SUPPLEMENTAL DATA GWAS of butyrylcholinesterase activity identifies four novel loci, independent effects within BCHE

Transcript

1 SULEMENTAL DATA GWAS of butyrylcholinesterase activity identifies four novel loci, independent effects within BCHE, and secondary associations with metabolic risk factors Beben Benyamin, Rita Middelberg, enelope A Lind, Anne M Valle, Scott Gordon, Dale R Nyholt, Sarah E Medland, Anjali K Henders, Andrew C Heath, amela AF Madden, eter M Visscher, Daniel T O Connor, Grant W Montgomery, Nicholas G Martin, John B Whitfield 1

2 Table S1. artial correlations (adjusted for sex) between BCHE activity and cardiovascular risk factors in adults (excluding Adult data, for which similar correlations have already been reported (1)) and in adolescents, with tests for adult/adolescent correlation heterogeneity. Adults Adolescents Heterogeneity Correlation N p Correlation N p p BMI x x10-5 HDL-C x x10-7 LDL-C (Calculated) x x Triglyceride (log) x x10-7 C-reactive protein (log) x Urate x x10-9 Ferritin (log) x GGT (log) x x10-12 ALT (log) x Glucose x Insulin (log) x Glucose and insulin measurements have been adjusted for time since last meal. 2

3 Table S2. The summary of the 8 genotyping projects and the quality controls undertaken roject name Migraine, decode Alcohol/Nicoti ne addiction extras, decode Chip Illumina 610K Illumina 610K # genotyped samples # genotyped SNs (as supplied) mean GenCall < 0.7 Adolescent, decode Illumina 610K Glaucoma, CIDR IRG/Alcohol, decode IRG/Alcohol, CIDR Endometriosis, decode QIMR EUTWIN Illumina 610K Illumina 370K Illumina 370K Illumina 670K Illumina 317K OVERALL # SNs failed due to this criterion (cumulative # SNs down page, in brackets) no GenCall data >5% missing 8038 (46290) 8547 (47513) 8447 (47668) (37258) 7537 (27800) (24640) (58220) 5021 (5021) p(hwe) 1221 (47048) 345 (47571) 2841 (49334) (51405) 1194 (28510) 4318 (27841) 1763 (59598) 67 (5051) < 10^-6 MAF< or (67972) (68907) (67839) 8976 (30195) 7874 (30059) (75381) 264 (5300) (69514) monomorphic # SNs left (%) % of genotyped SNs Dropout rate due to QIMR SN QC 89.64% 89.48% 89.38% 90.13% 93.14% 93.95% 92.32% 98.34% 93.40% 10.36% 10.52% 10.62% 9.87% 6.86% 6.05% 7.68% 1.66% 6.60% 3

4 SN CHR B Allele Freq R2 (%) meta Direct-ion hetero Table S3. Full list of SNs with initial p < 5.0E-08 for BCHE activity in combined data, as for Table 1 but including those not independently significant. Meta Analysis Adult ( Studies) Adult ( Study) Adolescent Study rs T E E E E-28 rs A E E E E-28 rs T E E E E-28 rs A E E E E-28 rs A E E E E-28 rs T E E E E-28 rs C E E E E-28 rs T E E E E-32 rs C E E E E-29 rs T E E E E-29 rs A E E E E-15 rs A E E E E-25 rs T E E E E-16 rs T E E E E-12 rs A E E E E-24 rs A E E E E-23 rs T E E E E-23 rs C E E E E-25 rs T E E E E-25 rs C E E E E-25 rs T E E E E-22 rs T E E E E-17 rs A E E E E-22 rs C E E E E-21 rs A E E E E-23 rs A E E E E-21 4

5 SN CHR B Allele Freq R2 (%) meta Direct-ion hetero Meta Analysis Adult ( Studies) Adult ( Study) Adolescent Study rs A E E E E-21 rs A E E E E-21 rs A E E E E-21 rs A E E E E-21 rs T E E E E-21 rs A E E E E-19 rs A E E E E-21 rs A E E E E-18 rs T E E E E-18 rs T E E E E-18 rs T E E E E-18 rs A E E E E-18 rs A E E E E-25 rs A E E E E-20 rs A E E E E-21 rs A E E E E-12 rs T E E E E-12 rs T E E E E-12 rs A E E E E-12 rs T E E E E-12 rs A E E E E-12 rs A E E E E-18 rs A E E E E-18 rs A E E E E-18 rs T E E E E-18 rs A E E E E-18 rs A E E E E-18 rs A E E E E-18 rs T E E E E-16 5

6 SN CHR B Allele Freq R2 (%) meta Direct-ion hetero Meta Analysis Adult ( Studies) Adult ( Study) Adolescent Study rs C E E E E-16 rs A E E E E-16 rs A E E E E-16 rs A E E E E-18 rs T E E E E-14 rs A E E E E-12 rs A E E E E-12 rs T E E E E-13 rs T E E E E-12 rs T E E E E-12 rs T E E E E-14 rs T E E E E-14 rs T E E E E-14 rs A E E E E-14 rs T E E E E-09 rs A E E E E-09 rs T E E E E-16 rs A E E E E-09 rs A E E E E-09 rs T E E E E-09 rs A E E E E-09 rs A E E E E-09 rs A E E E E-11 rs A E E E E-11 rs T E E E E-11 rs A E E E E-11 rs A E E E E-12 rs T E E E E-12 rs T E E E E-12 6

