Genetic Epidemiology, Translational Neurogenomics, Psychiatric Genetics and Statistical Genetics Laboratories investigate the pattern of disease in families, particularly identical and non-identical twins, to assess the relative importance of genes and environment in a variety of important health problems.
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PMID
22028671
TITLE
A genome-wide screen for interactions reveals a new locus on 4p15 modifying the effect of waist-to-hip ratio on total cholesterol.
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 4.79×10(-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.
DATE PUBLISHED
2011 Oct
HISTORY
PUBSTATUS PUBSTATUSDATE
received 2011/06/23
accepted 2011/08/23
epublish 2011/10/20
entrez 2011/10/27 06:00
pubmed 2011/10/27 06:00
medline 2012/03/01 06:00
AUTHORS
NAME COLLECTIVENAME LASTNAME FORENAME INITIALS AFFILIATION AFFILIATIONINFO
Surakka I Surakka Ida I Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland.
Isaacs A Isaacs Aaron A
Karssen LC Karssen Lennart C LC
Laurila PP Laurila Pirkka-Pekka P PP
Middelberg RP Middelberg Rita P S RP
Tikkanen E Tikkanen Emmi E
Ried JS Ried Janina S JS
Lamina C Lamina Claudia C
Mangino M Mangino Massimo M
Igl W Igl Wilmar W
Hottenga JJ Hottenga Jouke-Jan JJ
Lagou V Lagou Vasiliki V
van der Harst P van der Harst Pim P
Mateo Leach I Mateo Leach Irene I
Esko T Esko Tõnu T
Kutalik Z Kutalik Zoltán Z
Wainwright NW Wainwright Nicholas W NW
Struchalin MV Struchalin Maksim V MV
Sarin AP Sarin Antti-Pekka AP
Kangas AJ Kangas Antti J AJ
Viikari JS Viikari Jorma S JS
Perola M Perola Markus M
Rantanen T Rantanen Taina T
Petersen AK Petersen Ann-Kristin AK
Soininen P Soininen Pasi P
Johansson A Johansson Asa A
Soranzo N Soranzo Nicole N
Heath AC Heath Andrew C AC
Papamarkou T Papamarkou Theodore T
Prokopenko I Prokopenko Inga I
Tönjes A Tönjes Anke A
Kronenberg F Kronenberg Florian F
Döring A Döring Angela A
Rivadeneira F Rivadeneira Fernando F
Montgomery GW Montgomery Grant W GW
Whitfield JB Whitfield John B JB
Kähönen M Kähönen Mika M
Lehtimäki T Lehtimäki Terho T
Freimer NB Freimer Nelson B NB
Willemsen G Willemsen Gonneke G
de Geus EJ de Geus Eco J C EJ
Palotie A Palotie Aarno A
Sandhu MS Sandhu Manj S MS
Waterworth DM Waterworth Dawn M DM
Metspalu A Metspalu Andres A
Stumvoll M Stumvoll Michael M
Uitterlinden AG Uitterlinden André G AG
Jula A Jula Antti A
Navis G Navis Gerjan G
Wijmenga C Wijmenga Cisca C
Wolffenbuttel BH Wolffenbuttel Bruce H R BH
Taskinen MR Taskinen Marja-Riitta MR
Ala-Korpela M Ala-Korpela Mika M
Kaprio J Kaprio Jaakko J
Kyvik KO Kyvik Kirsten O KO
Boomsma DI Boomsma Dorret I DI
Pedersen NL Pedersen Nancy L NL
Gyllensten U Gyllensten Ulf U
Wilson JF Wilson James F JF
Rudan I Rudan Igor I
Campbell H Campbell Harry H
Pramstaller PP Pramstaller Peter P PP
Spector TD Spector Tim D TD
Witteman JC Witteman Jacqueline C M JC
Eriksson JG Eriksson Johan G JG
Salomaa V Salomaa Veikko V
Oostra BA Oostra Ben A BA
Raitakari OT Raitakari Olli T OT
Wichmann HE Wichmann H-Erich HE
Gieger C Gieger Christian C
Järvelin MR Järvelin Marjo-Riitta MR
Martin NG Martin Nicholas G NG
Hofman A Hofman Albert A
McCarthy MI McCarthy Mark I MI
Peltonen L Peltonen Leena L
van Duijn CM van Duijn Cornelia M CM
Aulchenko YS Aulchenko Yurii S YS
Ripatti S Ripatti Samuli S
ENGAGE Consortium
INVESTIGATORS
JOURNAL
VOLUME: 7
ISSUE: 10
TITLE: PLoS genetics
ISOABBREVIATION: PLoS Genet.
YEAR: 2011
MONTH: Oct
DAY:
MEDLINEDATE:
SEASON:
CITEDMEDIUM: Internet
ISSN: 1553-7404
ISSNTYPE: Electronic
MEDLINE JOURNAL
MEDLINETA: PLoS Genet
COUNTRY: United States
ISSNLINKING: 1553-7390
NLMUNIQUEID: 101239074
PUBLICATION TYPE
PUBLICATIONTYPE TEXT
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
COMMENTS AND CORRECTIONS
REFTYPE REFSOURCE REFPMID NOTE
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GRANTS
GRANTID AGENCY COUNTRY
090532 Wellcome Trust United Kingdom
1R01MH083268-01 NIMH NIH HHS United States
5R01HL087679 NHLBI NIH HHS United States
AA07535 NIAAA NIH HHS United States
AA10248 NIAAA NIH HHS United States
AA11998 NIAAA NIH HHS United States
AA13320 NIAAA NIH HHS United States
AA13321 NIAAA NIH HHS United States
AA13326 NIAAA NIH HHS United States
AA14041 NIAAA NIH HHS United States
AA17688 NIAAA NIH HHS United States
C865/A2883 Cancer Research UK United Kingdom
CZB/4/710 Chief Scientist Office United Kingdom
DA12854 NIDA NIH HHS United States
G0300128 Medical Research Council United Kingdom
G0801566 Medical Research Council United Kingdom
G9502233 Medical Research Council United Kingdom
K05 AA017688 NIAAA NIH HHS United States
MH66206 NIMH NIH HHS United States
PG/08/094/26019 British Heart Foundation United Kingdom
R01D0042157-01A PHS HHS United States
U24 MH068457-06 NIMH NIH HHS United States
g0500539 Medical Research Council United Kingdom
g600705 Medical Research Council United Kingdom
gr069224 Wellcome Trust United Kingdom
GENERAL NOTE
KEYWORDS
MESH HEADINGS
DESCRIPTORNAME QUALIFIERNAME
Adipose Tissue metabolism
Body Fat Distribution metabolism
Cadherins genetics
Cholesterol genetics
Chromosome Mapping genetics
Chromosomes, Human, Pair 4 genetics
European Continental Ancestry Group genetics
Genome-Wide Association Study genetics
Genotype genetics
Humans genetics
Lipids genetics
Lipoproteins genetics
Phenotype genetics
Polymorphism, Single Nucleotide genetics
Quantitative Trait Loci genetics
Risk Factors genetics
Triglycerides genetics
Waist-Hip Ratio genetics
SUPPLEMENTARY MESH
GENE SYMBOLS
CHEMICALS
REGISTRYNUMBER NAMEOFSUBSTANCE
0 Cadherins
0 Lipids
0 Lipoproteins
0 PCDH7 protein, human
0 Triglycerides
97C5T2UQ7J Cholesterol
OTHER ID's
OTHERID SOURCE
PMC3197672 NLM