Genetic determinants of P wave duration and PR segment.
BACKGROUND
The PR interval on the ECG reflects atrial depolarization and atrioventricular nodal delay which can be partially differentiated by P wave duration and PR segment, respectively. Genome-wide association studies have identified several genetic loci for PR interval, but it remains to be determined whether this is driven by P wave duration, PR segment, or both.


RESULTS
We replicated 7 of the 9 known PR interval loci in 16 468 individuals of European ancestry. Four loci were unambiguously associated with PR segment, while the others were shared for P wave duration and PR segment. Next, we performed a genome-wide analysis on P wave duration and PR segment separately and identified 5 novel loci. Single-nucleotide polymorphisms in KCND3 (P=8.3×10(-11)) and FADS2 (P=2.7×10(-8)) were associated with P wave duration, whereas single-nucleotide polymorphisms near IL17D (P=2.3×10(-8)), in EFHA1 (P=3.3×10(-10)), and in LRCH1 (P=2.1×10(-8)) were associated with PR segment. Analysis on DNA elements indicated that genome-wide significant single-nucleotide polymorphisms were enriched at genomic regions suggesting active gene transcription in the human right atrium. Quantitative polymerase chain reaction showed that genes were significantly higher expressed in the right atrium and atrioventricular node compared with left ventricle (P=5.6×10(-6)).


CONCLUSIONS
Genetic associations of PR interval seem to be mainly driven by genetic determinants of the PR segment. Some of the PR interval associations are strengthened by a directional consistent effect of genetic determinants of P wave duration. Through genome-wide association we also identified genetic variants specifically associated with P wave duration which might be relevant for cardiac biology.
From the Department of Cardiology (N.V., I.M.L., D.J.v.V., H.L.H., W.H.v.G., R.A.d.B., P.v.d.H.) and Department of Genetics (P.v.d.H.), University of Groningen, University Medical Center Groningen, Groningen, The Netherlands; Department of Anatomy, Embryology and Physiology, University of Amsterdam, Academic Medical Center, Amsterdam, The Netherlands (M.v.d.B., V.M.C., P.B.); and Durrer Center for Cardiogenetic Research, ICIN-Netherlands Heart Institute, Utrecht, The Netherlands (P.v.d.H.).
Niek
N
Verweij
From the Department of Cardiology (N.V., I.M.L., D.J.v.V., H.L.H., W.H.v.G., R.A.d.B., P.v.d.H.) and Department of Genetics (P.v.d.H.), University of Groningen, University Medical Center Groningen, Groningen, The Netherlands; Department of Anatomy, Embryology and Physiology, University of Amsterdam, Academic Medical Center, Amsterdam, The Netherlands (M.v.d.B., V.M.C., P.B.); and Durrer Center for Cardiogenetic Research, ICIN-Netherlands Heart Institute, Utrecht, The Netherlands (P.v.d.H.).
Irene
I
Mateo Leach
From the Department of Cardiology (N.V., I.M.L., D.J.v.V., H.L.H., W.H.v.G., R.A.d.B., P.v.d.H.) and Department of Genetics (P.v.d.H.), University of Groningen, University Medical Center Groningen, Groningen, The Netherlands; Department of Anatomy, Embryology and Physiology, University of Amsterdam, Academic Medical Center, Amsterdam, The Netherlands (M.v.d.B., V.M.C., P.B.); and Durrer Center for Cardiogenetic Research, ICIN-Netherlands Heart Institute, Utrecht, The Netherlands (P.v.d.H.).
Malou
M
van den Boogaard
From the Department of Cardiology (N.V., I.M.L., D.J.v.V., H.L.H., W.H.v.G., R.A.d.B., P.v.d.H.) and Department of Genetics (P.v.d.H.), University of Groningen, University Medical Center Groningen, Groningen, The Netherlands; Department of Anatomy, Embryology and Physiology, University of Amsterdam, Academic Medical Center, Amsterdam, The Netherlands (M.v.d.B., V.M.C., P.B.); and Durrer Center for Cardiogenetic Research, ICIN-Netherlands Heart Institute, Utrecht, The Netherlands (P.v.d.H.).
Dirk J
DJ
van Veldhuisen
From the Department of Cardiology (N.V., I.M.L., D.J.v.V., H.L.H., W.H.v.G., R.A.d.B., P.v.d.H.) and Department of Genetics (P.v.d.H.), University of Groningen, University Medical Center Groningen, Groningen, The Netherlands; Department of Anatomy, Embryology and Physiology, University of Amsterdam, Academic Medical Center, Amsterdam, The Netherlands (M.v.d.B., V.M.C., P.B.); and Durrer Center for Cardiogenetic Research, ICIN-Netherlands Heart Institute, Utrecht, The Netherlands (P.v.d.H.).
