Genome-wide association analysis identifies multiple loci related to resting heart rate.
Higher resting heart rate is associated with increased cardiovascular disease and mortality risk. Though heritable factors play a substantial role in population variation, little is known about specific genetic determinants. This knowledge can impact clinical care by identifying novel factors that influence pathologic heart rate states, modulate heart rate through cardiac structure and function or by improving our understanding of the physiology of heart rate regulation. To identify common genetic variants associated with heart rate, we performed a meta-analysis of 15 genome-wide association studies (GWAS), including 38,991 subjects of European ancestry, estimating the association between age-, sex- and body mass-adjusted RR interval (inverse heart rate) and approximately 2.5 million markers. Results with P < 5 × 10(-8) were considered genome-wide significant. We constructed regression models with multiple markers to assess whether results at less stringent thresholds were likely to be truly associated with RR interval. We identified six novel associations with resting heart rate at six loci: 6q22 near GJA1; 14q12 near MYH7; 12p12 near SOX5, c12orf67, BCAT1, LRMP and CASC1; 6q22 near SLC35F1, PLN and c6orf204; 7q22 near SLC12A9 and UfSp1; and 11q12 near FADS1. Associations at 6q22 400 kb away from GJA1, at 14q12 MYH6 and at 1q32 near CD34 identified in previously published GWAS were confirmed. In aggregate, these variants explain approximately 0.7% of RR interval variance. A multivariant regression model including 20 variants with P < 10(-5) increased the explained variance to 1.6%, suggesting that some loci falling short of genome-wide significance are likely truly associated. Future research is warranted to elucidate underlying mechanisms that may impact clinical care.
Eijgelsheim
Mark
M
Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands.
Newton-Cheh
Christopher
C
Sotoodehnia
Nona
N
de Bakker
Paul I W
PI
Müller
Martina
M
Morrison
Alanna C
AC
Smith
Albert V
AV
Isaacs
Aaron
A
Sanna
Serena
S
Dörr
Marcus
M
Navarro
Pau
P
Fuchsberger
Christian
C
Nolte
Ilja M
IM
de Geus
Eco J C
EJ
Estrada
Karol
K
Hwang
Shih-Jen
SJ
Bis
Joshua C
JC
Rückert
Ina-Maria
IM
Alonso
Alvaro
A
Launer
Lenore J
LJ
Hottenga
Jouke Jan
JJ
Rivadeneira
Fernando
F
Noseworthy
Peter A
PA
Rice
Kenneth M
KM
Perz
Siegfried
S
Arking
Dan E
DE
Spector
Tim D
TD
Kors
Jan A
JA
Aulchenko
Yurii S
YS
Tarasov
Kirill V
KV
Homuth
Georg
G
Wild
Sarah H
SH
Marroni
Fabio
F
Gieger
Christian
C
Licht
Carmilla M
CM
Prineas
Ronald J
RJ
Hofman
Albert
A
Rotter
Jerome I
JI
Hicks
Andrew A
AA
Ernst
Florian
F
Najjar
Samer S
SS
Wright
Alan F
AF
Peters
Annette
A
Fox
Ervin R
ER
Oostra
Ben A
BA
Kroemer
Heyo K
HK
Couper
David
D
Völzke
Henry
H
Campbell
Harry
H
Meitinger
Thomas
T
Uda
Manuela
M
Witteman
Jacqueline C M
JC
Psaty
Bruce M
BM
Wichmann
H-Erich
HE
Harris
Tamara B
TB
Kääb
Stefan
S
Siscovick
David S
DS
Jamshidi
Yalda
Y
Uitterlinden
André G
AG
Folsom
Aaron R
AR
Larson
Martin G
MG
Wilson
James F
JF
Penninx
Brenda W
BW
Snieder
Harold
H
Pramstaller
Peter P
PP
van Duijn
Cornelia M
CM
Lakatta
Edward G
EG
Felix
Stephan B
SB
Gudnason
Vilmundur
V
Pfeufer
Arne
A
Heckbert
Susan R
SR
Stricker
Bruno H Ch
BH
Boerwinkle
Eric
E
O'Donnell
Christopher J
CJ
D000328:Adult; D000368:Aged; D020029:Base Pairing / Q000235:genetics; D015331:Cohort Studies; D000090943:Delta-5 Fatty Acid Desaturase; D005260:Female; D056426:Genetic Loci / Q000235:genetics*; D015894:Genome, Human / Q000235:genetics*; D055106:Genome-Wide Association Study; D006339:Heart Rate / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D012146:Rest / Q000502:physiology*