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1. Additional file 1 of Circulating bilirubin levels and risk of colorectal cancer: serological and Mendelian randomization analyses

Author

Nazlisadat Seyed Khoei, Mazda Jenab, Murphy, Neil, Banbury, Barbara L., Carreras-Torres, Robert, Viallon, Vivian, Kühn, Tilman, Bueno-De-Mesquita, Bas, Aleksandrova, Krasimira, Cross, Amanda J., Weiderpass, Elisabete, Stepien, Magdalena, Bulmer, Andrew, Tjønneland, Anne, Marie-Christine Boutron-Ruault, Severi, Gianluca, Carbonnel, Franck, Katzke, Verena, Boeing, Heiner, Bergmann, Manuela M., Trichopoulou, Antonia, Karakatsani, Anna, Martimianaki, Georgia, Palli, Domenico, Tagliabue, Giovanna, Panico, Salvatore, Tumino, Rosario, Sacerdote, Carlotta, Skeie, Guri, Merino, Susana, Bonet, Catalina, Rodríguez-Barranco, Miguel, Gil, Leire, Maria-Dolores Chirlaque, Ardanaz, Eva, Myte, Robin, Hultdin, Johan, Perez-Cornago, Aurora, Aune, Dagfinn, Tsilidis, Konstantinos K., Albanes, Demetrius, Baron, John A., Berndt, Sonja I., Bézieau, Stéphane, Brenner, Hermann, Campbell, Peter T., Casey, Graham, Chan, Andrew T., Chang-Claude, Jenny, Chanock, Stephen J., Cotterchio, Michelle, Gallinger, Steven, Gruber, Stephen B., Haile, Robert W., Hampe, Jochen, Hoffmeister, Michael, Hopper, John L., Hsu, Li, Huyghe, Jeroen R., Jenkins, Mark A., Joshi, Amit D., Kampman, Ellen, Larsson, Susanna C., Loic Le Marchand, Li, Christopher I., Li, Li, Lindblom, Annika, Noralane M. Lindor, Martín, Vicente, Moreno, Victor, Newcomb, Polly A., Offit, Kenneth, Ogino, Shuji, Parfrey, Patrick S., Pharoah, Paul D. P., Rennert, Gad, Sakoda, Lori C., Schafmayer, Clemens, Schmit, Stephanie L., Schoen, Robert E., Slattery, Martha L., Thibodeau, Stephen N., Ulrich, Cornelia M., Franzel J. B. Van Duijnhoven, Weigl, Korbinian, Weinstein, Stephanie J., White, Emily, Wolk, Alicja, Woods, Michael O., Wu, Anna H., Xuehong Zhang, Ferrari, Pietro, Anton, Gabriele, Peters, Annette, Peters, Ulrike, Gunter, Marc J., Karl-Heinz Wagner, and Freisling, Heinz

Abstract

Additional file 1 Supplementary tables 1–6, supplementary figures 1–3, supplementary text 1. Suppl. table 1 - Summary statistics for the genetic association with bilirubin levels, and sex-stratified colorectal cancer risk. Suppl. table 2 - Participating studies in the genetic consortia (GECCO/ CCFR/ and CORECT). Suppl. table 3 - Associations between unconjugated bilirubin (UCB) levels and colorectal cancer risk after different sensitivity analyses in the EPIC study. Suppl. table 4 - Results for the Mendelian randomization sensitivity analyses. Suppl. table 5 - Results for the Mendelian randomization sensitivity analyses: positive control outcomes for pancreatic cancer. Suppl. table 6 - Results for genome-wide associations of instruments with other phenotypes. Suppl. figure 1 - Cubic spline modeling of unconjugated bilirubin (UCB) levels in relation to colorectal cancer risk in the EPIC study. Suppl. figure 2 - Association between UGT1A1 polymorphism (rs6431625) and unconjugated bilirubin (UCB) levels in the EPIC study (with available GWAS data). Suppl. figure 3 - Directed acyclic graph (DAG) of the causal structure of associations between unconjugated bilirubin (UCB) levels in relation to colorectal cancer risk in the EPIC study. Suppl. text 1 - Specific funding sources and acknowledgements of participating studies.

Published
2020
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2. Narrow-sense heritability estimation of complex traits using identity-by-descent information

Author

Evans, Luke M., Tahmasbi, Rasool, Jones, Matthew, Vrieze, Scott I., Abecasis, Gonçalo R., Das, Sayantan, Bjelland, Doug W., deCandia, Teresa R., Abecasis, Gonçalo, Altshuler, David, Anderson, Carl A, Angius, Andrea, Barrett, Jeffrey C, Berndt, Sonja, Boehnke, Michael, Boomsma, Dorrett, Branham, Kari, Breen, Gerome, Brummett, Chad M, Busonero, Fabio, Campbell, Harry, Campbell, Peter, Chan, Andrew, Chen, Sai, Chew, Emily, Cocca, Massimiliano, Collins, Francis S, Corbin, Laura J, Cucca, Francesco, Danecek, Petr, de Bakker, Paul I W, Dedoussis, George, Dekker, Annelot, Delaneau, Olivier, Dorr, Marcus, Durbin, Richard, Farmaki, Aliki-Eleni, Ferrucci, Luigi, Forer, Lukas, Fraser, Ross M, Frayling, Timothy, Fuchsberger, Christian, Gabriel, Stacey, Gandin, Ilaria, Gasparini, Paolo, Gillies, Christopher E, Gilly, Arthur, Groop, Leif, Harrison, Tabitha, Hattersley, Andrew, Holmen, Oddgeir L, Hveem, Kristian, Iacono, William, Joshi, Amit, Kang, Hyun Min, Khalili, Hamed, Kooperberg, Charles, Koskinen, Seppo, Kretzler, Matthias, Kretzschmar, Warren, Kwong, Alan, Lee, James C, Levy, Shawn, Luo, Yang, Mahajan, Anubha, Marchini, Jonathan, McCarroll, Steven, McCarthy, Mark I, McCarthy, Shane, McGue, Matt, McInnis, Melvin, Meitinger, Thomas, Melzer, David, Mezzavilla, Massimo, Min, Josine L, Mohlke, Karen L, Myers, Richard M, Nauck, Matthias, Nickerson, Deborah, Palotie, Aarno, Pato, Carlos, Pato, Michele, Peters, Ulrike, Pirastu, Nicola, Rheenen, Wouter Van, Richards, J Brent, Ripatti, Samuli, Sala, Cinzia, Salomaa, Veikko, Sampson, Matthew G, Schlessinger, David, Schoen, Robert E, Schoenherr, Sebastian, Scott, Laura J, Sharp, Kevin, Sidore, Carlo, Slagboom, P Eline, Small, Kerrin, Smith, George Davey, Soranzo, Nicole, Spector, Timothy, Stambolian, Dwight, Swaroop, Anand, Swertz, Morris A, Teumer, Alexander, Timpson, Nicholas, Toniolo, Daniela, Traglia, Michela, Tuke, Marcus, Tuomilehto, Jaakko, den Berg, Leonard H Van, van Duijn, Cornelia M, Veldink, Jan, Vincent, John B, Volker, Uwe, Vrieze, Scott, Walter, Klaudia, Wijmenga, Cisca, Willer, Cristen, Wilson, James F, Wood, Andrew R, Zeggini, Eleftheria, Zhang, He, Yang, Jian, Goddard, Michael E., Visscher, Peter M., and Keller, Matthew C.

