Phenotypic and Genetic Characterization of Lower LDL Cholesterol and Increased Type 2 Diabetes Risk in the UK Biobank
Article Figures & Tables
Figures
- Figure 1
T2D prevalence, HbA1c, and BMI by circulating LDL-C deciles in the UK Biobank. T2D prevalence is shown as a percentage, with error bars corresponding to the Clopper-Pearson CI. Whisker plots show the median value (horizontal line in box), the 25th and 75th percentile delimited by the box, and the vertical lines extending to the 5th and 95th percentile.
- Figure 2
Plot of β-coefficients for circulating LDL-C vs. T2D for SNPs with opposite directions of effect on these two traits. β-Coefficients correspond to log-ORs for T2D, and SDs for circulating LDL-C. Shaded area corresponds to the 95% CI for the best fit regression line.
- Figure 3
Association of T2D-increasing allele at 31 identified SNPs with nine cardiometabolic traits, based on univariate analyses, and hierarchical clustering dendogram based on corresponding standardized effect sizes. WHR, waist-to-hip ratio.
Tables
- Table 1
List of replicated genetic loci in which all SNPs have P < 5E−5 for both circulating LDL-C and T2D and with opposite directions of effect, for UK Biobank LDL-C and DIAGRAM T2D
UK Biobank LDL-C and DIAGRAM T2D GLGC Chr bp_min bp_max Nearest genes Top SNP-metaCCA metaCCA-min P T2D β T2D P LDL β LDL P Top SNP-metaCCA LDL P metaCCA P 1 109,285,825 109,285,825 FNDC7-STXBP3 rs12144658 6.7E−10 −0.095 8.3E−06 0.028 7.0E−06 rs12144658 1.7E−03 4.2E−07 1 109,843,746 110,078,255 SORT1-PSMA5 rs56218586 2.0E−178 −0.059 8.1E−06 0.095 2.6E−118 rs17647543 6.3E−27 2.5E−32 2 27,161,476 28,246,841 GCKR rs6547692 1.4E−194 −0.055 1.6E−17 0.043 8.1E−113 rs1260326 8.4E−10 1.3E−32 2 43,452,183 44,020,441 THADA rs116097055 2.2E−15 0.18 1.5E−10 −0.034 1.7E−06 rs55877805 1.1E−03 2.4E−29 2 121,306,440 121,350,667 LINC01101-GLI2 rs17050272 2.0E−51 −0.031 3.5E−06 0.026 6.4E−42 rs896499 8.9E−09 4.7E−12 2 234,508,963 234,565,917 UGT1A8 rs2741038 8.5E−09 −0.03 1.5E−05 0.009 3.8E−05 rs2741019 3.5E−06 2.5E−09 3 12,058,246 12,456,689 PPARG rs17036170 1.8E−19 −0.13 2.7E−06 0.073 9.9E−15 rs17036326 1.5E−08 1.2E−24 3 124,912,207 129,301,874 SLC12A8 rs9873519 1.8E−16 −0.039 1.4E−09 0.011 1.9E−08 rs4679370 3.2E−04 2.7E−10 3 170,631,635 170,743,747 SLC2A2 rs12496734 8.0E−18 0.05 2.5E−07 −0.020 4.5E−12 rs7430672 4.2E−05 1.1E−15 5 74,352,180 75,042,913 HMGCR-POC5 rs34361 6.9E−322 −0.05 8.7E−14 0.054 3.3E−156 rs7703051 3.0E−86 7.5E−118 5 78,350,390 78,385,845 BHMT2 rs592052 1.7E−10 0.031 1.1E−06 −0.008 1.3E−05 rs557302 3.0E−03 2.3E−07 6 31,145,920 31,372,569 HLA-C/B rs36057735 1.4E−15 −0.037 6.7E−06 0.016 2.3E−11 rs7743761 2.5E−11 2.5E−10 6 32,127,477 33,514,567 HLA-DQA1/B1 rs3130276 