Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2024 Apr 19;10(16):eadj1987.
doi: 10.1126/sciadv.adj1987. Epub 2024 Apr 19.

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

Laia Peruchet-Noray  1   2 , Anja M Sedlmeier  3   4   5 , Niki Dimou  1 , Hansjörg Baurecht  5 , Béatrice Fervers  6 , Emma Fontvieille  1 , Julian Konzok  5 , Kostas K Tsilidis  7   8 , Sofia Christakoudi  7   9 , Anna Jansana  1 , Reynalda Cordova  1   10 , Patricia Bohmann  5 , Michael J Stein  5 , Andrea Weber  5 , Stéphane Bézieau  11 , Hermann Brenner  12   13   14 , Andrew T Chan  15 , Iona Cheng  16 , Jane C Figueiredo  17 , Koldo Garcia-Etxebarria  18   19 , Victor Moreno  2   20   21   22 , Christina C Newton  23 , Stephanie L Schmit  24   25 , Mingyang Song  15   26 , Cornelia M Ulrich  27 , Pietro Ferrari  1 , Vivian Viallon  1 , Robert Carreras-Torres  28 , Marc J Gunter  1   7 , Heinz Freisling  1
Affiliations

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

Laia Peruchet-Noray et al. Sci Adv. .

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.

PubMed Disclaimer

Figures

Fig. 1.
Fig. 1.. Flowchart summarizing study methods.
Body shape phenotypes have been derived by a PCA on six anthropometric traits (BMI, weight, height, WHR, WC, and HC). PC1 showed high and same sign loadings for all traits except height. PC2 showed high but opposite loadings for height and WHR. PC3 was characterized by high and same direction loadings for height and WHR. PC4 showed high loadings for weight and BMI and low loadings for HC and WC. QC, quality control.
Fig. 2.
Fig. 2.. Observational (dark blue) and MR (light blue) estimates of associations between body shape phenotype PC1, PC2, PC3, and PC4, per 1 standard deviation increments, and the risk of CRC (overall, among men, among women, and CRC subsites).
CI, confidence interval; CRC, colorectal cancer; PC, principal component. For observational and MR analyses, cancer cases were 3728 and 52,775 for overall CRC, 2239 and 28,207 among men, 1489 and 24,568 among women, 2443 and 27,817 colon, 1285 and 13,713 rectal, 966 and 14,016 distal colon, and 1370 and 12,360 proximal colon subsites, respectively.
Fig. 3.
Fig. 3.. Manhattan plots showing the genetic associations of the four body shapes.
Fig. 4.
Fig. 4.. Genetic architecture and tissue expression profile analyses of the four body shape phenotypes (PC1 to PC4).
Genetic architecture (A) and tissue expression profile (B). Tissues reaching a P value of <1.67 × 10−3, after Bonferroni correction, are highlighted in darker colors. MAF, minor allele frequency.
Fig. 5.
Fig. 5.. Associations between body shape phenotype (PC1 to PC4) grouped gene sets and the risk of overall CRC.
OR, odds ratio.
Fig. 6.
Fig. 6.. Directed acyclic graph depicting the assumed causal relationship between body shape phenotypes and CRC risk with its confounding and mediating paths.
See this image and copyright information in PMC

