supplementary data - diabetes · supplementary data ©2013 american diabetes association. published...

SUPPLEMENTARY DATA

©2013 American Diabetes Association. Published online at http://care.diabetesjournals.org/lookup/suppl/doi:10.2337/dc13-0949/-/DC1

Genotyping and quality control Genotyping data was obtained de novo for eleven studies and in silico (HapMap imputed) for four studies. Initial association testing for each cohort was performed using Merlin, STATA 10.1, R (LMEKIN package, R 2.10.0 and R 2.9.2), SNPTEST v1.1.4, SPSS 18.0, and SAS (9.1.3 and 9.1.9). Prior to meta-analysis, low quality SNPs were filtered in individual cohorts using the following criteria: (1) call rate for directly genotyped SNPs <0.70, (2) SNP Hardy-Weinberg equilibrium P<10-6, (3) SNPs minor allele count (MAC) ≥10 (calculated as total number of observed alleles [twice the sample size] at each SNP multiplied by minor allele frequency [MAF]). In samples where initial genotyping of an index SNP failed, a proxy SNP in strong linkage disequilibrium (LD) with the original SNP was genotyped and reported wherever possible. Supplementary Table 1. Cohort descriptions and baseline characteristics

SUPPLEMENTARY DATA


SUPPLEMENTARY DATA


Supplementary Table 2. Definitions of physiological measurements.

Index Equation Reference Insulinogenic Index

[(30-min insulin-fasting insulin)]/[(30-min glucose-fasting glucose)]

ISI Belfiore 2/[({[0.5*fasting PG (mmol/L)] + OGTT 1-h PG + (0.5*OGTT 2-h PG)} / 11.36) * ({[0.5*fasting PI (pmol/L)] + OGTT 1-h PI + (0.5*OGTT 2-h PI)} / 638) + 1]

(1)

ISI Gutt {75000 + [fasting PG (mg/L) - OGTT 2-h PG] * 0.19 * body weight (kg)/120} / [(fasting PG + OGTT 2-h PG) / 2] / log10{[fasting PI (mU/L) + OGTT 2-h PI] / 2}

(2)

ISI Matsuda 10 000√{fasting PG (mg/dL) * fasting PI (µU/mL) * [mean OGTT PG * mean OGTT PI]}

(3)

ISI Stumvoll 0.226 - [0.0032 * BMI (kg/m2)] - [0.0000645 * OGTT 2-h PI (pmol/L)] - [0.00375 * OGTT 1.5-h PG (mmol/L)]

(4)

Abbreviations: PG: plasma glucose, OGTT: oral glucose tolerance test, PI: plasma insulin. Supplementary Table 3. Genetic markers investigated.

Lead SNP Chr Position

(b36) Nearest

gene

Effect allele*/Other MAF Proxy used

r2 with lead

SNP† rs10830963 11 92348358 MNTR1B G/C 0.30 rs7112766 0.861

rs11020124 0.725 rs1387153 0.703 rs10830956 0.703

rs4607517 7 44202193 GCK A/G 0.20 rs730497 1 rs2908289 1 rs1799884 1 rs6975024 1

rs13081389 3 12264800 PPARG A/G 0.04 rs1596417 1 rs17036130 1 rs1562040 1 rs1801282 0.536

rs972283 7 130117394 KLF14 G/A 0.45 rs4731702 1 rs3996352 1 rs11765979 1 rs10954284 1

rs7578326 2 226728897 IRS1 A/G 0.36 rs2943651 0.964 rs2943632 0.964 rs13423088 0.929 rs2943641 0.74

rs780094 2 27594741 GCKR C/T 0.38 rs780093 1 rs1260326 0.932 rs2911711 0.87 rs1260333 0.87

SUPPLEMENTARY DATA


rs1552224 11 72110746 ARAP1 A/C 0.13 rs11603334 1 rs11605166 0.853 rs613937 0.736

rs7903146 10 114748339 TCF7L2 T/C 0.25 rs4506565 0.917 rs4132670 0.917

rs3802177 8 118254206 SLC30A8 G/A 0.25 rs13266634 1 rs11558471 0.957

rs5015480 10 94455539 HHEX/

IDE C/T 0.45 rs10882102 1 rs1111875 1 rs12778642 0.904

rs2191349 7 15030834 DGKB/

TMEM195 T/G 0.47 rs2191348 1 rs4719433 1 rs6947830 1 rs2215383 1 rs10244051 1

rs340874 1 212225879 PROX1 C/T 0.49 rs340835 0.765 rs340883 0.548

rs10965250 9 22123284 CDKN2A/

B G/A 0.19 rs10965250 1 rs10811661 0.95 rs2383208 0.95

rs10440833 6 20796100 CDKAL1 A/T 0.25 rs9368222 1 rs7766070 1 rs7756992 1 rs7754840 0.677

rs11899863 2 43472323 THADA C/T 0.07 rs7607777 1 rs6743071 1 rs13408002 1 rs17406646 1 rs7578597 0.786

