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Multi-Ethnic Genome-Wide Association Study of Decomposed Cardioelectric Phenotypes Illustrates Strategies to Identify and Characterize Evidence of Shared Genetic Effects for Complex Traits.
Baldassari, Antoine R; Sitlani, Colleen M; Highland, Heather M; Arking, Dan E; Buyske, Steve; Darbar, Dawood; Gondalia, Rahul; Graff, Misa; Guo, Xiuqing; Heckbert, Susan R; Hindorff, Lucia A; Hodonsky, Chani J; Ida Chen, Yii-Der; Kaplan, Robert C; Peters, Ulrike; Post, Wendy; Reiner, Alex P; Rotter, Jerome I; Shohet, Ralph V; Seyerle, Amanda A; Sotoodehnia, Nona; Tao, Ran; Taylor, Kent D; Wojcik, Genevieve L; Yao, Jie; Kenny, Eimear E; Lin, Henry J; Soliman, Elsayed Z; Whitsel, Eric A; North, Kari E; Kooperberg, Charles; Avery, Christy L.
Afiliação
  • Baldassari AR; Gillings School of Global Public Health (A.R.B., H.M.H., R.G., M.G., C.J.H., A.A.S., E.A.W., K.E.N., C.L.A.), University of North Carolina at Chapel Hill.
  • Sitlani CM; Cardiovascular Health Research Unit, Department of Medicine (C.M.S.), University of Washington, Seattle.xs.
  • Highland HM; Gillings School of Global Public Health (A.R.B., H.M.H., R.G., M.G., C.J.H., A.A.S., E.A.W., K.E.N., C.L.A.), University of North Carolina at Chapel Hill.
  • Arking DE; McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD (D.E.A.).
  • Buyske S; Department of Statistics and Biostatistics, Rutgers University, New Brunswick, NJ (S.B.).
  • Darbar D; Department of Medicine, University of Illinois at Chicago (D.D.).
  • Gondalia R; Gillings School of Global Public Health (A.R.B., H.M.H., R.G., M.G., C.J.H., A.A.S., E.A.W., K.E.N., C.L.A.), University of North Carolina at Chapel Hill.
  • Graff M; Gillings School of Global Public Health (A.R.B., H.M.H., R.G., M.G., C.J.H., A.A.S., E.A.W., K.E.N., C.L.A.), University of North Carolina at Chapel Hill.
  • Guo X; Institute for Translational Genomics and Population Sciences, Department of Pediatrics, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance (X.G., Y.-D.I.C., J.I.R., K.D.T., J.Y., H.J.L.).
  • Heckbert SR; Department of Pediatrics, David Geffen School of Medicine at UCLA, Los Angeles, CA (X.G., Y.-D.I.C., J.I.R., K.D.T., J.Y., H.J.L.).
  • Hindorff LA; Cardiovascular Health Research Unit, Division of Cardiology, Department of Medicine (S.R.H., N.S.), University of Washington, Seattle.
  • Hodonsky CJ; Division of Genomic Medicine, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD (L.A.H.).
  • Ida Chen YD; Gillings School of Global Public Health (A.R.B., H.M.H., R.G., M.G., C.J.H., A.A.S., E.A.W., K.E.N., C.L.A.), University of North Carolina at Chapel Hill.
  • Kaplan RC; Institute for Translational Genomics and Population Sciences, Department of Pediatrics, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance (X.G., Y.-D.I.C., J.I.R., K.D.T., J.Y., H.J.L.).
  • Peters U; Department of Pediatrics, David Geffen School of Medicine at UCLA, Los Angeles, CA (X.G., Y.-D.I.C., J.I.R., K.D.T., J.Y., H.J.L.).
  • Post W; Albert Einstein College of Medicine, Bronx, NY (R.C.K.).
  • Reiner AP; Fred Hutchinson Cancer Research Center, Public Health Sciences Division, Seattle, WA (U.P., A.P.R., C.K.).
  • Rotter JI; Departments of Medicine and Epidemiology, Johns Hopkins University, Baltimore, MD (W.P.).
  • Shohet RV; Fred Hutchinson Cancer Research Center, Public Health Sciences Division, Seattle, WA (U.P., A.P.R., C.K.).
  • Seyerle AA; Institute for Translational Genomics and Population Sciences, Department of Pediatrics, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance (X.G., Y.-D.I.C., J.I.R., K.D.T., J.Y., H.J.L.).
  • Sotoodehnia N; Department of Pediatrics, David Geffen School of Medicine at UCLA, Los Angeles, CA (X.G., Y.-D.I.C., J.I.R., K.D.T., J.Y., H.J.L.).
  • Tao R; Center for Cardiovascular Research, John A. Burns School of Medicine, Honolulu, HI (R.V.S.).
  • Taylor KD; Gillings School of Global Public Health (A.R.B., H.M.H., R.G., M.G., C.J.H., A.A.S., E.A.W., K.E.N., C.L.A.), University of North Carolina at Chapel Hill.
  • Wojcik GL; Cardiovascular Health Research Unit, Division of Cardiology, Department of Medicine (S.R.H., N.S.), University of Washington, Seattle.
  • Yao J; Department of Biostatistics, Vanderbilt University, Nashville, TN (R.T.).
  • Kenny EE; Institute for Translational Genomics and Population Sciences, Department of Pediatrics, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance (X.G., Y.-D.I.C., J.I.R., K.D.T., J.Y., H.J.L.).
  • Lin HJ; Department of Pediatrics, David Geffen School of Medicine at UCLA, Los Angeles, CA (X.G., Y.-D.I.C., J.I.R., K.D.T., J.Y., H.J.L.).
  • Soliman EZ; Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD (G.L.W.).
  • Whitsel EA; Institute for Translational Genomics and Population Sciences, Department of Pediatrics, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance (X.G., Y.-D.I.C., J.I.R., K.D.T., J.Y., H.J.L.).
  • North KE; Department of Pediatrics, David Geffen School of Medicine at UCLA, Los Angeles, CA (X.G., Y.-D.I.C., J.I.R., K.D.T., J.Y., H.J.L.).
  • Kooperberg C; Center for Genomic Health (E.E.K.), Icahn School of Medicine at Mount Sinai, New York, NY.
  • Avery CL; Charles Bronfman Institute of Personalized Medicine (E.E.K.), Icahn School of Medicine at Mount Sinai, New York, NY.
Circ Genom Precis Med ; 13(4): e002680, 2020 08.
Article em En | MEDLINE | ID: mdl-32602732
ABSTRACT