Subjects
0301 basic medicine, Genome-wide association study, Biology, Population stratification, Genetic correlation, Polymorphism, Single Nucleotide, Identity by descent, Article, 03 medical and health sciences, 0302 clinical medicine, Gene Frequency, Missing heritability problem, Genetic variation, Genetics, Chromosomes, Human, Humans, Human height, Genetics (clinical), 030304 developmental biology, 0303 health sciences, Genome, Human, Heritability, Twin study, Minor allele frequency, Phenotype, 030104 developmental biology, Haplotypes, Evolutionary biology, Trait, 030217 neurology & neurosurgery
Abstract

Heritability is a fundamental parameter in genetics. Traditional estimates based on family or twin studies can be biased due to shared environmental or non-additive genetic variance. Alternatively, those based on genotyped or imputed variants typically underestimate narrow-sense heritability contributed by rare or otherwise poorly tagged causal variants. Identical-by-descent (IBD) segments of the genome share all variants between pairs of chromosomes except new mutations that have arisen since the last common ancestor. Therefore, relating phenotypic similarity to degree of IBD sharing among classically unrelated individuals is an appealing approach to estimating the near full additive genetic variance while possibly avoiding biases that can occur when modeling close relatives. We applied an IBD-based approach (GREML-IBD) to estimate heritability in unrelated individuals using phenotypic simulation with thousands of whole-genome sequences across a range of stratification, polygenicity levels, and the minor allele frequencies of causal variants (CVs). In simulations, the IBD-based approach produced unbiased heritability estimates, even when CVs were extremely rare, although precision was low. However, population stratification and non-genetic familial environmental effects shared across generations led to strong biases in IBD-based heritability. We used data on two traits in ~120,000 people from the UK Biobank to demonstrate that, depending on the trait and possible confounding environmental effects, GREML-IBD can be applied to very large genetic datasets to infer the contribution of very rare variants lost using other methods. However, we observed apparent biases in these real data, suggesting that more work may be required to understand and mitigate factors that influence IBD-based heritability estimates.

Published
2018

3. Neuropilin-1 Amplifies Regulatory T cell Function in Human Cancer

Author

Chuckran, Christopher A., Cillo, Anthony R., Moskovitz, Jessica, Overacre-Delgoffe, Abigail E., Somasundaram, Ashwin, Kirkwood, John M., Luketich, James, Pennathur, Arjun, Lan Coffman, Modugno, Francesmary, Edwards, Robert, Schoen, Robert E., Ferris, Robert L., Bruno, Tullis C., and Vignali, Dario A. A.

Subjects
Immunology, Immunology and Allergy
Abstract

Regulatory T cells (Tregs) maintain peripheral tolerance but also contribute to cancer progression by dampening anti-tumor immunity. Knocking out neuropilin-1 (NRP1) on murine Tregs attenuates tumor growth by rendering intratumoral Tregs non-suppressive. Whereas NRP1 is constitutively expressed on all mouse Tregs, NRP1 is infrequently expressed on Tregs in the peripheral blood of healthy humans. We hypothesized that (1) NRP1 expression is upregulated in cancer patients, (2) NRP1 marks highly suppressive human Tregs, and (3) sustained Treg activation initiates NRP1 expression. NRP1+ Tregs are enriched in tumors across numerous cancer types but largely devoid in non-cancerous inflamed and healthy tissues. Intratumoral NRP1 expression negatively correlates with disease-free survival in head and neck squamous cell carcinoma (HNSCC; p = 0.03; Hazard ratio = 5.4). Intratumoral NRP1+ Tregs upregulate a suppressive module indicated by co-expression of TIGIT, CCR8, and multiple TNF receptor super family members. Correspondingly, NRP1+ Tregs potently suppress CD8+ T cell proliferation in vitro, which can be disrupted with NRP1-specific blockade. Furthermore, Treg activation in vitro drives NRP1 expression, and sustained TCR signals are required to maintain NRP1 expression. We conclude that NRP1+ Tregs are selectively enriched in human cancer and oppose anti-tumor immunity. Therefore, destabilizing intratumoral Tregs using NRP1 blockade may complement other T cell therapies such as anti-PD1 blockade.

Published
2020

4. Relationship of prediagnostic body mass index with survival after colorectal cancer: Stage-specific associations

Author

Kocarnik, Jonathan M, Chan, Andrew T, Slattery, Martha L, Potter, John D, Meyerhardt, Jeffrey, Phipps, Amanda, Nan, Hongmei, Harrison, Tabitha, Rohan, Thomas E, Qi, Lihong, Hou, Lifang, Caan, Bette, Kroenke, Candyce H, Strickler, Howard, Hayes, Richard B, Schoen, Robert E, Chong, Dawn Q, White, Emily, Berndt, Sonja I, Peters, Ulrike, and Newcomb, Polly A

Subjects
Male, Oncology and Carcinogenesis, body mass index, colorectal cancer, survival, Article, Body Mass Index, cancer stage, Risk Factors, 80 and over, Humans, Oncology & Carcinogenesis, Obesity, Nutrition, Cancer, Aged, Neoplasm Staging, Proportional Hazards Models, Aged, 80 and over, screening and diagnosis, Prevention, Middle Aged, Overweight, mortality, Colo-Rectal Cancer, 4.1 Discovery and preclinical testing of markers and technologies, Survival Rate, Detection, Good Health and Well Being, Population Surveillance, Female, Digestive Diseases, Colorectal Neoplasms
Abstract

Higher body mass index (BMI) is a well-established risk factor for colorectal cancer (CRC), but is inconsistently associated with CRC survival. In 6 prospective studies participating in the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO), 2,249 non-Hispanic white CRC cases were followed for a median 4.5 years after diagnosis, during which 777 died, 554 from CRC-related causes. Associations between prediagnosis BMI and survival (overall and CRC-specific) were evaluated using Cox regression models adjusted for age at diagnosis, sex, study and smoking status (current/former/never). The association between BMI category and CRC survival varied by cancer stage at diagnosis (I-IV) for both all-cause (p-interaction = 0.03) and CRC-specific mortality (p-interaction = 0.04). Compared to normal BMI (18.5-24.9 kg/m(2) ), overweight (BMI 25.0-29.9) was associated with increased mortality among those with Stage I disease, and decreased mortality among those with Stages II-IV disease. Similarly, obesity (BMI ≥30) was associated with increased mortality among those with Stages I-II disease, and decreased mortality among those with Stages III-IV disease. These results suggest the relationship between BMI and survival after CRC diagnosis differs by stage at diagnosis, and may emphasize the importance of adequate metabolic reserves for colorectal cancer survival in patients with late-stage disease.