Vincent M
VM
Christoffels
From the Department of Cardiology (N.V., I.M.L., D.J.v.V., H.L.H., W.H.v.G., R.A.d.B., P.v.d.H.) and Department of Genetics (P.v.d.H.), University of Groningen, University Medical Center Groningen, Groningen, The Netherlands; Department of Anatomy, Embryology and Physiology, University of Amsterdam, Academic Medical Center, Amsterdam, The Netherlands (M.v.d.B., V.M.C., P.B.); and Durrer Center for Cardiogenetic Research, ICIN-Netherlands Heart Institute, Utrecht, The Netherlands (P.v.d.H.).
Hans L
HL
Hillege
From the Department of Cardiology (N.V., I.M.L., D.J.v.V., H.L.H., W.H.v.G., R.A.d.B., P.v.d.H.) and Department of Genetics (P.v.d.H.), University of Groningen, University Medical Center Groningen, Groningen, The Netherlands; Department of Anatomy, Embryology and Physiology, University of Amsterdam, Academic Medical Center, Amsterdam, The Netherlands (M.v.d.B., V.M.C., P.B.); and Durrer Center for Cardiogenetic Research, ICIN-Netherlands Heart Institute, Utrecht, The Netherlands (P.v.d.H.).
Wiek H
WH
van Gilst
From the Department of Cardiology (N.V., I.M.L., D.J.v.V., H.L.H., W.H.v.G., R.A.d.B., P.v.d.H.) and Department of Genetics (P.v.d.H.), University of Groningen, University Medical Center Groningen, Groningen, The Netherlands; Department of Anatomy, Embryology and Physiology, University of Amsterdam, Academic Medical Center, Amsterdam, The Netherlands (M.v.d.B., V.M.C., P.B.); and Durrer Center for Cardiogenetic Research, ICIN-Netherlands Heart Institute, Utrecht, The Netherlands (P.v.d.H.).
Phil
P
Barnett
From the Department of Cardiology (N.V., I.M.L., D.J.v.V., H.L.H., W.H.v.G., R.A.d.B., P.v.d.H.) and Department of Genetics (P.v.d.H.), University of Groningen, University Medical Center Groningen, Groningen, The Netherlands; Department of Anatomy, Embryology and Physiology, University of Amsterdam, Academic Medical Center, Amsterdam, The Netherlands (M.v.d.B., V.M.C., P.B.); and Durrer Center for Cardiogenetic Research, ICIN-Netherlands Heart Institute, Utrecht, The Netherlands (P.v.d.H.).
Rudolf A
RA
de Boer
From the Department of Cardiology (N.V., I.M.L., D.J.v.V., H.L.H., W.H.v.G., R.A.d.B., P.v.d.H.) and Department of Genetics (P.v.d.H.), University of Groningen, University Medical Center Groningen, Groningen, The Netherlands; Department of Anatomy, Embryology and Physiology, University of Amsterdam, Academic Medical Center, Amsterdam, The Netherlands (M.v.d.B., V.M.C., P.B.); and Durrer Center for Cardiogenetic Research, ICIN-Netherlands Heart Institute, Utrecht, The Netherlands (P.v.d.H.). p.van.der.harst@umcg.nl.
Pim
P
van der Harst
D001283:Atrioventricular Node / Q000378:metabolism; D002135:Calcium-Binding Proteins / Q000235:genetics; D015331:Cohort Studies; D004562:Electrocardiography; D044943:Fatty Acid Desaturases / Q000235:genetics; D005786:Gene Expression Regulation; D056426:Genetic Loci; D055106:Genome-Wide Association Study; D005838:Genotype; D006325:Heart Atria / Q000378:metabolism; D006352:Heart Ventricles / Q000378:metabolism; D006801:Humans; D020381:Interleukin-17 / Q000235:genetics; D007676:Kidney Failure, Chronic / Q000235:genetics* / Q000473:pathology; D008840:Microfilament Proteins / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D051672:Shal Potassium Channels / Q000235:genetics
D002135:Calcium-Binding Proteins; C464462:IL17D protein, human; D020381:Interleukin-17; C497021:KCND3 protein, human; C508643:LRCH1 protein, human; D008840:Microfilament Proteins; D051672:Shal Potassium Channels; D044943:Fatty Acid Desaturases; C533241:FADS2 protein, human
aging; electrocardiography; genetics