7 SN CHR B Allele Freq R2 (%) meta Direct-ion hetero Meta Analysis Adult ( Studies) Adult ( Study) Adolescent Study rs A E E E E-12 rs A E E E E-12 rs C E E E E-12 rs A E E E E-12 rs T E E E E-12 rs T E E E E-12 rs A E E E E-12 rs A E E E E-14 rs A E E E E-09 rs A E E E E-09 rs T E E E E-09 rs T E E E E-09 rs T E E E E-09 rs C E E E E-09 rs A E E E E-10 rs A E E E E-09 rs T E E E E-09 rs T E E E E-08 rs T E E E E-09 rs A E E E E-19 rs T E E E E-12 rs T E E E E-11 rs T E E E E-11 rs A E E E E-08 rs A E E E E-09 rs T E E E E-06 rs A E E E E-08 rs T E E E E-08 rs A E E E E-08 7

8 SN CHR B Allele Freq R2 (%) meta Direct-ion hetero Meta Analysis Adult ( Studies) Adult ( Study) Adolescent Study rs T E E E E-06 rs A E E E E-10 rs T E E E E-10 rs A E E E E-10 rs T E E E E-10 rs A E E E E-10 rs C E E E E-10 rs T E E E E-07 rs A E E E E-07 rs T E E E E-06 rs A E E E E-06 rs A E E E E-06 rs C E E E E-06 rs A E E E E-06 rs A E E E E-06 rs A E E E E-06 rs A E E E E-08 rs T E E E E-08 rs C E E E E-08 rs T E E E E-08 rs A E E E E-08 rs T E E E E-08 rs A E E E E-07 rs A E E E E-09 rs A E E E E-06 rs T E E E E-07 rs A E E E E-07 rs A E E E E-07 rs A E E E E-09 8

9 SN CHR B Allele Freq R2 (%) meta Direct-ion hetero Meta Analysis Adult ( Studies) Adult ( Study) Adolescent Study rs T E E E E-09 rs A E E E E-08 rs T E E E E-08 rs T E E E E-06 rs A E E E E-09 rs C E E E E-09 rs A E E E E-08 rs T E E E E-13 rs T E E E E-13 rs T E E E E-14 rs T E E E E-14 rs A E E E E-14 rs A E E E E-14 rs T E E E E-14 rs T E E E E-14 rs A E E E E-05 rs A E E E E-05 rs T E E E E-14 rs A E E E E-07 rs T E E E E-07 rs T E E E E-06 rs A E E E E-06 rs A E E E E-08 rs C E E E E-08 rs T E E E E-04 rs A E E E E-07 rs A E E E E-03 rs A E E E E-03 rs C E E E E-04 9

10 SN CHR B Allele Freq R2 (%) meta Direct-ion hetero Meta Analysis Adult ( Studies) Adult ( Study) Adolescent Study rs T E E E E-03 rs T E E E E-08 rs A E E E E-03 rs C E E E E-03 rs T E E E E-04 rs A E E E E-04 rs A E E E E-04 rs A E E E E-04 rs T E E E E-04 rs T E E E E-04 rs A E E E E-04 rs A E E E E-04 rs T E E E E-04 rs A E E E E-04 rs T E E E E-05 rs A E E E E-05 rs A E E E E-05 rs T E E E E-04 rs T E E E E-05 rs T E E E E-07 rs A E E E E-05 rs C E E E E-05 rs C E E E E-04 rs C E E E E-06 rs A E E E E-04 rs A E E E E-05 rs A E E E E-04 rs T E E E E-05 rs A E E E E-05 10

11 SN CHR B Allele Freq R2 (%) meta Direct-ion hetero Meta Analysis Adult ( Studies) Adult ( Study) Adolescent Study rs A E E E E-04 rs A E E E E-04 rs A E E E E-04 rs A E E E E-04 rs A E E E E-04 rs A E E E E-04 rs T E E E E-05 rs T E E E E-05 rs A E E E E-05 rs T E E E E-05 rs T E E E E-02 rs A E E E E-02 rs T E E E E-03 rs A E E E E-04 rs C E E E E-04 rs T E E E E-04 rs A E E E E-04 rs T E E E E-04 rs A E E E E-04 rs T E E E E-04 rs T E E E E-04 rs T E E E E-04 rs A E E E E-04 rs A E E E E-04 rs A E E E E-03 rs T E E E E-03 rs A E E E E-03 rs A E E E E-03 rs C E E E E-03 11

12 SN CHR B Allele Freq R2 (%) meta Direct-ion hetero Meta Analysis Adult ( Studies) Adult ( Study) Adolescent Study rs A E E E E-03 rs A E E E E-03 rs A E E E E-03 rs T E E E E-03 rs A E E E E-03 rs T E E E E-03 rs T E E E E-03 rs T E E E E-03 rs A E E E E-03 rs A E E E E-03 rs C E E E E-03 rs A E E E E-03 rs A E E E E-03 rs A E E E E-03 rs A E E E E-03 rs A E E E E-02 rs C E E E E-02 rs C E E E E-02 rs A E E E E-02 rs T E E E E-02 rs T E E E E-02 rs T E E E E-02 rs T E E E E-02 rs T E E E E-02 rs C E E E E-02 rs A E E E E-02 rs A E E E E-02 rs T E E E E-02 rs A E E E E-02 12

