05E-29 7.13E-04

rs781928603 X 154175499 GA G intron F8 2919 7 0.305 -0.07 0.01 6.24E-07 2347 7 0.297 -0.05 0.02 3.74E-03 5266 0.302 -0.06 0.01 1.64E-08 2.71E-01

rs138637045 X 154217608 C G intron F8 4582 9 0.061 -0.12 0.01 1.02E-12 4923 11 0.058 -0.07 0.02 5.03E-04 9505 0.059 -0.10 0.01 9.12E-14 1.36E-02

rs145219253 X 154309293 A T intron BRCC3 4582 9 0.080 -0.09 0.01 7.92E-11 4923 11 0.078 -0.05 0.02 2.89E-03 9505 0.079 -0.08 0.01 2.77E-11 2.61E-02

rs150453895 X 154364023 C T upstream_gene RP11-143H17.1 4582 9 0.080 -0.10 0.01 4.94E-11 4923 11 0.078 -0.05 0.02 7.02E-03 9505 0.079 -0.08 0.01 7.83E-11 1.23E-02

rs182573065 X 154372449 G A intron MTCP1 2844 5 0.025 -0.31 0.02 6.56E-27 3947 8 0.016 -0.18 0.03 6.52E-08 6791 0.019 -0.27 0.02 1.74E-28 4.89E-04

rs781843659 X 154408847 G C intergenic 2844 5 0.025 -0.31 0.02 5.89E-27 3090 7 0.019 -0.17 0.03 3.25E-07 5934 0.022 -0.27 0.02 9.06E-29 2.89E-04

rs148112010 X 154409817 G A intergenic 2844 5 0.026 -0.31 0.02 6.19E-27 3947 8 0.016 -0.18 0.03 5.36E-08 6791 0.020 -0.27 0.02 1.24E-28 4.29E-04

. X 154681796 CT C downstream_gene F8A3 1135 2 0.013 -0.70 0.07 1.94E-16 2690 5 0.006 -0.39 0.09 2.43E-06 3825 0.008 -0.59 0.05 3.35E-17 5.35E-03

rs782120990 X 154773326 GA G intron TMLHE 2844 5 0.018 -0.46 0.03 1.24E-26 1394 4 0.018 -0.18 0.06 1.15E-02 4238 0.018 -0.39 0.03 1.99E-24 1.81E-05

Sex-combined

Supplementary Table 4. Summary of chromosome X associations with HbA1c in East Asians.

Variant name Chr Position EA NEA Annotation GeneMen Women



N EAF Effect SE P -value N EAF Effect SE P -value N EAF Effect SE P -value N EAF Effect SE P -value N EAF Effect SE P -value N EAF Effect SE P -value

Human610-Quadv1 - - - - - - - - - - - - - - - - - - - - - - - - - - - - - -

HumanOmniExpress-24v1-0_a - - - - - - - - - - - - - - - - - - - - - - - - - - - - - -

Chinese - - - - - - - - - - 156 0.03 -0.58 0.09 1.09E-06 - - - - - - - - - - - - - - -

Indian - - - - - - - - - - - - - - - - - - - - - - - - - - - - - -

Human610-Quadv1 791 0.02 -0.33 0.05 3.29E-09 780 0.01 -0.25 0.07 4.23E-04 - - - - - - - - - - - - - - - - - - - -

HumanOmniExpress-12v1-Multi_c - - - - - - - - - - - - - - - - - - - - - - - - - - - - - -

MIa cases 306 0.02 -0.18 0.09 2.46E-01 146 0.02 -0.10 0.15 9.79E-01 - - - - - - - - - - - - - - - - - - - -

MIa controls 624 0.03 -0.56 0.06 3.64E-13 375 0.02 -0.28 0.09 1.78E-02 - - - - - 375 0.01 -0.39 0.23 1.28E-01 - - - - - - - - - -

Human1M-Duov3 511 0.03 -0.46 0.05 9.11E-12 279 0.03 -0.45 0.11 9.58E-05 - - - - - - - - - - - - - - - - - - - -

Human610-Quadv1 - - - - - 662 0.02 -0.24 0.10 1.38E-02 - - - - - - - - - - - - - - - - - - - -

Chinese HumanOmniExpress-24v1-0_a 612 0.01 -0.26 0.07 8.28E-03 594 0.02 -0.04 0.09 6.88E-01 612 0.01 -0.56 0.06 9.59E-11 594 0.01 -0.39 0.09 7.93E-05 - - - - - - - - - -

Malay HumanOmniExpress-24v1-0_a - - - - - - - - - - - - - - - - - - - - - - - - - - - - - -

SIMES Malay Human610-Quadv1 population-based - - - - - - - - - - - - - - - - - - - - 835 0.01 -0.32 0.07 7.21E-05 857 0.01 -0.11 0.09 2.48E-01

SINDI Indian Human610-Quadv1 population-based - - - - - - - - - - - - - - - - - - - - - - - - - - - - -

Effect allele frequency denotes sample-size weighted allele frequency across all studies. P -values are obtained from sample-size weighted meta-analysis using derived inverse normalized residuals of HbA1c (%) after adjustment for age, age2 and first three principal components. Effect and standard error shown are per

allele effect for untransformed HbA1c trait values, assuming that males are homozygous diploid in non pseudo-autosomal region. P -het refers to test of heterogeneity between men and women.

Chr, chromosome; EA, effect allele; NEA, non-effect allele; N, sample size; EAF, effect allele frequency; SE, standard error.

aMyocardial Infraction.

Men Women

BES

SCES

SP2

Living Biobank

Men Women

Chinese

HumanOmniZhongHua-8v1_a

population-based

population-based

Sample ascertainment

population-based

SCHS Chinese

Chinese

Chinese

MEC Illumina HiSeq 4000 population-based

Viangchan (rs137852327)

Men Women

Supplementary Table 5. Summary of association results at three missense G6PD variants by study.

population-based

Study acroymn

Canton (rs72554665) Kaiping (rs72554664)

Genotyping arrayEthnic group



N # of studies EAF Effect SE P -value N # of studies EAF Effect SE P -value N EAF Effect SE P -value

rs782517039 X 152548691 G C 2538 4 0.01 -0.25 0.04 4.85E-07 2411 4 0.01 -0.07 0.06 2.35E-01 4949 0.01 -0.19 0.03 1.09E-05

rs199621559 X 152653880 ACCCTGAG A 2538 4 0.02 -0.22 0.03 3.36E-07 2242 5 0.02 -0.15 0.05 4.75E-03 4780 0.02 -0.20 0.03 1.94E-08

rs782333428 X 152654882 CCA C 2538 4 0.01 -0.29 0.04 8.49E-09 2690 5 0.01 -0.15 0.06 2.26E-02 5228 0.01 -0.24 0.03 2.02E-08

. X 152656962 C T 2538 4 0.01 -0.27 0.04 1.41E-08 2690 5 0.01 -0.13 0.06 3.09E-02 5228 0.01 -0.22 0.03 4.67E-08

. X 152666564 C A 1135 2 0.01 -0.04 0.06 6.63E-01 2836 6 0.01 -0.16 0.06 1.85E-02 3971 0.01 -0.09 0.04 2.63E-02

rs192820967 X 152707771 A G 2538 4 0.02 -0.18 0.03 1.23E-07 2690 5 0.02 -0.07 0.04 5.87E-02 5228 0.02 -0.14 0.02 5.51E-07

rs373841096 X 152795192 C A 1403 2 0.01 -0.32 0.05 4.36E-06 2036 3 0.01 -0.12 0.07 1.22E-01 3439 0.01 -0.26 0.04 4.22E-05

rs781851814 X 152996405 C T 2844 5 0.02 -0.05 0.05 5.69E-01 2836 6 0.01 -0.05 0.06 4.78E-01 5680 0.01 -0.05 0.04 3.68E-01

. X 153104014 C T 2844 5 0.02 -0.07 0.05 4.47E-01 2836 6 0.02 -0.01 0.06 8.85E-01 5680 0.02 -0.05 0.04 5.25E-01

rs371161739 X 153122712 AAGAG AAG 2538 4 0.01 -0.29 0.04 8.04E-09 2690 5 0.01 -0.24 0.06 2.61E-04 5228 0.01 -0.28 0.03 4.11E-11

rs781895939 X 153330135 A G 2844 5 0.02 -0.10 0.06 4.19E-01 2836 6 0.02 -0.05 0.08 7.79E-01 5680 0.02 -0.08 0.05 4.45E-01

rs782552292 X 153332795 C T 2844 5 0.02 -0.05 0.05 6.56E-01 2836 6 0.02 0.00 0.08 9.93E-01 5680 0.02 -0.04 0.04 7.60E-01

rs782435838 X 153381469 C T 2232 4 0.02 0.12 0.06 4.29E-02 2836 6 0.02 -0.06 0.06 4.42E-01 5068 0.02 0.04 0.04 4.50E-01

rs149897670 X 153418524 T C 1441 3 0.10 -0.06 0.04 4.85E-01 800 3 0.10 -0.10 0.06 3.49E-01 2241 0.10 -0.06 0.03 2.65E-01

rs782130010 X 153421043 T G 1123 2 0.02 -0.47 0.06 1.53E-07 800 3 0.02 -0.40 0.13 9.87E-04 1923 0.02 -0.46 0.05 1.07E-09

rs190709425 X 153534488 A G 2844 5 0.08 -0.01 0.02 9.74E-01 2836 6 0.07 -0.01 0.03 8.12E-01 5680 0.07 -0.01 0.02 8.85E-01

