Table 1.
Common genetic variants at loci associated with QT interval (P < 5×10-8) on meta-analysis of GWAS+replication results (Supplementary Table 6). N is the effective number of samples contributing to the signal. For a given SNP, the effective sample size is the sum of the product of the cohort-specific sample size and imputation quality (ranging from 0 to 1). Function (Fxn) shown for coding variants with r2 = 1 to sentinel SNP or proxy with 1.0 > r2 > 0.8 (-p) to the sentinel SNP. Expression quantitative trait loci (eQTL) transcripts are shown if associated at P < 5×10-8 with sentinel SNPs or their close proxies (r2 > 0.8, Supplementary Table 12, bolded if eQTL found in left ventricle for the sentinel SNP). Protein-protein interactor (PPI) relationships for nearby genes to genes in loci previously established to influence myocardial repolarization are provided (Supplementary Table 17). Interactors from immunoprecipitation (IP) experiments are shown from murine cardiac tissue using 5 baits (K1=KCNQ1, K2=KCNH2, CV=CAV3, CA=CACNA1C, S1=SNTA1) with protein identified in parentheses if different from the nearest gene listed.Loci at which a SNP (index or secondary) or a close proxy (r2>0.8) falls in a left ventricular enhancer are marked with I or S. Brackets indicate annotations for secondary signals of association (Supplementary Table 8a).
| Nearest gene |
SNP | chr | position hg18 |
coded/ noncoded allele |
coded allele freq |
N | effect msec (SE) |
P | LQTS gene locus |
Fxn | eQTL transcript |
PPI interactor known QT loci |
IP interactor |
LV enhancer |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Previously discovered loci | ||||||||||||||
|
| ||||||||||||||
| RNF207 | rs846111 | 1p36 | 6,201,957 | C/G | 0.28 | 47,041 | 1.73 (0.13) | 7×10-40 | G603A | |||||
| NOS1AP | rs12143842 | 1q23 | 160,300,514 | T/C | 0.24 | 75,053 | 3.50 (0.11) | 1×10-213 | S | |||||
| ATP1B1 | rs10919070 | 1q24 | 167,365,661 | C/A | 0.13 | 75,707 | -1.68 (0.14) | 1×10-31 | intron | ATP1B1,NME7 | ATP1B1-K1, ATP1B1-K2, ATP1B1-CA, ATP1B1-CV | I,S | ||
| SLC8A1 | rs12997023 | 2p22 | 40,606,486 | C/T | 0.05 | 70,311 | -1.69 (0.22) | 5×10-14 | ANK2,CAV3 | I,S | ||||
| SCN5A-SCN10A | rs6793245 | 3p22 | 38,574,041 | A/G | 0.32 | 73,697 | -1.12 (0.10) | 4×10-27 | LQT3 | intron | SCN5A-SNTA1 | S | ||
| SLC35F1-PLN | rs11153730 | 6q22 | 118,774,215 | T/C | 0.50 | 74,932 | -1.65 (0.10) | 2×10-67 | PLN-CV, PLN-CA | S | ||||
| KCNH2 | rs2072413 | 7q36 | 150,278,902 | T/C | 0.27 | 65,331 | -1.68 (0.11) | 1×10-49 | LQT2, SQT1 | intron | KCNE1 | S | ||
| KCNQ1 | rs7122937 | 11p15 | 2,443,126 | T/C | 0.19 | 72,978 | 1.93 (0.12) | 1×10-54 | LQT1, SQT2 | intron | C11ORF21,PHEMX,TSPAN32 | KCNE1,KCNH2 | I | |
| LITAF | rs735951 | 16p13 | 11,601,037 | A/G | 0.46 | 62,994 | -1.15 (0.10) | 2×10-28 | LITAF | S | ||||
| CNOT1 | rs246196 | 16q21 | 57,131,754 | C/T | 0.26 | 76,513 | -1.73 (0.11) | 2×10-57 | intron | NDRG4,CNOT1 | GOT2-CV, GOT2-K1 | I,S | ||