13 SN CHR B Allele Freq R2 (%) meta Direct-ion hetero Meta Analysis Adult ( Studies) Adult ( Study) Adolescent Study rs A E E E E-02 rs A E E E E-02 rs T E E E E-02 rs A E E E E-02 rs T E E E E-02 rs T E E E E-02 rs T E E E E-02 rs T E E E E-02 rs T E E E E-02 rs A E E E E-02 rs A E E E E-02 rs A E E E E-02 rs A E E E E-02 rs A E E E E-02 rs A E E E E-02 rs A E E E E-02 rs A E E E E-03 rs C E E E E-04 rs T E E E E-02 rs A E E E E-02 rs T E E E E-02 rs T E E E E-02 rs T E E E E-04 rs A E E E E-01 rs A E E E E-02 rs A E E E E-02 rs C E E E E-02 rs A E E E E-01 rs T E E E E-01 13

14 SN CHR B Allele Freq R2 (%) meta Direct-ion hetero Meta Analysis Adult ( Studies) Adult ( Study) Adolescent Study rs T E E E E-01 rs A E E E E-01 rs A E E E E-01 rs T E E E E-01 rs A E E E E-01 rs A E E E E-01 rs A E E E E-06 rs A E E E E-06 rs T E E E E-05 rs T E E E E-05 rs A E E E E-05 rs C E E E E-05 rs C E E E E-05 rs A E E E E-05 rs T E E E E-05 rs C E E E E-01 rs T E E E E-07 rs T E E E E-02 rs T E E E E-01 rs A E E E E-01 rs T E E E E-01 rs A E E E E-01 rs A E E E E-01 rs A E E E E-01 rs A E E E E-04 rs T E E E E-04 rs T E E E E-06 rs A E E E E-01 rs T E E E E-04 14

15 SN CHR B Allele Freq R2 (%) meta Direct-ion hetero Meta Analysis Adult ( Studies) Adult ( Study) Adolescent Study rs A E E E E-04 rs A E E E E-04 rs A E E E E-04 rs T E E E E-04 rs T E E E E-04 rs A E E E E-05 rs A E E E E-05 rs A E E E E-05 rs T E E E E-05 rs A E E E E-05 rs A E E E E-02 rs A E E E E-02 rs A E E E E-05 rs A E E E E-05 rs T E E E E-05 rs A E E E E-05 rs A E E E E-05 rs T E E E E-05 rs C E E E E-05 rs C E E E E-04 rs A E E E E-05 rs A E E E E-05 rs A E E E E-04 rs A E E E E-04 rs A E E E E-01 rs A E E E E-01 rs A E E E E-04 rs A E E E E-04 rs T E E E E-03 15

16 SN CHR B Allele Freq R2 (%) meta Direct-ion hetero Meta Analysis Adult ( Studies) Adult ( Study) Adolescent Study rs T E E E E-05 rs A E E E E-04 rs A E E E E-04 rs A E E E E-01 rs A E E E E-01 rs A E E E E-01 rs A E E E E-01 rs A E E E E-04 rs A E E E E-04 rs A E E E E-04 rs T E E E E-04 rs A E E E E-04 rs A E E E E-04 rs T E E E E-04 rs T E E E E-03 rs A E E E E-03 rs A E E E E-04 rs A E E E E-04 rs A E E E E-03 rs T E E E E-03 rs T E E E E-03 rs A E E E E-02 rs T E E E E-03 rs T E E E E-04 rs A E E E E-04 rs T E E E E-04 rs T E E E E-04 rs T E E E E-04 rs A E E E E-04 16

17 SN CHR B Allele Freq R2 (%) meta Direct-ion hetero Meta Analysis Adult ( Studies) Adult ( Study) Adolescent Study rs A E E E E-04 rs A E E E E-04 rs A E E E E-02 rs T E E E E-03 rs A E E E E-04 rs T E E E E-04 rs T E E E E-04 rs T E E E E-03 rs T E E E E-03 rs T E E E E-04 rs A E E E E-04 rs T E E E E-03 rs T E E E E-03 rs A E E E E-03 rs A E E E E-03 rs A E E E E-03 rs T E E E E-03 rs T E E E E-03 rs A E E E E-03 rs T E E E E-03 rs A E E E E-02 rs T E E E E-03 rs A E E E E-03 rs T E E E E-03 rs T E E E E-03 rs A E E E E-03 rs C E E E E-02 rs T E E E E-02 rs C E E E E-02 17

18 SN CHR B Allele Freq R2 (%) meta Direct-ion hetero Meta Analysis Adult ( Studies) Adult ( Study) Adolescent Study rs A E E E E-02 rs A E E E E-03 rs A E E E E-03 rs T E E E E-03 rs A E E E E-03 rs C E E E E-03 rs A E E E E-02 rs A E E E E-01 rs A E E E E-01 rs A E E E E-01 rs A E E E E-03 rs A E E E E-01 rs T E E E E-01 rs C E E E E-03 rs A E E E E-05 rs C E E E E-05 rs A E E E E-05 rs T E E E E-04 rs A E E E E-02 rs A E E E E-01 rs T E E E E-01 rs A E E E E-01 rs A E E E E-01 rs A E E E E-01 rs A E E E E-05 rs A E E E E-05 rs T E E E E-05 rs A E E E E-01 rs A E E E E-01 18

