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

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, heig...

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Main Authors: Peruchet-Noray, Laia (Author) , Sedlmeier, Anja M. (Author) , Dimou, Niki (Author) , Baurecht, Hansjörg (Author) , Fervers, Béatrice (Author) , Fontvieille, Emma (Author) , Konzok, Julian (Author) , Tsilidis, Kostas K. (Author) , Christakoudi, Sofia (Author) , Jansana, Anna (Author) , Cordova, Reynalda (Author) , Bohmann, Patricia (Author) , Stein, Michael J. (Author) , Weber, Andrea (Author) , Bézieau, Stéphane (Author) , Brenner, Hermann (Author) , Chan, Andrew T. (Author) , Cheng, Iona (Author) , Figueiredo, Jane C. (Author) , Garcia-Etxebarria, Koldo (Author) , Moreno, Victor (Author) , Newton, Christina C. (Author) , Schmit, Stephanie L. (Author) , Song, Mingyang (Author) , Ulrich, Cornelia (Author) , Ferrari, Pietro (Author) , Viallon, Vivian (Author) , Carreras-Torres, Robert (Author) , Gunter, Marc J.R. (Author) , Freisling, Heinz (Author)
Format: Article (Journal)
Language:English
Published: Apr 2024
In: Science advances
Year: 2024, Volume: 10, Issue: 16, Pages: 1-15
ISSN:2375-2548
DOI:10.1126/sciadv.adj1987
Online Access:Verlag, kostenfrei, Volltext: https://doi.org/10.1126/sciadv.adj1987
Verlag, kostenfrei, Volltext: https://www.science.org/doi/10.1126/sciadv.adj1987
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Author Notes: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

MARC

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520 |a 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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