rs11708067 3 124548468 ADCY5 A/G 0.22 rs11717195 0.86 rs2124500 0.819 rs6798189 0.795 rs7613951 0.753

rs4430796 17 33172153 HNF1B (TCF2) G/A 0.47 rs2005705 0.632

rs757210 0.615 rs2334499 11 1653425 HCCA2 T/C 0.44 rs4752780 0.964

rs4417225 0.934 rs4752781 0.931 rs10839220 0.583

rs7957197 12 119945069 HNF1A T/A 0.15 rs12427353 0.832 rs7965349 0.818 rs7305618 0.55

rs10923931 1 120319482 NOTCH2 T/G 0.12 rs2641317 1

SUPPLEMENTARY DATA


rs2934381 1 rs1493694 1 rs2453040 1 rs2793831 1

rs13292136 9 81141948 CHCHD9 C/T 0.07 rs17791555 1 rs13297387 1 rs1328405 1 rs1328405 1

rs1801214 4 6353923 WFS1 T/C 0.27 rs6446480 0.917 rs10937720 0.917 rs13108780 0.917 rs13128674 0.917 rs10010131 0.917

rs4457053 5 76460705 ZBED3 G/A 0.26 rs6878122 0.864 rs7708285 0.862

rs8042680 15 89322341 PRC1 A/C 0.22 rs6496743 1 rs6496742 0.811 rs11853073 0.811 rs8028856 0.81

rs1470579 3 187011774 IGF2BP2 C/A 0.29 rs1470579 1 rs6767484 1 rs6769511 1 rs11711477 1 rs9859406 1

rs896854 8 96029687 TP53INP1 T/C 0.48 rs13255935 1 rs13257021 0.967 rs7845219 0.846 rs12548874 0.743

rs12779790 10 12368016 CDC123/ CAMK1D G/A 0.23 rs11257655 0.802

rs7069060 0.617 rs10906111 0.562

rs11634397 15 78219277 ZFAND6 G/A 0.41 rs870185 0.897 rs12441266 0.897 rs1357335 0.897 rs4778582 0.896

rs4760790 12 69921061 TSPAN8/

LGR5 A/G 0.23 rs4760915 1 rs7306184 1 rs1353362 0.955 rs7961581 0.909

rs5215 11 17365206 KCNJ11 C/T 0.41 rs1557765 0.902 rs757110 0.899 rs7124355 0.745

rs243021 2 60438323 BCL11A A/G 0.46 rs243020 1 rs243019 1 rs243018 0.967

SUPPLEMENTARY DATA


rs849134 7 28162747 JAZF1 A/G 0.47 rs849135 1 rs849133 1 rs1635852 1 rs864745 0.967

rs1531343 12 64461161 HMGA2 C/G 0.10 rs2612067 1 rs2583922 1 rs2358949 1 rs1122590 1 rs2884592 1

rs231362 11 2648047 KCNQ1 G/A 0.49 rs163184 11 2803645 KCNQ1 G/T 0.44 rs6795735 3 64680405 ADAMTS9 C/T 0.45 rs7428936 1

rs4611812 1 rs17727064 1 rs4607103 0.28

rs5945326 X 152553116 DUSP9 A/G 0.21 rs3020789 0.939 rs2301142 0.548

*-Effect allele defined as the type 2 diabetes risk increasing allele. †-r2 values based on HapMap CEU, release 22

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Supplementary Table 4. Effects of 37 SNPs previously associated with type 2 diabetes on physiologic glycemic measures with genetic data available in more than 10,000 non-diabetic individuals.

Dynamic traits

Fasting traits

Insulino- genic index (n=11,268)

ISI Belfiore (n=10,34)

ISI Stumvoll (n=10,239)

ISI Matsuda (n=10,364)

ISI Gutt (n=13,158)

Proinsulin (n=13,912)

Fasting Glucose* (n=58,614)

Fasting Insulin* (n=52,379)

HOMA-B* (n=50,908)

HOMA-IR* (n=50,908)

SNP Nearest gene

Alleles (effect/ other)

Effect (SE)

P

Effect (SE)

P

Effect (SE)

P

Effect (SE)

P

Effect (SE)

P

Effect (SE)

P

Effect (SE)

P

Effect (SE)

P

Effect (SE)

P

Effect (SE)

P Insulin Resistance (IR)

rs13081389 PPARG A/G 0.0092 (0.017)

-0.019 (0.0069)

-0.021 (0.0082)

-0.035 (0.012)

-0.015 (0.0071)

0.0082 (0.0088)

0.0097 (0.0062)

0.025 (0.0052)

0.017 (0.0048)

0.025 (0.0055)

0.59 0.0055 0.012 0.0037 0.039 0.35 0.12 1.6×10-6 4.96×10-4 4.37×10-6

rs972283 KLF14 G/A -0.0020 (0.011)

-0.0030 (0.0042)

