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Table 2 Results of conditional analysis, Mendelian randomization and structural equational modeling for the 38 significant SNP-MET-LIP sets

From: Interrogating causal pathways linking genetic variants, small molecule metabolites, and circulating lipids

  

Conditional analysis

Mendelian randomization

Structural equation modeling

  

KORA

TwinsUK

KORA

TwinsUK

KORA

TwinsUK

Locus

SNP - MET - LIP

Beta

Beta

Beta

Beta

Beta

Beta

95% CI for Beta (MET → LIP using SNP as an IV)

90% CI for Beta (MET → LIP using SNP as an IV)

Best fitted model

Best fitted model

  

(LIP ~ SNP)

(LIP ~ SNP + MET)

Changes

(LIP ~ SNP)

(LIP ~ SNP + MET)

Changes

GCKR

rs1260326 - PC aa C40:5 - TC

2.789

0.685

−75%

4.770

2.747

−42%

0.34, 177.04

−21.33, 168.93

Model 4 (SNP → MET → LIP)

Model 4 (SNP → MET → LIP)

 

rs1260326 - PC aa C40:5 - TG

0.081

0.054

−33%

0.075

0.058

−24%

0.28, 3.86

−0.38, 2.30

Model 8 (SNP → LIP → MET)

 

LPA

rs1564348 - C3 - HDL-C

1.095

1.640

50%

0.248

1.171

372%

−26.39, 46.60

−50.74, 35.81

  
 

rs1564348 - C8:1 - HDL-C

1.095

1.328

21%

0.248

1.319

432%

−24.00, 35.48

−16.69, 16.23

  

FADS1

rs174546 - PC aa C32:0 - TG

0.043

0.061

43%

0.048

0.050

3%

−2.02, 0.35

−2.45, 2.68

 

Model 10 (MET ← SNP → LIP)

 

rs174546 - PC aa C32:2 - TG

0.043

0.017

−61%

0.048

0.034

−29%

0.02, 0.88

−0.59, 1.56

Model 4 (SNP → MET → LIP)

Model 4 (SNP → MET → LIP)

 

rs174546 - PC aa C34:2 - TG

0.043

0.006

−87%

0.048

0.037

−22%

0.20, 2.25

−0.52, 1.75

Model 4 (SNP → MET → LIP)

Model 4 (SNP → MET → LIP)

 

rs174546 - PC aa C34:3 - TG

0.043

0.021

−50%

0.048

0.035

−27%

−0.41, 2.08

−1.09, 1.87

Model 4 (SNP → MET → LIP)

Model 4 (SNP → MET → LIP)

 

rs174546 - PC aa C34:4 - TG

0.043

0.102

139%

0.048

0.076

58%

−0.77, 0.04

−1.13, 0.44

  
 

rs174546 - PC aa C36:2 - TG

0.043

0.004

−90%

0.048

0.041

−15%

0.14, 1.78

−1.20, 2.20

Model 4 (SNP → MET → LIP)

Model 4 (SNP → MET → LIP)

 

rs174546 - PC aa C36:3 - TG

0.043

−0.016

−138%

0.048

0.022

−54%

0.20, 1.55

−0.10, 1.43

Model 4 (SNP → MET → LIP)

Model 4 (SNP → MET → LIP)

 

rs174546 - PC aa C36:4 - TG

0.043

0.157

268%

0.048

0.084

75%

−0.72, −0.02

−0.83, 0.07

  
 

rs174546 - PC aa C36:5 - TG

0.043

0.077

79%

0.048

0.054

13%

−0.54, 0.03

−0.95, 0.12

 

Model 10 (MET ← SNP → LIP)

 

rs174546 - PC aa C36:6 - TG

0.043

0.060

40%

0.048

0.053

10%

−1.52, 0.73

−1.92, 2.04

  
 

rs174546 - PC aa C38:4 - TG

0.043

0.177

315%

0.048

0.097

102%

−0.59, 0.01

−0.67, 0.06

  
 

rs174546 - PC aa C38:5 - TG

0.043

0.131

206%

0.048

0.069

44%

−0.74, −0.02

−0.96, 0.07

  
 

rs174546 - PC aa C40:4 - TG

0.043

0.103

140%

0.048

0.076

58%

−1.10, 0.13

−1.27, 0.44

  
 

rs174546 - PC aa C40:5 - TG

0.043

0.115

168%

0.048

0.077

60%

−1.07, 0.15

−1.22, 0.33

  
 

rs174546 - PC aa C40:6 - TG

0.043

0.071

65%

0.048

0.055

14%

−1.84, 0.84

−2.20, 2.10

  
 

rs174546 - PC aa C42:0 - TG

0.043

0.025

−41%

0.048

0.030

−37%

−2.62, 0.72

−1.73, 0.53

Model 4 (SNP → MET → LIP)