1.8E−10 0.031 3.8E−06 −0.009 4.4E−06 rs9275221 3.6E−15 1.0E−23 6 126,629,425 127,167,072 CENPW rs9388490 3.2E−29 −0.049 4.5E−14 0.015 3.2E−15 rs9388490 3.8E−03 8.9E−15 7 44,585,052 44,709,372 NPC1L1-DDX56 rs2008428 2.9E−78 0.031 4.8E−05 −0.038 4.5E−63 rs217386 6.3E−22 4.3E−23 7 100,266,081 100,414,386 GIGYF1-POP7-EPO rs221793 2.5E−24 −0.047 1.9E−05 0.029 6.7E−20 rs506597 4.8E−04 3.5E−08 8 9,168,146 9,740,317 PPP1R3B rs9987289 1.6E−88 0.066 3.9E−09 −0.057 1.1E−65 rs9987289 1.4E−27 1.4E−36 10 64,988,931 65,340,897 REEP3 rs3847326 8.4E−15 −0.028 1.3E−05 0.012 9.2E−11 rs12775231 1.1E−03 6.7E−06 10 101,900,579 102,039,463 ERLIN1-CWF19L1 rs35614792 2.8E−15 0.031 1.9E−06 −0.012 2.2E−10 rs369136533 1.8E−03 8.5E−08 11 65,422,853 65,604,195 OVOL1-SNX32 rs34381009 1.2E−09 0.037 2.3E−05 −0.012 2.8E−06 rs3814707 4.3E−04 6.5E−08 12 50,881,148 50,987,378 DIP2B rs7316864 3.3E−11 −0.029 4.6E−05 0.011 6.7E−08 rs10876041 1.1E−06 1.2E−06 12 121,435,778 123,891,209 HNF1A-OASL rs12231806 8.5E−17 −0.05 8.0E−08 0.018 1.4E−10 rs7131696 4.4E−06 1.4E−15 15 62,383,155 63,314,519 C2CD4A/B rs1881415 2.8E−17 0.047 4.7E−13 −0.008 1.8E−05 rs4502156 1.1E−04 5.0E−14 17 29,628,549 29,749,444 NF1-EVI2A rs7502556 9.7E−19 0.032 5.3E−07 −0.014 2.8E−13 rs1129506 5.8E−06 9.2E−08 17 46,044,031 46,114,620 COPZ2 rs12935890 3.0E−17 −0.032 6.6E−06 0.015 6.2E−13 rs11651275 3.6E−03 2.4E−07 19 19,320,825 19,793,545 TM6SF2 rs59148799 9.9E−324 −0.054 3.4E−08 0.077 1.4E−162 rs10401969 4.6E−61 1.6E−86 19 45,324,756 45,428,234 APOE rs10119 4.9E−42 0.043 3.5E−09 −0.024 3.1E−31 rs2075650 0.0E+00 0.0E+00 19 46,123,929 46,314,504 GIPR rs2238689 2.0E−33 −0.05 1.3E−14 0.017 9.4E−19 rs10422601 1.9E−09 3.4E−22 20 42,958,768 43,042,364 HNF4A rs1800961 5.3E−72 −0.16 3.2E−20 0.076 1.8E−42 rs1800961 5.2E−11 7.1E−31 22 18,415,158 18,486,514 MICAL3 rs5992928 3.6E−11 0.035 3.1E−06 −0.011 7.9E−07 rs7286607 3.4E−05 2.4E−08 22 44,324,730 44,394,402 PNPLA3 rs738408 4.6E−19 −0.049 1.8E−10 0.014 7.1E−10 rs738408 2.9E−05 1.9E−11 β-Coefficients refer to the SNP with the lowest P value for each trait in the respective region. The minimum univariate P value for LDL-C in GLGC summary statistics as well as the top SNP and P value of the top metaCCA SNP for the region discovered in UK Biobank is also shown. bp_min and bp_max are the minimum and maximum base pair position for which all SNPs have P < 5E−5 for LDL-C and T2D, with opposite directions of effect, and with metaCCA P < 5E−8. Human build GRCh37/hg19; β-coefficients correspond to log-ORs for T2D and SDs for LDL-C. P values from GLGC LDL-C associations are for SNPs showing opposite direction of association with T2D (DIAGRAM). Chr, chromosome.
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