Published
2016

5. Corrigendum: genome-wide association study of colorectal cancer identifies six new susceptibility loci

Author

Schumacher, Fredrick R, Schmit, Stephanie L, Jiao, Shuo, Edlund, Christopher K, Wang, Hansong, Zhang, Ben, Hsu, Li, Huang, Shu-Chen, Fischer, Christopher P, Harju, John F, Idos, Gregory E, Lejbkowicz, Flavio, Manion, Frank J, McDonnell, Kevin, McNeil, Caroline E, Melas, Marilena, Rennert, Hedy S, Shi, Wei, Thomas, Duncan C, Van Den Berg, David J, Hutter, Carolyn M, Aragaki, Aaron K, Butterbach, Katja, Caan, Bette J, Carlson, Christopher S, Chanock, Stephen J, Curtis, Keith R, Fuchs, Charles S, Gala, Manish, Giovannucci, Edward L, Gogarten, Stephanie M, Hayes, Richard B, Henderson, Brian, Hunter, David J, Jackson, Rebecca D, Kolonel, Laurence N, Kooperberg, Charles, Küry, Sébastien, LaCroix, Andrea, Laurie, Cathy C, Laurie, Cecelia A, Lemire, Mathieu, Levine, David, Ma, Jing, Makar, Karen W, Qu, Conghui, Taverna, Darin, Ulrich, Cornelia M, Wu, Kana, Kono, Suminori, West, Dee W, Berndt, Sonja I, Bezieau, Stephane, Brenner, Hermann, Campbell, Peter T, Chan, Andrew T, Chang-Claude, Jenny, Coetzee, Gerhard A, Conti, David V, Duggan, David, Figueiredo, Jane C, Fortini, Barbara K, Gallinger, Steven J, Gauderman, W James, Giles, Graham, Green, Roger, Haile, Robert, Harrison, Tabitha A, Hoffmeister, Michael, Hopper, John L, Hudson, Thomas J, Jacobs, Eric, Iwasaki, Motoki, Jee, Sun Ha, Jenkins, Mark, Jia, Wei-Hua, Joshi, Amit, Li, Li, Lindor, Noralene M, Matsuo, Keitaro, Moreno, Victor, Mukherjee, Bhramar, Newcomb, Polly A, Potter, John D, Raskin, Leon, Rennert, Gad, Rosse, Stephanie, Severi, Gianluca, Schoen, Robert E, Seminara, Daniela, Shu, Xiao-Ou, Slattery, Martha L, Tsugane, Shoichiro, White, Emily, Xiang, Yong-Bing, Zanke, Brent W, Zheng, Wei, Le Marchand, Loic, Casey, Graham, and Gruber, Stephen B

Subjects
MD Multidisciplinary, Digestive Diseases, Cancer, Colo-Rectal Cancer
Published
2015

6. Identification of a common variant with potential pleiotropic effect on risk of inflammatory bowel disease and colorectal cancer

Author

Khalili, Hamed, Gong, Jian, Brenner, Hermann, Austin, Thomas R, Hutter, Carolyn M, Baba, Yoshifumi, Baron, John A, Berndt, Sonja I, Bézieau, Stéphane, Caan, Bette, Campbell, Peter T, Chang-Claude, Jenny, Chanock, Stephen J, Chen, Constance, Hsu, Li, Jiao, Shuo, Conti, David V, Duggan, David, Fuchs, Charles S, Gala, Manish, Gallinger, Steven, Haile, Robert W, Harrison, Tabitha A, Hayes, Richard, Hazra, Aditi, Henderson, Brian, Haiman, Chris, Hoffmeister, Michael, Hopper, John L, Jenkins, Mark A, Kolonel, Laurence N, Küry, Sébastien, LaCroix, Andrea, Marchand, Loic Le, Lemire, Mathieu, Lindor, Noralane M, Ma, Jing, Manson, JoAnn E, Morikawa, Teppei, Nan, Hongmei, Ng, Kimmie, Newcomb, Polly A, Nishihara, Reiko, Potter, John D, Qu, Conghui, Schoen, Robert E, Schumacher, Fredrick R, Seminara, Daniela, Taverna, Darin, Thibodeau, Stephen, Wactawski-Wende, Jean, White, Emily, Wu, Kana, Zanke, Brent W, Casey, Graham, Hudson, Thomas J, Kraft, Peter, Peters, Ulrike, Slattery, Martha L, Ogino, Shuji, Chan, Andrew T, and GECCO and CCFR

Subjects
Risk, European Continental Ancestry Group, Oncology and Carcinogenesis, Ulcerative, Crohn's Disease, Autoimmune Disease, White People, Crohn Disease, Gene Frequency, Clinical Research, Genetics, Humans, 2.1 Biological and endogenous factors, Genetic Predisposition to Disease, Oncology & Carcinogenesis, Aetiology, Polymorphism, Cancer, Whites, Prevention, Human Genome, Inflammatory Bowel Disease, Single Nucleotide, Colitis, digestive system diseases, Colo-Rectal Cancer, GECCO and CCFR, Microsatellite Instability, Colorectal Neoplasms, Digestive Diseases, Microsatellite Repeats, Genome-Wide Association Study
Abstract

Although genome-wide association studies (GWAS) have separately identified many genetic susceptibility loci for ulcerative colitis (UC), Crohn's disease (CD) and colorectal cancer (CRC), there has been no large-scale examination for pleiotropy, or shared genetic susceptibility, for these conditions. We used logistic regression modeling to examine the associations of 181 UC and CD susceptibility variants previously identified by GWAS with risk of CRC using data from the Genetics and Epidemiology of Colorectal Cancer Consortium and the Colon Cancer Family Registry. We also examined associations of significant variants with clinical and molecular characteristics in a subset of the studies. Among 11794 CRC cases and 14190 controls, rs11676348, the susceptibility single nucleotide polymorphism (SNP) for UC, was significantly associated with reduced risk of CRC (P = 7E-05). The multivariate-adjusted odds ratio of CRC with each copy of the T allele was 0.93 (95% CI 0.89-0.96). The association of the SNP with risk of CRC differed according to mucinous histological features (P heterogeneity = 0.008). In addition, the (T) allele was associated with lower risk of tumors with Crohn's-like reaction but not tumors without such immune infiltrate (P heterogeneity = 0.02) and microsatellite instability-high (MSI-high) but not microsatellite stable or MSI-low tumors (P heterogeneity = 0.03). The minor allele (T) in SNP rs11676348, located downstream from CXCR2 that has been implicated in CRC progression, is associated with a lower risk of CRC, particularly tumors with a mucinous component, Crohn's-like reaction and MSI-high. Our findings offer the promise of risk stratification of inflammatory bowel disease patients for complications such as CRC.