19 SN CHR B Allele Freq R2 (%) meta Direct-ion hetero Meta Analysis Adult ( Studies) Adult ( Study) Adolescent Study rs T E E E E-01 rs A E E E E-05 rs A E E E E-02 rs T E E E E-02 rs T E E E E-01 rs A E E E E-02 rs T E E E E-03 rs T E E E E-03 rs T E E E E-03 rs A E E E E-03 rs A E E E E-04 rs A E E E E-04 rs A E E E E-05 rs A E E E E-05 rs A E E E E-05 rs T E E E E-05 rs A E E E E-05 rs T E E E E-05 rs T E E E E-04 rs A E E E E-04 rs A E E E E-02 rs C E E E E-03 rs T E E E E-03 rs C E E E E-03 rs A E E E E-03 rs T E E E E rs A E E E E-03 rs T E E E E-03 19

20 SN CHR B Allele Freq R2 (%) meta Direct-ion hetero Meta Analysis Adult ( Studies) Adult ( Study) Adolescent Study rs T E E E E-03 rs A E E E E-03 rs T E E E E-03 rs A E E E E-03 rs T E E E E-03 rs A E E E E-03 rs C E E E E-03 rs T E E E E-03 rs T E E E E-03 rs T E E E E-05 rs A E E E E-05 rs A E E E E-05 20

21 ALT BMI CR Ferritin GGT Glucose HDL Insulin LDL Triglyceride Urate Table S4. Tests for effects of SNs showing genome-wide significant results for BCHE activity, on other variables related to metabolic syndrome. SN Locus rs Chr. 1 RNE β β p rs Chr.2 ABI2 β β p rs Chr 2 UGT1A1 rs Chr. 3 BCHE rs Chr. 3 BCHE rs Chr. 3 BCHE rs Chr. 8 Intergenic β β p β β p β β p β β p β β p E

22 Table S5. Loci reported to affect variables associated with BCHE activity, and results for their allelic associations with BCHE. See result for the same SN in the line or lines above. NA, not available because this SN was neither typed nor imputed in our dataset. Reported associations with variables related to metabolic syndrome Source SN Chr Location henotype p for reported phenotype Gene(s) for BCHE (2) rs ,797,044 SB 2.00E-13 MTHFR (3) rs ,641,524 Cholesterol 5.00E-10 TMEM (4) rs ,268,627 LDL-C 4.00E-11 CSK (5) rs ,268,627 LDL-C 4.00E-08 CSK9 (5) rs ,278,235 LDL-C 2.00E-44 CSK9 NA (3) rs ,704,220 Triglycerides 2.00E-12 DOCK (4) rs ,822,181 Triglycerides 2.00E-10 ANGTL (3) rs ,890,784 Cholesterol 4.00E-12 DOCK (3) rs ,890,784 Triglycerides 8.20E-11 DOCK7 (5) rs ,890,784 Triglycerides 3.00E-07 ANGTL3 (5) rs ,964,365 Triglycerides 2.00E-08 ANGTL3, DOCK7, ATG4C (6) rs ,862,370 CR 3.10E 14 LER (7) rs ,878,532 CR 7.00E-21 LER (8) rs ,942,267 CR 4.00E-07 LER (9) rs ,523,773 BMI 2.50E-11 NEGR (9) rs ,537,704 BMI 1.20E-11 NEGR (10) rs ,585,028 BMI 1.00E-12 NEGR

23 Reported associations with variables related to metabolic syndrome Source SN Chr Location henotype p for reported phenotype Gene(s) for BCHE (5) rs ,619,113 LDL-C 2.00E-42 CELSR2, SRC1, SORT (3) rs ,620,053 Cholesterol 9.00E-22 CELSR (5) rs ,620,053 LDL-C 3.00E-29 CELSR2,SRC1,SORT1 (3) rs ,620,053 LDL-C 7.80E-23 CELSR2 (8) rs ,620,053 LDL-C 2.00E-12 CELSR2, SRC1, SORT1 (11) rs ,623,689 LDL-C 1.00E-33 CELSR2,SRC (4) rs ,623,689 LDL-C 6.00E-33 CELSR2,SRC1,SORT1 (12) rs ,623,689 LDL-C 1.00E-07 CELSR2,SRC1 (13) rs ,437,046 Urate 2.68E-09 DZK (6) rs ,685,503 CR 1.80E 14 IL6R (7) rs ,693,594 CR 2.00E-08 IL6R (8) rs ,945,440 CR 3.21E-22 CR (7) rs ,951,289 CR 6.00E-28 CR NA (6) rs ,965,173 CR 7.6E 44 CR (9) rs ,180,142 BMI 6.00E-08 C16B, RASAL (8) rs ,941,798 LDL-C 2.11E-07 CR1L (14) rs ,710,847 Waist/Hip Ratio 3.00E-08 LYLAL (4) rs ,361,539 HDL-C 3.00E-14 GALNT (5) rs ,362,314 HDL-C 2.00E-13 GALNT (5) rs ,362,314 HDL-C 4.00E-08 GALNT2 (8) rs ,362,314 LDL-C 2.00E-07 CR1L 23

