A genome-wide screen for interactions reveals a new locus on 4p15 modifying the effect of waist-to-hip ratio on total cholesterol

Ida Surakka; Aaron Isaacs; Lennart C Karssen; Pirkka-Pekka P Laurila; Rita P S Middelberg; Emmi Tikkanen; Janina S Ried; Claudia Lamina; Massimo Mangino; Wilmar Igl; Jouke-Jan Hottenga; Vasiliki Lagou; Pim van der Harst; Irene Mateo Leach; Tõnu Esko; Zoltán Kutalik; Nicholas W Wainwright; Maksim V Struchalin; Antti-Pekka Sarin; Antti J Kangas; Jorma S Viikari; Markus Perola; Taina Rantanen; Ann-Kristin Petersen; Pasi Soininen; Asa Johansson; Nicole Soranzo; Andrew C Heath; Theodore Papamarkou; Inga Prokopenko; Anke Tönjes; Florian Kronenberg; Angela Döring; Fernando Rivadeneira; Grant W Montgomery; John B Whitfield; Mika Kähönen; Terho Lehtimäki; Nelson B Freimer; Gonneke Willemsen; Eco J C de Geus; Aarno Palotie; Manj S Sandhu; Dawn M Waterworth; Andres Metspalu; Michael Stumvoll; André G Uitterlinden; Antti Jula; Gerjan Navis; Bruce H R Wolffenbuttel; ENGAGE Consortium

doi:10.1371/journal.pgen.1002333

A genome-wide screen for interactions reveals a new locus on 4p15 modifying the effect of waist-to-hip ratio on total cholesterol

Ida Surakka^*, Aaron Isaacs, Lennart C Karssen, Pirkka-Pekka P Laurila, Rita P S Middelberg, Emmi Tikkanen, Janina S Ried, Claudia Lamina, Massimo Mangino, Wilmar Igl, Jouke-Jan Hottenga, Vasiliki Lagou, Pim van der Harst, Irene Mateo Leach, Tõnu Esko, Zoltán Kutalik, Nicholas W Wainwright, Maksim V Struchalin, Antti-Pekka Sarin, Antti J KangasJorma S Viikari, Markus Perola, Taina Rantanen, Ann-Kristin Petersen, Pasi Soininen, Asa Johansson, Nicole Soranzo, Andrew C Heath, Theodore Papamarkou, Inga Prokopenko, Anke Tönjes, Florian Kronenberg, Angela Döring, Fernando Rivadeneira, Grant W Montgomery, John B Whitfield, Mika Kähönen, Terho Lehtimäki, Nelson B Freimer, Gonneke Willemsen, Eco J C de Geus, Aarno Palotie, Manj S Sandhu, Dawn M Waterworth, Andres Metspalu, Michael Stumvoll, André G Uitterlinden, Antti Jula, Gerjan Navis, Bruce H R Wolffenbuttel, ENGAGE Consortium

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

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.

Original language	English
Pages (from-to)	e1002333
Journal	Plos Genetics
Volume	7
Issue number	10
DOIs	https://doi.org/10.1371/journal.pgen.1002333
Publication status	Published - Oct 2011
Externally published	Yes

Keywords

Adipose Tissue/metabolism
Body Fat Distribution
Cadherins/genetics
Cholesterol/blood
Chromosome Mapping
Chromosomes, Human, Pair 4/genetics
European Continental Ancestry Group/genetics
Genome-Wide Association Study
Genotype
Humans
Lipids/blood
Lipoproteins/blood
Phenotype
Polymorphism, Single Nucleotide
Quantitative Trait Loci/genetics
Risk Factors
Triglycerides/blood
Waist-Hip Ratio

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10.1371/journal.pgen.1002333Licence: CC BY

Cite this

Surakka, I., Isaacs, A., Karssen, L. C., Laurila, P.-P. P., Middelberg, R. P. S., Tikkanen, E., Ried, J. S., Lamina, C., Mangino, M., Igl, W., Hottenga, J.-J., Lagou, V., van der Harst, P., Mateo Leach, I., Esko, T., Kutalik, Z., Wainwright, N. W., Struchalin, M. V., Sarin, A.-P., ... 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 Genetics, 7(10), e1002333. https://doi.org/10.1371/journal.pgen.1002333