Published
2015

7. Genome-wide association study of colorectal cancer identifies six new susceptibility loci

Author

Schumacher, Fredrick R, Schmit, Stephanie L, Jiao, Shuo, Edlund, Christopher K, Wang, Hansong, Zhang, Ben, Hsu, Li, Huang, Shu-Chen, Fischer, Christopher P, Harju, John F, Idos, Gregory E, Lejbkowicz, Flavio, Manion, Frank J, McDonnell, Kevin, McNeil, Caroline E, Melas, Marilena, Rennert, Hedy S, Shi, Wei, Thomas, Duncan C, Van Den Berg, David J, Hutter, Carolyn M, Aragaki, Aaron K, Butterbach, Katja, Caan, Bette J, Carlson, Christopher S, Chanock, Stephen J, Curtis, Keith R, Fuchs, Charles S, Gala, Manish, Giovannucci, Edward L, Gogarten, Stephanie M, Hayes, Richard B, Henderson, Brian, Hunter, David J, Jackson, Rebecca D, Kolonel, Laurence N, Kooperberg, Charles, Küry, Sébastien, LaCroix, Andrea, Laurie, Cathy C, Laurie, Cecelia A, Lemire, Mathieu, Levine, David, Ma, Jing, Makar, Karen W, Qu, Conghui, Taverna, Darin, Ulrich, Cornelia M, Wu, Kana, Kono, Suminori, West, Dee W, Berndt, Sonja I, Bezieau, Stéphane, Brenner, Hermann, Campbell, Peter T, Chan, Andrew T, Chang-Claude, Jenny, Coetzee, Gerhard A, Conti, David V, Duggan, David, Figueiredo, Jane C, Fortini, Barbara K, Gallinger, Steven J, Gauderman, W James, Giles, Graham, Green, Roger, Haile, Robert, Harrison, Tabitha A, Hoffmeister, Michael, Hopper, John L, Hudson, Thomas J, Jacobs, Eric, Iwasaki, Motoki, Jee, Sun Ha, Jenkins, Mark, Jia, Wei-Hua, Joshi, Amit, Li, Li, Lindor, Noralene M, Matsuo, Keitaro, Moreno, Victor, Mukherjee, Bhramar, Newcomb, Polly A, Potter, John D, Raskin, Leon, Rennert, Gad, Rosse, Stephanie, Severi, Gianluca, Schoen, Robert E, Seminara, Daniela, Shu, Xiao-Ou, Slattery, Martha L, Tsugane, Shoichiro, White, Emily, Xiang, Yong-Bing, Zanke, Brent W, and Zheng, Wei

Subjects
Prevention, Human Genome, Single Nucleotide, Colo-Rectal Cancer, Case-Control Studies, MD Multidisciplinary, Odds Ratio, Genetics, Humans, 2.1 Biological and endogenous factors, Genetic Predisposition to Disease, Polymorphism, Colorectal Neoplasms, Digestive Diseases, Genome-Wide Association Study, Cancer
Abstract

Genetic susceptibility to colorectal cancer is caused by rare pathogenic mutations and common genetic variants that contribute to familial risk. Here we report the results of a two-stage association study with 18,299 cases of colorectal cancer and 19,656 controls, with follow-up of the most statistically significant genetic loci in 4,725 cases and 9,969 controls from two Asian consortia. We describe six new susceptibility loci reaching a genome-wide threshold of P

Published
2015

8. Identification of Genetic Susceptibility Loci for Colorectal Tumors in a Genome-Wide Meta-analysis

Author

Peters, Ulrike, Jiao, Shuo, Schumacher, Fredrick R, Hutter, Carolyn M, Aragaki, Aaron K, Baron, John A, Berndt, Sonja I, Bézieau, Stéphane, Brenner, Hermann, Butterbach, Katja, Caan, Bette J, Campbell, Peter T, Carlson, Christopher S, Casey, Graham, Chan, Andrew T, Chang-Claude, Jenny, Chanock, Stephen J, Chen, Lin S, Coetzee, Gerhard A, Coetzee, Simon G, Conti, David V, Curtis, Keith R, Duggan, David, Edwards, Todd, Fuchs, Charles S, Gallinger, Steven, Giovannucci, Edward L, Gogarten, Stephanie M, Gruber, Stephen B, Haile, Robert W, Harrison, Tabitha A, Hayes, Richard B, Henderson, Brian E, Hoffmeister, Michael, Hopper, John L, Hudson, Thomas J, Hunter, David J, Jackson, Rebecca D, Jee, Sun Ha, Jenkins, Mark A, Jia, Wei-Hua, Kolonel, Laurence N, Kooperberg, Charles, Küry, Sébastien, Lacroix, Andrea Z, Laurie, Cathy C, Laurie, Cecelia A, Le Marchand, Loic, Lemire, Mathieu, Levine, David, Lindor, Noralane M, Liu, Yan, Ma, Jing, Makar, Karen W, Matsuo, Keitaro, Newcomb, Polly A, Potter, John D, Prentice, Ross L, Qu, Conghui, Rohan, Thomas, Rosse, Stephanie A, Schoen, Robert E, Seminara, Daniela, Shrubsole, Martha, Shu, Xiao-Ou, Slattery, Martha L, Taverna, Darin, Thibodeau, Stephen N, Ulrich, Cornelia M, White, Emily, Xiang, Yongbing, Zanke, Brent W, Zeng, Yi-Xin, Zhang, Ben, Zheng, Wei, Hsu, Li, and Colon Cancer Family Registry and the Genetics and Epidemiology of Colorectal Cancer Consortium

Subjects
Male, Clinical Sciences, and over, Risk Assessment, Paediatrics and Reproductive Medicine, Age Distribution, 80 and over, Genetics, Humans, Cyclin D2, 2.1 Biological and endogenous factors, Genetic Predisposition to Disease, Aetiology, Sex Distribution, Polymorphism, Aged, Cancer, Gastroenterology & Hepatology, Incidence, Prevention, Human Genome, Neurosciences, Single Nucleotide, Middle Aged, Prognosis, Colo-Rectal Cancer, DNA-Binding Proteins, Genetic Loci, Female, Laminin, Colorectal Neoplasms, T-Box Domain Proteins, Digestive Diseases, Colon Cancer Family Registry and the Genetics and Epidemiology of Colorectal Cancer Consortium, Genome-Wide Association Study
Abstract