-0.0083 (0.0052)

-0.0013 (0.0077)

-0.0079 (0.0041)

0.0045 (0.0052)

0.0066 (0.0032)

0.013 (0.0027)

0.0091 (0.0026)

0.014 (0.0029)

0.85 0.47 0.11 0.86 0.055 0.39 0.040 4.41×10-6 4.16×10-4 6.84×10-7

rs7578326 IRS1 A/G 0.037 (0.010)

-0.023 (0.0043)

-0.013 (0.0050)

-0.040 (0.0075)

-0.020 (0.0042)

0.014 (0.0052)

0.0045 (0.0034)

0.019 (0.0029)

0.014 (0.0027)

0.019 (0.0031)

0.00038 1.19×10-7 0.0090 1.46×10-7 2.47×10-6 0.0063 0.19 2.68×10-

11 2.65×10-7 6.95×10-10

rs780094 GCKR C/T 0.0090 (0.010)

-0.0077 (0.0041)

-0.015 (0.0048)

-0.019 (0.0073)

0.0072 (0.0039)

0.010 (0.0053)

0.033 (0.0032)

0.019 (0.0027)

0.0058 (0.0026)

0.023 (0.0029)

0.38 0.061 0.0020 0.0077 0.061 0.050 3.30×10-

24 3.36×10-

12 0.022 4.68×10-16 Hyperglycemic (HG)

rs10830963 MTNR1B G/C

-0.083 (0.011)

0.0057 (0.0043)

-0.0073 (0.0051)

-0.0043 (0.0076)

-0.0059 (0.0043)

0.0093 (0.0058)

0.079 (0.0038)

0.0004 (0.0033)

-0.033 (0.0031)

0.011 (0.0035)

1.23×10-14 0.18 0.15 0.57 0.17 0.11 8.72×10- 0.91 4.23×10- 0.0018

SUPPLEMENTARY DATA


95 26

rs4607517 GCK A/G -0.036 (0.017)

-0.0048 (0.0070)

-0.015 (0.0083)

-0.0078 (0.012)

-0.016 (0.0060)

-0.00068 (0.0080)

0.065 (0.0043)

0.0064 (0.0037)

-0.024 (0.0035)

0.014 (0.0039)

0.031 0.49 0.077 0.52 0.0069 0.93 1.39×10-

51 0.081 1.32×10-

11 3.89×10-4 Proinsulin (PI)

rs1552224 ARAP1 A/C -0.054 (0.012)

-0.00038 (0.0048)

-0.013 (0.0062)

-0.013 (0.0089)

-0.010 (0.0052)

-0.093 (0.0062)

0.024 (0.0042)

-0.0075 (0.0034)

-0.015 (0.0032)

-0.0051 (0.0037)

1.54×10-5 0.94 0.033 0.15 0.050 2.16×10-

50 9.40×10-9 0.029 3.16×10-6 0.16 Beta Cell (BC)

rs7903146 TCF7L2 T/C -0.063 (0.012)

0.0094 (0.0051)

-0.0085 (0.0058)

0.010 (0.0085)

-0.017 (0.0046)

0.044 (0.0061)

0.026 (0.0036)

-0.014 (0.0031)

-0.019 (0.0029)

-0.010 (0.0033)

1.40×10-7 0.064 0.14 0.24 0.00021 4.20×10-

13 9.55×10-

13 4.81×10-6 4.25×10-

11 0.0022

rs3802177 SLC30A8 G/A

-0.041 (0.011)

0.00066 (0.0043)

-0.0039 (0.0055)

-0.0012 (0.0081)

-0.011 (0.0050)

0.038 (0.0062)

0.033 (0.0035)

-0.0035 (0.0031)

-0.016 (0.0028)

0.0002 (0.0033)

0.00024 0.88 0.47 0.88 0.034 1.25×10-9 4.32×10-

21 0.26 3.41×10-8 0.96

rs5015480 HHEX/IDE C/T

-0.10 (0.011)

0.020 (0.0042)

-0.010 (0.0053)

0.017 (0.0078)

-0.0052 (0.0041)

0.0063 (0.0053)

0.010 (0.0032)

-0.0008 (0.0027)

-0.0051 (0.0025)

0.0007 (0.0028)

3.63×10-21 1.46×10-6 0.054 0.030 0.21 0.23 0.0011 0.77 0.042 0.81

rs2191349

DGKB/TMEM195 T/G

-0.028 (0.010)

0.011 (0.0040)

0.0071 (0.0047)

0.027 (0.0072)

0.0060 (0.0038)

-0.0011 (0.0049)

0.032 (0.0032)

-0.0017 (0.0027)

-0.017 (0.0025)

0.0018 (0.0028)

0.0058 0.0059 0.13 0.00018 0.12 0.83 1.15×10-

24 0.51 2.07×10-

11 0.52

rs340874 PROX1 C/T -0.028 (0.010)

0.0082 (0.0041)

0.0079 (0.0047)