24 Reported associations with variables related to metabolic syndrome Source SN Chr Location henotype p for reported phenotype Gene(s) for BCHE (5) rs ,362,314 Triglycerides 7.00E-15 GALNT2 (14) rs ,666,752 Waist 3.00E-07 TBCE (9) rs ,827 BMI 1.70E-16 TMEM (10) rs ,905 BMI 3.20E-26 TMEM (9) rs ,144 BMI 6.80E-17 TMEM (9) rs ,953 BMI 4.20E-17 TMEM (3) rs ,059,688 HDL-C 4.40E-08 AOB (3) rs ,059,688 Triglycerides 2.50E-08 AOB (5) rs ,061,717 Triglycerides 9.00E-12 AOB (3) rs ,085,700 Cholesterol 9.00E-23 AOB (5) rs ,085,700 LDL-C 1.00E-21 AOB (3) rs ,085,700 LDL-C 3.60E-17 AOB (8) rs ,085,700 LDL-C 3.00E-11 AOB (5) rs ,085,700 Triglycerides 2.00E-07 AOB (3) rs ,091,049 Triglycerides 1.10E-08 AOB (8) rs ,091,049 Triglycerides 2.00E-08 AOB (5) rs ,139,562 LDL-C 5.00E-29 AOB (4) rs ,141,826 LDL-C 6.00E-22 AOB (11) rs ,141,826 LDL-C 1.00E-09 AOB (5) rs ,584,444 Triglycerides 2.00E-31 GCKR 3.17E-04 (8) rs ,584,444 Triglycerides 4.00E-10 GCKR (15) rs ,584,444 Triglycerides 4.00E-08 GCKR (7) rs ,594,741 CR 6.73E-15 GCKR 2.49E-04 (12) rs ,594,741 LDL-C 5.00E-07 GCKR 24

25 Reported associations with variables related to metabolic syndrome Source SN Chr Location henotype p for reported phenotype Gene(s) for BCHE (4) rs ,594,741 Triglycerides 6.00E-32 GCKR (3) rs ,594,741 Triglycerides 3.10E-20 GCKR (5) rs ,594,741 Triglycerides 3.00E-14 GCKR (13) rs ,594,741 Urate 1.40E-09 GCKR (3) rs ,918,594 Cholesterol 2.00E-11 ABCG (3) rs ,918,594 LDL-C 2.60E-10 ABCG5 (5) rs ,927,385 LDL-C 2.00E-20 ABCG (16) rs ,749,632 Blood pressure 2.00E-07 STK (17) rs ,465,600 HbA1c 5.00E-10 G6C (18) rs ,471,394 Glucose 1.10E-57 G6C (19) rs ,471,394 Glucose 4.00E-23 G6C2 (8) rs ,471,394 Glucose 3.41E-10 G6C2-ABCB11 (8) rs ,471,394 Glucose 6.00E-10 G6C2, ABCB11 (20) rs ,482,317 Glucose 4.00E-07 G6C2,ABCB (21) rs ,423,619 Blood pressure 3.00E-07 CCL20, WDR (21) rs ,887,655 DB 3.00E-09 ULK (21) rs ,583,593 SB 1.00E-07 MDS (2) rs ,648,582 DB 8.00E-08 MDS (9) rs ,316,984 BMI 7.20E-11 SFRS10, ETV5, DGKG (22) rs ,531,265 Urate 0.00E+00 SLC2A

26 Reported associations with variables related to metabolic syndrome Source SN Chr Location henotype p for reported phenotype Gene(s) for BCHE (23) rs ,531,265 Urate 1.00E-11 GLUT9, WDR1 (13) rs ,532,102 Urate 5.22E-201 SLC2A (13) rs ,532,102 Urate 1.00E-41 SLC2A9 (24) rs ,536,065 Urate 1.00E-09 SLC2A (25) rs ,543,842 Urate 3.00E-09 SLC2A (26) rs ,545,008 Urate 2.00E-16 GLUT (27) rs ,575,478 Urate 3.00E-70 SLC2A (12) rs ,575,478 Urate 2.00E-15 SLC2A9,WDR1 (10) rs ,023,455 BMI 3.40E-16 GNDA (2) rs ,541,520 DB 1.00E-21 FGF (22) rs ,271,347 Urate 3.00E-60 ABCG (13) rs ,271,347 Urate 3.10E-26 ABCG2 (28) rs ,661,243 LDL-C 1.00E-08 HMGCR (5) rs ,684,359 LDL-C 1.00E-20 HMGCR (3) rs ,686,840 Cholesterol 3.00E-19 HMGCR (3) rs ,686,840 LDL-C 1.50E-11 HMGCR (5) rs ,691,482 LDL-C 8.00E-12 HMGCR (5) rs ,330,747 LDL-C 1.00E-11 TIMD4-HAVCR (13) rs ,715,550 Urate 8.50E-09 LRRC16A (13) rs ,931,423 Urate 3.04E-14 SLC17A (22) rs ,978,521 Urate 4.00E-29 SLC17A

