Genome-Wide Screen for G6E Interactions on Lipids Bolzano, Italy, 57 Affiliated Institute of the University of Lu¨ beck, Lu¨ beck, Germany, 58 Department of Neurology, University of Lu¨ beck, Lu¨ beck, Germany, 59 Department of Neurology, Central Hospital of Bolzano, Bolzano, Italy, 60 Department of General Practice and Primary Health Care, University of Helsinki, Helsinki, Finland, 61 Unit of General Practice, Helsinki University Central Hospital, Helsinki, Finland, 62 Folkha¨lsan Research Centre, Helsinki, Finland, 63 Vasa Central Hospital, Vasa, Finland, 64 Department of Health Promotion and Chronic Disease Prevention, National Institute for Health and Welfare, Helsinki, Finland, 65 Unit of Chronic Disease Epidemiology and Prevention, National Institute for Health and Welfare, Helsinki, Finland, 66 Department of Clinical Genetics, Erasmus MC, Rotterdam, The Netherlands, 67 Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Turku, Finland, 68 Clinical Physiology, University of Turku and Turku University Hospital, Turku, Finland, 69 Institute of Medical Informatics, Biometry and Epidemiology, Chair of Epidemiology, Ludwig-Maximilians-Universita¨t, Munich, Germany, 70 Klinikum Grosshadern, Munich, Germany, 71 Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, United Kingdom, 72 Oxford NIHR Biomedical Research Centre, Churchill Hospital, Oxford, United Kingdom Abstract 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 4.7961029. 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. Citation: Surakka I, Isaacs A, Karssen LC, Laurila P-PP, Middelberg RPS, et al. (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): e1002333. doi:10.1371/journal.pgen.1002333 Editor: Greg Gibson, Georgia Institute of Technology, United States of America Received June 23, 2011; Accepted August 23, 2011; Published October 20, 2011 Copyright: 2011 Surakka et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: This research was supported through funds from The European Community’s Seventh Framework Programme (FP7/2007–2013), ENGAGE Consortium, grant agreement HEALTH-F4-2007-201413. SR was supported by the Academy of Finland Center of Excellence in Complex Disease Genetics (213506 and 129680), Academy of Finland (251217), the Finnish foundation for Cardiovascular Research, and the Sigrid Juselius Foundation. The ATFS cohort was funded by the Australian National Health and Medical Research Council (241944, 339462, 389927, 389875, 389891, 389892, 389938, 442915, 442981, 496739, 552485, 552498), the Australian Research Council (A7960034, A79906588, A79801419, DP0770096, DP0212016, DP0343921), the EU 5th Framework Programme GenomEUtwin Project (QLG2-CT-2002-01254), and the U.S. National Institutes of Health (AA07535, AA10248, AA11998, AA13320, AA13321, AA13326, AA14041, AA17688, DA12854, MH66206). RPSM and GWM are supported by National Health and Medical Research Council (NHMRC) Fellowship Schemes. Special Population Research Network (EUROSPAN) was supported b’ European Commission FP6 STRP grant number 018947 (LSHG-CT-2006-01947). In South Tyrol, the MICROS Study was supported by the Ministry of Health of the Autonomous Province of Bolzano and the South Tyrolean Sparkasse Foundation. The Vis Study in the Croatian island of Vis was supported through the grants from the Medical research Council UK to HC and IR and from the Ministry of Science, Education, and Sport of the Republic of Croatia to IR (number 108-1080315-0302). Erasmus Ruchpen Family (ERF) was supported by grants from The Netherlands Organization for Scientific Research (NOW; Pionier Grant), Erasmus MC, and the Netherlands Genomics Initiative (NGI)–sponsored Center for Medical Systems Biology (CMSB). The Northern Swedish Population Health Study (NSPHS) was funded by the Swedish Medical Research Council (Project Number K2007-66X-20270-01-3) and the Foundation for Strategic Research (SSF). The KORA research platform was initiated and financed by the Helmholtz Center Munich, German Research Center for Environmental Health, which is funded by the German Federal Ministry of Education and Research (BMBF) and by the State of Bavaria. Part of this work was financed by the German National Genome Research Network (NGFN-2 and NGFNPlus: 01GS0823) and by the ‘‘Genomics of Lipid-associated Disorders - GOLD’’ of the ‘‘Austrian Genome Research Programme GEN-AU.’’ The KORA research was supported within the Munich Center of Health Sciences (MC Health) as part of LMUinnovativ. The Northern Finland Birth Cohort 1966 received financial support from the Academy of Finland (project grants 104781, 120315, 129269 (SALVE), 114194, and Center of Excellence in Complex Disease Genetics), University Hospital Oulu, Biocenter, University of Oulu, Finland, NHLBI grant 5R01HL087679 through the STAMPEED program (1RL1MH083268-01), ENGAGE project and grant agreement HEALTH-F4-2007-201413, the Medical Research Council (grant G0500539, centre grant G0600705, PrevMetSyn), and the Wellcome Trust (project grant GR069224), UK. The genotyping of NFBC1966 was funded by NHLBI grant 5R01HL087679, the Academy of Finland, and Biocentrum Helsinki. Helsinki Birth Cohort Study has been supported by grants from Academy of Finland (project numbers 114382, 126775, 127437, 129255, 129306, 130326, 209072, 210595, 213225, 216374), Finnish Diabetes Research Society, Samfundet Folkha¨lsan, Juho Vainio Foundation, Novo Nordisk Foundation, Finska La¨karesa¨llskapet, Pa¨ivikki and Sakari Sohlberg Foundation, Signe and Ane Gyllenberg Foundation, and Yrjo¨ Jahnsson Foundation. The Young Finns Study has been financially supported by the Academy of Finland (grants 126925, 121584, and 124282), Finnish Cultural Foundation, Emil Aaltonen Foundation, the Social Institution of Finland, Kuopio, Tampere (grants for TL and MK) and Turku University Hospital Medical Funds, Juho Vainio Foundation, Paavo Nurmi Foundation, Finnish Foundation of Cardiovascular Research (TL and OTR). The GenomEUtwin project is supported by the European Commission under the programme ‘Quality of Life and Management of the Living Resources’ of 5th Framework Programme (no. QLG2-CT-2002-01254). JK has been supported by the Academy of Finland Centre of Excellence in Complex Disease Genetics. The Swedish Twin Cohort has been financially supported by the Swedish Research Council and Swedish Foundation for Strategic Research. The Danish Twin Registry has been supported by the Danish Medical Research Council, the Danish Diabetes Foundation, the Danish Heart Association, and the Novo Nordic Foundation. The TWINSUK study was funded by the Wellcome Trust (Grant ref. 079771); European Community’s Seventh Framework Programme (FP7/2007-2013)/grant agreement HEALTH-F2-2008-ENGAGE and Framework 6 Project EUroClot. The study also receives support from the National Institute for Health Research (NIHR) comprehensive Biomedical Research Centre award to Guy’s and St Thomas’ NHS Foundation Trust in partnership with King’s College London. NS acknowledges financial support from the Wellcome Trust (Grant 091746/Z/10/Z). NTR, NTR2, and NLDTWIN funding was obtained from the Netherlands Organization for Scientific Research (NWO: MagW/ZonMW): Genetic basis of anxiety and depression (904-61-090); Genetics of individual differences in smoking initiation and persistence (NWO 985-10-002); Resolving cause and effect in the association between exercise and well-being (904-61-193); Twin family database for behavior genomics studies (480-04-004); Twin research focusing on behavior (400-05- 717); Genetic determinants of risk behavior in relation to alcohol use and alcohol use disorder (Addiction-31160008); Genotype/phenotype database for behavior genetic and genetic epidemiological studies (911-09-032); Spinozapremie (SPI 56-464-14192); CMSB: Center for Medical Systems Biology (NWO Genomics); NBIC/ BioAssist/RK/2008.024); BBMRI –NL: Biobanking and Biomolecular Resources Research Infrastructure; the VU University: Institute for Health and Care Research (EMGO+) and Neuroscience Campus Amsterdam (NCA); the European Science Foundation (ESF): Genomewide analyses of European twin and population cohorts (EU/QLRT-2001-01254); European Community’s Seventh Framework Program (FP7/2007-2013): ENGAGE (HEALTH-F4-2007-201413); the European Science Council PLoS Genetics | www.plosgenetics.org 2 October 2011 | Volume 7 | Issue 10 | e1002333