Background & aimsHeritable factors contribute to the development of colorectal cancer. Identifying the genetic loci associated with colorectal tumor formation could elucidate the mechanisms of pathogenesis.MethodsWe conducted a genome-wide association study that included 14 studies, 12,696 cases of colorectal tumors (11,870 cancer, 826 adenoma), and 15,113 controls of European descent. The 10 most statistically significant, previously unreported findings were followed up in 6 studies; these included 3056 colorectal tumor cases (2098 cancer, 958 adenoma) and 6658 controls of European and Asian descent.ResultsBased on the combined analysis, we identified a locus that reached the conventional genome-wide significance level at less than 5.0 × 10(-8): an intergenic region on chromosome 2q32.3, close to nucleic acid binding protein 1 (most significant single nucleotide polymorphism: rs11903757; odds ratio [OR], 1.15 per risk allele; P = 3.7 × 10(-8)). We also found evidence for 3 additional loci with P values less than 5.0 × 10(-7): a locus within the laminin gamma 1 gene on chromosome 1q25.3 (rs10911251; OR, 1.10 per risk allele; P = 9.5 × 10(-8)), a locus within the cyclin D2 gene on chromosome 12p13.32 (rs3217810 per risk allele; OR, 0.84; P = 5.9 × 10(-8)), and a locus in the T-box 3 gene on chromosome 12q24.21 (rs59336; OR, 0.91 per risk allele; P = 3.7 × 10(-7)).ConclusionsIn a large genome-wide association study, we associated polymorphisms close to nucleic acid binding protein 1 (which encodes a DNA-binding protein involved in DNA repair) with colorectal tumor risk. We also provided evidence for an association between colorectal tumor risk and polymorphisms in laminin gamma 1 (this is the second gene in the laminin family to be associated with colorectal cancers), cyclin D2 (which encodes for cyclin D2), and T-box 3 (which encodes a T-box transcription factor and is a target of Wnt signaling to β-catenin). The roles of these genes and their products in cancer pathogenesis warrant further investigation.

Published
2013

9. Physical activity and risks of breast and colorectal cancer: a Mendelian randomisation analysis

Author

Papadimitriou, Nikos, Dimou, Niki, Tsilidis, Konstantinos K, Banbury, Barbara, Martin, Richard M, Lewis, Sarah J, Kazmi, Nabila, Robinson, Timothy M, Albanes, Demetrius, Aleksandrova, Krasimira, Berndt, Sonja I, Timothy Bishop, D, Brenner, Hermann, Buchanan, Daniel D, Bueno-De-Mesquita, Bas, Campbell, Peter T, Castellví-Bel, Sergi, Chan, Andrew T, Chang-Claude, Jenny, Ellingjord-Dale, Merete, Figueiredo, Jane C, Gallinger, Steven J, Giles, Graham G, Giovannucci, Edward, Gruber, Stephen B, Gsur, Andrea, Hampe, Jochen, Hampel, Heather, Harlid, Sophia, Harrison, Tabitha A, Hoffmeister, Michael, Hopper, John L, Hsu, Li, María Huerta, José, Huyghe, Jeroen R, Jenkins, Mark A, Keku, Temitope O, Kühn, Tilman, La Vecchia, Carlo, Le Marchand, Loic, Li, Christopher I, Li, Li, Lindblom, Annika, Lindor, Noralane M, Lynch, Brigid, Markowitz, Sanford D, Masala, Giovanna, May, Anne M, Milne, Roger, Monninkhof, Evelyn, Moreno, Lorena, Moreno, Victor, Newcomb, Polly A, Offit, Kenneth, Perduca, Vittorio, Pharoah, Paul DP, Platz, Elizabeth A, Potter, John D, Rennert, Gad, Riboli, Elio, Sánchez, Maria-Jose, Schmit, Stephanie L, Schoen, Robert E, Severi, Gianluca, Sieri, Sabina, Slattery, Martha L, Song, Mingyang, Tangen, Catherine M, Thibodeau, Stephen N, Travis, Ruth C, Trichopoulou, Antonia, Ulrich, Cornelia M, Van Duijnhoven, Franzel JB, Van Guelpen, Bethany, Vodicka, Pavel, White, Emily, Wolk, Alicja, Woods, Michael O, Wu, Anna H, Peters, Ulrike, Gunter, Marc J, and Murphy, Neil

Subjects
Risk Factors, Accelerometry, Odds Ratio, Humans, Breast Neoplasms, Female, Genetic Predisposition to Disease, Mendelian Randomization Analysis, Colorectal Neoplasms, Exercise, Polymorphism, Single Nucleotide, 3. Good health
Abstract

Physical activity has been associated with lower risks of breast and colorectal cancer in epidemiological studies; however, it is unknown if these associations are causal or confounded. In two-sample Mendelian randomisation analyses, using summary genetic data from the UK Biobank and GWA consortia, we found that a one standard deviation increment in average acceleration was associated with lower risks of breast cancer (odds ratio [OR]: 0.51, 95% confidence interval [CI]: 0.27 to 0.98, P-value = 0.04) and colorectal cancer (OR: 0.66, 95% CI: 0.48 to 0.90, P-value = 0.01). We found similar magnitude inverse associations for estrogen positive (ER+ve) breast cancer and for colon cancer. Our results support a potentially causal relationship between higher physical activity levels and lower risks of breast cancer and colorectal cancer. Based on these data, the promotion of physical activity is probably an effective strategy in the primary prevention of these commonly diagnosed cancers.

10. Additional file 2 of Adiposity, metabolites, and colorectal cancer risk: Mendelian randomization study

Author

Bull, Caroline J., Bell, Joshua A., Murphy, Neil, Sanderson, Eleanor, Smith, George Davey, Timpson, Nicholas J., Banbury, Barbara L., Albanes, Demetrius, Berndt, Sonja I., Bézieau, Stéphane, D. Timothy Bishop, Brenner, Hermann, Buchanan, Daniel D., Burnett-Hartman, Andrea, Casey, Graham, Castellví-Bel, Sergi, Chan, Andrew T., Chang-Claude, Jenny, Cross, Amanda J., Chapelle, Albert De La, Figueiredo, Jane C., Gallinger, Steven J., Gapstur, Susan M., Giles, Graham G., Gruber, Stephen B., Gsur, Andrea, Hampe, Jochen, Hampel, Heather, Harrison, Tabitha A., Hoffmeister, Michael, Hsu, Li, Huang, Wen-Yi, Huyghe, Jeroen R., Jenkins, Mark A., Joshu, Corinne E., Temitope O. Keku, Kühn, Tilman, Sun-Seog Kweon, Loic Le Marchand, Li, Christopher I., Li, Li, Lindblom, Annika, Martín, Vicente, May, Anne M., Milne, Roger L., Moreno, Victor, Newcomb, Polly A., Offit, Kenneth, Ogino, Shuji, Phipps, Amanda I., Platz, Elizabeth A., Potter, John D., Conghui Qu, J. Ramón Quirós, Rennert, Gad, Riboli, Elio, Sakoda, Lori C., Schafmayer, Clemens, Schoen, Robert E., Slattery, Martha L., Tangen, Catherine M., Tsilidis, Kostas K., Ulrich, Cornelia M., Fränzel J. B. Van Duijnhoven, Guelpen, Bethany Van, Visvanathan, Kala, Vodicka, Pavel, Vodickova, Ludmila, Hansong Wang, White, Emily, Wolk, Alicja, Woods, Michael O., Wu, Anna H., Campbell, Peter T., Zheng, Wei, Peters, Ulrike, Vincent, Emma E., and Gunter, Marc J.