0.0090 (0.0072)

-0.00066 (0.0040)

0.0086 (0.0055)

0.017 (0.0032)

-0.0019 (0.0028)

-0.0094 (0.0026)

-0.0003 (0.003)

0.0060 0.044 0.096 0.21 0.87 0.12 6.80×10-8 0.50 2.45×10-4 0.91

rs10965250 CDKN2A/B G/A

-0.045 (0.014)

0.013 (0.0057)

-0.00072 (0.0070)

0.012 (0.010)

0.0046 (0.0054)

-0.00039 (0.0071)

0.017 (0.0042)

-0.0049 (0.0037)

-0.012 (0.0035)

-0.0023 (0.0039)

0.0013 0.023 0.92 0.26 0.39 0.96 5.17×10-5 0.18 4.27×10-4 0.55

rs10440833 CDKAL1 A/T

-0.10 (0.023)

0.0047 (0.0090)

-0.011 (0.010)

-0.0095 (0.017)

-0.0013 (0.0066)

0.0077 (0.0085)

0.014 (0.0035)

-0.0061 (0.0029)

-0.0088 (0.0027)

-0.0043 (0.0031)

SUPPLEMENTARY DATA


6.84×10-6 0.60 0.30 0.58 0.84 0.37 5.19×10-5 0.036 0.0012 0.17

rs11899863 THADA C/T 0.0078 (0.020)

0.0096 (0.0080)

-0.0036 (0.0095)

0.016 (0.015)

-0.0071 (0.0072)

0.015 (0.0097)

0.020 (0.0054)

-0.010 (0.0048)

-0.020 (0.0046)

-0.0080 (0.0051)

0.70 0.23 0.70 0.28 0.32 0.12 2.28×10-4 0.036 1.30×10-5 0.12

rs11708067 ADCY5 A/G -0.0089 (0.013)

-0.0079 (0.0051)

0.0012 (0.0062)

-0.0025 (0.0093)

-0.014 (0.0047)

0.016 (0.0064)

0.022 (0.0039)

-0.0060 (0.0034)

-0.015 (0.0032)

-0.0011 (0.0036)

0.49 0.13 0.85 0.79 0.0024 0.012 1.89×10-8 0.076 5.39×10-6 0.76 Unclassified (UC)

rs4430796 HNF1B (TCF2) G/A

-0.044 (0.023)

0.0072 (0.0091)

-0.011 (0.011)

0.0082 (0.018)

-0.013 (0.0095)

-0.00053 (0.016)

-0.0007 (0.0039)

-0.012 (0.0035)

-0.011 (0.0031)

-0.012 (0.0037)

0.061 0.43 0.32 0.64 0.17 0.97 0.85 8.25×10-4 5.14×10-4 9.08×10-4

rs2334499 HCCA2 T/C -0.018 (0.023)

0.0098 (0.0089)

0.016 (0.0099)

0.015 (0.017)

-0.0057 (0.0068)

-0.017 (0.0086)

0.0011 (0.0032)

-0.0044 (0.0027)

-0.0036 (0.0026)

-0.0037 (0.0029)

0.43 0.27 0.11 0.38 0.40 0.043 0.73 0.11 0.16 0.21

rs7957197 HNF1A T/A -0.036 (0.018)

0.0086 (0.0075)

-0.0062 (0.0091)

-0.0029 (0.014)

0.00049 (0.0061)

-0.011 (0.0087)

-0.0014 (0.004)

-0.0043 (0.0033)

-0.0028 (0.0031)

-0.0045 (0.0035)

0.049 0.25 0.49 0.83 0.94 0.22 0.73 0.20 0.36 0.20

rs10923931 NOTCH2 T/G

-0.012 (0.016)

0.011 (0.0065)

0.0026 (0.0078)

0.019 (0.012)

0.0011 (0.0065)

-0.000015 (0.0084)

0.0025 (0.005)

-0.0034 (0.0042)

-0.0043 (0.0039)

-0.0014 (0.0044)

0.45 0.085 0.74 0.11 0.87 1.00 0.63 0.41 0.28 0.76

rs13292136 CHCHD9 C/T

-0.025 (0.016)

0.012 (0.0069)

-0.0013 (0.0084)

0.026 (0.012)

0.0063 (0.0069)

-0.00054 (0.0086)

-0.0028 (0.0057)

-0.0054 (0.0046)

-0.0022 (0.0042)

-0.0050 (0.0049)

0.13 0.078 0.87 0.028 0.36 0.95 0.63 0.24 0.61 0.30

rs1801214 WFS1 T/C -0.017 (0.011)

0.0016 (0.0045)

-0.00084 (0.0052)

0.0082 (0.0080)

-0.0076 (0.0042)

-0.019 (0.0053)

0.0081 (0.0033)

-0.0011 (0.0028)

-0.0054 (0.0027)

0.0003 (0.003)

