Surakka, I and Isaacs, A and Karssen, LC and Laurila, PPP and Middelberg, RPS and Tikkanen, E and Ried, JS and Lamina, C and Mangino, M and Igl, W and Hottenga, JJ and Lagou, V and van der Harst, P and Leach, IM and Esko, T and Kutalik, Z and Wainwright, NW and Struchalin, MV and Sarin, AP and Kangas, AJ and Viikari, JS and Perola, M and Rantanen, T and Petersen, AK and Soininen, P and Johansson, A and Soranzo, N and Heath, AC and Papamarkou, T and Prokopenko, I and Tonjes, A and Kronenberg, F and Doring, A and Rivadeneira, F and Montgomery, GW and Whitfield, JB and Kahonen, M and Lehtimaki, T and Freimer, NB and Willemsen, G and de Geus, EJC and Palotie, A and Sandhu, MS and Waterworth, DM and Metspalu, A and Stumvoll, M and Uitterlinden, AG and Jula, A and Navis, G and Wijmenga, C and Wolffenbuttel, BHR and Taskinen, MR and Ala-Korpela, M and Kaprio, J and Kyvik, KO and Boomsma, DI and Pedersen, NL and Gyllensten, U and Wilson, JF and Rudan, I and Campbell, H and Pramstaller, PP and Spector, TD and Witteman, JCM and Eriksson, JG and Salomaa, V and Oostra, BA and Raitakari, OT and Wichmann, HE and Gieger, C and Jarvelin, MR and Martin, NG and Hofman, A and McCarthy, MI and Peltonen, L and van Duijn, CM and Aulchenko, YS and Ripatti, S and ENGAGE Consortium, (2011) A Genome-Wide Screen for Interactions Reveals a New Locus on 4p15 Modifying the Effect of Waist-to-Hip Ratio on Total Cholesterol. PLOS GENET , 7 (10) , Article e1002333.
Recent genome-wide association (GWA) studies described 95 loci controlling serum lipid levels. These common variants explain similar to 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 x 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.
|Title:||A Genome-Wide Screen for Interactions Reveals a New Locus on 4p15 Modifying the Effect of Waist-to-Hip Ratio on Total Cholesterol|
|Open access status:||An open access publication|
|Keywords:||DENSITY-LIPOPROTEIN CHOLESTEROL, HDL CHOLESTEROL, ASSOCIATION, GENE, SMOKING, PLASMA, TRIGLYCERIDE, OBESITY, LIPIDS, POLYMORPHISMS|
|UCL classification:||UCL > School of BEAMS > Faculty of Maths and Physical Sciences > Statistical Science|
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