Subjects
2. Zero hunger, nutritional and metabolic diseases
Abstract

Additional file 2: Figure S1. Scatter plot of SNP-BMI and SNP-CRC associations. Figure S2. Scatter plot of SNP-BMI and SNP-CRC associations (female specific). Figure S3. Scatter plot of SNP-BMI and SNP-CRC associations (male specific). Figure S4. Scatter plot of SNP-BMI and SNP-colon cancer associations. Figure S5. Scatter plot of SNP-BMI and SNP-proximal colon cancer associations. Figure S6. Scatter plot of SNP-BMI and SNP-distal colon cancer associations. Figure S7. Scatter plot of SNP-BMI and SNP-rectal cancer associations. Figure S8. Forest plot showing individual SNP (black) and combined MR estimates (red; Egger and IVW) for the effect of BMI on CRC. Figure S9. Forest plot showing individual SNP (black) and combined MR estimates (red; Egger and IVW) for the effect of BMI on CRC (female specific). Figure S10. Forest plot showing individual SNP (black) and combined MR estimates (red; Egger and IVW) for the effect of BMI on CRC (male specific). Figure S11. Forest plot showing individual SNP (black) and combined MR estimates (red; Egger and IVW) for the effect of BMI on colon cancer. Figure S12. Forest plot showing individual SNP (black) and combined MR estimates (red; Egger and IVW) for the effect of BMI on proximal colon cancer. Figure S13. Forest plot showing individual SNP (black) and combined MR estimates (red; Egger and IVW) for the effect of BMI on distal colon cancer. Figure S14. Forest plot showing individual SNP (black) and combined MR estimates (red; Egger and IVW) for the effect of BMI on rectal cancer. Figure S15. Leave-one-out plot showing the association between BMI and CRC, following SNP-by-SNP removal from the model. Figure S16. Leave-one-out plot showing the association between BMI and CRC (femalespecific), following SNP-by-SNP removal from the model. Figure S17. Leave-one-out plot showing the association between BMI and CRC (malespecific), following SNP-by-SNP removal from the model. Figure S18. Leave-one-out plot showing the association between BMI and colon cancer, following SNP-by-SNP removal from the model. Figure S19. Leave-one-out plot showing the association between BMI and proximal colon cancer, following SNP-by-SNP removal from the model. Figure S20. Leave-one-out plot showing the association between BMI and distal colon cancer, following SNP-by-SNP removal from the model. Figure S21. Leave-one-out plot showing the association between BMI and rectal cancer, following SNP-by-SNP removal from the model. Figure S22. Scatter plot of SNP-WHR and SNP-CRC associations. Figure S23. Scatter plot of SNP-WHR and SNP-CRC associations (female specific). Figure S24. Scatter plot of SNP-WHR and SNP-CRC associations (male specific). Figure S25. Scatter plot of SNP-WHR and SNP-colon cancer associations. Figure S26. Scatter plot of SNP-WHR and SNP-proximal colon cancer associations. Figure S27. Scatter plot of SNP-WHR and SNP-distal colon cancer associations. Figure S28. Scatter plot of SNP-WHR and SNP-rectal cancer associations. Figure S29. Forest plot showing individual SNP (black) and combined MR estimates (red; Egger and IVW) for the effect of WHR on CRC. Figure S30. Forest plot showing individual SNP (black) and combined MR estimates (red; Egger and IVW) for the effect of WHR on CRC (female specific). Figure S31. Forest plot showing individual SNP (black) and combined MR estimates (red; Egger and IVW) for the effect of WHR on CRC (male specific). Figure S32. Forest plot showing individual SNP (black) and combined MR estimates (red; Egger and IVW) for the effect of WHR on colon cancer. Figure S33. Forest plot showing individual SNP (black) and combined MR estimates (red; Egger and IVW) for the effect of WHR on proximal colon cancer. Figure S34. Forest plot showing individual SNP (black) and combined MR estimates (red; Egger and IVW) for the effect of WHR on distal colon cancer. Figure S35. Forest plot showing individual SNP (black) and combined MR estimates (red; Egger and IVW) for the effect of WHR on rectal cancer. Figure S36. Leave-one-out plot showing the association between WHR and CRC, following SNP-by-SNP removal from the model. Figure S37. Leave-one-out plot showing the association between WHR and CRC, following SNP-by-SNP removal from the model (female specific). Figure S38. Leave-one-out plot showing the association between WHR and CRC, following SNP-by-SNP removal from the model (male specific). Figure S39. Leave-one-out plot showing the association between WHR and colon cancer, following SNP-by-SNP removal from the model. Figure S40. Leave-one-out plot showing the association between WHR and proximal colon cancer, following SNP-by-SNP removal from the model. Figure S41. Leave-one-out plot showing the association between WHR and distal colon cancer, following SNP-by-SNP removal from the model. Figure S42. Leave-one-out plot showing the association between WHR and rectal cancer, following SNP-by-SNP removal from the model. Figure S43. Effects of BMI and WHR on circulating metabolite levels (NMR-detected metabolites, 1 of 5), based on two-sample MR (IVW models) in summary GWAS consortia data. Figure S44. Effects of BMI and WHR on circulating metabolite levels (NMR-detected metabolites, 2 of 5), based on two-sample MR (IVW models) in summary GWAS consortia data. Figure S45. Effects of BMI and WHR on circulating metabolite levels (NMR-detected metabolites, 3 of 5), based on two-sample MR (IVW models) in summary GWAS consortia data. Figure S46. Effects of BMI and WHR on circulating metabolite levels (NMR-detected metabolites, 4 of 5), based on two-sample MR (IVW models) in summary GWAS consortia data. Figure S47. Effects of BMI and WHR on circulating metabolite levels (NMR-detected metabolites, 5 of 5), based on two-sample MR (IVW models) in summary GWAS consortia data. Figure S48. Power curves for MR analyses, based on samples sizes for colorectal cancer in the present study (black), Thrift et al., 2015 (blue) and Jarvis et al., 2016 (purple). Upper and lower power curves describe genetic instruments explaining 5% and 0.3% of variance respectively for each study.

