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Fine mapping of QT interval regions in global populations refines previously identified QT interval loci and identifies signals unique to African and Hispanic descent populations.
Tuesday,2017-09-12 15:46 America/Los_Angeles — ecterry
| Title | Fine mapping of QT interval regions in global populations refines previously identified QT interval loci and identifies signals unique to African and Hispanic descent populations. |
| Publication Type | Journal Article |
| Year of Publication | 2017 |
| Authors | Avery, CL, Wassel, CL, Richard, MA, Highland, HM, Bien, S, Zubair, N, Soliman, EZ, Fornage, M, Bielinski, SJ, Tao, R, Seyerle, AA, Shah, SJ, Lloyd-Jones, DM, Buyske, S, Rotter, JI, Post, WS, Rich, SS, Hindorff, LA, Jeff, JM, Shohet, RV, Sotoodehnia, N, Lin, DYu, Whitsel, EA, Peters, U, Haiman, CA, Crawford, DC, Kooperberg, C, North, KE |
| Journal | Heart Rhythm |
| Volume | 14 |
| Issue | 4 |
| Pagination | 572-580 |
| Date Published | 2017 Apr |
| ISSN | 1556-3871 |
| Abstract | <p><b>BACKGROUND: </b>The electrocardiographically measured QT interval (QT) is heritable and its prolongation is an established risk factor for several cardiovascular diseases. Yet, most QT genetic studies have been performed in European ancestral populations, possibly reducing their global relevance.</p><p><b>OBJECTIVE: </b>To leverage diversity and improve biological insight, we fine mapped 16 of the 35 previously identified QT loci (46%) in populations of African American (n = 12,410) and Hispanic/Latino (n = 14,837) ancestry.</p><p><b>METHODS: </b>Racial/ethnic-specific multiple linear regression analyses adjusted for heart rate and clinical covariates were examined separately and in combination after inverse-variance weighted trans-ethnic meta-analysis.</p><p><b>RESULTS: </b>The 16 fine-mapped QT loci included on the Illumina Metabochip represented 21 independent signals, of which 16 (76%) were significantly (P-value≤9.1×10(-5)) associated with QT. Through sequential conditional analysis we also identified three trans-ethnic novel SNPs at ATP1B1, SCN5A-SCN10A, and KCNQ1 and three Hispanic/Latino-specific novel SNPs at NOS1AP and SCN5A-SCN10A (two novel SNPs) with evidence of associations with QT independent of previous identified GWAS lead SNPs. Linkage disequilibrium patterns helped to narrow the region likely to contain the functional variants at several loci, including NOS1AP, USP50-TRPM7, and PRKCA, although intervals surrounding SLC35F1-PLN and CNOT1 remained broad in size (>100 kb). Finally, bioinformatics-based functional characterization suggested a regulatory function in cardiac tissues for the majority of independent signals that generalized and the novel SNPs.</p><p><b>CONCLUSION: </b>Our findings suggest that a majority of identified SNPs implicate gene regulatory dysfunction in QT prolongation, that the same loci influence variation in QT across global populations, and that additional, novel, population-specific QT signals exist.</p> |
| DOI | 10.1016/j.hrthm.2016.12.021 |
| Alternate Journal | Heart Rhythm |
| PubMed ID | 27988371 |
| PubMed Central ID | PMC5448160 |
| Grant List | HHSN268201100012C / HL / NHLBI NIH HHS / United States UL1 TR000445 / TR / NCATS NIH HHS / United States HHSN268201300026C / HL / NHLBI NIH HHS / United States N01HC95160 / HL / NHLBI NIH HHS / United States HHSN268201100010C / HL / NHLBI NIH HHS / United States N01HC95163 / HL / NHLBI NIH HHS / United States HHSN268201100008C / HL / NHLBI NIH HHS / United States U01 HL080295 / HL / NHLBI NIH HHS / United States U01 HG004790 / HG / NHGRI NIH HHS / United States U01 HG004802 / HG / NHGRI NIH HHS / United States HHSN268201100007C / HL / NHLBI NIH HHS / United States HHSN268200800007C / HL / NHLBI NIH HHS / United States N01HC95169 / HL / NHLBI NIH HHS / United States HHSN268201100046C / HL / NHLBI NIH HHS / United States HHSN268201100011C / HL / NHLBI NIH HHS / United States N01HC65236 / HL / NHLBI NIH HHS / United States HHSN268201100003C / WH / WHI NIH HHS / United States N01HC65235 / HL / NHLBI NIH HHS / United States R01 HL087652 / HL / NHLBI NIH HHS / United States N01HC95164 / HL / NHLBI NIH HHS / United States HHSN268201300025C / HL / NHLBI NIH HHS / United States N01HC55222 / HL / NHLBI NIH HHS / United States N01HC95162 / HL / NHLBI NIH HHS / United States N01HC85086 / HL / NHLBI NIH HHS / United States N01HC65234 / HL / NHLBI NIH HHS / United States HHSN268201300027C / HL / NHLBI NIH HHS / United States HHSN268201100006C / HL / NHLBI NIH HHS / United States N01HC65233 / HL / NHLBI NIH HHS / United States HHSN268201200036C / HL / NHLBI NIH HHS / United States HHSN268200900041C / HL / NHLBI NIH HHS / United States HHSN268201300028C / HL / NHLBI NIH HHS / United States N01HC65237 / HL / NHLBI NIH HHS / United States U01 HG004803 / HG / NHGRI NIH HHS / United States HHSN271201100004C / AG / NIA NIH HHS / United States N01HC95165 / HL / NHLBI NIH HHS / United States N01HC95159 / HL / NHLBI NIH HHS / United States N01HC95161 / HL / NHLBI NIH HHS / United States HHSN268201100002C / WH / WHI NIH HHS / United States N01HC85082 / HL / NHLBI NIH HHS / United States N01HC95167 / HL / NHLBI NIH HHS / United States HHSN268201100009C / HL / NHLBI NIH HHS / United States N01HC85083 / HL / NHLBI NIH HHS / United States HHSN268201100005C / HL / NHLBI NIH HHS / United States UL1 RR024975 / RR / NCRR NIH HHS / United States U01 HG004798 / HG / NHGRI NIH HHS / United States N01HC85079 / HL / NHLBI NIH HHS / United States N01HC95166 / HL / NHLBI NIH HHS / United States N01HC85080 / HL / NHLBI NIH HHS / United States HHSN268201100001C / WH / WHI NIH HHS / United States HHSN268201100004C / WH / WHI NIH HHS / United States R01 HL111089 / HL / NHLBI NIH HHS / United States R01 HL116747 / HL / NHLBI NIH HHS / United States N01HC85081 / HL / NHLBI NIH HHS / United States U01 HG004801 / HG / NHGRI NIH HHS / United States |
ePub date:
17/04