TY - JOUR
T1 - A genome-wide screen for interactions reveals a new locus on 4p15 modifying the effect of waist-to-hip ratio on total cholesterol
AU - Surakka, Ida
AU - Isaacs, Aaron
AU - Karssen, Lennart C
AU - Laurila, Pirkka-Pekka P
AU - Middelberg, Rita P S
AU - Tikkanen, Emmi
AU - Ried, Janina S
AU - Lamina, Claudia
AU - Mangino, Massimo
AU - Igl, Wilmar
AU - Hottenga, Jouke-Jan
AU - Lagou, Vasiliki
AU - van der Harst, Pim
AU - Mateo Leach, Irene
AU - Esko, Tõnu
AU - Kutalik, Zoltán
AU - Wainwright, Nicholas W
AU - Struchalin, Maksim V
AU - Sarin, Antti-Pekka
AU - Kangas, Antti J
AU - Viikari, Jorma S
AU - Perola, Markus
AU - Rantanen, Taina
AU - Petersen, Ann-Kristin
AU - Soininen, Pasi
AU - Johansson, Asa
AU - Soranzo, Nicole
AU - Heath, Andrew C
AU - Papamarkou, Theodore
AU - Prokopenko, Inga
AU - Tönjes, Anke
AU - Kronenberg, Florian
AU - Döring, Angela
AU - Rivadeneira, Fernando
AU - Montgomery, Grant W
AU - Whitfield, John B
AU - Kähönen, Mika
AU - Lehtimäki, Terho
AU - Freimer, Nelson B
AU - Willemsen, Gonneke
AU - de Geus, Eco J C
AU - Palotie, Aarno
AU - Sandhu, Manj S
AU - Waterworth, Dawn M
AU - Metspalu, Andres
AU - Stumvoll, Michael
AU - Uitterlinden, André G
AU - Jula, Antti
AU - Navis, Gerjan
AU - Wolffenbuttel, Bruce H R
AU - ENGAGE Consortium
PY - 2011/10
Y1 - 2011/10
N2 - 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.
AB - 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.
KW - Adipose Tissue/metabolism
KW - Body Fat Distribution
KW - Cadherins/genetics
KW - Cholesterol/blood
KW - Chromosome Mapping
KW - Chromosomes, Human, Pair 4/genetics
KW - European Continental Ancestry Group/genetics
KW - Genome-Wide Association Study
KW - Genotype
KW - Humans
KW - Lipids/blood
KW - Lipoproteins/blood
KW - Phenotype
KW - Polymorphism, Single Nucleotide
KW - Quantitative Trait Loci/genetics
KW - Risk Factors
KW - Triglycerides/blood
KW - Waist-Hip Ratio
U2 - 10.1371/journal.pgen.1002333
DO - 10.1371/journal.pgen.1002333
M3 - Article
C2 - 22028671
SN - 1553-7390
VL - 7
SP - e1002333
JO - Plos Genetics
JF - Plos Genetics
IS - 10
ER -