Variants conferring risk of atrial fibrillation on chromosome 4q25.
Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia in humans and is characterized by chaotic electrical activity of the atria. It affects one in ten individuals over the age of 80 years, causes significant morbidity and is an independent predictor of mortality. Recent studies have provided evidence of a genetic contribution to AF. Mutations in potassium-channel genes have been associated with familial AF but account for only a small fraction of all cases of AF. We have performed a genome-wide association scan, followed by replication studies in three populations of European descent and a Chinese population from Hong Kong and find a strong association between two sequence variants on chromosome 4q25 and AF. Here we show that about 35% of individuals of European descent have at least one of the variants and that the risk of AF increases by 1.72 and 1.39 per copy. The association with the stronger variant is replicated in the Chinese population, where it is carried by 75% of individuals and the risk of AF is increased by 1.42 per copy. A stronger association was observed in individuals with typical atrial flutter. Both variants are adjacent to PITX2, which is known to have a critical function in left-right asymmetry of the heart.
Gudbjartsson
Daniel F
DF
deCODE genetics, Sturlugata 8, 101 Reykjavik, Iceland. daniel.gudbjartsson@decode.is
Arnar
David O
DO
Helgadottir
Anna
A
Gretarsdottir
Solveig
S
Holm
Hilma
H
Sigurdsson
Asgeir
A
Jonasdottir
Adalbjorg
A
Baker
Adam
A
Thorleifsson
Gudmar
G
Kristjansson
Kristleifur
K
Palsson
Arnar
A
Blondal
Thorarinn
T
Sulem
Patrick
P
Backman
Valgerdur M
VM
Hardarson
Gudmundur A
GA
Palsdottir
Ebba
E
Helgason
Agnar
A
Sigurjonsdottir
Runa
R
Sverrisson
Jon T
JT
Kostulas
Konstantinos
K
Ng
Maggie C Y
MC
Baum
Larry
L
So
Wing Yee
WY
Wong
Ka Sing
KS
Chan
Juliana C N
JC
Furie
Karen L
KL
Greenberg
Steven M
SM
Sale
Michelle
M
Kelly
Peter
P
MacRae
Calum A
CA
Smith
Eric E
EE
Rosand
Jonathan
J
Hillert
Jan
J
Ma
Ronald C W
RC
Ellinor
Patrick T
PT
Thorgeirsson
Gudmundur
G
Gulcher
Jeffrey R
JR
Kong
Augustine
A
Thorsteinsdottir
Unnur
U
Stefansson
Kari
K
D017677:Age Distribution; D000368:Aged; D000369:Aged, 80 and over; D044466:Asian People / Q000235:genetics; D001281:Atrial Fibrillation / Q000175:diagnosis / Q000235:genetics*; D002894:Chromosomes, Human, Pair 4 / Q000235:genetics*; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D014644:Genetic Variation / Q000235:genetics*; D015894:Genome, Human / Q000235:genetics; D006239:Haplotypes / Q000235:genetics; D006723:Hong Kong; D006801:Humans; D007055:Iceland; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D013548:Sweden; D014481:United States; D044465:White People / Q000235:genetics