0.12 0.72 0.87 0.30 0.071 0.00023 0.016 0.67 0.042 0.92

rs4457053 ZBED3 G/A -0.014 (0.012)

0.00038 (0.0049)

0.0021 (0.0058)

0.00039 (0.0083)

-0.0040 (0.0045)

-0.0078 (0.0055)

0.019 (0.004)

0.0016 (0.0033)

-0.0053 (0.0031)

0.0031 (0.0035)

0.21 0.94 0.72 0.96 0.36 0.16 2.38×10-6 0.61 0.084 0.38

rs8042680 PRC1 A/C -0.016 (0.011)

0.0030 (0.0046)

0.0074 (0.0053)

0.011 (0.0081)

-0.0021 (0.0043)

-0.0082 (0.0057)

0.011 (0.0034)

-0.0016 (0.0028)

-0.0036 (0.0027)

-0.0003 (0.003)

0.15 0.51 0.16 0.19 0.62 0.15 0.0015 0.56 0.17 0.93

rs1470579 IGF2BP2 C/A

-0.038 (0.018)

0.013 (0.0068)

0.0096 (0.0079)

0.0096 (0.013)

-0.00083 (0.0054)

-0.011 (0.0073)

0.016 (0.0034)

-0.0012 (0.0028)

-0.0062 (0.0027)

0.0001 (0.003)

SUPPLEMENTARY DATA


0.030 0.062 0.23 0.46 0.88 0.15 2.34×10-6 0.66 0.022 0.96

rs896854 TP53INP1 T/C

-0.0035 (0.010)

-0.0013 (0.0038)

-0.0056 (0.0049)

-0.0025 (0.0069)

0.00026 (0.0040)

-0.0031 (0.0049)

0.0069 (0.0031)

-0.0023 (0.0026)

-0.0045 (0.0025)

-0.0013 (0.0028)

0.73 0.74 0.26 0.72 0.95 0.53 0.028 0.38 0.070 0.65

rs12779790

CDC123/CAMK1D G/A

-0.029 (0.013)

0.0014 (0.0055)

-0.0021 (0.0064)

-0.0060 (0.0096)

0.0016 (0.0053)

-0.0082 (0.0068)

0.014 (0.0042)

-0.0018 (0.0036)

-0.0068 (0.0034)

-0.0009 (0.0038)

0.029 0.80 0.74 0.53 0.76 0.23 5.61×10-4 0.62 0.046 0.81

rs11634397 ZFAND6 G/A -0.0098 (0.010)

-0.00098 (0.0043)

-0.0055 (0.0052)

-0.0068 (0.0071)

-0.0054 (0.0042)

0.0081 (0.0051)

0.0014 (0.0035)

0.0030 (0.0029)

0.0023 (0.0028)

0.0029 (0.0031)

0.34 0.82 0.29 0.34 0.19 0.11 0.68 0.31 0.41 0.35

rs4760790 TSPAN8/LGR5 A/G

-0.016 (0.013)

0.00096 (0.0050)

0.0096 (0.0061)

-0.0035 (0.0092)

-0.00039 (0.0046)

0.0061 (0.0060)

0.0040 (0.0036)

-0.0005 (0.003)

-0.0021 (0.0029)

0.0005 (0.0032)

0.21 0.85 0.11 0.70 0.93 0.31 0.27 0.88 0.47 0.89

rs5215 KCNJ11 C/T -0.024 (0.017)

0.0017 (0.0065)

-0.015 (0.0076)

0.00091 (0.012)

0.0035 (0.0052)

0.0010 (0.0071)

-0.0040 (0.0032)

-0.0010 (0.0027)

0.0027 (0.0025)

-0.0020 (0.0029)

0.15 0.79 0.057 0.94 0.50 0.89 0.22 0.72 0.28 0.48

rs243021 BCL11A A/G 0.018 (0.011)

0.0045 (0.0040)

0.0084 (0.0051)

0.013 (0.0074)

0.0090 (0.0041)

0.0070 (0.0052)

0.0038 (0.0032)

0.0009 (0.0027)

0.0003 (0.0025)

0.00 (0.0029)

0.093 0.26 0.10 0.067 0.029 0.18 0.23 0.72 0.89 0.99

rs849134 JAZF1 A/G 0.013 (0.011)

-0.0052 (0.0042)

-0.0047 (0.0052)

-0.014 (0.0077)

-0.0061 (0.0041)

0.0035 (0.0052)

0.0074 (0.0032)

-0.0001 (0.0027)

-0.0014 (0.0025)

-0.0002 (0.0029)

0.23 0.21 0.37 0.068 0.14 0.50 0.019 0.97 0.57 0.943

rs1531343 HMGA2 C/G 0.030 (0.019)

-0.013 (0.0076)

0.0017 (0.0087)

-0.027 (0.014)

0.0012 (0.0067)

0.010 (0.0090)

0.013 (0.0054)

0.0074 (0.0045)

-0.0013 (0.0043)

0.011 (0.0048)