| LIG3 | rs1052536 | 17q12 | 30,355,688 | C/T | 0.53 | 75,961 | 0.98 (0.10) | 6×10-25 | 3′UTR | LIG3,CCT6B | UNC45B-K1, UNC45B-CV | I | ||
| KCNJ2 | rs1396515 | 17q24 | 65,942,588 | C/G | 0.52 | 77,058 | -0.98 (0.09) | 2×10-25 | LQT7, SQT3 | S | ||||
| KCNE1 | rs1805128 | 21q22 | 34,743,550 | T/C | 0.01 | 20,061 | 7.42 (0.85) | 2×10-18 | LQT5 | D85N | KCNQ1,KCNH2 | |||
| Novel loci | ||||||||||||||
| TCEA3 | rs2298632 | 1p36 | 23,583,062 | T/C | 0.50 | 83,031 | 0.70 (0.09) | 1×10-14 | intron | TCEA3 | ||||
| SP3 | rs938291 | 2q31.1 | 174,450,854 | G/C | 0.39 | 101,902 | 0.53 (0.09) | 6×10-10 | ||||||
| TTN-CCDC141 | rs7561149 | 2q31.2 | 179,398,101 | C/T | 0.42 | 85,299 | -0.52 (0.09) | 7×10-9 | CCDC141-CV,TTN-K2, TTN-CV | I | ||||
| SPATS2L | rs295140 | 2q33 | 200,868,944 | T/C | 0.42 | 103,331 | 0.57 (0.09) | 2×10-11 | SPATS2L | SGOL2-SCN5A | I | |||
| C3ORF75 | rs17784882 | 3p21 | 47,519,007 | A/C | 0.40 | 76,184 | -0.54 (0.10) | 3×10-8 | intron | KLHL18,PTPN23, SCAP,SETD2 | MYL3-CA | I | ||
| SLC4A4 | rs2363719 | 4q13 | 72,357,080 | A/G | 0.11 | 70,821 | 0.97 (0.16) | 8×10-10 | intron | |||||
| SMARCAD1 | rs3857067 | 4q22 | 95,245,457 | A/T | 0.46 | 101,382 | -0.51 (0.08) | 1×10-9 | ||||||
| GFRA3 | rs10040989 | 5q31 | 137,601,624 | A/G | 0.13 | 87,942 | -0.85 (0.13) | 5×10-11 | FAM13B | ETF1-RPL22 | ||||
| GMPR | rs7765828 | 6p22 | 16,402,701 | G/C | 0.40 | 93,262 | 0.55 (0.09) | 3×10-10 | intron (F256I-p) | ATXN1 | ATXN1-ACOT7,ATXN1-KCNAB2 | I | ||
| CAV1 | rs9920 | 7q31 | 115,987,328 | C/T | 0.09 | 102,060 | 0.79 (0.14) | 3×10-8 | 3′ UTR | CAV-ATP1B1, CAV2-ATP1B1 | CAV1-CA, CAV1-S1, CAV1-CV, CAV2-CV | |||
| NCOA2 | rs16936870 | 8q13 | 71,351,896 | A/T | 0.10 | 74,196 | 0.99 (0.16) | 1×10-9 | intron | I | ||||
| LAPTM4B | rs11779860 | 8q22.1 | 98,919,506 | C/T | 0.47 | 73,404 | -0.61 (0.10) | 2×10-10 | intron | I | ||||
| AZIN1 | rs1961102 | 8q22.3 | 104,002,021 | T/C | 0.33 | 82,677 | 0.57 (0.10) | 3×10-9 | ||||||
| GBF1 | rs2485376 | 10q24 | 104,039,996 | A/G | 0.39 | 70,552 | -0.56 (0.10) | 3×10-8 | intron | ACTR1A-CV | I | |||
| FEN1-FADS2 | rs174583 | 11q12 | 61,366,326 | T/C | 0.34 | 100,900 | -0.57 (0.09) | 8×10-11 | intron | FADS1, FADS2, FADS3 | I | |||
| ATP2A2 | rs3026445 | 12q24 | 109,207,586 | C/T | 0.36 | 95,768 | 0.62 (0.09) | 3×10-12 | intron | VPS29, GPN3, ARPC3, C12ORF24 | PLN | ATP2A2-CV, ATP2A2-CA | I | |
| KLF12 | rs728926 | 13q22 | 73,411,123 | T/C | 0.36 | 69,219 | 0.57 (0.10) | 2×10-8 | intron | KLF12 | I | |||
| ANKRD9 | rs2273905 | 14q32 | 102,044,752 | T/C | 0.35 | 83,532 | 0.61 (0.09) | 4×10-11 | 5′ UTR | ANKRD9 | I | |||
| USP50-TRPM7 | rs3105593 | 15q21 | 48,632,310 | T/C | 0.45 | 77,240 | 0.66 (0.10) | 3×10-12 | ||||||
| CREBBP | rs1296720 | 16p13.3 | 3,813,643 | C/A | 0.20 | 59,812 | 0.83 (0.13) | 4×10-10 | intron | CV-TRAP1 | ||||
| MKL2 | rs246185 | 16p13.12 | 14,302,933 | C/T | 0.34 | 77,411 | 0.72 (0.10) | 3×10-13 | ||||||
| PRKCA | rs9892651 | 17q24 | 61,734,255 | C/T | 0.43 | 74,683 | -0.74 (0.10) | 3×10-14 | intron | PRKCA | CACNA1C,KCNE1 | I | ||