. X 153597853 A G 2232 4 0.02 0.17 0.08 1.64E-01 2836 6 0.01 -0.03 0.11 7.85E-01 5068 0.01 0.10 0.06 4.77E-01

rs781841740 X 153646539 A G 2844 5 0.02 0.00 0.11 9.03E-01 2836 6 0.02 -0.17 0.13 7.07E-01 5680 0.02 -0.07 0.09 7.26E-01

rs145693545 X 153687009 T C 2844 5 0.06 -0.01 0.03 9.19E-01 2836 6 0.06 0.01 0.03 8.24E-01 5680 0.06 -0.01 0.02 9.32E-01

rs782462814 X 153734352 A G 2844 5 0.02 0.47 0.72 7.89E-01 2836 6 0.02 -1.10 0.68 9.94E-01 5680 0.02 -0.36 0.49 8.56E-01

rs72554664 X 153760472 T C 612 1 0.01 -0.56 0.06 7.57E-11 969 2 0.01 -0.39 0.08 5.99E-05 1581 0.01 -0.50 0.05 8.42E-13

rs72554665 X 153760484 A C - - 0.02 - - - - - 0.02 - - - - - - - -

rs141157031 X 153893477 G T 2844 5 0.02 -0.10 0.25 6.43E-01 2836 6 0.02 0.47 0.59 8.41E-01 5680 0.02 -0.02 0.23 6.41E-01

rs781989359 X 153893654 A G 2844 5 0.02 -0.10 0.25 6.43E-01 2836 6 0.02 0.48 0.58 8.40E-01 5680 0.02 -0.01 0.23 6.40E-01

rs782121509 X 154010689 T TCTACAA 2844 5 0.02 -0.18 0.04 3.97E-03 2690 5 0.02 0.02 0.06 5.96E-01 5534 0.02 -0.12 0.04 9.37E-02

rs3795233 X 154019671 A G 2844 5 0.08 -0.02 0.01 4.03E-01 2836 6 0.08 0.00 0.02 8.21E-01 5680 0.08 -0.01 0.01 6.70E-01

rs5945243 X 154027171 A G 2844 5 0.11 -0.02 0.01 4.04E-01 2836 6 0.11 -0.01 0.02 7.51E-01 5680 0.11 -0.01 0.01 4.18E-01

rs190054725 X 154039603 G A 1236 2 0.01 -0.66 0.06 1.07E-14 969 2 0.01 -0.43 0.10 6.00E-05 2205 0.01 -0.60 0.05 4.67E-17

rs144356084 X 154059605 G A 2844 5 0.08 -0.02 0.01 4.90E-01 2836 6 0.08 0.00 0.02 7.66E-01 5680 0.08 -0.01 0.01 7.85E-01

rs201920434 X 154062475 GAGCCC G 2844 5 0.06 -0.03 0.02 5.07E-01 2836 6 0.06 0.00 0.03 8.16E-01 5680 0.06 -0.02 0.02 7.64E-01

rs34700571 X 154064658 T C 1236 2 0.01 -0.55 0.05 1.40E-12 1115 3 0.01 -0.21 0.07 1.74E-03 2351 0.01 -0.42 0.04 4.31E-13

rs370772371 X 154167861 T C 2844 5 0.02 -0.23 0.07 6.50E-01 2836 6 0.02 -0.02 0.11 9.99E-01 5680 0.02 -0.17 0.06 7.51E-01

rs781928603 X 154175499 GA G 2053 4 0.31 -0.05 0.01 9.15E-03 1394 4 0.31 -0.03 0.02 3.13E-01 3447 0.31 -0.04 0.01 8.43E-03

rs138637045 X 154217608 C G 2844 5 0.06 -0.03 0.02 4.65E-01 2836 6 0.06 0.00 0.03 8.09E-01 5680 0.06 -0.02 0.02 7.32E-01

rs145219253 X 154309293 A T 2844 5 0.07 -0.03 0.02 3.32E-01 2836 6 0.08 0.00 0.02 9.38E-01 5680 0.07 -0.02 0.01 5.32E-01

rs150453895 X 154364023 C T 2844 5 0.08 -0.03 0.02 2.88E-01 2836 6 0.08 0.01 0.02 7.17E-01 5680 0.08 -0.02 0.01 6.25E-01

rs182573065 X 154372449 G A 2844 5 0.02 -0.16 0.06 7.36E-01 2836 6 0.02 0.12 0.11 6.47E-01 5680 0.02 -0.10 0.05 9.30E-01

rs781843659 X 154408847 G C 2844 5 0.02 -0.17 0.06 7.27E-01 2836 6 0.02 0.12 0.11 6.36E-01 5680 0.02 -0.10 0.05 9.28E-01

rs148112010 X 154409817 G A 2844 5 0.03 -0.17 0.06 7.30E-01 2836 6 0.02 0.12 0.11 6.32E-01 5680 0.02 -0.10 0.05 9.23E-01

. X 154681796 CT C 1135 2 0.01 0.09 0.12 7.89E-01 2690 5 0.01 0.06 0.15 9.47E-01 3825 0.01 0.08 0.09 9.29E-01

rs782120990 X 154773326 GA G 2844 5 0.02 -0.30 0.08 7.30E-01 1394 4 0.02 0.41 0.20 4.27E-01 4238 0.02 -0.20 0.07 8.61E-01


Supplementary Table 6. Conditional analyses on G6PD -Canton (rs72554665).

Samples included in association analyses are non-diabetic: no self-reported diabetes and not on diabetes medication use and (fasting glucose <7mmol/l or random glucose <11.1mmol/l where available) and

HbA1c<6.5%.

Variant name Chr Position EA NEAMen Women Sex-combined

For the number of studies, samples genotyped on different arrays were analysed separately. For SCHS, cases and controls were analysed separately.Effect allele frequency denotes sample-size weighted allele frequency across all studies. P -values are obtained from sample-size weighted meta-analysis using derived inverse normalized residuals of HbA1c

(%) after adjustment for age, age2 and first three principal components. Effect and standard error shown are per allele effect for untransformed HbA1c trait values, assuming that males are homozygous

diploid in non pseudo-autosomal region. P -het refers to test of heterogeneity between men and women.



N EAF Effect SE P -value N EAF Effect SE P -value N EAF Effect SE P -value N EAF Effect SE P -value

rs782517039 X 152548691 G C 612 0.01 -0.38 0.07 2.12E-04 612 0.01 0.01 0.08 9.73E-01 612 0.01 -0.38 0.07 1.48E-04 612 0.01 0.01 0.08 9.68E-01

rs199621559 X 152653880 ACCCTGAG A 612 0.02 -0.28 0.06 4.29E-03 612 0.02 0.06 0.07 5.30E-01 612 0.02 -0.28 0.06 2.92E-03 612 0.02 0.05 0.07 5.47E-01

rs782333428 X 152654882 CCA C 612 0.01 -0.42 0.07 4.00E-05 612 0.01 0.00 0.09 9.40E-01 612 0.01 -0.43 0.07 2.58E-05 612 0.01 0.00 0.08 9.40E-01

- X 152656962 C T 612 0.01 -0.47 0.08 3.03E-05 612 0.01 0.03 0.09 8.78E-01 612 0.01 -0.47 0.08 1.93E-05 612 0.01 0.02 0.09 8.75E-01

- X 152666564 C A - - - - - - - - - - - - - - - - - - - -

rs192820967 X 152707771 A G 612 0.02 -0.31 0.05 2.23E-05 612 0.02 -0.06 0.06 4.09E-01 612 0.02 -0.32 0.05 1.48E-05 612 0.02 -0.06 0.06 4.12E-01

rs373841096 X 152795192 C A 612 0.01 -0.47 0.06 2.04E-07 612 0.01 -0.01 0.09 8.99E-01 612 0.01 -0.48 0.06 1.08E-07 612 0.01 -0.01 0.09 9.11E-01

rs781851814 X 152996405 C T 612 0.01 -0.35 0.09 1.31E-03 612 0.01 -0.33 0.08 5.65E-04 612 0.01 -0.26 0.12 1.53E-01 612 0.01 -0.21 0.11 1.90E-01

