A Genome-Wide Screen for Interactions Reveals a New Locus on 4p15 Modifying the Effect of Waist-to-Hip Ratio on Total Cholesterol

I Surakka; Aaron Isaacs; Lennart Karssen; PPP Laurila; RPS Middelberg; E Tikkanen; JS Ried; C Lamina; M Mangino; W Igl; JJ (Jouke Jan) Hottenga; V Lagou; P van der Harst; IM Leach; T Esko; Z Kutalik; NW Wainwright; Maksim Struchalin; AP Sarin; AJ Kangas; JS Viikari; M Perola; T Rantanen; AK Petersen; P Soininen; A Johansson; N Soranzo; AC Heath; T Papamarkou; I Prokopenko; A Tonjes; F Kronenberg; A Doring; Fernando Rivadeneira; GW Montgomery; JB Whitfield; M Kahonen; T Lehtimaki; NB Freimer; G Willemsen; EJC de Geus; A Palotie; MS Sandhu; DM Waterworth; A Metspalu; M Stumvoll; André Uitterlinden; A Jula; G Navis; C Wijmenga; BHR Wolffenbuttel; MR Taskinen; M Ala-Korpela; J Kaprio; KO Kyvik; DI Boomsma; NL Pedersen; U Gyllensten; JF Wilson; I Rudan; H Campbell; PP Pramstaller; TD Spector; JCM Witteman; JG Eriksson; V Salomaa; Ben Oostra; OT Raitakari; HE Wichmann; C Gieger; MR Jarvelin; NG Martin; Bert Hofman; MI McCarthy; L Peltonen; Cornelia Duijn; YS Aulchenko; S Ripatti

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

I Surakka, Aaron Isaacs, Lennart Karssen, PPP Laurila, RPS Middelberg, E Tikkanen, JS Ried, C Lamina, M Mangino, W Igl, JJ (Jouke Jan) Hottenga, V Lagou, P van der Harst, IM Leach, T Esko, Z Kutalik, NW Wainwright, Maksim Struchalin, AP Sarin, AJ KangasJS Viikari, M Perola, T Rantanen, AK Petersen, P Soininen, A Johansson, N Soranzo, AC Heath, T Papamarkou, I Prokopenko, A Tonjes, F Kronenberg, A Doring, Fernando Rivadeneira, GW Montgomery, JB Whitfield, M Kahonen, T Lehtimaki, NB Freimer, G Willemsen, EJC de Geus, A Palotie, MS Sandhu, DM Waterworth, A Metspalu, M Stumvoll, André Uitterlinden, A Jula, G Navis, C Wijmenga, BHR Wolffenbuttel, MR Taskinen, M Ala-Korpela, J Kaprio, KO Kyvik, DI Boomsma, NL Pedersen, U Gyllensten, JF Wilson, I Rudan, H Campbell, PP Pramstaller, TD Spector, JCM Witteman, JG Eriksson, V Salomaa, Ben Oostra, OT Raitakari, HE Wichmann, C Gieger, MR Jarvelin, NG Martin, Bert Hofman, MI McCarthy, L Peltonen, Cornelia Duijn, YS Aulchenko, S Ripatti

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

26 Citations (Scopus)

9 Downloads (Pure)

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.

Original language	Undefined/Unknown
Journal	PLoS Genetics (print)
Volume	7
Issue number	10
DOIs	https://doi.org/10.1371/journal.pgen.1002333
Publication status	Published - 2011

Research programs

EMC MGC-02-96-01
EMC MM-01-25-01
EMC MM-01-39-09-A
EMC NIHES-01-64-01
EMC NIHES-01-64-02

Access to Document

10.1371/journal.pgen.1002333

fulltext.pdfFinal published version, 342 KB

http://hdl.handle.net/1765/34445

Cite this

Surakka, I., Isaacs, A., Karssen, L., Laurila, PPP., Middelberg, RPS., Tikkanen, E., Ried, JS., Lamina, C., Mangino, M., Igl, W., Hottenga, JJ., Lagou, V., van der Harst, P., Leach, IM., Esko, T., Kutalik, Z., Wainwright, NW., Struchalin, M., Sarin, AP., ... Ripatti, S. (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 (print), 7(10). https://doi.org/10.1371/journal.pgen.1002333

@article{3b13d908886546698d22826fa2065580,

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 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.",

author = "I Surakka and Aaron Isaacs and Lennart Karssen and PPP Laurila and RPS Middelberg and E Tikkanen and JS Ried and C Lamina and M Mangino and W Igl and Hottenga, {JJ (Jouke Jan)} and V Lagou and {van der Harst}, P and IM Leach and T Esko and Z Kutalik and NW Wainwright and Maksim Struchalin and AP Sarin and AJ Kangas and JS Viikari and M Perola and T Rantanen and AK Petersen and P Soininen and A Johansson and N Soranzo and AC Heath and T Papamarkou and I Prokopenko and A Tonjes and F Kronenberg and A Doring and Fernando Rivadeneira and GW Montgomery and JB Whitfield and M Kahonen and T Lehtimaki and NB Freimer and G Willemsen and {de Geus}, EJC and A Palotie and MS Sandhu and DM Waterworth and A Metspalu and M Stumvoll and Andr{\'e} Uitterlinden and A Jula and G Navis and C Wijmenga and BHR Wolffenbuttel and MR Taskinen and M Ala-Korpela and J Kaprio and KO Kyvik and DI Boomsma and NL Pedersen and U Gyllensten and JF Wilson and I Rudan and H Campbell and PP Pramstaller and TD Spector and JCM Witteman and JG Eriksson and V Salomaa and Ben Oostra and OT Raitakari and HE Wichmann and C Gieger and MR Jarvelin and NG Martin and Bert Hofman and MI McCarthy and L Peltonen and Cornelia Duijn and YS Aulchenko and S Ripatti",

