Tissue-specific genetic variation suggests distinct molecular pathways between body shape phenotypes and colorectal cancer

Laia Peruchet-Noray; Anja M. Sedlmeier; Niki Dimou; Hansjörg Baurecht; Béatrice Fervers; Emma Fontvieille; Julian Konzok; Kostas K. Tsilidis; Sofia Christakoudi; Anna Jansana; Reynalda Cordova; Patricia Bohmann; Michael J. Stein; Andrea Weber; Stéphane Bézieau; Hermann Brenner; Andrew T. Chan; Iona Cheng; Jane C. Figueiredo; Koldo Garcia-Etxebarria; Victor Moreno; Christina C. Newton; Stephanie L. Schmit; Mingyang Song; Cornelia M. Ulrich; Pietro Ferrari; Vivian Viallon; Robert Carreras-Torres; Marc J. Gunter; Heinz Freisling

doi:10.1126/sciadv.adj1987

Tissue-specific genetic variation suggests distinct molecular pathways between body shape phenotypes and colorectal cancer

Laia Peruchet-Noray, Anja M. Sedlmeier, Niki Dimou, Hansjörg Baurecht, Béatrice Fervers, Emma Fontvieille, Julian Konzok, Kostas K. Tsilidis, Sofia Christakoudi, Anna Jansana, Reynalda Cordova, Patricia Bohmann, Michael J. Stein, Andrea Weber, Stéphane Bézieau, Hermann Brenner, Andrew T. Chan, Iona Cheng, Jane C. Figueiredo, Koldo Garcia-EtxebarriaVictor Moreno, Christina C. Newton, Stephanie L. Schmit, Mingyang Song, Cornelia M. Ulrich, Pietro Ferrari, Vivian Viallon, Robert Carreras-Torres, Marc J. Gunter, Heinz Freisling

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

4 Scopus citations

Abstract

It remains unknown whether adiposity subtypes are differentially associated with colorectal cancer (CRC). To move beyond single-trait anthropometric indicators, we derived four multi-trait body shape phenotypes reflecting adiposity subtypes from principal components analysis on body mass index, height, weight, waist-to-hip ratio, and waist and hip circumference. A generally obese (PC1) and a tall, centrally obese (PC3) body shape were both positively associated with CRC risk in observational analyses in 329,828 UK Biobank participants (3728 cases). In genome-wide association studies in 460,198 UK Biobank participants, we identified 3414 genetic variants across four body shapes and Mendelian randomization analyses confirmed positive associations of PC1 and PC3 with CRC risk (52,775 cases/45,940 controls from GECCO/CORECT/CCFR). Brain tissue–specific genetic instruments, mapped to PC1 through enrichment analysis, were responsible for the relationship between PC1 and CRC, while the relationship between PC3 and CRC was predominantly driven by adipose tissue–specific genetic instruments. This study suggests distinct putative causal pathways between adiposity subtypes and CRC.

Original language	English
Article number	eadj1987
Journal	Science advances
Volume	10
Issue number	16
DOIs	https://doi.org/10.1126/sciadv.adj1987
State	Published - Apr 2024
Externally published	Yes

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Peruchet-Noray, L., Sedlmeier, A. M., Dimou, N., Baurecht, H., Fervers, B., Fontvieille, E., Konzok, J., Tsilidis, K. K., Christakoudi, S., Jansana, A., Cordova, R., Bohmann, P., Stein, M. J., Weber, A., Bézieau, S., Brenner, H., Chan, A. T., Cheng, I., Figueiredo, J. C., ... Freisling, H. (2024). Tissue-specific genetic variation suggests distinct molecular pathways between body shape phenotypes and colorectal cancer. Science advances, 10(16), Article eadj1987. https://doi.org/10.1126/sciadv.adj1987

@article{4a02fc34e0064336ad58adda7764a732,

title = "Tissue-specific genetic variation suggests distinct molecular pathways between body shape phenotypes and colorectal cancer",

abstract = "It remains unknown whether adiposity subtypes are differentially associated with colorectal cancer (CRC). To move beyond single-trait anthropometric indicators, we derived four multi-trait body shape phenotypes reflecting adiposity subtypes from principal components analysis on body mass index, height, weight, waist-to-hip ratio, and waist and hip circumference. A generally obese (PC1) and a tall, centrally obese (PC3) body shape were both positively associated with CRC risk in observational analyses in 329,828 UK Biobank participants (3728 cases). In genome-wide association studies in 460,198 UK Biobank participants, we identified 3414 genetic variants across four body shapes and Mendelian randomization analyses confirmed positive associations of PC1 and PC3 with CRC risk (52,775 cases/45,940 controls from GECCO/CORECT/CCFR). Brain tissue–specific genetic instruments, mapped to PC1 through enrichment analysis, were responsible for the relationship between PC1 and CRC, while the relationship between PC3 and CRC was predominantly driven by adipose tissue–specific genetic instruments. This study suggests distinct putative causal pathways between adiposity subtypes and CRC.",