- X 153104014 C T 612 0.01 -0.24 0.07 9.11E-03 612 0.01 -0.25 0.07 2.52E-03 612 0.01 -0.08 0.12 7.18E-01 612 0.01 -0.09 0.11 6.61E-01

rs371161739 X 153122712 AAGAG AAG 612 0.01 -0.45 0.06 7.90E-07 612 0.01 0.08 0.10 6.51E-01 612 0.01 -0.46 0.06 3.53E-07 612 0.01 0.06 0.10 6.80E-01

rs781895939 X 153330135 A G 612 0.01 -0.27 0.07 2.35E-03 612 0.01 -0.28 0.07 5.17E-04 612 0.01 -0.19 0.16 7.05E-01 612 0.01 -0.20 0.15 6.59E-01

rs782552292 X 153332795 C T 612 0.02 -0.18 0.06 3.28E-02 612 0.02 -0.19 0.06 1.17E-02 612 0.02 0.05 0.12 6.78E-01 612 0.02 0.05 0.11 7.20E-01

rs782435838 X 153381469 C T - - - - - - - - - - - - - - - - - - - -

rs149897670 X 153418524 T C - - - - - - - - - - - - - - - - - - - -

rs782130010 X 153421043 T G 612 0.02 -0.56 0.07 2.16E-09 612 0.02 -0.02 0.14 9.02E-01 612 0.02 -0.57 0.06 8.44E-10 612 0.02 -0.04 0.13 8.92E-01

rs190709425 X 153534488 A G 612 0.06 -0.06 0.04 3.03E-01 612 0.06 -0.07 0.04 1.45E-01 612 0.06 0.03 0.05 5.78E-01 612 0.06 0.01 0.04 7.45E-01

- X 153597853 A G - - - - - - - - - - - - - - - - - - - -

rs781841740 X 153646539 A G 612 0.01 -0.32 0.08 2.12E-03 612 0.01 -0.33 0.08 4.18E-04 612 0.01 -0.71 0.36 8.23E-01 612 0.01 -0.69 0.33 7.56E-01

rs145693545 X 153687009 T C 612 0.05 -0.10 0.05 8.33E-02 612 0.05 -0.11 0.04 2.91E-02 612 0.05 -0.01 0.05 9.73E-01 612 0.05 -0.02 0.05 7.69E-01

rs782462814 X 153734352 A G 612 0.01 -0.27 0.07 6.00E-03 612 0.01 -0.28 0.07 1.31E-03 612 0.01 -2.09 1.18 8.57E-01 612 0.01 -2.06 1.09 9.52E-01

rs72554664 X 153760472 T C 612 0.01 -0.56 0.06 9.59E-11 - 0.01 - - - 612 0.01 -0.56 0.06 4.62E-11 0.01 - - -

rs72554665 X 153760484 A C 612 0.01 -0.26 0.07 8.28E-03 612 0.01 -0.27 0.07 1.90E-03 0.01 - - - - 0.01 - - -

rs141157031 X 153893477 G T 612 0.01 -0.22 0.07 1.40E-02 612 0.01 -0.23 0.06 3.64E-03 612 0.01 0.16 0.28 6.77E-01 612 0.01 0.16 0.26 7.72E-01

rs781989359 X 153893654 A G 612 0.01 -0.22 0.07 1.40E-02 612 0.01 -0.23 0.06 3.66E-03 612 0.01 0.17 0.28 6.76E-01 612 0.01 0.16 0.26 7.71E-01

rs782121509 X 154010689 T TCTACAA 612 0.02 -0.14 0.06 8.75E-02 612 0.02 -0.15 0.05 3.35E-02 612 0.02 0.01 0.08 7.36E-01 612 0.02 0.00 0.08 8.86E-01

rs3795233 X 154019671 A G 612 0.07 -0.06 0.03 7.35E-02 612 0.07 -0.07 0.02 2.62E-02 612 0.07 -0.01 0.03 8.18E-01 612 0.07 -0.02 0.03 6.04E-01

rs5945243 X 154027171 A G 612 0.09 -0.05 0.02 1.15E-01 612 0.09 -0.06 0.02 4.03E-02 612 0.09 -0.01 0.03 8.75E-01 612 0.09 -0.02 0.02 6.12E-01

rs190054725 X 154039603 G A 612 0.01 -0.72 0.08 9.98E-11 612 0.01 -0.19 1.90 9.14E-01 612 0.01 -0.73 0.08 4.67E-11 612 0.01 -0.61 1.88 9.40E-01

rs144356084 X 154059605 G A 612 0.07 -0.06 0.03 7.26E-02 612 0.07 -0.07 0.02 2.55E-02 612 0.07 -0.01 0.03 8.18E-01 612 0.07 -0.02 0.03 6.01E-01

rs201920434 X 154062475 GAGCCC G 612 0.05 -0.08 0.03 7.35E-02 612 0.05 -0.09 0.03 2.50E-02 612 0.05 0.00 0.04 8.67E-01 612 0.05 -0.01 0.04 9.24E-01

rs34700571 X 154064658 T C 612 0.01 -0.75 0.08 9.44E-11 612 0.01 -0.25 0.76 8.92E-01 612 0.01 -0.75 0.08 4.03E-11 612 0.01 -0.46 0.75 9.06E-01

rs370772371 X 154167861 T C 612 0.02 -0.15 0.05 5.20E-02 612 0.02 -0.16 0.05 1.84E-02 612 0.02 0.21 0.15 4.05E-01 612 0.02 0.21 0.14 4.72E-01

rs781928603 X 154175499 GA G 612 0.30 -0.05 0.02 2.46E-01 612 0.30 -0.01 0.02 9.03E-01 612 0.30 -0.03 0.02 7.13E-01 612 0.30 0.02 0.02 2.96E-01

rs138637045 X 154217608 C G 612 0.05 -0.08 0.04 8.12E-02 612 0.05 -0.09 0.03 2.79E-02 612 0.05 0.00 0.05 8.01E-01 612 0.05 -0.01 0.04 9.94E-01

rs145219253 X 154309293 A T 612 0.06 -0.07 0.03 8.22E-02 612 0.06 -0.08 0.03 2.83E-02 612 0.06 -0.01 0.04 9.87E-01 612 0.06 -0.02 0.03 7.57E-01

rs150453895 X 154364023 C T 612 0.06 -0.07 0.03 7.74E-02 612 0.06 -0.08 0.03 2.64E-02 612 0.06 -0.01 0.04 9.54E-01 612 0.06 -0.02 0.03 7.31E-01

rs182573065 X 154372449 G A 612 0.02 -0.11 0.05 1.77E-01 612 0.02 -0.11 0.04 8.53E-02 612 0.02 0.15 0.09 2.31E-01 612 0.02 0.15 0.08 2.75E-01

rs781843659 X 154408847 G C 612 0.02 -0.11 0.05 1.80E-01 612 0.02 -0.11 0.04 8.78E-02 612 0.02 0.15 0.09 2.28E-01 612 0.02 0.15 0.08 2.70E-01

rs148112010 X 154409817 G A 612 0.02 -0.11 0.05 1.83E-01 612 0.02 -0.11 0.04 8.89E-02 612 0.02 0.15 0.09 2.24E-01 612 0.02 0.15 0.08 2.67E-01

- X 154681796 CT C - - - - - - - - - - - - - - - - - - - -

rs782120990 X 154773326 GA G 612 0.01 -0.18 0.08 1.78E-01 612 0.01 -0.19 0.08 8.54E-02 612 0.01 0.26 0.16 2.31E-01 612 0.01 0.26 0.15 2.76E-01


Conditioned on bothSupplementary Table 7. Reciprocal conditional analyses on G6PD -Kaiping (rs72554664) and G6PD- Canton (rs72554665) in Living Biobank Chinese males.

Conditioned on CantonConditioned on KaipingVariant name Chr Position EA NEA

Unconditioned

Effect allele frequency denotes sample-size weighted allele frequency across all studies. P -values are obtained from sample-size weighted meta-analysis using derived inverse normalized residuals of HbA1c (%) after

adjustment for age, age2 and first three principal components. Effect and standard error shown are per allele effect for untransformed HbA1c trait values, assuming that males are homozygous diploid in non pseudo-

autosomal region. P -het refers to test of heterogeneity between men and women.