11. Mendelian randomisation study of age at menarche and age at menopause and the risk of colorectal cancer

Author

Neumeyer, Sonja, Banbury, Barbara L, Arndt, Volker, Berndt, Sonja I, Bezieau, Stephane, Bien, Stephanie A, Buchanan, Dan D, Butterbach, Katja, Caan, Bette J, Campbell, Peter T, Casey, Graham, Chan, Andrew T, Chanock, Stephen J, Dai, James Y, Gallinger, Steven, Giovannucci, Edward L, Giles, Graham G, Grady, William M, Hampe, Jochen, Hoffmeister, Michael, Hopper, John L, Hsu, Li, Jenkins, Mark A, Joshi, Amit, Larsson, Susanna C, Le Marchand, Loic, Lindblom, Annika, Moreno, Victor, Lemire, Mathieu, Li, Li, Lin, Yi, Offit, Kenneth, Newcomb, Polly A, Pharaoh, Paul D, Potter, John D, Qi, Lihong, Rennert, Gad, Schafmayer, Clemens, Schoen, Robert E, Slattery, Martha L, Song, Mingyang, Ulrich, Cornelia M, Win, Aung K, White, Emily, Wolk, Alicja, Woods, Michael O, Wu, Anna H, Gruber, Stephen B, Brenner, Hermann, Peters, Ulrike, and Chang-Claude, Jenny

Subjects
2. Zero hunger, Menarche, Age Factors, Mendelian Randomization Analysis, Polymorphism, Single Nucleotide, digestive system diseases, 3. Good health, Logistic Models, Case-Control Studies, Humans, Female, Genetic Predisposition to Disease, Registries, Menopause, Colorectal Neoplasms
Abstract

BACKGROUND: Substantial evidence supports an association between use of menopausal hormone therapy and decreased colorectal cancer (CRC) risk, indicating a role of exogenous sex hormones in CRC development. However, findings on endogenous oestrogen exposure and CRC are inconsistent. METHODS: We used a Mendelian randomisation approach to test for a causal effect of age at menarche and age at menopause as surrogates for endogenous oestrogen exposure on CRC risk. Weighted genetic risk scores based on 358 single-nucleotide polymorphisms associated with age at menarche and 51 single-nucleotide polymorphisms associated with age at menopause were used to estimate the association with CRC risk using logistic regression in 12,944 women diagnosed with CRC and 10,741 women without CRC from three consortia. Sensitivity analyses were conducted to address pleiotropy and possible confounding by body mass index. RESULTS: Genetic risk scores for age at menarche (odds ratio per year 0.98, 95% confidence interval: 0.95-1.02) and age at menopause (odds ratio 0.98, 95% confidence interval: 0.94-1.01) were not significantly associated with CRC risk. The sensitivity analyses yielded similar results. CONCLUSIONS: Our study does not support a causal relationship between genetic risk scores for age at menarche and age at menopause and CRC risk.

12. Salicylic Acid and Risk of Colorectal Cancer: A Two-Sample Mendelian Randomization Study

Author

Nounu, Aayah, Richmond, Rebecca C, Stewart, Isobel D, Surendran, Praveen, Wareham, Nicholas J, Butterworth, Adam, Weinstein, Stephanie J, Albanes, Demetrius, Baron, John A, Hopper, John L, Figueiredo, Jane C, Newcomb, Polly A, Lindor, Noralane M, Casey, Graham, Platz, Elizabeth A, Marchand, Loïc Le, Ulrich, Cornelia M, Li, Christopher I, Van Dujinhoven, Fränzel JB, Gsur, Andrea, Campbell, Peter T, Moreno, Víctor, Vodicka, Pavel, Vodickova, Ludmila, Amitay, Efrat, Alwers, Elizabeth, Chang-Claude, Jenny, Sakoda, Lori C, Slattery, Martha L, Schoen, Robert E, Gunter, Marc J, Castellví-Bel, Sergi, Kim, Hyeong-Rok, Kweon, Sun-Seog, Chan, Andrew T, Li, Li, Zheng, Wei, Bishop, D Timothy, Buchanan, Daniel D, Giles, Graham G, Gruber, Stephen B, Rennert, Gad, Stadler, Zsofia K, Harrison, Tabitha A, Lin, Yi, Keku, Temitope O, Woods, Michael O, Schafmayer, Clemens, Van Guelpen, Bethany, Gallinger, Steven, Hampel, Heather, Berndt, Sonja I, Pharoah, Paul DP, Lindblom, Annika, Wolk, Alicja, Wu, Anna H, White, Emily, Peters, Ulrike, Drew, David A, Scherer, Dominique, Bermejo, Justo Lorenzo, Brenner, Hermann, Hoffmeister, Michael, Williams, Ann C, and Relton, Caroline L

Subjects
Male, Aspirin, Genotyping Techniques, salicylic acid, colorectal cancer, Mendelian Randomization Analysis, Polymorphism, Single Nucleotide, 3. Good health, Diet, Risk Factors, Case-Control Studies, Mendelian randomization, Humans, Female, Colorectal Neoplasms, Genome-Wide Association Study
Abstract

Salicylic acid (SA) has observationally been shown to decrease colorectal cancer (CRC) risk. Aspirin (acetylsalicylic acid, that rapidly deacetylates to SA) is an effective primary and secondary chemopreventive agent. Through a Mendelian randomization (MR) approach, we aimed to address whether levels of SA affected CRC risk, stratifying by aspirin use. A two-sample MR analysis was performed using GWAS summary statistics of SA (INTERVAL and EPIC-Norfolk, N = 14,149) and CRC (CCFR, CORECT, GECCO and UK Biobank, 55,168 cases and 65,160 controls). The DACHS study (4410 cases and 3441 controls) was used for replication and stratification of aspirin-use. SNPs proxying SA were selected via three methods: (1) functional SNPs that influence the activity of aspirin-metabolising enzymes; (2) pathway SNPs present in enzymes' coding regions; and (3) genome-wide significant SNPs. We found no association between functional SNPs and SA levels. The pathway and genome-wide SNPs showed no association between SA and CRC risk (OR: 1.03, 95% CI: 0.84-1.27 and OR: 1.08, 95% CI: 0.86-1.34, respectively). Results remained unchanged upon aspirin use stratification. We found little evidence to suggest that an SD increase in genetically predicted SA protects against CRC risk in the general population and upon stratification by aspirin use.

