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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, PPP; Middelberg, RPS; Tikkanen, E; ... ENGAGE Consortium,; + view all (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. 10.1371/journal.pgen.1002333. Green and gold open access

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Abstract

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.

Type:Article
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. A version is also available from UCL Discovery.
DOI:10.1371/journal.pgen.1002333
Publisher version:http://dx.doi.org/10.1371/journal.pgen.1002333
Language:English
Additional information:© 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. 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 Folkhälsan, Juho Vainio Foundation, Novo Nordisk Foundation, Finska Läkaresällskapet, Päivikki and Sakari Sohlberg Foundation, Signe and Ane Gyllenberg Foundation, and Yrjö 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 (ERC) Genetics of Mental Illness (230374); Rutgers University Cell and DNA Repository cooperative agreement (NIMH U24 MH068457-06); Collaborative study of the genetics of DZ twinning (NIH R01D0042157-01A); the Genetic Association Information Network, a public–private partnership between the NIH and Pfizer, Affymetrix, and Abbott Laboratories. The generation and management of GWAS genotype data for the Rotterdam Study is supported by the Netherlands Organisation of Scientific Research NWO Investments (nr. 175.010.2005.011, 911-03-012). This study is funded by the Research Institute for Diseases in the Elderly (014-93-015; RIDE2), the Netherlands Genomics Initiative (NGI)/Netherlands Organisation for Scientific Research (NWO) project nr. 050-060-810. The Rotterdam Study is funded by Erasmus Medical Center and Erasmus University, Rotterdam, Netherlands Organization for the Health Research and Development (ZonMw), the Research Institute for Diseases in the Elderly (RIDE), the Ministry of Education, Culture and Science, the Ministry for Health, Welfare and Sports, the European Commission (DG XII), and the Municipality of Rotterdam. The LifeLines Cohort Study, and generation and management of GWAS genotype data for the LifeLines Cohort Study is supported by the Netherlands Organization of Scientific Research NWO (grant 175.010.2007.006), the Economic Structure Enhancing Fund (FES) of the Dutch government, the Ministry of Economic Affairs, the Ministry of Education, Culture and Science, the Ministry for Health, Welfare and Sports, the Northern Netherlands Collaboration of Provinces (SNN), the Province of Groningen, University Medical Center Groningen, the University of Groningen, Dutch Kidney Foundation and Dutch Diabetes Research Foundation. PREVEND genetics is supported by the Dutch Kidney Foundation (Grant E033), the EU project grant GENECURE (FP-6 LSHM CT 2006 037697), the National Institutes of Health (grant LM010098), The Netherlands organisation for health research and development (NWO VENI grant 916.761.70), and the Dutch Inter UniversityCardiology Institute Netherlands (ICIN). EGCUT was supported by the Estonian Ministry of E&R (SF0180142s08), EU FP7 OPENGENE (#245536) and ENGAGE (201413), by EurRDF grant to the Centre of Excellence in Genomics, Estonian Biocentre and University of Tartu and by Estoinian Research Infrastructure's Roadmap. Genmets was supported through funds from The European Community's Seventh Framework Programme (FP7/2007-2013), BioSHaRE Consortium, grant agreement 261433. VS was supported by the Sigrid Juselius Foundation, Finnish Foundation for Cardiovascular research, and the Finnish Academy (grant number 129494). The CoLaus study received financial contributions from GlaxoSmithKline, the Faculty of Biology and Medicine of Lausanne, and the Swiss National Science Foundation (33CSCO-122661). EPIC–Norfolk is supported by programme grants from the Medical Research Council UK (G9502233, G0300128) and Cancer Research UK (C865/A2883). Adipose Tissue eQTL dataset has been funded by Finnish Foundation for Cardiovascular Research, Helsinki University, Sigrid Juselius Foundation Central Hospital Research Foundation. Metabonomic datasets are supported by the Academy of Finland (grant number 137870 to PS) and the Responding to Public Health Challenges Research Programme of the Academy of Finland (grant number 129429 to MA-K), the Finnish Cardiovascular Research Foundation (MA-K), and the Jenny and Antti Wihuri Foundation (AJK). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
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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