A genome-wide screen for interactions reveals a new locus on 4p15 modifying the effect of waist-to-hip ratio on total cholesterol.
Recent genome-wide association (GWA) studies described 95 loci controlling serum lipid levels. These common variants explain ∼25% of the heritability of the phenotypes. To date, no unbiased screen for gene-environment interactions for circulating lipids has been reported. We screened for variants that modify the relationship between known epidemiological risk factors and circulating lipid levels in a meta-analysis of genome-wide association (GWA) data from 18 population-based cohorts with European ancestry (maximum N = 32,225). We collected 8 further cohorts (N = 17,102) for replication, and rs6448771 on 4p15 demonstrated genome-wide significant interaction with waist-to-hip-ratio (WHR) on total cholesterol (TC) with a combined P-value of 4.79×10(-9). There were two potential candidate genes in the region, PCDH7 and CCKAR, with differential expression levels for rs6448771 genotypes in adipose tissue. The effect of WHR on TC was strongest for individuals carrying two copies of G allele, for whom a one standard deviation (sd) difference in WHR corresponds to 0.19 sd difference in TC concentration, while for A allele homozygous the difference was 0.12 sd. Our findings may open up possibilities for targeted intervention strategies for people characterized by specific genomic profiles. However, more refined measures of both body-fat distribution and metabolic measures are needed to understand how their joint dynamics are modified by the newly found locus.
Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland.
Ida
I
Surakka
Aaron
A
Isaacs
Lennart C
LC
Karssen
Pirkka-Pekka P
PP
Laurila
Rita P S
RP
Middelberg
Emmi
E
Tikkanen
Janina S
JS
Ried
Claudia
C
Lamina
Massimo
M
Mangino
Wilmar
W
Igl
Jouke-Jan
JJ
Hottenga
Vasiliki
V
Lagou
Pim
P
van der Harst
Irene
I
Mateo Leach
Tõnu
T
Esko
Zoltán
Z
Kutalik
Nicholas W
NW
Wainwright
Maksim V
MV
Struchalin
Antti-Pekka
AP
Sarin
Antti J
AJ
Kangas
Jorma S
JS
Viikari
Markus
M
Perola
Taina
T
Rantanen
Ann-Kristin
AK
Petersen
Pasi
P
Soininen
Asa
A
Johansson
Nicole
N
Soranzo
Andrew C
AC
Heath
Theodore
T
Papamarkou
Inga
I
Prokopenko
Anke
A
Tönjes
Florian
F
Kronenberg
Angela
A
Döring
Fernando
F
Rivadeneira
Grant W
GW
Montgomery
John B
JB
Whitfield
Mika
M
Kähönen
Terho
T
Lehtimäki
Nelson B
NB
Freimer
Gonneke
G
Willemsen
Eco J C
EJ
de Geus
Aarno
A
Palotie
Manj S
MS
Sandhu
Dawn M
DM
Waterworth
Andres
A
Metspalu
Michael
M
Stumvoll
André G
AG
Uitterlinden
Antti
A
Jula
Gerjan
G
Navis
Cisca
C
Wijmenga
Bruce H R
BH
Wolffenbuttel
Marja-Riitta
MR
Taskinen
Mika
M
Ala-Korpela
Jaakko
J
Kaprio
Kirsten O
KO
Kyvik
Dorret I
DI
Boomsma
Nancy L
NL
Pedersen
Ulf
U
Gyllensten
James F
JF
Wilson
Igor
I
Rudan
Harry
H
Campbell
Peter P
PP
Pramstaller
Tim D
TD
Spector
Jacqueline C M
JC
Witteman
Johan G
JG
Eriksson
Veikko
V
Salomaa
Ben A
BA
Oostra
Olli T
OT
Raitakari
H-Erich
HE
Wichmann
Christian
C
Gieger
Marjo-Riitta
MR
Järvelin
Nicholas G
NG
Martin
Albert
A
Hofman
Mark I
MI
McCarthy
Leena
L
Peltonen
Cornelia M
CM
van Duijn
Yurii S
YS
Aulchenko
Samuli
S
Ripatti
D000273:Adipose Tissue / Q000378:metabolism; D050218:Body Fat Distribution; D015820:Cadherins / Q000235:genetics*; D002784:Cholesterol / Q000097:blood / Q000235:genetics*; D002874:Chromosome Mapping; D002894:Chromosomes, Human, Pair 4 / Q000235:genetics*; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D008055:Lipids / Q000097:blood* / Q000235:genetics*; D008074:Lipoproteins / Q000097:blood / Q000235:genetics; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D000091363:Protocadherins; D040641:Quantitative Trait Loci / Q000235:genetics; D012307:Risk Factors; D014280:Triglycerides / Q000097:blood / Q000235:genetics; D049629:Waist-Hip Ratio; D044465:White People / Q000235:genetics
D015820:Cadherins; D008055:Lipids; D008074:Lipoproteins; C113391:PCDH7 protein, human; D000091363:Protocadherins; D014280:Triglycerides; D002784:Cholesterol