0.11 0.084 0.84 0.050 0.86 0.26 0.018 0.10 0.76 0.029

rs231362 KCNQ1 G/A 0.0045 (0.011)

-0.000085 (0.0045)

-0.0039 (0.0053)

-0.0033 (0.0079)

-0.0051 (0.0044)

-0.0037 (0.0052)

0.017 (0.0035)

0.0069 (0.003)

-0.0010 (0.0028)

0.0066 (0.0032)

0.68 0.98 0.46 0.67 0.24 0.48 2.7×10-6 0.020 0.72 0.038

rs163184 KCNQ1 G/T -0.011 (0.022)

0.0024 (0.0088)

0.0092 (0.0096)

0.0087 (0.017)

-0.0037 (0.0079)

0.016 (0.010)

0.012 (0.0032)

0.0019 (0.0028)

-0.0045 (0.0027)

0.0039 (0.003)

0.63 0.79 0.34 0.60 0.64 0.11 1.90×10-4 0.51 0.091 0.20

rs6795735 ADAMTS9 C/T

0.0088 (0.010)

0.0060 (0.0043)

0.0027 (0.0051)

0.011 (0.0076)

0.0012 (0.0041)

0.00056 (0.0050)

0.0076 (0.0032)

0.0025 (0.0027)

-0.0014 (0.0025)

0.0032 (0.0029)

SUPPLEMENTARY DATA


0.40 0.16 0.60 0.14 0.77 0.91 0.017 0.35 0.57 0.26 Other

rs5945326 DUSP9 A/G -0.037 (0.010)

0.012 (0.0038)

0.010 (0.0048)

0.022 (0.0067)

0.0059 (0.0047)

-0.013 (0.0060)

0.011 (0.013)

-0.013 (0.0138)

-2.89 (1.3345)

-0.066 (0.041)

0.00032 0.0017 0.033 0.00085 0.21 0.030 0.40 0.35 0.030 0.11 Supplementary Table 5. Effects of 37 SNPs previously associated with type 2 diabetes on physiologic glycemic measures with genetic data available in fewer than 10,000 non-diabetic individuals. IR: insulin resistance, HG: hyperglycemic, PI: proinsulin, BC: beta cell, UC: unclassified.

SNP Nearest gene Alleles (effect/other)

M/I, SI, SSPG

(n=4,180)

Acute Insulin Response (n=1,135)

C-Peptide (n=5,059)

32,33 Split Proinsulin (n=2,568)

Effect (SE) P

Effect (SE) P

Effect (SE) P

Effect (SE) P

IR

rs13081389 PPARG A/G -0.025 (0.049) -0.025 (0.066) 0.015 (0.012) 0.0050 (0.032) 0.60 0.70 0.22 0.88

rs972283 KLF14 G/A -0.0023 (0.020)

0.019 (0.043) 0.0068 (0.0084) 0.0024 (0.017)

0.91 0.65 0.42 0.88 rs7578326 IRS1 A/G -0.070 (0.021) -0.0061 (0.043) 0.021 (0.0083) 0.021 (0.018)

0.00065 0.89 0.013 0.24 rs780094 GCKR C/T -0.019 (0.019) 0.034 (0.033) 0.020 (0.0074) 0.027 (0.017)

0.32 0.31 0.0079 0.12

HG rs10830963 MTNR1B G/C 0.012 (0.021) -0.16 (0.035) -0.0069 (0.0080) -0.0034 (0.019)

0.55 4.81×10-6 0.39 0.86 rs4607517 GCK A/G 0.015 (0.025) -0.097 (0.050) -0.014 (0.014) -0.0097 (0.038)

0.55 0.051 0.32 0.80

SUPPLEMENTARY DATA


PI

rs1552224

ARAP1

A/C -0.010 (0.026)

0.69

-0.0064 (0.054)

0.91

0.019 (0.012)

0.11

-0.13 (0.023)

1.39×10-8

BC

rs7903146 TCF7L2 T/C 0.014 (0.021) -0.054 (0.039) -0.021 (0.011) 0.012 (0.030) 0.50 0.17 0.051 0.68

rs3802177 SLC30A8 G/A -0.014 (0.020) -0.11 (0.033) 0.0096 (0.0077) 0.066 (0.018) 0.47 0.0016 0.21 0.00019

rs5015480 HHEX/IDE C/T -0.0040 (0.020)

-0.11 (0.044) 0.0011 (0.0087) 0.017 (0.017)

0.84 0.013 0.90 0.33 rs2191349 DGKB/TMEM195 T/G -0.00054

(0.018) -0.013 (0.032) -0.0055 (0.0072) -0.00057 (0.017)

0.98 0.67 0.44 0.97 rs340874 PROX1 C/T -0.0020

(0.018) -0.043 (0.032) -0.00058

(0.0072) 0.00035 (0.016)

0.91 0.18 0.94 0.98 rs10965250 CDKN2A/B G/A 0.047 (0.024) -0.18 (0.044) -0.0022 (0.011) 0.011 (0.022)