27 Reported associations with variables related to metabolic syndrome Source SN Chr Location henotype p for reported phenotype Gene(s) for BCHE (10) rs ,251,926 LDL-C 5.00E-08 B3GALT (14) rs ,911,009 Waist 2.00E-11 TFA2B (8) rs ,030,358 Glucose 1.00E-07 Intergenic (3) rs ,573,877 LDL-C 6.10E-09 DNAH (17) rs ,190,246 HbA1c 6.00E-12 GCK (18) rs ,202,193 Glucose 1.00E-25 GCK (3) rs ,494,205 Triglycerides 1.10E-12 MLXIL (5) rs ,502,805 Triglycerides 3.00E-15 MLXIL (5) rs ,620,810 Triglycerides 7.00E-22 BCL7B, TBL2, MLXIL (10) rs ,620,810 Triglycerides 2.00E-12 MLXIL (29) rs ,658,273 Triglycerides 1.00E-10 MLXIL NA (30) rs ,104,065 BMI 1.00E-07 Intergenic (14) rs ,879,490 Waist 9.00E-09 MSRA (5) rs ,082,571 Triglycerides 3.00E-08 XKR6-AMAC1L (29) rs ,863,719 Triglycerides 5.00E-12 LL, C8orf35, SLC18A1 NA (5) rs ,864,004 HDL-C 9.00E-23 LL (5) rs ,864,004 Triglycerides 2.00E-28 LL (31) rs ,864,004 Triglycerides 5.00E-07 LL 27

28 Reported associations with variables related to metabolic syndrome Source SN Chr Location henotype p for reported phenotype Gene(s) for BCHE (3) rs ,875,201 HDL-C 6.10E-16 LL (3) rs ,875,201 Triglycerides 1.90E-18 LL (8) rs ,875,201 Triglycerides 5.00E-08 LL (5) rs ,888,502 HDL-C 2.00E-34 LL (5) rs ,888,502 Triglycerides 2.00E-41 LL (10) rs ,891,970 HDL-C 4.00E-19 LL (10) rs ,891,970 Triglycerides 4.00E-22 LL (3) rs ,909,455 HDL-C 5.50E-18 LL (3) rs ,909,455 Triglycerides 1.00E-14 LL (32) rs ,603,396 Glucose 2.00E-08 ZMAT (30) rs ,457,530 Waist 2.00E-07 GDA (17) rs ,253,964 HbA1c 5.00E-08 SLC30A (5) rs ,555,591 Triglycerides 4.00E-17 TRIB (10) rs ,555,591 Triglycerides 7.00E-13 TRIB1 (5) rs ,560,154 Triglycerides 3.00E-19 TRIB (3) rs ,573,908 Cholesterol 3.00E-09 TRIB (5) rs ,279,578 HDL-C 3.00E-10 TTC39B (10) rs ,687,041 HDL-C 1.00E-10 ABCA (5) rs ,687,476 HDL-C 3.00E-10 ABCA (3) rs ,696,891 HDL-C 8.60E-13 ABCA (5) rs ,704,122 HDL-C 1.00E-09 ABCA

29 Reported associations with variables related to metabolic syndrome Source SN Chr Location henotype p for reported phenotype Gene(s) for BCHE (33) rs ,339,957 Obesity 2.00E-07 TER (21) rs ,748,804 DB 1.00E-08 CACNB (13) rs ,083,359 Urate 1.07E-08 SLC16A (2) rs ,194,597 DB 1.00E-09 c10orf (17) rs ,769,919 HbA1c 2.00E-25 HK (8) rs ,362,513 Insulin 3.00E-07 ANK (34) rs ,851,425 ALT 1.50E-08 CN (34) rs ,943,695 ALT 1.80E-08 CHUK (34) rs ,966,491 ALT 3.00E-08 CHUK (21) rs ,584,497 SB 1.00E-10 CY17A (2) rs ,836,168 SB 7.00E-24 CNNM2/NT5C (21) rs ,858,844 SB 2.00E-09 LEKHA (9) rs ,603,861 BMI 4.40E-11 LGR4, LIN7C,BDNF (9) rs ,613,486 BMI 3.20E-11 LGR4, LIN7C,BDNF (9) rs ,623,778 BMI 8.50E-10 LGR4, LIN7C,BDNF (9) rs ,626,684 BMI 8.70E-11 LGR4, LIN7C,BDNF (9) rs ,636,492 BMI 5.10E-10 LGR4, LIN7C,BDNF (8) rs ,242,866 HDL-C 4.00E-08 NR1H

30 Reported associations with variables related to metabolic syndrome Source SN Chr Location henotype p for reported phenotype Gene(s) for BCHE (10) rs ,619,625 BMI 1.90E-11 MTCH (3) rs ,475,469 HDL-C 6.00E-11 MADD-FOLH (8) rs ,326,406 LDL-C 1.00E-07 FADS1, FADS (5) rs ,326,406 Triglycerides 2.00E-14 FADS1-FADS2-FADS (5) rs ,327,359 HDL-C 2.00E-12 FADS1-FADS2-FADS3 (3) rs ,353,788 Cholesterol 2.00E-10 FADS2, FADS (3) rs ,353,788 LDL-C 4.40E-13 FADS2/3 (13) rs ,088,038 Urate 6.68E-14 SLC22A11 NA (13) rs ,113,648 Urate 2.04E-09 SLC22A (19) rs ,313,476 Glucose 2.00E-36 MTNR1B (15) rs ,331,180 Glucose 2.00E-09 MTNR1B (18) rs ,348,358 Glucose 3.20E-50 MTNR1B (8) rs ,362,409 Glucose 6.00E-08 MTNR1B (3) rs ,108,934 LDL-C 5.00E-13 AO(A1/A4/A5/C3) (3) rs ,108,934 Triglycerides 5.40E-13 AO(A1/A4/A5/C3) (29) rs ,112,647 Triglycerides 2.00E-26 LOC440069, MGC13125 NA (5) rs ,124,283 Triglycerides 2.00E-17 AO(A1/A4/A5), ZNF259, BUD13 NA (5) rs ,154,127 HDL-C 1.00E-12 AO(A1/A4/A5/C3) (5) rs ,154,127 Triglycerides 4.00E-62 AO(A1/A4/A5/C3) (10) rs ,157,417 Triglycerides 1.00E-26 AO(A1/A4/A5/C3) (12) rs ,157,633 LDL-C 3.00E-11 AO(A1/A5/C3) (29) rs ,237,722 Triglycerides 5.00E-08 AOA1,KIAA0999, LOC