N # of studies EAF Effect SE P -value N # of studies EAF Effect SE P -value N EAF Effect SE P -value P -het

rs137852327 Viangchang X 153761337 T C 835 1 0.009 -0.32 0.07 7.21E-05 857 1 0.011 -0.11 0.09 2.48E-01 1692 0.010 -0.24 0.06 3.06E-04 7.18E-02

rs137852327a Viangchang X 153761337 T C 1331 2 0.008 -0.31 0.06 3.44E-06 1388 2 0.008 -0.10 0.08 1.66E-01 2719 0.008 -0.23 0.05 2.79E-05

rs2230037 RFLP X 153760654 A G 5006 12 0.143 -0.02 0.01 2.06E-02 4999 12 0.155 0.00 0.01 8.50E-01 10005 0.149 -0.01 0.01 1.33E-01 1.41E-01

rs72554664 Kaiping X 153760472 T C 768 2 0.016 -0.56 0.05 3.11E-15 969 2 0.008 -0.39 0.08 7.51E-05 1737 0.012 -0.52 0.04 2.37E-16 7.12E-02

rs72554665 Canton X 153760484 A C 2844 5 0.022 -0.38 0.03 1.25E-27 2836 6 0.018 -0.22 0.04 1.40E-07 5680 0.020 -0.33 0.02 3.00E-30 5.13E-04

For the number of studies, samples genotyped on different arrays were analysed separately. For SCHS, cases and controls were analysed separately.

aIncluding Viangchang variant from Living Biobank whole exome sequence and meta-analysed with SiMES


Effect allele frequency denotes sample-size weighted allele frequency across all studies. P -values are obtained from sample-size weighted meta-analysis using derived inverse normalized residuals of HbA1c (%) after

adjustment for age, age2 and first three principal components. Effect and standard error shown are per allele effect for untransformed HbA1c trait values, assuming that males are homozygous diploid in non pseudo-

autosomal region. P -het refers to test of heterogeneity between men and women.

Supplementary Table 8. Summary of missense G6PD -variants association with HbA1c in East Asians.

Variant name G6PD variants Chr Position EA NEAMen Women Combined



N # of studies EAF Effect SE P -value N # of studies EAF Effect SE P -value EAF Effect SE P -value N # of studies EAF Effect SE P -value N # of studies EAF Effect SE P -value EAF Effect SE P -value

rs782517039 X 152548691 G C intergenic 1134 2 0.01 0.10 0.07 1.37E-01 1677 3 0.01 0.13 0.10 2.40E-01 0.01 0.11 0.06 6.39E-02 791 1 0.01 0.23 0.29 7.43E-01 780 1 0.01 -0.29 0.35 6.14E-01 0.01 0.01 0.23 9.02E-01

rs199621559 X 152653880 ACCCTGAG A intergenic 1798 4 0.02 0.01 0.05 7.80E-01 1588 3 0.02 -0.03 0.09 6.28E-01 0.02 0.00 0.04 8.98E-01 1630 2 0.02 0.00 0.17 9.05E-01 1894 3 0.02 -0.16 0.20 4.00E-01 0.02 -0.07 0.13 4.85E-01

rs782333428 X 152654882 CCA C intergenic 1134 2 0.01 0.06 0.07 3.98E-01 1666 3 0.01 0.12 0.11 2.74E-01 0.01 0.07 0.06 1.67E-01 791 1 0.01 0.29 0.28 3.98E-01 1034 2 0.01 -0.21 0.30 7.59E-01 0.01 0.06 0.20 7.46E-01

. X 152656962 C T intergenic 1134 2 0.01 0.06 0.07 4.00E-01 2118 4 0.01 0.09 0.08 3.65E-01 0.01 0.07 0.05 2.20E-01 791 1 0.01 0.04 0.24 9.79E-01 1640 2 0.01 -0.09 0.32 7.53E-01 0.01 -0.01 0.19 7.84E-01

. X 152666564 C A upstream_gene U82695.5 586 1 0.01 0.27 0.10 1.24E-02 1666 3 0.01 -0.20 0.10 3.86E-02 0.01 0.04 0.07 6.15E-01 - - - - - - 1034 2 0.01 0.14 0.30 5.84E-01 - - - -

rs192820967 X 152707771 A G regulatory_region 1134 2 0.02 0.06 0.05 2.30E-01 2013 4 0.01 0.02 0.07 9.79E-01 0.02 0.04 0.04 4.58E-01 791 1 0.01 0.32 0.19 1.07E-01 1034 2 0.01 -0.06 0.22 8.14E-01 0.01 0.16 0.14 2.16E-01

rs373841096 X 152795192 C A intron ATP2B3 548 1 0.01 -0.02 0.09 8.04E-01 1330 2 0.01 0.19 0.12 1.61E-01 0.01 0.06 0.07 2.95E-01 791 1 0.01 0.30 0.27 3.39E-01 780 1 0.01 -0.43 0.44 5.17E-01 0.01 0.10 0.23 8.25E-01

rs781851814 X 152996405 C T regulatory_region 586 1 0.01 0.17 0.09 4.71E-02 1666 3 0.01 -0.09 0.08 3.21E-01 0.01 0.02 0.06 8.73E-01 791 1 0.02 0.14 0.19 3.23E-01 780 1 0.01 0.26 0.26 5.42E-01 0.01 0.18 0.15 2.59E-01

. X 153104014 C T upstream_gene CYCSP45 1134 2 0.01 0.08 0.06 2.40E-01 1666 3 0.02 -0.05 0.06 4.60E-01 0.02 0.01 0.04 8.58E-01 791 1 0.02 0.17 0.15 2.13E-01 1894 3 0.01 0.30 0.22 4.09E-01 0.01 0.21 0.13 1.71E-01

rs371161739 X 153122712 AAGAG AAG downstream_gene L1CAM 1134 2 0.01 0.02 0.07 6.66E-01 1666 3 0.01 0.06 0.09 4.01E-01 0.01 0.04 0.05 3.56E-01 791 1 0.01 -0.05 0.29 9.74E-01 780 1 0.01 -0.31 0.51 7.51E-01 0.01 -0.12 0.25 8.05E-01

rs781895939 X 153330135 A G intron MECP2 1134 2 0.02 0.08 0.06 2.53E-01 1666 3 0.02 -0.04 0.06 6.33E-01 0.02 0.02 0.04 7.19E-01 791 1 0.02 0.20 0.16 2.06E-01 1034 2 0.01 0.35 0.25 2.04E-01 0.02 0.24 0.14 7.37E-02

rs782552292 X 153332795 C T regulatory_region 1134 2 0.02 0.09 0.06 1.26E-01 1666 3 0.02 -0.02 0.06 7.43E-01 0.02 0.04 0.04 4.71E-01 791 1 0.02 0.19 0.16 2.27E-01 1034 2 0.01 0.34 0.24 2.05E-01 0.02 0.23 0.14 8.03E-02

rs782435838 X 153381469 C T intergenic 586 1 0.02 0.15 0.08 6.18E-02 1666 3 0.02 -0.10 0.08 2.72E-01 0.02 0.02 0.06 9.93E-01 791 1 0.02 0.16 0.26 5.21E-01 780 1 0.01 0.18 0.32 7.90E-01 0.01 0.16 0.20 5.20E-01

rs149897670 X 153418524 T C missense OPN1LW 742 2 0.08 0.05 0.04 2.92E-01 412 2 0.10 0.03 0.07 8.00E-01 0.09 0.04 0.04 3.19E-01 - - - - - - - - - - - - - - - -

rs782130010 X 153421043 T G intron OPN1LW 1134 2 0.02 -0.01 0.07 9.71E-01 336 1 0.01 -0.31 0.27 2.90E-01 0.02 -0.03 0.07 5.91E-01 - - - - - - - - - - - - - - - -

rs190709425 X 153534488 A G intron TKTL1 1798 4 0.07 -0.02 0.03 2.70E-01 1666 3 0.07 0.03 0.04 3.95E-01 0.07 0.00 0.02 8.38E-01 1044 2 0.06 0.13 0.12 3.59E-01 1034 2 0.07 0.12 0.14 5.25E-01 0.07 0.13 0.09 2.72E-01

