Identifying genetic variants for heart rate variability in the acetylcholine pathway.
Heart rate variability is an important risk factor for cardiovascular disease and all-cause mortality. The acetylcholine pathway plays a key role in explaining heart rate variability in humans. We assessed whether 443 genotyped and imputed common genetic variants in eight key genes (CHAT, SLC18A3, SLC5A7, CHRNB4, CHRNA3, CHRNA, CHRM2 and ACHE) of the acetylcholine pathway were associated with variation in an established measure of heart rate variability reflecting parasympathetic control of the heart rhythm, the root mean square of successive differences (RMSSD) of normal RR intervals. The association was studied in a two stage design in individuals of European descent. First, analyses were performed in a discovery sample of four cohorts (n = 3429, discovery stage). Second, findings were replicated in three independent cohorts (n = 3311, replication stage), and finally the two stages were combined in a meta-analysis (n = 6740). RMSSD data were obtained under resting conditions. After correction for multiple testing, none of the SNPs showed an association with RMSSD. In conclusion, no common genetic variants for heart rate variability were identified in the largest and most comprehensive candidate gene study on the acetylcholine pathway to date. Future gene finding efforts for RMSSD may want to focus on hypothesis free approaches such as the genome-wide association study.
Interdisciplinary Center Psychopathology and Emotion regulation (ICPE), Department of Psychiatry, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands; Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
Harriëtte
H
Riese
Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
Loretto M
LM
Muñoz
Interdisciplinary Center Psychopathology and Emotion regulation (ICPE), Department of Psychiatry, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
Catharina A
CA
Hartman
Departments of Biostatistics & Epidemiology, College of Public Health, University of Kentucky, Lexington, Kentucky, United States of America.
Xiuhua
X
Ding
Georgia Prevention Institute, Department of Pediatrics, Georgia Regents University, Augusta, Georgia, United States of America.
Shaoyong
S
Su
Interdisciplinary Center Psychopathology and Emotion regulation (ICPE), Department of Psychiatry, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
Albertine J
AJ
Oldehinkel
Department of Vascular Medicine, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
Arie M
AM
van Roon
Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
Peter J
PJ
van der Most
Department of Vascular Medicine, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
Joop
J
Lefrandt
Division of Nephrology, Department of Internal Medicine, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
Ron T
RT
Gansevoort
University of Groningen, University Medical Center Groningen, Department of Cardiology, Groningen, The Netherlands.
Pim
P
van der Harst
University of Groningen, University Medical Center Groningen, Department of Cardiology, Groningen, The Netherlands.
Niek
N
Verweij
VU University Medical Center, Amsterdam, The Netherlands.
Carmilla M M
CM
Licht
Department of Biological Psychology, EMGO institute for Health and Care research, VU University & VU Medical Center, Amsterdam, The Netherlands.
Dorret I
DI
Boomsma
Department of Biological Psychology, EMGO institute for Health and Care research, VU University & VU Medical Center, Amsterdam, The Netherlands.
Jouke-Jan
JJ
Hottenga
Department of Biological Psychology, EMGO institute for Health and Care research, VU University & VU Medical Center, Amsterdam, The Netherlands.
Gonneke
G
Willemsen
VU University Medical Center, Amsterdam, The Netherlands.
Brenda W J H
BW
Penninx
Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
Ilja M
IM
Nolte
Department of Biological Psychology, EMGO institute for Health and Care research, VU University & VU Medical Center, Amsterdam, The Netherlands.
Eco J C
EJ
de Geus
Georgia Prevention Institute, Department of Pediatrics, Georgia Regents University, Augusta, Georgia, United States of America.
Xiaoling
X
Wang
Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
Harold
H
Snieder
D000109:Acetylcholine / Q000378:metabolism*; D000293:Adolescent; D000328:Adult; D002318:Cardiovascular Diseases / Q000235:genetics / Q000378:metabolism; D002648:Child; D015331:Cohort Studies; D005260:Female; D056726:Genetic Association Studies; D006339:Heart Rate / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D015398:Signal Transduction; D044465:White People / Q000235:genetics*; D055815:Young Adult
D000109:Acetylcholine