A genome-wide screen for interactions reveals a new locus on 4p15 modifying the effect of waist-to-hip ratio on total cholesterol.
Surakka I., Isaacs A., Karssen LC., Laurila P-PP., Middelberg RPS., Tikkanen E., Ried JS., Lamina C., Mangino M., Igl W., Hottenga J-J., Lagou V., van der Harst P., Mateo Leach I., Esko T., Kutalik Z., Wainwright NW., Struchalin MV., Sarin A-P., Kangas AJ., Viikari JS., Perola M., Rantanen T., Petersen A-K., Soininen P., Johansson A., Soranzo N., Heath AC., Papamarkou T., Prokopenko I., Tönjes A., Kronenberg F., Döring A., Rivadeneira F., Montgomery GW., Whitfield JB., Kähönen M., Lehtimäki T., Freimer NB., Willemsen G., de Geus EJC., Palotie A., Sandhu MS., Waterworth DM., Metspalu A., Stumvoll M., Uitterlinden AG., Jula A., Navis G., Wijmenga C., Wolffenbuttel BHR., Taskinen M-R., Ala-Korpela M., Kaprio J., Kyvik KO., Boomsma DI., Pedersen NL., Gyllensten U., Wilson JF., Rudan I., Campbell H., Pramstaller PP., Spector TD., Witteman JCM., Eriksson JG., Salomaa V., Oostra BA., Raitakari OT., Wichmann H-E., Gieger C., Järvelin M-R., Martin NG., Hofman A., McCarthy MI., Peltonen L., van Duijn CM., Aulchenko YS., Ripatti S., ENGAGE Consortium None.
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.