0.051 3.57×10-5 0.84 0.60

rs10440833 CDKAL1 A/T 0.047 (0.021) -0.15 (0.048) 0.00083 (0.013) -0.042 (0.029) 0.026 0.0020 0.95 0.15

rs11899863 THADA C/T -0.053 (0.032) 0.013 (0.066) 0.012 (0.013) 0.038 (0.028) 0.10 0.84 0.38 0.17

rs11708067 ADCY5 A/G -0.063 (0.023) -0.013 (0.040) -0.0018 (0.0088) 0.062 (0.019) 0.0061 0.75 0.84 0.0012

UC

rs4430796 HNF1B (TCF2) G/A 0.025 (0.032)

-0.021 (0.042) 0.00040 (0.0087)

0.030 (0.022)

0.45 0.61 0.96 0.18 rs2334499 HCCA2 T/C 0.031 (0.021) - 0.0043 (0.018) -0.016 (0.026)

0.14 - 0.81 0.53 rs7957197 HNF1A T/A 0.0053 (0.024) -0.079 (0.054) 0.0094 (0.011) -0.094 (0.021)

0.82 0.14 0.39 8.08×10-6

SUPPLEMENTARY DATA


rs10923931 NOTCH2 T/G 0.038 (0.030) -0.083 (0.066) -0.017 (0.014) -0.0073 (0.027) 0.21 0.21 0.22 0.78

rs13292136 CHCHD9 C/T 0.034 (0.042) 0.040 (0.068) -0.0091 (0.017) -0.010 (0.044) 0.43 0.56 0.58 0.82

rs1801214 WFS1 T/C -0.016 (0.023) -0.063 (0.034) -0.0083 (0.0079) -0.0048 (0.021) 0.48 0.063 0.29 0.82

rs4457053 ZBED3 G/A -0.0084 (0.023)

-0.013 (0.046) -0.017 (0.0098) -0.014 (0.018)

0.72 0.77 0.084 0.43 rs8042680 PRC1 A/C 0.0034 (0.025) 0.00053 (0.043) -0.014 (0.0092) -0.013 (0.024)

0.89 0.99 0.12 0.57 rs1470579 IGF2BP2 C/A 0.013 (0.021) -0.15 (0.046) -0.0026 (0.0091) -0.0040 (0.018)

0.54 0.0014 0.77 0.82 rs896854 TP53INP1 T/C 0.0071 (0.019) 0.030 (0.041) -0.012 (0.0086) -0.022 (0.017)

0.70 0.46 0.16 0.19 rs12779790 CDC123/CAMK1D G/A 0.020 (0.024) -0.015 (0.053) -0.028 (0.011) -0.016 (0.021)

0.40 0.78 0.015 0.46 rs11634397 ZFAND6 G/A 0.032 (0.021) 0.075 (0.045) -0.0070 (0.0093) -0.022 (0.017)

0.12 0.096 0.45 0.21 rs4760790 TSPAN8/LGR5 A/G 0.016 (0.022) 0.019 (0.046) -0.012 (0.0087) -0.026 (0.018)

0.45 0.68 0.18 0.15 rs5215 KCNJ11 C/T -0.018 (0.020) -0.099 (0.042) -0.0053 (0.0088) 0.035 (0.017)

0.37 0.018 0.54 0.042 rs243021 BCL11A A/G -0.0056

(0.023) 0.0037 (0.041) -0.0053 (0.0086) 0.027 (0.022)

0.81 0.93 0.54 0.22 rs849134 JAZF1 A/G 0.015 (0.019) -0.0017 (0.041) 0.0092 (0.0084) 0.021 (0.017)

0.44 0.97 0.27 0.20 rs1531343 HMGA2 C/G -0.034 (0.036) -0.12 (0.075) 0.0062 (0.014) -0.0042 (0.034)

0.35 0.11 0.65 0.90 rs231362 KCNQ1 G/A -0.021 (0.020) -0.18 (0.041) 0.0065 (0.0091) 0.0096 (0.017)

SUPPLEMENTARY DATA


0.28 1.63×10-5 0.47 0.58

rs163184 KCNQ1 G/T 0.015 (0.021) - 0.0076 (0.017) 0.041 (0.027) 0.48 - 0.66 0.12

rs6795735 ADAMTS9 C/T -0.0045 (0.020)

0.031 (0.051) -0.0017 (0.0095) 0.012 (0.018)

0.82 0.54 0.86 0.52

Other rs5945326 DUSP9 A/G 0.069 (0.047) -0.019 (0.038) -0.018 (0.015) -

0.15 0.63 0.23 -

SUPPLEMENTARY DATA


Supplementary Figure 1. Forest plots for meta-analyses of insulinogenic index, split proinsulin and acute insulin response (AIR). (A) insulinogenic index at HHEX/IDE, (B) insulinogenic index at CDKAL1, (C) 32,33 split proinsulin at HNF1A, (D) AIR at MTNR1B, (E) AIR at KCNQ1, (F) AIR at CDKN2A/B.