31 Reported associations with variables related to metabolic syndrome Source SN Chr Location henotype p for reported phenotype Gene(s) for BCHE (35) rs ,036,941 Triglycerides 3.00E-29 AO(A1/A4/A5/C3), DSCAML (9) rs ,533,735 BMI 1.00E-07 BCDIN3D, FAIM (21) rs ,533,090 DB 1.00E-09 AT2B (36) rs ,537,220 DB 4.60E-08 AT2B (36) rs ,537,220 SB 3.00E-11 AT2B1 (7) rs ,019,281 CR 1.00E-10 Unknown (5) rs ,379,551 HDL-C 1.00E-10 MMAB, MVK (10) rs ,379,551 HDL-C 3.00E-08 MVK,MMAB (21) rs ,368,991 DB 3.00E-14 SH2B (21) rs ,368,991 SB 5.00E-09 SH2B3 (2) rs ,470,476 DB 3.00E-18 ATXN (21) rs ,837,114 DB 4.00E-08 TBX3, TBX (8) rs ,873,345 CR 1.64E-11 LEF (8) rs ,873,345 CR 3.00E-11 LEF1 (5) rs ,873,345 LDL-C 2.00E-08 HNF1A (6) rs ,905,190 CR 1.20E 30 HNF1A (7) rs ,909,244 CR 7.00E-17 HNF1A (37) rs ,923,816 CR 2.00E-08 HNF1A (34) rs ,927,053 GGT 1.80E-10 HNF1A

32 Reported associations with variables related to metabolic syndrome Source SN Chr Location henotype p for reported phenotype Gene(s) for BCHE (38) rs ,014,915 Waist 5.00E-08 NRXN (8) rs ,935,941 Triglycerides 4.00E-07 Intergenic (10) rs ,461,987 HDL-C 3.00E-20 LIC (10) rs ,461,987 Triglycerides 2.00E-08 LIC (5) rs ,465,804 HDL-C 8.00E-23 LIC (3) rs ,470,658 Cholesterol 4.00E-07 LIC (3) rs ,470,658 HDL-C 9.70E-36 LIC (8) rs ,470,658 HDL-C 2.00E-10 LIC (5) rs ,510,967 HDL-C 2.00E-32 LIC (2) rs ,864,420 DB 1.00E-23 CSK (21) rs ,912,698 DB 2.00E-10 CSK, ULK (9) rs ,745,016 BMI 1.40E-09 SH2B1, AT2A (9) rs ,780,899 BMI 6.40E-10 SH2B1, AT2A (10) rs ,790,742 BMI 2.20E-14 SH2B (9) rs ,790,742 BMI 3.20E-10 SH2B1, AT2A1 (9) rs ,327,178 BMI 4.00E-13 RGRI1L, FTO (33) rs ,358,455 Obesity 1.00E-28 FTO (38) rs ,361,075 Waist 5.00E-19 FTO (39) rs ,366,748 BMI 4.00E-08 FTO (40) rs ,366,748 Obesity 1.00E-07 FTO (9) rs ,373,776 BMI 1.10E-47 RGRI1L, FTO (9) rs ,375,961 BMI 4.10E-47 RGRI1L, FTO (10) rs ,378,028 BMI 4.90E-74 FTO

33 Reported associations with variables related to metabolic syndrome Source SN Chr Location henotype p for reported phenotype Gene(s) for BCHE (41) rs ,378,028 BMI 2.00E-20 FTO (42) rs ,382,989 Obesity 6.00E-12 FTO (9) rs ,386,253 BMI 8.10E-23 RGRI1L, FTO (43) rs ,387,966 Hip 3.00E-08 FTO (9) rs ,396,636 BMI 7.60E-31 RGRI1L, FTO (10) rs ,542,640 HDL-C 3.00E-31 CET (5) rs ,545,545 HDL-C 4.00E-75 CET (10) rs ,550,825 HDL-C 2.00E-57 CET (8) rs ,550,825 HDL-C 7.00E-29 CET (15) rs ,550,825 HDL-C 1.00E-27 CET (44) rs ,550,825 LDL-C 3.00E-12 CET (7) rs ,552,737 HDL-C 4.00E-93 CET, NU93, SLC12A3, HERUD (5) rs ,552,737 HDL-C 1.00E-73 CET (31) rs ,552,737 Triglycerides 3.00E-13 CET (10) rs ,554,734 HDL-C 7.00E-39 CET (3) rs ,562,980 HDL-C 9.40E-94 CET (3) rs ,459,571 HDL-C 8.30E-16 CTCF-RMT (5) rs ,459,571 HDL-C 9.00E-13 LCAT (8) rs ,570,972 HDL-C 3.00E-08 LCAT (10) rs ,582,496 HDL-C 1.00E-07 LCAT (33) rs ,240,252 Obesity 4.00E-13 MAF (21) rs ,321,705 Blood pressure 1.00E-09 CDH (8) rs ,375,258 HDL-C 2.00E-07 Intergenic