@article{4d6fe9e7612249fb9daa65362061fe7e,

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.",

keywords = "Adipose Tissue/metabolism, Body Fat Distribution, Cadherins/genetics, Cholesterol/blood, Chromosome Mapping, Chromosomes, Human, Pair 4/genetics, European Continental Ancestry Group/genetics, Genome-Wide Association Study, Genotype, Humans, Lipids/blood, Lipoproteins/blood, Phenotype, Polymorphism, Single Nucleotide, Quantitative Trait Loci/genetics, Risk Factors, Triglycerides/blood, Waist-Hip Ratio",

author = "Ida Surakka and Aaron Isaacs and Karssen, {Lennart C} and Laurila, {Pirkka-Pekka P} and Middelberg, {Rita P S} and Emmi Tikkanen and Ried, {Janina S} and Claudia Lamina and Massimo Mangino and Wilmar Igl and Jouke-Jan Hottenga and Vasiliki Lagou and {van der Harst}, Pim and {Mateo Leach}, Irene and T{\~o}nu Esko and Zolt{\'a}n Kutalik and Wainwright, {Nicholas W} and Struchalin, {Maksim V} and Antti-Pekka Sarin and Kangas, {Antti J} and Viikari, {Jorma S} and Markus Perola and Taina Rantanen and Ann-Kristin Petersen and Pasi Soininen and Asa Johansson and Nicole Soranzo and Heath, {Andrew C} and Theodore Papamarkou and Inga Prokopenko and Anke T{\"o}njes and Florian Kronenberg and Angela D{\"o}ring and Fernando Rivadeneira and Montgomery, {Grant W} and Whitfield, {John B} and Mika K{\"a}h{\"o}nen and Terho Lehtim{\"a}ki and Freimer, {Nelson B} and Gonneke Willemsen and {de Geus}, {Eco J C} and Aarno Palotie and Sandhu, {Manj S} and Waterworth, {Dawn M} and Andres Metspalu and Michael Stumvoll and Uitterlinden, {Andr{\'e} G} and Antti Jula and Gerjan Navis and Wolffenbuttel, {Bruce H R} and {ENGAGE Consortium}",

year = "2011",

month = oct,

doi = "10.1371/journal.pgen.1002333",

language = "English",

volume = "7",

pages = "e1002333",

journal = "Plos Genetics",

issn = "1553-7390",

publisher = "Public Library of Science",

number = "10",

}

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, Wolffenbuttel, BHR & 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 Genetics, vol. 7, no. 10, pp. e1002333. https://doi.org/10.1371/journal.pgen.1002333

TY - JOUR

T1 - A genome-wide screen for interactions reveals a new locus on 4p15 modifying the effect of waist-to-hip ratio on total cholesterol

AU - Surakka, Ida

AU - Isaacs, Aaron

AU - Karssen, Lennart C

AU - Laurila, Pirkka-Pekka P

AU - Middelberg, Rita P S

AU - Tikkanen, Emmi

AU - Ried, Janina S

AU - Lamina, Claudia

AU - Mangino, Massimo

AU - Igl, Wilmar

AU - Hottenga, Jouke-Jan

AU - Lagou, Vasiliki

AU - van der Harst, Pim

AU - Mateo Leach, Irene

AU - Esko, Tõnu

AU - Kutalik, Zoltán

AU - Wainwright, Nicholas W

AU - Struchalin, Maksim V

AU - Sarin, Antti-Pekka

AU - Kangas, Antti J

AU - Viikari, Jorma S

AU - Perola, Markus

AU - Rantanen, Taina

AU - Petersen, Ann-Kristin

AU - Soininen, Pasi

AU - Johansson, Asa

AU - Soranzo, Nicole

AU - Heath, Andrew C

AU - Papamarkou, Theodore

AU - Prokopenko, Inga

AU - Tönjes, Anke

AU - Kronenberg, Florian

AU - Döring, Angela

AU - Rivadeneira, Fernando

AU - Montgomery, Grant W

AU - Whitfield, John B

AU - Kähönen, Mika

AU - Lehtimäki, Terho

AU - Freimer, Nelson B

AU - Willemsen, Gonneke

AU - de Geus, Eco J C

AU - Palotie, Aarno

AU - Sandhu, Manj S

AU - Waterworth, Dawn M

AU - Metspalu, Andres

AU - Stumvoll, Michael

AU - Uitterlinden, André G

AU - Jula, Antti

AU - Navis, Gerjan

AU - Wolffenbuttel, Bruce H R

AU - ENGAGE Consortium

PY - 2011/10

Y1 - 2011/10

N2 - 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.

AB - 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.

KW - Adipose Tissue/metabolism

KW - Body Fat Distribution

KW - Cadherins/genetics

KW - Cholesterol/blood

KW - Chromosome Mapping

KW - Chromosomes, Human, Pair 4/genetics

KW - European Continental Ancestry Group/genetics

KW - Genome-Wide Association Study

KW - Genotype

KW - Humans

KW - Lipids/blood

KW - Lipoproteins/blood

KW - Phenotype

KW - Polymorphism, Single Nucleotide

KW - Quantitative Trait Loci/genetics

KW - Risk Factors

KW - Triglycerides/blood

KW - Waist-Hip Ratio

U2 - 10.1371/journal.pgen.1002333

DO - 10.1371/journal.pgen.1002333

M3 - Article

C2 - 22028671

SN - 1553-7390

VL - 7

SP - e1002333

JO - Plos Genetics

JF - Plos Genetics

IS - 10

ER -