author = "Laia Peruchet-Noray and Sedlmeier, {Anja M.} and Niki Dimou and Hansj{\"o}rg Baurecht and B{\'e}atrice Fervers and Emma Fontvieille and Julian Konzok and Tsilidis, {Kostas K.} and Sofia Christakoudi and Anna Jansana and Reynalda Cordova and Patricia Bohmann and Stein, {Michael J.} and Andrea Weber and St{\'e}phane B{\'e}zieau and Hermann Brenner and Chan, {Andrew T.} and Iona Cheng and Figueiredo, {Jane C.} and Koldo Garcia-Etxebarria and Victor Moreno and Newton, {Christina C.} and Schmit, {Stephanie L.} and Mingyang Song and Ulrich, {Cornelia M.} and Pietro Ferrari and Vivian Viallon and Robert Carreras-Torres and Gunter, {Marc J.} and Heinz Freisling",

note = "Publisher Copyright: Copyright {\textcopyright} 2024 The Authors, some rights reserved.",

year = "2024",

month = apr,

doi = "10.1126/sciadv.adj1987",

language = "English",

volume = "10",

journal = "Science advances",

issn = "2375-2548",

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Peruchet-Noray, L, Sedlmeier, AM, Dimou, N, Baurecht, H, Fervers, B, Fontvieille, E, Konzok, J, Tsilidis, KK, Christakoudi, S, Jansana, A, Cordova, R, Bohmann, P, Stein, MJ, Weber, A, Bézieau, S, Brenner, H, Chan, AT, Cheng, I, Figueiredo, JC, Garcia-Etxebarria, K, Moreno, V, Newton, CC, Schmit, SL, Song, M, Ulrich, CM, Ferrari, P, Viallon, V, Carreras-Torres, R, Gunter, MJ & Freisling, H 2024, 'Tissue-specific genetic variation suggests distinct molecular pathways between body shape phenotypes and colorectal cancer', Science advances, vol. 10, no. 16, eadj1987. https://doi.org/10.1126/sciadv.adj1987

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AU - Peruchet-Noray, Laia

AU - Sedlmeier, Anja M.

AU - Dimou, Niki

AU - Baurecht, Hansjörg

AU - Fervers, Béatrice

AU - Fontvieille, Emma

AU - Konzok, Julian

AU - Tsilidis, Kostas K.

AU - Christakoudi, Sofia

AU - Jansana, Anna

AU - Cordova, Reynalda

AU - Bohmann, Patricia

AU - Stein, Michael J.

AU - Weber, Andrea

AU - Bézieau, Stéphane

AU - Brenner, Hermann

AU - Chan, Andrew T.

AU - Cheng, Iona

AU - Figueiredo, Jane C.

AU - Garcia-Etxebarria, Koldo

AU - Moreno, Victor

AU - Newton, Christina C.

AU - Schmit, Stephanie L.

AU - Song, Mingyang

AU - Ulrich, Cornelia M.

AU - Ferrari, Pietro

AU - Viallon, Vivian

AU - Carreras-Torres, Robert

AU - Gunter, Marc J.

AU - Freisling, Heinz

PY - 2024/4

Y1 - 2024/4

N2 - It remains unknown whether adiposity subtypes are differentially associated with colorectal cancer (CRC). To move beyond single-trait anthropometric indicators, we derived four multi-trait body shape phenotypes reflecting adiposity subtypes from principal components analysis on body mass index, height, weight, waist-to-hip ratio, and waist and hip circumference. A generally obese (PC1) and a tall, centrally obese (PC3) body shape were both positively associated with CRC risk in observational analyses in 329,828 UK Biobank participants (3728 cases). In genome-wide association studies in 460,198 UK Biobank participants, we identified 3414 genetic variants across four body shapes and Mendelian randomization analyses confirmed positive associations of PC1 and PC3 with CRC risk (52,775 cases/45,940 controls from GECCO/CORECT/CCFR). Brain tissue–specific genetic instruments, mapped to PC1 through enrichment analysis, were responsible for the relationship between PC1 and CRC, while the relationship between PC3 and CRC was predominantly driven by adipose tissue–specific genetic instruments. This study suggests distinct putative causal pathways between adiposity subtypes and CRC.

AB - It remains unknown whether adiposity subtypes are differentially associated with colorectal cancer (CRC). To move beyond single-trait anthropometric indicators, we derived four multi-trait body shape phenotypes reflecting adiposity subtypes from principal components analysis on body mass index, height, weight, waist-to-hip ratio, and waist and hip circumference. A generally obese (PC1) and a tall, centrally obese (PC3) body shape were both positively associated with CRC risk in observational analyses in 329,828 UK Biobank participants (3728 cases). In genome-wide association studies in 460,198 UK Biobank participants, we identified 3414 genetic variants across four body shapes and Mendelian randomization analyses confirmed positive associations of PC1 and PC3 with CRC risk (52,775 cases/45,940 controls from GECCO/CORECT/CCFR). Brain tissue–specific genetic instruments, mapped to PC1 through enrichment analysis, were responsible for the relationship between PC1 and CRC, while the relationship between PC3 and CRC was predominantly driven by adipose tissue–specific genetic instruments. This study suggests distinct putative causal pathways between adiposity subtypes and CRC.

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U2 - 10.1126/sciadv.adj1987

DO - 10.1126/sciadv.adj1987

M3 - Article

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SN - 2375-2548

VL - 10

JO - Science advances

JF - Science advances

IS - 16

M1 - eadj1987

ER -

Tissue-specific genetic variation suggests distinct molecular pathways between body shape phenotypes and colorectal cancer

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