34 Reported associations with variables related to metabolic syndrome Source SN Chr Location henotype p for reported phenotype Gene(s) for BCHE (2) rs ,563,647 SB 1.00E-08 LCD (2) rs ,795,465 DB 5.00E-09 ZNF (33) rs ,394,430 Obesity 3.00E-07 NC (3) rs ,421,212 Cholesterol 2.00E-11 LIG (5) rs ,421,212 HDL-C 7.00E-15 LIG (3) rs ,421,212 HDL-C 1.60E-11 LIG (10) rs ,435,666 HDL-C 6.00E-12 LIG (5) rs ,435,666 HDL-C 2.00E-07 LIG, ACAA2 (10) rs ,002,077 BMI 1.10E-20 MC4R (39) rs ,002,077 BMI 3.00E-15 MC4R (33) rs ,002,077 Obesity 5.00E-15 MC4R (38) rs ,033,767 Waist 4.00E-07 MC4R (9) rs ,035,730 BMI 1.20E-12 MC4R (15) rs ,035,730 Waist 1.70E-09 MC4R (5) rs ,375,738 HDL-C 1.00E-08 ANGTL (8) rs ,056,030 LDL-C 2.00E-07 LDLR (5) rs ,063,306 LDL-C 2.00E-51 LDLR (5) rs ,063,306 LDL-C 2.00E-26 LDLR (10) rs ,063,306 LDL-C 4.00E-26 LDLR (3) rs ,071,912 Cholesterol 9.00E-24 LDLR (3) rs ,071,912 LDL-C 4.20E-14 LDLR 34

35 Reported associations with variables related to metabolic syndrome Source SN Chr Location henotype p for reported phenotype Gene(s) for BCHE (5) rs ,268,718 LDL-C 2.00E-08 SF (10) rs ,519,472 LDL-C 3.00E-09 CIL (5) rs ,519,472 LDL-C 3.00E-08 CIL2 (10) rs ,519,472 Triglycerides 3.00E-09 CIL2 (5) rs ,519,472 Triglycerides 4.00E-09 CIL2 (5) rs ,523,220 Triglycerides 4.00E-11 CIL (3) rs ,650,528 Cholesterol 2.00E-15 ZNF (9) rs ,001,372 BMI 7.30E-12 CHST8, KCTD (10) rs ,013,977 BMI 4.50E-12 KCTD (3) rs ,087,106 LDL-C 2.10E-19 TOMM40-AOE (8) rs ,087,106 LDL-C 5.00E-08 AO cluster (3) rs ,087,106 Triglycerides 1.20E-08 TOMM40-AOE (3) rs ,087,459 Cholesterol 3.00E-19 TOMM40, AOE (37) rs ,087,459 CR 1.00E-07 AOE (3) rs ,087,459 LDL-C 9.30E-19 TOMM40-AOE (7) rs ,101,842 CR 9.00E-21 AOE NA (3) rs ,106,291 Triglycerides 1.80E-09 TOMM40-AOE (6) rs ,114,786 CR 4.50E 27 AOE-CI-CII cluster (10) rs ,114,786 LDL-C 3.00E-43 AOE,AOC1,AOC4 (5) rs ,114,786 LDL-C 4.00E-27 AOE-AOC1-AOC4-AOC2 (11) rs ,114,786 LDL-C 1.00E-20 AOC1 (28) rs ,114,786 LDL-C 2.00E-07 AOE, AOC1, AOC4, AOC2 (31) rs ,114,786 Triglycerides 3.00E-13 AOE cluster (5) rs ,662,198 LDL-C 4.00E-09 MAFB

36 Reported associations with variables related to metabolic syndrome Source SN Chr Location henotype p for reported phenotype Gene(s) for BCHE (5) rs ,475,778 HDL-C 8.00E-10 HNF4A (5) rs ,009,909 HDL-C 4.00E-09 LT (5) rs ,009,909 Triglycerides 7.00E-11 LT (34) rs ,314,767 GGT 4.00E-11 GGT (34) rs ,657,471 ALT 8.40E-16 NLA (34) rs ,716,587 ALT 7.20E-09 SAMM (8) rs ,859,350 LDL-C 2.00E-07 AR NA 36

37 Table S6. The mediation analysis results using a Mendelian Randomisation method as described in Freathy et al (45). All effect sizes are presented in SD units. The analysis was performed in statistical packages SIB-AIR and Mendel. Marker Trait Other trait Observed change in trait per minor allele (O) Expected change in trait per minor allele effect in the other trait (E) value difference (O-E) Observed change in trait per minor allele (adjusted for the other trait) value value rs BCHE Activity BMI ± ± ± rs BCHE Activity Triglycerides ± ± ±

38 Supplementary Figure 1. Comparison of distributions of BCHE activity results, and sources of variation, in adolescents and adults. Left-hand panel, cumulative frequency distributions and total variance; right-hand panel, absolute magnitude of estimated variance components (A = additive genetic variance, E = non-shared environmental variance). 38