References

    1. Sung H., Ferlay J., Siegel R. L., Laversanne M., Soerjomataram I., Jemal A., Bray F., Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin. 71, 209–249 (2021). - PubMed
    1. Ferlay J., Colombet M., Soerjomataram I., Parkin D. M., Piñeros M., Znaor A., Bray F., Cancer statistics for the year 2020: An overview. Int. J. Cancer 149, 778–789 (2021). - PubMed
    1. World Cancer Research Fund/American Institute for Cancer Research. Continuous Update Project Expert Report, Diet, nutrition, physical activity and colorectal cancer (2018).
    1. Freisling H., Arnold M., Soerjomataram I., O’Doherty M. G., Ordóñez-Mena J. M., Bamia C., Kampman E., Leitzmann M., Romieu I., Kee F., Tsilidis K., Tjønneland A., Trichopoulou A., Boffetta P., Benetou V., Bueno-De-Mesquita H. B., Huerta J. M., Brenner H., Wilsgaard T., Jenab M., Comparison of general obesity and measures of body fat distribution in older adults in relation to cancer risk: Meta-analysis of individual participant data of seven prospective cohorts in Europe. Br. J. Cancer 116, 1486–1497 (2017). - PMC - PubMed
    1. Ried J. S., Jeff J. M., Chu A. Y., Bragg-Gresham J. L., van Dongen J., Huffman J. E., Ahluwalia T. S., Cadby G., Eklund N., Eriksson J., Esko T., Feitosa M. F., Goel A., Gorski M., Hayward C., Heard-Costa N. L., Jackson A. U., Jokinen E., Kanoni S., Kristiansson K., Kutalik Z., Lahti J., Luan J., Mägi R., Mahajan A., Mangino M., Medina-Gomez C., Monda K. L., Nolte I. M., Pérusse L., Prokopenko I., Qi L., Rose L. M., Salvi E., Smith M. T., Snieder H., Stančáková A., Sung Y. J., Tachmazidou I., Teumer A., Thorleifsson G., van der Harst P., Walker R. W., Wang S. R., Wild S. H., Willems S. M., Wong A., Zhang W., Albrecht E., Alves A. C., Bakker S. J. L., Barlassina C., Bartz T. M., Beilby J., Bellis C., Bergman R. N., Bergmann S., Blangero J., Blüher M., Boerwinkle E., Bonnycastle L. L., Bornstein S. R., Bruinenberg M., Campbell H., Chen Y.-D. I., Chiang C. W. K., Chines P. S., Collins F. S., Cucca F., Cupples L. A., D'Avila F., de Geus E. J. C., Dedoussis G., Dimitriou M., Döring A., Eriksson J. G., Farmaki A.-E., Farrall M., Ferreira T., Fischer K., Forouhi N. G., Friedrich N., Gjesing A. P., Glorioso N., Graff M., Grallert H., Grarup N., Gräßler J., Grewal J., Hamsten A., Harder M. N., Hartman C. A., Hassinen M., Hastie N., Hattersley A. T., Havulinna A. S., Heliövaara M., Hillege H., Hofman A., Holmen O., Homuth G., Hottenga J.-J., Hui J., Husemoen L. L., Hysi P. G., Isaacs A., Ittermann T., Jalilzadeh S., James A. L., Jørgensen T., Jousilahti P., Jula A., Justesen J. M., Justice A. E., Kähönen M., Karaleftheri M., Khaw K. T., Keinanen-Kiukaanniemi S. M., Kinnunen L., Knekt P. B., Koistinen H. A., Kolcic I., Kooner I. K., Koskinen S., Kovacs P., Kyriakou T., Laitinen T., Langenberg C., Lewin A. M., Lichtner P., Lindgren C. M., Lindström J., Linneberg A., Lorbeer R., Lorentzon M., Luben R., Lyssenko V., Männistö S., Manunta P., Leach I. M., Ardle W. L. M., Mcknight B., Mohlke K. L., Mihailov E., Milani L., Mills R., Montasser M. E., Morris A. P., Müller G., Musk A. W., Narisu N., Ong K. K., Oostra B. A., Osmond C., Palotie A., Pankow J. S., Paternoster L., Penninx B. W., Pichler I., Pilia M. G., Polašek O., Pramstaller P. P., Raitakari O. T., Rankinen T., Rao D. C., Rayner N. W., Ribel-Madsen R., Rice T. K., Richards M., Ridker P. M., Rivadeneira F., Ryan K. A., Sanna S., Sarzynski M. A., Scholtens S., Scott R. A., Sebert S., Southam L., Sparsø T. H., Steinthorsdottir V., Stirrups K., Stolk R. P., Strauch K., Stringham H. M., Swertz M. A., Swift A. J., Tönjes A., Tsafantakis E., van der Most P. J., Van Vliet-Ostaptchouk J. V., Vandenput L., Vartiainen E., Venturini C., Verweij N., Viikari J. S., Vitart V., Vohl M.-C., Vonk J. M., Waeber G., Widén E., Willemsen G., Wilsgaard T., Winkler T. W., Wright A. F., Yerges-Armstrong L. M., Zhao J. H., Zillikens M. C., Boomsma D. I., Bouchard C., Chambers J. C., Chasman D. I., Cusi D., Gansevoort R. T., Gieger C., Hansen T., Hicks A. A., Hu F., Hveem K., Jarvelin M.-R., Kajantie E., Kooner J. S., Kuh D., Kuusisto J., Laakso M., Lakka T. A., Lehtimäki T., Metspalu A., Njølstad I., Ohlsson C., Oldehinkel A. J., Palmer L. J., Pedersen O., Perola M., Peters A., Psaty B. M., Puolijoki H., Rauramaa R., Rudan I., Salomaa V., Schwarz P. E. H., Shudiner A. R., Smit J. H., Sørensen T. I. A., Spector T. D., Stefansson K., Stumvoll M., Tremblay A., Tuomilehto J., Uitterlinden A. G., Uusitupa M., Völker U., Vollenweider P., Wareham N. J., Watkins H., Wilson J. F., Zeggini E., Abecasis G. R., Boehnke M., Borecki I. B., Deloukas P., van Duijn C. M., Fox C., Groop L. C., Heid I. M., Hunter D. J., Kaplan R. C., Carthy M. I. M., North K. E., O'Connell J. R., Schlessinger D., Thorsteinsdottir U., Strachan D. P., Frayling T., Hirschhorn J. N., Müller-Nurasyid M., Loos R. J. F., A principal component meta-analysis on multiple anthropometric traits identifies novel loci for body shape. Nat. Commun. 7, 13357 (2016). - PMC - PubMed

Publication types