BACKGROUND:

We examined how expanding electrocardiographic trait genome-wide association studies to include ancestrally diverse populations, prioritize more precise phenotypic measures, and evaluate evidence for shared genetic effects enabled the detection and characterization of loci.

METHODS:

We decomposed 10 seconds, 12-lead electrocardiograms from 34 668 multi-ethnic participants (15% Black; 30% Hispanic/Latino) into 6 contiguous, physiologically distinct (P wave, PR segment, QRS interval, ST segment, T wave, and TP segment) and 2 composite, conventional (PR interval and QT interval) interval scale traits and conducted multivariable-adjusted, trait-specific univariate genome-wide association studies using 1000-G imputed single-nucleotide polymorphisms. Evidence of shared genetic effects was evaluated by aggregating meta-analyzed univariate results across the 6 continuous electrocardiographic traits using the combined phenotype adaptive sum of powered scores test.

RESULTS:

We identified 6 novels (CD36, PITX2, EMB, ZNF592, YPEL2, and BC043580) and 87 known loci (adaptive sum of powered score test P<5×10-9). Lead single-nucleotide polymorphism rs3211938 at CD36 was common in Blacks (minor allele frequency=10%), near monomorphic in European Americans, and had effects on the QT interval and TP segment that ranked among the largest reported to date for common variants. The other 5 novel loci were observed when evaluating the contiguous but not the composite electrocardiographic traits. Combined phenotype testing did not identify novel electrocardiographic loci unapparent using traditional univariate approaches, although this approach did assist with the characterization of known loci.

CONCLUSIONS:

Despite including one-third as many participants as published electrocardiographic trait genome-wide association studies, our study identified 6 novel loci, emphasizing the importance of ancestral diversity and phenotype resolution in this era of ever-growing genome-wide association studies.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Doenças Cardiovasculares / Eletrocardiografia / Estudo de Associação Genômica Ampla Tipo de estudo: Prognostic_studies / Risk_factors_studies Limite: Humans Idioma: En Revista: Circ Genom Precis Med Ano de publicação: 2020 Tipo de documento: Article
Texto completo
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Doenças Cardiovasculares / Eletrocardiografia / Estudo de Associação Genômica Ampla Tipo de estudo: Prognostic_studies / Risk_factors_studies Limite: Humans Idioma: En Revista: Circ Genom Precis Med Ano de publicação: 2020 Tipo de documento: Article