year = "2011",

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

language = "Undefined/Unknown",

volume = "7",

journal = "PLoS Genetics (print)",

issn = "1553-7390",

publisher = "Public Library of Science",

number = "10",

}

Surakka, I, Isaacs, A, Karssen, L, Laurila, PPP, Middelberg, RPS, Tikkanen, E, Ried, JS, Lamina, C, Mangino, M, Igl, W, Hottenga, JJ, Lagou, V, van der Harst, P, Leach, IM, Esko, T, Kutalik, Z, Wainwright, NW, Struchalin, M, Sarin, AP, Kangas, AJ, Viikari, JS, Perola, M, Rantanen, T, Petersen, AK, Soininen, P, Johansson, A, Soranzo, N, Heath, AC, Papamarkou, T, Prokopenko, I, Tonjes, A, Kronenberg, F, Doring, A, Rivadeneira, F, Montgomery, GW, Whitfield, JB, Kahonen, M, Lehtimaki, T, Freimer, NB, Willemsen, G, de Geus, EJC, Palotie, A, Sandhu, MS, Waterworth, DM, Metspalu, A, Stumvoll, M, Uitterlinden, A, Jula, A, Navis, G, Wijmenga, C, Wolffenbuttel, BHR, Taskinen, MR, Ala-Korpela, M, Kaprio, J, Kyvik, KO, Boomsma, DI, Pedersen, NL, Gyllensten, U, Wilson, JF, Rudan, I, Campbell, H, Pramstaller, PP, Spector, TD, Witteman, JCM, Eriksson, JG, Salomaa, V, Oostra, B, Raitakari, OT, Wichmann, HE, Gieger, C, Jarvelin, MR, Martin, NG, Hofman, B, McCarthy, MI, Peltonen, L, Duijn, C, Aulchenko, YS & Ripatti, S 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 (print), vol. 7, no. 10. 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, I

AU - Isaacs, Aaron

AU - Karssen, Lennart

AU - Laurila, PPP

AU - Middelberg, RPS

AU - Tikkanen, E

AU - Ried, JS

AU - Lamina, C

AU - Mangino, M

AU - Igl, W

AU - Hottenga, JJ (Jouke Jan)

AU - Lagou, V

AU - van der Harst, P

AU - Leach, IM

AU - Esko, T

AU - Kutalik, Z

AU - Wainwright, NW

AU - Struchalin, Maksim

AU - Sarin, AP

AU - Kangas, AJ

AU - Viikari, JS

AU - Perola, M

AU - Rantanen, T

AU - Petersen, AK

AU - Soininen, P

AU - Johansson, A

AU - Soranzo, N

AU - Heath, AC

AU - Papamarkou, T

AU - Prokopenko, I

AU - Tonjes, A

AU - Kronenberg, F

AU - Doring, A

AU - Rivadeneira, Fernando

AU - Montgomery, GW

AU - Whitfield, JB

AU - Kahonen, M

AU - Lehtimaki, T

AU - Freimer, NB

AU - Willemsen, G

AU - de Geus, EJC

AU - Palotie, A

AU - Sandhu, MS

AU - Waterworth, DM

AU - Metspalu, A

AU - Stumvoll, M

AU - Uitterlinden, André

AU - Jula, A

AU - Navis, G

AU - Wijmenga, C

AU - Wolffenbuttel, BHR

AU - Taskinen, MR

AU - Ala-Korpela, M

AU - Kaprio, J

AU - Kyvik, KO

AU - Boomsma, DI

AU - Pedersen, NL

AU - Gyllensten, U

AU - Wilson, JF

AU - Rudan, I

AU - Campbell, H

AU - Pramstaller, PP

AU - Spector, TD

AU - Witteman, JCM

AU - Eriksson, JG

AU - Salomaa, V

AU - Oostra, Ben

AU - Raitakari, OT

AU - Wichmann, HE

AU - Gieger, C

AU - Jarvelin, MR

AU - Martin, NG

AU - Hofman, Bert

AU - McCarthy, MI

AU - Peltonen, L

AU - Duijn, Cornelia

AU - Aulchenko, YS

AU - Ripatti, S

PY - 2011

Y1 - 2011

N2 - 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.

AB - 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.

U2 - 10.1371/journal.pgen.1002333

DO - 10.1371/journal.pgen.1002333

M3 - Article

C2 - 22028671

SN - 1553-7390

VL - 7

JO - PLoS Genetics (print)

JF - PLoS Genetics (print)

IS - 10

ER -