SUPPLEMENTARY DATA


SUPPLEMENTARY DATA


Supplementary Figure 2. Forest plots for meta-analyses of intravenous (IV) insulin sensitivity traits (A) IRS1, (B) ADCY5.

SUPPLEMENTARY DATA


Supplementary Figure 3. Results of cluster analysis using principal traits. (A) Clustering of ten traits with meta-analysis results from at least 10,000 individuals (principal traits). Traits include: insulinogenic index, proinsulin, ISI Belfiore, ISI Gutt, ISI Matsuda, ISI Stumvoll and four fasting traits: fasting glucose (FG), fasting insulin (FI), HOMA-B, HOMA-IR. Closest links are observed between the four ISIs, which are connected to the HOMA-IR/FI branch and constitute a larger clade of traits linked to insulin sensitivity and resistance. This clade is linked to proinsulin, making up a cluster bearing insulin secretion and sensitivity traits. In turn, this is connected to the HOMA-B/insulinogenic index clade representing effects of type 2 diabetes loci on beta-cell function and early insulin secretion. Finally, the effects of type 2 diabetes loci on FG cluster separately from all other traits. (B) Calinski index computed as a measure of clustering support. The most robust set contained eight trait groups underscoring a clear distinction between most of the investigated physiologic phenotypes.

SUPPLEMENTARY DATA


Supplementary Figure 4. Results of cluster analysis using all 14 traits. (A) Complete linkage dendrogram of the 14 traits. Cluster analysis confirmed the trait connectivity observed for principal traits and revealed a direct link between AIR and insulinogenic index. C-peptide and split proinsulin were connected directly and linked subsequently to the clade of insulin secretion measurements. IV measures cluster with the ISIs (Matsuda/Belfiore clade). The C-peptide/split proinsulin cluster was connected directly to ISIs/ IV measures and this whole clade was linked subsequently to the group of insulin secretion measurements. (B) Calinski index computed as a measure of clustering support. The most robust set contained twelve trait groups underscoring a clear distinction between the investigated physiologic phenotypes.

SUPPLEMENTARY DATA


Supplementary Figure 5. Principal component analysis (PCA) of type 2 diabetes SNPs. Loci are grouped using centroid-based clustering. Each group is represented using a specific color and group name is shown next to each ellipse (see main text for loci belonging to each group). The two components explain the 64.29% of the total phenotypic variance. Numbers on ellipses correspond to locus groups: 1: hyperglycemic (HG), 2: insulin resistance (IR), 3: proinsulin (PI), 4: beta cell (BC), 5: unclassified (UC).

SUPPLEMENTARY DATA


Supplementary Figure 6. Scatter plots of allelic effect size estimates for selected trait pairs. For each scatter plot, loci are assigned into the groups defined from the cluster analysis of principal traits (groups highlighted by different colours). (A) Insulinogenic index vs. M/I SI SSPG reveals elevated insulinogenic index at IRS1 and a negative correlation of insulinogenic index with the compensatory effects IV measures. (B) Proinsulin vs. HOMA-B, this plot highlights the effect of ARAP1 on proinsulin. (C) Proinsulin vs. 32,33 split proinsulin shows the diminished proinsulin levels at ARAP1. (D) Insulinogenic index vs. 32,33 split proinsulin reveals a similar effect for ARAP1 on insulinogenic index. (E) Acute insulin response vs. M/I SI SSPG (combined IV measures): this plot illustrates a weak negative correlation of acute insulin response with compensatory effects IV measures. (F) ISI Belfiore vs. M/I SI SSPG plot reflects good correlation between the two measures of insulin sensitivity. Cluster group colors are HG: orange, IR: green, PI: pink, BC: red, UC: blue.

SUPPLEMENTARY DATA


SUPPLEMENTARY DATA


REFERENCES 1. Belfiore F, Iannello S, Volpicelli G: Insulin sensitivity indices calculated from basal and OGTT-induced insulin, glucose, and FFA levels. Mol Genet Metab 1998;63:134-141 2. Gutt M, Davis CL, Spitzer SB, Llabre MM, Kumar M, Czarnecki EM, Schneiderman N, Skyler JS, Marks JB: Validation of the insulin sensitivity index (ISI(0,120)): comparison with other measures. Diabetes Res Clin Pract 2000;47:177-184 3. Matsuda M, DeFronzo RA: Insulin sensitivity indices obtained from oral glucose tolerance testing: comparison with the euglycemic insulin clamp. Diabetes care 1999;22:1462-1470 4. Stumvoll M, Mitrakou A, Pimenta W, Jenssen T, Yki-Jarvinen H, Van Haeften T, Renn W, Gerich J: Use of the oral glucose tolerance test to assess insulin release and insulin sensitivity. Diabetes care 2000;23:295-301

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