. X 153597853 A G regulatory_region 586 1 0.02 0.14 0.07 3.79E-02 1666 3 0.01 -0.09 0.07 2.79E-01 0.02 0.03 0.05 8.98E-01 791 1 0.01 0.10 0.22 6.27E-01 780 1 0.01 0.22 0.33 6.87E-01 0.01 0.14 0.18 5.30E-01

rs781841740 X 153646539 A G intron TAZ 1134 2 0.02 0.07 0.06 3.29E-01 1666 3 0.02 -0.06 0.07 4.96E-01 0.02 0.02 0.04 9.24E-01 791 1 0.02 0.13 0.19 4.34E-01 780 1 0.01 0.24 0.30 5.55E-01 0.02 0.16 0.16 3.33E-01

rs145693545 X 153687009 T C regulatory_region 2063 5 0.06 0.00 0.03 7.09E-01 2578 5 0.06 0.04 0.04 2.14E-01 0.06 0.01 0.02 2.40E-01 1883 3 0.05 -0.03 0.09 9.53E-01 1894 3 0.06 -0.05 0.11 4.19E-01 0.06 -0.04 0.07 5.39E-01

rs782462814 X 153734352 A G regulatory_region 1134 2 0.02 0.04 0.05 5.42E-01 1666 3 0.02 -0.01 0.06 9.85E-01 0.02 0.02 0.04 6.87E-01 791 1 0.02 0.12 0.19 4.66E-01 780 1 0.01 0.23 0.28 3.95E-01 0.02 0.15 0.15 2.65E-01

rs72554664 X 153760472 T C missense G6PD 704 2 0.02 0.04 0.06 6.23E-01 530 1 0.01 -0.08 0.11 4.98E-01 0.01 0.02 0.05 9.43E-01 - - - - - - - - - - - - - - - -

rs72554665 X 153760484 A C missense G6PD 1134 2 0.02 0.04 0.05 5.33E-01 1666 3 0.02 -0.01 0.06 9.80E-01 0.02 0.02 0.04 6.77E-01 791 1 0.02 0.12 0.19 4.85E-01 780 1 0.01 0.22 0.28 4.02E-01 0.02 0.15 0.15 2.78E-01

rs141157031 X 153893477 G T intergenic 1134 2 0.02 0.04 0.05 4.97E-01 1666 3 0.02 0.00 0.06 9.57E-01 0.02 0.02 0.04 6.35E-01 791 1 0.02 0.11 0.18 5.18E-01 780 1 0.01 0.21 0.27 4.09E-01 0.02 0.14 0.15 2.99E-01

rs781989359 X 153893654 A G intergenic 1134 2 0.02 0.04 0.05 4.96E-01 1666 3 0.02 0.00 0.06 9.57E-01 0.02 0.02 0.04 6.36E-01 791 1 0.02 0.11 0.18 5.19E-01 780 1 0.01 0.21 0.27 4.09E-01 0.02 0.14 0.15 2.99E-01

rs782121509 X 154010689 T TCTACAA regulatory_region 1576 3 0.02 -0.03 0.06 5.15E-01 2473 5 0.02 0.13 0.07 5.48E-02 0.02 0.03 0.05 2.74E-01 791 1 0.02 0.23 0.22 3.24E-01 1034 2 0.02 0.24 0.31 2.65E-01 0.02 0.23 0.18 1.37E-01

rs3795233 X 154019671 A G intron MPP1 2317 6 0.08 0.00 0.02 8.93E-01 2925 6 0.08 0.02 0.02 3.22E-01 0.08 0.01 0.01 4.07E-01 1883 3 0.09 0.01 0.05 9.02E-01 1894 3 0.09 -0.04 0.06 4.79E-01 0.09 -0.01 0.04 6.79E-01

rs5945243 X 154027171 A G regulatory_region 2317 6 0.10 -0.02 0.02 5.97E-01 2925 6 0.11 0.02 0.02 2.37E-01 0.11 0.00 0.01 5.95E-01 1883 3 0.13 -0.01 0.05 7.00E-01 1894 3 0.14 -0.03 0.06 7.03E-01 0.13 -0.02 0.04 5.89E-01

rs190054725 X 154039603 G A intron MPP1 548 1 0.01 0.03 0.10 8.89E-01 530 1 0.01 -0.02 0.16 8.67E-01 0.01 0.01 0.09 9.86E-01 - - - - - - - - - - - - - - - -

rs144356084 X 154059605 G A downstream_gene F8 2317 6 0.08 0.00 0.02 8.64E-01 2925 6 0.08 0.02 0.02 3.53E-01 0.08 0.01 0.01 4.19E-01 1883 3 0.09 0.01 0.05 8.41E-01 1894 3 0.09 -0.04 0.06 4.76E-01 0.09 -0.01 0.04 7.16E-01

rs201920434 X 154062475 GAGCCC G upstream_gene SMIM9 1798 4 0.06 0.00 0.03 9.80E-01 2925 6 0.05 0.02 0.03 3.61E-01 0.05 0.01 0.02 4.63E-01 1883 3 0.06 0.04 0.07 4.99E-01 1894 3 0.06 -0.05 0.09 5.75E-01 0.06 0.00 0.06 9.37E-01

rs34700571 X 154064658 T C 3_prime_UTR F8 548 1 0.01 0.02 0.11 9.44E-01 530 1 0.01 0.01 0.17 9.97E-01 0.01 0.02 0.09 9.57E-01 - - - - - - - - - - - - - - -

rs370772371 X 154167861 T C regulatory_region 1134 2 0.02 0.04 0.05 3.86E-01 1666 3 0.02 -0.02 0.06 8.09E-01 0.02 0.02 0.04 7.15E-01 791 1 0.02 0.12 0.16 4.15E-01 1034 2 0.01 0.25 0.25 3.73E-01 0.02 0.16 0.14 2.28E-01

rs781928603 X 154175499 GA G intron F8 1830 4 0.30 0.00 0.02 8.22E-01 1673 4 0.28 0.00 0.03 8.11E-01 0.29 0.00 0.01 7.43E-01 253 1 0.32 -0.17 0.13 6.08E-02 254 1 0.30 0.24 0.14 8.92E-02 0.31 0.01 0.09 9.06E-01

rs138637045 X 154217608 C G intron F8 1798 4 0.06 0.00 0.03 9.64E-01 2925 6 0.05 0.02 0.03 4.00E-01 0.05 0.01 0.02 4.90E-01 1883 3 0.06 0.06 0.08 3.78E-01 1894 3 0.06 -0.07 0.09 4.47E-01 0.06 0.01 0.06 9.34E-01

rs145219253 X 154309293 A T intron BRCC3 2317 6 0.07 -0.01 0.02 9.63E-01 2925 6 0.07 0.02 0.03 3.37E-01 0.07 0.00 0.02 4.55E-01 1883 3 0.08 0.02 0.07 7.94E-01 1894 3 0.08 -0.05 0.08 5.09E-01 0.08 -0.01 0.05 7.77E-01

rs150453895 X 154364023 C T upstream_gene RP11-143H17.1 2317 6 0.07 -0.01 0.02 9.23E-01 2925 6 0.07 0.02 0.03 3.49E-01 0.07 0.00 0.02 5.25E-01 1883 3 0.08 0.02 0.07 7.52E-01 1894 3 0.08 -0.05 0.08 4.76E-01 0.08 -0.01 0.05 7.78E-01

rs182573065 X 154372449 G A intron MTCP1 1134 2 0.02 0.02 0.04 5.56E-01 1666 3 0.02 0.01 0.05 7.55E-01 0.02 0.02 0.03 5.39E-01 791 1 0.02 0.12 0.16 4.31E-01 1894 3 0.01 0.13 0.21 8.80E-01 0.01 0.12 0.13 7.65E-01

rs781843659 X 154408847 G C intergenic 1134 2 0.02 0.03 0.04 5.48E-01 1666 3 0.02 0.01 0.05 7.62E-01 0.02 0.02 0.03 5.38E-01 791 1 0.02 0.12 0.17 4.36E-01 1034 2 0.01 0.24 0.23 2.76E-01 0.02 0.16 0.13 1.83E-01

rs148112010 X 154409817 G A intergenic 1134 2 0.02 0.03 0.04 5.46E-01 1666 3 0.02 0.01 0.05 7.62E-01 0.02 0.02 0.03 5.37E-01 791 1 0.02 0.12 0.17 4.31E-01 1894 3 0.01 0.13 0.22 9.07E-01 0.01 0.13 0.13 7.43E-01

. X 154681796 CT C downstream_gene F8A3 586 1 0.01 0.23 0.13 6.02E-02 1666 3 0.01 -0.25 0.15 1.61E-01 0.01 0.04 0.10 8.05E-01 - - - - - - 780 1 0.00 0.53 0.75 6.76E-01 - - - -

rs782120990 X 154773326 GA G intron TMLHE 1134 2 0.01 0.06 0.07 4.19E-01 866 2 0.01 -0.03 0.11 9.17E-01 0.01 0.03 0.06 5.89E-01 791 1 0.01 0.28 0.37 4.10E-01 - - - - - - - - - -

Men Women


Effect allele frequency denotes sample-size weighted allele frequency across all studies. P -values are obtained from sample-size weighted meta-analysis using derived inverse normalized residuals of HbA1c (%) after adjustment for age, age2 and first three principal components. Effect and standard error shown are per allele effect for untransformed HbA1c trait values, assuming that males are homozygous diploid in

non pseudo-autosomal region. P -het refers to test of heterogeneity between men and women.*Including Viangchang variant from Living Biobank whole exome sequence and meta-analysed with SiMES


Supplementary Table 9. Variants associated with HbA1c and their associations with fasting and random glucose in East Asians.