Model 4 (SNP → MET → LIP)

 

rs174546 - PC aa C42:1 - TG

0.043

0.016

−62%

0.048

0.030

−38%

−1.39, −0.07

−1.24, 0.15

Model 4 (SNP → MET → LIP)

Model 4 (SNP → MET → LIP)

 

rs174546 - PC aa C42:4 - TG

0.043

0.054

26%

0.048

0.051

6%

−1.29, 0.03

−1.20, 0.63

 

Model 10 (MET ← SNP → LIP)

 

rs174546 - PC aa C42:6 - TG

0.043

0.067

57%

0.048

0.048

0%

−1.77, 0.33

−1.76, 0.48

 

Model 10 (MET ← SNP → LIP)

 

rs174546 - PC ae C36:2 - TG

0.043

0.058

36%

0.048

0.054

12%

−0.06, 1.14

−3.89, 2.77

  
 

rs174546 - PC ae C36:3 - TG

0.043

0.069

61%

0.048

0.062

29%

−0.01, 1.03

−0.76, 1.89

  
 

rs174546 - PC ae C36:4 - TG

0.043

0.044

2%

0.048

0.037

−23%

−1.39, 0.11

−1.13, 0.10

 

Model 4 (SNP → MET → LIP)

 

rs174546 - PC ae C36:5 - TG

0.043

0.031

−29%

0.048

0.016

−66%

−0.93, −0.07

−0.84, 0.02

Model 4 (SNP → MET → LIP)

Model 4 (SNP → MET → LIP)

 

rs174546 - PC ae C38:4 - TG

0.043

0.036

−16%

0.048

0.044

−8%

−1.10, −0.06

−1.01, 0.07

 

Model 10 (MET ← SNP → LIP)

 

rs174546 - PC ae C38:5 - TG

0.043

0.030

−30%

0.048

0.022

−55%

−1.18, −0.05

−1.02, −0.01

Model 4 (SNP → MET → LIP)

Model 4 (SNP → MET → LIP)

 

rs174546 - PC ae C38:6 - TG

0.043

0.039

−10%

0.048

0.030

−37%

−1.99, 0.18

−1.52, 0.13

 

Model 4 (SNP → MET → LIP)

 

rs174546 - PC ae C40:1 - TG

0.043

0.056

30%

0.048

0.046

−3%

−1.19, 0.10

−2.02, 1.04

 

Model 10 (MET ← SNP → LIP)

 

rs174546 - PC ae C40:4 - TG

0.043

0.013

−71%

0.048

0.049

2%

−1.36, −0.08

−1.20, 0.23

Model 4 (SNP → MET → LIP)

Model 10 (MET ← SNP → LIP)

 

rs174546 - PC ae C40:5 - TG

0.043

0.014

−68%

0.048

0.042

−13%

−1.35, −0.05

−1.26, 0.19

Model 4 (SNP → MET → LIP)

Model 4 (SNP → MET → LIP)

 

rs174546 - PC ae C40:6 - TG

0.043

0.037

−13%

0.048

0.034

−29%

−2.90, 2.54

−1.99, 0.64

Model 4 (SNP → MET → LIP)

Model 4 (SNP → MET → LIP)

 

rs174546 - PC ae C42:1 - TG

0.043

0.060

41%

0.048

0.051

6%

−1.81, 0.26

−1.74, 1.72

 

Model 10 (MET ← SNP → LIP)

 

rs174546 - PC ae C42:5 - TG

0.043

−0.003

−106%

0.048

0.031

−36%

−1.43, −0.11

−1.35, 0.15

Model 4 (SNP → MET → LIP)

Model 4 (SNP → MET → LIP)

 

rs174546 - PC ae C44:5 – TG

0.043

−0.001

−102%

0.048

0.022

−54%

−1.26, −0.14

−1.16, 0.12

Model 4 (SNP → MET → LIP)

Model 4 (SNP → MET → LIP)

 

rs174546 - PC ae C44:6 – TG

0.043

−0.007

−117%

0.048

0.006

−87%

−1.10, −0.10

−1.02, −0.05

Model 4 (SNP → MET → LIP)

Model 4 (SNP → MET → LIP)

  1. Effect size declines in conditional analysis, confidence intervals not containing 0 in Mendelian randomization, and Model 4 reported as the best fitted model in structural equation modeling in each cohort were highlighted in bold to provide evidence for the mediating role of MET in SNP-LIP pathways. SEM Model 4: SNP → MET → LIP; Model 8: SNP → LIP → MET; Model 10: SNP → MET; SNP → LIP.