Sex-combined Sex-combined

Fasting glucose Random glucose

Variant name Chr Position EA NEA Annotation Gene Men Women



N # of studies Effect SE P -value N # of studies Effect SE P -value Effect SE P -value N # of studies Effect SE P -value N # of studies Effect SE P -value Effect SE P -value Effect SE P -value Effect SE P -value Effect SE P -value

rs782517039 X 152548691 G C 1058 2 -0.41 0.05 1.49E-07 1189 2 -0.06 0.08 3.76E-01 -0.31 0.04 2.15E-05 791 1 -0.24 0.07 9.54E-03 780 1 -0.12 0.08 1.61E-01 -0.19 0.05 4.69E-03 -0.35 0.04 1.43E-08 -0.09 0.06 1.16E-01 -0.26 0.03 3.91E-07

rs199621559 X 152653880 ACCCTGAG A 1431 3 -0.27 0.04 1.08E-05 1233 3 -0.21 0.08 6.96E-03 -0.25 0.04 4.17E-07 1782 2 -0.17 0.05 2.22E-02 2015 3 -0.02 0.07 6.34E-01 -0.11 0.04 5.56E-02 -0.23 0.03 3.49E-06 -0.10 0.05 4.15E-02 -0.19 0.03 2.39E-06

rs782333428 X 152654882 CCA C 1058 2 -0.47 0.05 2.35E-09 1468 3 -0.13 0.09 1.15E-01 -0.38 0.05 4.08E-07 791 1 -0.25 0.07 2.60E-03 1034 2 -0.08 0.08 3.69E-01 -0.17 0.05 7.84E-03 -0.39 0.04 8.76E-11 -0.10 0.06 7.45E-02 -0.28 0.03 2.39E-08

. X 152656962 C T 1058 2 -0.44 0.05 9.79E-08 1760 4 -0.16 0.07 2.64E-02 -0.34 0.04 5.15E-07 791 1 -0.21 0.06 3.69E-03 1761 2 -0.15 0.09 1.74E-01 -0.19 0.05 6.04E-03 -0.34 0.04 3.01E-09 -0.16 0.06 1.14E-02 -0.27 0.03 3.21E-08

. X 152666564 C A 511 1 -0.41 0.09 6.77E-05 1468 3 -0.29 0.09 2.08E-03 -0.35 0.06 2.92E-06 - - - - - 1034 2 -0.28 0.08 1.41E-03 - - - -0.41 0.09 6.77E-05 -0.29 0.06 1.03E-05 -0.33 0.05 1.51E-08

rs192820967 X 152707771 A G 1058 2 -0.30 0.04 1.65E-08 1468 3 -0.04 0.05 3.29E-01 -0.21 0.03 1.09E-05 791 1 -0.21 0.05 1.83E-04 1034 2 -0.08 0.05 1.67E-01 -0.15 0.04 4.58E-04 -0.26 0.03 1.85E-11 -0.06 0.04 1.02E-01 -0.19 0.02 1.91E-08

rs373841096 X 152795192 C A 547 1 -0.46 0.07 1.45E-06 1189 2 -0.06 0.09 4.15E-01 -0.32 0.05 7.29E-04 791 1 -0.31 0.07 1.34E-04 780 1 -0.29 0.10 6.13E-03 -0.31 0.06 3.47E-06 -0.39 0.05 1.78E-09 -0.16 0.07 1.84E-02 -0.32 0.04 1.64E-08

rs781851814 X 152996405 C T 511 1 -0.53 0.08 8.95E-08 1468 3 -0.24 0.07 8.55E-04 -0.37 0.05 2.29E-08 791 1 -0.27 0.05 3.09E-06 780 1 -0.14 0.06 4.32E-02 -0.22 0.04 2.19E-06 -0.34 0.04 2.84E-12 -0.19 0.05 1.02E-04 -0.28 0.03 2.43E-13

. X 153104014 C T 1058 2 -0.40 0.05 1.16E-08 1468 3 -0.18 0.05 9.72E-04 -0.31 0.04 5.38E-10 791 1 -0.29 0.04 2.02E-09 2015 3 -0.15 0.06 4.58E-01 -0.24 0.03 1.38E-04 -0.33 0.03 1.75E-16 -0.17 0.04 6.82E-03 -0.27 0.02 1.95E-12

rs371161739 X 153122712 AAGAG AAG 1058 2 -0.43 0.05 1.77E-07 1468 3 -0.20 0.07 2.29E-02 -0.35 0.04 3.15E-07 791 1 -0.10 0.07 2.14E-01 780 1 -0.26 0.12 4.13E-02 -0.14 0.06 2.04E-02 -0.31 0.04 1.91E-06 -0.22 0.06 2.36E-03 -0.28 0.04 4.98E-08

rs781895939 X 153330135 A G 1058 2 -0.41 0.05 4.31E-09 1468 3 -0.19 0.06 8.56E-04 -0.32 0.04 2.27E-10 791 1 -0.30 0.04 2.53E-09 1034 2 -0.22 0.06 4.68E-04 -0.28 0.03 5.49E-11 -0.35 0.03 7.44E-17 -0.20 0.04 1.56E-06 -0.30 0.02 1.10E-19

rs782552292 X 153332795 C T 1058 2 -0.35 0.04 9.22E-08 1468 3 -0.18 0.05 1.20E-03 -0.28 0.03 3.12E-09 791 1 -0.30 0.04 2.13E-09 1034 2 -0.20 0.06 9.06E-04 -0.27 0.03 1.20E-10 -0.33 0.03 1.77E-15 -0.19 0.04 3.96E-06 -0.28 0.02 3.78E-18

rs782435838 X 153381469 C T 511 1 -0.54 0.07 1.62E-08 1468 3 -0.26 0.07 1.63E-04 -0.39 0.05 9.53E-10 791 1 -0.21 0.07 8.76E-03 780 1 -0.20 0.08 1.48E-02 -0.21 0.05 3.48E-04 -0.36 0.05 2.38E-08 -0.23 0.05 7.40E-06 -0.30 0.03 3.74E-12

rs149897670 X 153418524 T C 667 2 -0.23 0.04 2.41E-06 355 2 -0.22 0.08 2.67E-03 -0.23 0.03 2.42E-08 - - - - - - - - - - - - - -0.29 0.04 5.52E-07 -0.27 0.09 2.34E-03 -0.29 0.04 5.35E-09

rs782130010 X 153421043 T G 1058 2 -0.46 0.06 2.32E-05 279 1 -0.38 0.26 1.54E-01 -0.46 0.06 1.00E-05 - - - - - - - - - - - - - -0.46 0.06 2.32E-05 -0.38 0.26 1.54E-01 -0.46 0.06 1.00E-05

rs190709425 X 153534488 A G 1594 4 -0.09 0.02 1.68E-02 1468 3 -0.09 0.04 2.02E-02 -0.09 0.02 8.58E-04 1044 2 -0.21 0.03 1.75E-08 1034 2 -0.08 0.04 3.24E-02 -0.16 0.02 3.72E-08 -0.14 0.02 6.55E-08 -0.08 0.03 1.60E-03 -0.12 0.01 1.26E-09

. X 153597853 A G 511 1 -0.54 0.06 6.02E-11 1468 3 -0.26 0.06 2.70E-04 -0.41 0.04 1.03E-10 791 1 -0.31 0.05 4.44E-06 780 1 -0.27 0.08 1.66E-03 -0.29 0.04 4.41E-08 -0.41 0.04 1.64E-14 -0.26 0.05 1.61E-06 -0.35 0.03 2.54E-17

rs781841740 X 153646539 A G 1058 2 -0.46 0.05 1.83E-10 1468 3 -0.22 0.06 4.75E-04 -0.37 0.04 1.13E-11 791 1 -0.34 0.05 1.01E-08 780 1 -0.26 0.07 1.00E-03 -0.31 0.04 1.74E-10 -0.40 0.03 1.05E-17 -0.24 0.05 1.92E-06 -0.34 0.03 1.64E-20

rs145693545 X 153687009 T C 1745 5 -0.09 0.02 9.47E-03 2164 5 -0.05 0.03 3.27E-02 -0.07 0.02 8.92E-04 2035 3 -0.14 0.03 2.12E-02 2015 3 -0.04 0.04 7.92E-01 -0.10 0.02 6.89E-02 -0.11 0.02 5.54E-04 -0.05 0.02 8.55E-02 -0.08 0.01 2.88E-04

rs782462814 X 153734352 A G 1058 2 -0.42 0.04 3.89E-10 1468 3 -0.20 0.06 9.80E-04 -0.33 0.03 5.27E-11 791 1 -0.34 0.05 6.35E-09 780 1 -0.25 0.07 3.01E-04 -0.31 0.04 2.60E-11 -0.38 0.03 1.43E-17 -0.22 0.04 1.65E-06 -0.32 0.03 1.66E-20

rs72554664 X 153760472 T C 703 2 -0.58 0.05 5.85E-15 527 1 -0.37 0.09 9.82E-05 -0.53 0.04 2.87E-17 - - - - - - - - - - - - - -0.58 0.06 5.53E-10 -0.37 0.09 9.82E-05 -0.51 0.05 8.34E-13

rs72554665 X 153760484 A C 1058 2 -0.41 0.04 5.78E-10 1468 3 -0.19 0.06 1.03E-03 -0.33 0.03 7.42E-11 791 1 -0.34 0.05 5.10E-09 780 1 -0.26 0.07 2.52E-04 -0.31 0.04 1.75E-11 -0.38 0.03 1.75E-17 -0.22 0.04 1.53E-06 -0.32 0.03 1.73E-20

rs141157031 X 153893477 G T 1058 2 -0.38 0.04 1.03E-09 1468 3 -0.19 0.05 1.19E-03 -0.31 0.03 1.34E-10 791 1 -0.34 0.05 3.73E-09 780 1 -0.26 0.06 1.86E-04 -0.31 0.04 9.31E-12 -0.36 0.03 2.36E-17 -0.22 0.04 1.42E-06 -0.31 0.02 1.96E-20

rs781989359 X 153893654 A G 1058 2 -0.38 0.04 1.04E-09 1468 3 -0.19 0.05 1.19E-03 -0.31 0.03 1.35E-10 791 1 -0.34 0.05 3.73E-09 780 1 -0.26 0.06 1.86E-04 -0.31 0.04 9.30E-12 -0.36 0.03 2.38E-17 -0.22 0.04 1.43E-06 -0.31 0.02 1.98E-20

rs782121509 X 154010689 T TCTACAA 1431 3 -0.19 0.04 7.24E-04 1872 4 -0.06 0.06 2.63E-01 -0.14 0.04 2.15E-03 791 1 -0.43 0.05 3.77E-10 1034 2 -0.19 0.08 1.86E-02 -0.35 0.04 3.75E-09 -0.28 0.03 1.12E-10 -0.11 0.05 2.13E-02 -0.22 0.03 2.24E-09

rs3795233 X 154019671 A G 1745 5 -0.04 0.01 3.16E-02 2348 6 -0.02 0.02 1.61E-01 -0.03 0.01 1.37E-02 2035 3 -0.08 0.02 4.91E-03 2015 3 -0.03 0.02 5.85E-01 -0.06 0.01 1.73E-02 -0.06 0.01 4.25E-04 -0.02 0.01 1.61E-01 -0.04 0.01 6.12E-04

rs5945243 X 154027171 A G 1745 5 -0.04 0.01 1.97E-02 2348 6 -0.02 0.02 1.34E-01 -0.03 0.01 7.86E-03 2035 3 -0.07 0.02 4.55E-03 2015 3 -0.02 0.02 7.53E-01 -0.05 0.01 2.55E-02 -0.05 0.01 2.46E-04 -0.02 0.01 1.89E-01 -0.04 0.01 5.41E-04

rs190054725 X 154039603 G A 547 1 -0.75 0.08 5.25E-10 527 1 -0.52 0.12 1.61E-04 -0.68 0.07 1.48E-12 - - - - - - - - - - - - - -0.75 0.08 5.25E-10 -0.52 0.12 1.61E-04 -0.68 0.07 1.48E-12

rs144356084 X 154059605 G A 1745 5 -0.04 0.01 3.05E-02 2348 6 -0.02 0.02 1.87E-01 -0.03 0.01 1.59E-02 2035 3 -0.08 0.02 3.13E-03 2015 3 -0.03 0.02 6.03E-01 -0.06 0.01 1.39E-02 -0.06 0.01 2.75E-04 -0.02 0.01 1.86E-01 -0.04 0.01 5.69E-04

rs201920434 X 154062475 GAGCCC G 1594 4 -0.08 0.02 2.91E-03 2348 6 -0.04 0.03 4.22E-02 -0.07 0.02 5.38E-04 2035 3 -0.13 0.02 7.41E-04 2015 3 -0.06 0.03 2.80E-01 -0.11 0.02 1.61E-03 -0.10 0.02 6.80E-06 -0.05 0.02 2.61E-02 -0.08 0.01 2.93E-06

rs34700571 X 154064658 T C 547 1 -0.78 0.08 5.39E-10 527 1 -0.53 0.13 2.63E-04 -0.71 0.07 2.82E-12 - - - - - - - - - - - - - -0.78 0.08 5.39E-10 -0.53 0.13 2.63E-04 -0.71 0.07 2.82E-12

rs370772371 X 154167861 T C 1058 2 -0.32 0.04 3.86E-08 1468 3 -0.14 0.05 3.25E-03 -0.25 0.03 6.58E-09 791 1 -0.31 0.04 7.04E-10 1034 2 -0.29 0.06 1.46E-05 -0.31 0.03 2.44E-13 -0.32 0.03 2.60E-16 -0.20 0.04 4.62E-07 -0.27 0.02 5.07E-20

rs781928603 X 154175499 GA G 1557 4 -0.05 0.01 2.10E-02 1394 4 -0.06 0.02 3.88E-03 -0.05 0.01 2.50E-04 253 1 -0.05 0.03 1.87E-01 254 1 -0.08 0.04 8.52E-02 -0.06 0.03 3.16E-02 -0.05 0.01 8.44E-03 -0.07 0.02 8.62E-04 -0.06 0.01 2.60E-05

rs138637045 X 154217608 C G 1594 4 -0.09 0.02 2.99E-03 2348 6 -0.04 0.03 6.29E-02 -0.07 0.02 8.89E-04 2035 3 -0.14 0.02 2.60E-04 2015 3 -0.08 0.03 1.51E-01 -0.12 0.02 3.17E-04 -0.11 0.02 2.57E-06 -0.06 0.02 1.93E-02 -0.09 0.01 9.69E-07

rs145219253 X 154309293 A T 1745 5 -0.06 0.02 1.15E-02 2348 6 -0.03 0.02 1.39E-01 -0.05 0.01 5.60E-03 2035 3 -0.12 0.02 2.21E-04 2015 3 -0.05 0.03 2.51E-01 -0.09 0.02 6.09E-04 -0.08 0.01 9.57E-06 -0.04 0.02 6.22E-02 -0.07 0.01 1.18E-05

rs150453895 X 154364023 C T 1745 5 -0.06 0.02 9.92E-03 2348 6 -0.03 0.02 2.47E-01 -0.05 0.01 1.05E-02 2035 3 -0.12 0.02 2.36E-04 2015 3 -0.05 0.03 2.90E-01 -0.09 0.02 7.99E-04 -0.09 0.01 8.58E-06 -0.04 0.02 1.17E-01 -0.07 0.01 2.91E-05

rs182573065 X 154372449 G A 1058 2 -0.26 0.03 5.46E-07 1468 3 -0.11 0.05 1.04E-02 -0.20 0.03 2.05E-07 791 1 -0.31 0.04 5.69E-10 2015 3 -0.27 0.06 1.56E-04 -0.30 0.03 8.26E-11 -0.28 0.03 4.37E-15 -0.18 0.04 5.64E-06 -0.24 0.02 1.15E-16

rs781843659 X 154408847 G C 1058 2 -0.26 0.03 4.83E-07 1468 3 -0.11 0.05 1.23E-02 -0.20 0.03 2.40E-07 791 1 -0.32 0.04 5.58E-10 2015 3 -0.28 0.06 1.24E-04 -0.30 0.03 5.96E-11 -0.28 0.03 3.73E-15 -0.18 0.04 5.53E-06 -0.24 0.02 1.02E-16

rs148112010 X 154409817 G A 1058 2 -0.26 0.03 4.66E-07 1468 3 -0.11 0.05 1.23E-02 -0.20 0.03 2.34E-07 791 1 -0.32 0.04 5.76E-10 2015 3 -0.28 0.06 1.22E-04 -0.31 0.03 5.93E-11 -0.28 0.03 3.68E-15 -0.18 0.04 5.45E-06 -0.25 0.02 9.85E-17

. X 154681796 CT C 511 1 -0.86 0.11 2.37E-09 1468 3 -0.42 0.13 1.03E-03 -0.68 0.08 4.63E-09 - - - - - 780 1 -0.63 0.18 1.17E-03 - - - -0.86 0.11 2.37E-09 -0.49 0.11 5.01E-06 -0.68 0.08 2.24E-11

rs782120990 X 154773326 GA G 1058 2 -0.45 0.06 5.78E-07 806 2 -0.14 0.09 1.37E-01 -0.36 0.05 2.10E-06 791 1 -0.72 0.09 5.80E-10 - - - - - - - - -0.52 0.05 4.74E-15 -0.14 0.09 1.37E-01 -0.44 0.04 1.89E-13


Supplementary Table 10. Variants associated with HbA1c adjusted for fasting and random glucose.


Effect allele frequency denotes sample-size weighted allele frequency across all studies. P -values are obtained from sample-size weighted meta-analysis using derived inverse normalized residuals of HbA1c (%) after adjustment for age, age2 and first three principal components. Effect and standard error shown are per allele effect for untransformed HbA1c trait values, assuming that males are homozygous

diploid in non pseudo-autosomal region. P -het refers to test of heterogeneity between men and women.

Variant name Chr Position EA NEA

Conditioned on fasting glucose

Men Sex-combinedWomen Men Women Sex-combined Men Women Sex-combined

Conditioned on random glucose Meta-analysis



C A CC CA/AAa

C/CC CA A/AA*

N 3830 77 3119 105 6949 104 78Age, years 56.2 (14.5) 58.8 (11.5) 51.1 (14.1) 51.5 (13.8) 53.9 (14.5) 51.4 (13.8) 58.8 (11.4)

Fasting glucose, mmol/L 4.78 (0.52) 4.89 (0.42) 4.75 (0.84) 4.75 (0.87) 4.76 (0.73) 4.75 (0.87) 4.89 (0.42)Random glucose, mmol/L 6.66 (2.74) 6.28 (1.10) 6.04 (2.23) 6.88 (3.53) 6.36 (2.52) 6.88 (3.53) 6.28 (1.10)

HbA1c, % 6.05 (1.12) 5.33 (1.09) 5.81 (0.76) 5.65 (0.97) 5.95 (0.99) 5.67 (0.97) 5.32 (1.09)

BMI kg/m2

23.5 (3.4) 23.4 (3.0) 22.8 (3.8) 22.5 (3.8) 23.2 (3.6) 22.5 (3.8) 23.4 (2.9)Diabetes

(on medication or self-reported physician diagnosis)326 (8.5) 6 (7.8) 198 (6.3) 8 (7.6) 524 (7.5) 8 (7.7) 6 (7.7)

Summary statistics are presented in mean (SD) or counts (%).

Supplementary Table 11. Sample characteristics stratified by sex and genotypes at G6PD -Canton (rs72554665).

aOnly 1 woman is homozygous AA at rs72554665.

WomenMen AllSample characteristics



C A CC CA/AA C/CC CA A/AA

<4.5 254 (24.3)

5.36 (0.31)

4 (18.2)

5.25 (0.37)

511 (35.3)

5.37 (0.37)

22 (44.9)

5.07 (0.50)

765 (30.7)

5.36 (0.35)

22 (44.9)

5.07 (0.50)

4 (18.2)

5.25 (0.37)

4.5-5.0 491 (46.9)

5.50 (0.34)

9 (40.9)

4.84 (0.66)

622 (43.0)

5.51 (0.35)

18 (36.7)

5.42 (0.43)

1113 (44.6)

5.51 (0.34)

18 (36.7)

5.42 (0.43)

9 (40.9)

4.84 (0.66)

5.0-5.5235 (22.4)

5.67 (0.41)

7 (31.8)

4.71 (0.64)

227 (15.7)

5.68 (0.39)

4 (8.2)

5.47 (0.84)

462 (18.5)

5.68 (0.40)

4 (8.2)

5.47 (0.84)

7 (31.8)

4.71 (0.64)

5.5-6.055 (5.3)

5.80 (0.34)

2 (9.1)

4.50 (0.56)

60 (4.1)

5.89 (0.45)

4 (8.2)

6.10 (0.66)

115 (4.6)

5.85 (0.40)

4 (8.2)

6.10 (0.66)

2 (9.1)

4.50 (0.56)

≥6.012 (1.1)

6.37 (1.45)-

28 (1.9)

6.78 (1.24)

1 (2.0)

6.29 (-)

40 (1.6)

6.65 (1.30)

1 (2.0)

6.29 (-)-

Overall1047 (100.0)

5.53 (0.41)

22

4.84 (0.60)

1448

5.53 (0.46)

49

5.34 (0.59)

2495

5.81 (0.79)

49

5.52 (0.85)

22

5.23 (1.03)

Individuals with diabetes are excluded (on medication or self-reported physician diagnosis).

Each cell contains the count (%) in the first row and mean (standard deviation) in the second row.

Summary statistics are presented for individuals with both HbA1c and glucose measurements.

Supplementary Table 12. Change in HbA1c levels with fasting glucose, stratified by sex and G6PD -Canton genotypes

(rs72554665).

FG, mmol/L

HbA1c (%)

Men Women All



Supplementary Table 13. Correlation and association of HbA1c with fasting glucose in men and women.


Within sex

Within sex

and G6PD-

Canton

genotypes

0.37 -0.32 0.54 0.53 0.48 0.53 -0.32

Effecta 0.29 -0.47 0.40 0.43 0.36 0.43 -0.47

SEa 0.03 0.36 0.02 0.15 0.01 0.15 0.36

Pa < 2E-16 0.20 < 2E-16 5.12E-03 < 2E-16 5.12E-03 0.20

Pinteraction

between FG

and Canton

carrier

status)

Pearson correlation r between Hba1c and FG

0.33

Linear regresssion of HbA1c on FG

Individuals with diabetes are excluded (on medication or self-reported physician diagnosis).a Regression model estimates from modelling HbA1c against age, array type, fasting glocose within each sex

and Canton genotypes

0.54 0.47

3.32E-05 2.89E-01 -

AllWomenMen




Normoglycemia

(HbA1c <5.7)

730

(0.70)

21

(0.95)

1014

(0.70)

36

(0.73)

1744

(0.70)

36

(0.73)

21

(0.95)

Pre-diabetes

(HbA1c 5.7 - 6.5)

307

(0.29)

1

(0.05)

407

(0.28)

12

(0.24)

714

(0.29)

12

(0.24)

1

(0.05)

Undiagnosed

(HbA1c ≥6.5)

10

(0.01) 0

27

(0.02)

1

(0.02)

37

(0.01)

1

(0.02) 0

P -value (comparing normoglcemia with pre-diabetes+

undiagnosed)

P -value (All three categories)

Normoglycemia

(FG <5.6)

1008

(0.96)

20

(0.91)

1388

(0.96)

45

(0.92)

2396

(0.96)

45

(0.92)

20

(0.91)

Pre-diabetes

(FG 5.6 - 7.0)

38

(0.04)

2

(0.09)

49

(0.03)

4

(0.08)

87

(0.03)

4

(0.08)

2

(0.09)

Undiagnosed

(FG ≥7.0)

1

(0.00) 0

11

(0.01) 0

12

(0.00) 0 0


undiagnosed)


Normoglycemia

(HbA1c <6.0)

943

(0.90) 22

1301

(0.90)

41

(0.84)

2244

(0.90)

41

(0.84) 22

Pre-diabetes

(HbA1c 6.0 - 6.5)

94

(0.09) 0

120

(0.08)

7

(0.14)

214

(0.9)

7

(0.14) 0

Undiagnosed

(HbA1c ≥6.5)

10

(0.01) 0

27

(0.02)

1

(0.02)

37

(0.01)

1

(0.02) 0


undiagnosed)


Normoglcemia

(FG <6.1)

1041

(0.99) 22

1426

(0.98) 49

2467

(0.99) 49 22

Prediabetes/Diabetes

(FG 6.1 - 7.0)

5

(0.00) 0

11

(0.01) 0

16

(0.01) 0 0

Undiagnosed

(FG ≥7.0)

1

(0.00) 0

11

(0.01) 0

12

(0.00) 0 0


undiagnosed)


Individuals with diabetes are excluded (on medication or self-reported physician diagnosis).

Counts and percentages (%; in parentheses) are presented for both HbA1c and glucose measurements.

P -values are from Fisher's exact test.

By fasting

glucose

(mmol/l)

- - -

- - -

WHO guidelines

By HbA1c

(%)

1.57E-01 1.56E-01 7.70E-02

3.91E-01 2.49E-01 2.71E-01

By fasting

glucose

(mmol/l)

2.05E-01 1.54E-01 1.18E-01

2.14E-01 2.20E-01 1.56E-01

ADA guidelines

By HbA1c

(%)

7.73E-03 7.51E-01 1.82E-02

2.74E-02 7.16E-01 7.00E-02

Supplementary Table 14. Distribution of diabetes status by G6PD -Canton (rs72554665) genotype classes.

Glycemic

measuresDiabetes status

Men Women All



Documents

SUPPLEMENTARY APPENDIX - BMJ