13. Physical activity and risks of breast and colorectal cancer: a Mendelian randomisation analysis

Author

Papadimitriou, Nikos, Dimou, Niki, Tsilidis, Konstantinos K., Banbury, Barbara, Martin, Richard M., Lewis, Sarah J., Kazmi, Nabila, Robinson, Timothy M., Albanes, Demetrius, Aleksandrova, Krasimira, Berndt, Sonja I., Timothy Bishop, D., Brenner, Hermann, Buchanan, Daniel D., Bueno-De-Mesquita, Bas, Campbell, Peter T., Castellví-Bel, Sergi, Chan, Andrew T., Chang-Claude, Jenny, Ellingjord-Dale, Merete, Figueiredo, Jane C., Gallinger, Steven J., Giles, Graham G., Giovannucci, Edward, Gruber, Stephen B., Gsur, Andrea, Hampe, Jochen, Hampel, Heather, Harlid, Sophia, Harrison, Tabitha A., Hoffmeister, Michael, Hopper, John L., Hsu, Li, María Huerta, José, Huyghe, Jeroen R., Jenkins, Mark A., Keku, Temitope O., Kühn, Tilman, La Vecchia, Carlo, Le Marchand, Loic, Li, Christopher I., Li, Li, Lindblom, Annika, Lindor, Noralane M., Lynch, Brigid, Markowitz, Sanford D., Masala, Giovanna, May, Anne M., Milne, Roger, Monninkhof, Evelyn, Moreno, Lorena, Moreno, Victor, Newcomb, Polly A., Offit, Kenneth, Perduca, Vittorio, Pharoah, Paul D. P., Platz, Elizabeth A., Potter, John D., Rennert, Gad, Riboli, Elio, Sánchez, Maria-Jose, Schmit, Stephanie L., Schoen, Robert E., Severi, Gianluca, Sieri, Sabina, Slattery, Martha L., Song, Mingyang, Tangen, Catherine M., Thibodeau, Stephen N., Travis, Ruth C., Trichopoulou, Antonia, Ulrich, Cornelia M., Van Duijnhoven, Franzel J. B., Van Guelpen, Bethany, Vodicka, Pavel, White, Emily, Wolk, Alicja, Woods, Michael O., Wu, Anna H., Peters, Ulrike, Gunter, Marc J., and Murphy, Neil

Subjects
631/67, 631/67/1504/1885, 141, 45, 631/67/68, article, 631/67/2324, 45/23, 631/67/1347, 3. Good health
Abstract

Physical activity has been associated with lower risks of breast and colorectal cancer in epidemiological studies; however, it is unknown if these associations are causal or confounded. In two-sample Mendelian randomisation analyses, using summary genetic data from the UK Biobank and GWA consortia, we found that a one standard deviation increment in average acceleration was associated with lower risks of breast cancer (odds ratio [OR]: 0.51, 95% confidence interval [CI]: 0.27 to 0.98, P-value = 0.04) and colorectal cancer (OR: 0.66, 95% CI: 0.48 to 0.90, P-value = 0.01). We found similar magnitude inverse associations for estrogen positive (ER+ve) breast cancer and for colon cancer. Our results support a potentially causal relationship between higher physical activity levels and lower risks of breast cancer and colorectal cancer. Based on these data, the promotion of physical activity is probably an effective strategy in the primary prevention of these commonly diagnosed cancers.

14. Mendelian randomization analysis of C-reactive protein on colorectal cancer risk

Author

Wang, Xiaoliang, Dai, James Y, Albanes, Demetrius, Arndt, Volker, Berndt, Sonja I, Bézieau, Stéphane, Brenner, Hermann, Buchanan, Daniel D, Butterbach, Katja, Caan, Bette, Casey, Graham, Campbell, Peter T, Chan, Andrew T, Chen, Zhengyi, Chang-Claude, Jenny, Cotterchio, Michelle, Easton, Douglas F, Giles, Graham G, Giovannucci, Edward, Grady, William M, Hoffmeister, Michael, Hopper, John L, Hsu, Li, Jenkins, Mark A, Joshi, Amit D, Lampe, Johanna W, Larsson, Susanna C, Lejbkowicz, Flavio, Li, Li, Lindblom, Annika, Le Marchand, Loic, Martin, Vicente, Milne, Roger L, Moreno, Victor, Newcomb, Polly A, Offitt, Kenneth, Ogino, Shuji, Pharoah, Paul DP, Pinchev, Mila, Potter, John D, Rennert, Hedy S, Rennert, Gad, Saliba, Walid, Schafmayer, Clemens, Schoen, Robert E, Schrotz-King, Petra, Slattery, Martha L, Song, Mingyang, Stegmaier, Christa, Weinstein, Stephanie J, Wolk, Alicja, Woods, Michael O, Wu, Anna H, Gruber, Stephen B, Peters, Ulrike, and White, Emily

Subjects
Male, colorectal cancer, Mendelian Randomization Analysis, Middle Aged, Polymorphism, Single Nucleotide, 3. Good health, C-reactive protein, Causality, Logistic Models, Mendelian randomization, Humans, epidemiology, Female, Genetic Predisposition to Disease, Colorectal Neoplasms, Aged
Abstract

BACKGROUND: Chronic inflammation is a risk factor for colorectal cancer (CRC). Circulating C-reactive protein (CRP) is also moderately associated with CRC risk. However, observational studies are susceptible to unmeasured confounding or reverse causality. Using genetic risk variants as instrumental variables, we investigated the causal relationship between genetically elevated CRP concentration and CRC risk, using a Mendelian randomization approach. METHODS: Individual-level data from 30 480 CRC cases and 22 844 controls from 33 participating studies in three international consortia were used: the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO), the Colorectal Transdisciplinary Study (CORECT) and the Colon Cancer Family Registry (CCFR). As instrumental variables, we included 19 single nucleotide polymorphisms (SNPs) previously associated with CRP concentration. The SNP-CRC associations were estimated using a logistic regression model adjusted for age, sex, principal components and genotyping phases. An inverse-variance weighted method was applied to estimate the causal effect of CRP on CRC risk. RESULTS: Among the 19 CRP-associated SNPs, rs1260326 and rs6734238 were significantly associated with CRC risk (P = 7.5 × 10-4, and P = 0.003, respectively). A genetically predicted one-unit increase in the log-transformed CRP concentrations (mg/l) was not associated with increased risk of CRC [odds ratio (OR) = 1.04; 95% confidence interval (CI): 0.97, 1.12; P = 0.256). No evidence of association was observed in subgroup analyses stratified by other risk factors. CONCLUSIONS: In spite of adequate statistical power to detect moderate association, we found genetically elevated CRP concentration was not associated with increased risk of CRC among individuals of European ancestry. Our findings suggested that circulating CRP is unlikely to be a causal factor in CRC development.

15. Protein-altering variants associated with body mass index implicate pathways that control energy intake and expenditure in obesity

Author

Turcot, Valérie, Lu, Yingchang, Highland, Heather M, Schurmann, Claudia, Justice, Anne E, Fine, Rebecca S, Bradfield, Jonathan P, Esko, Tõnu, Giri, Ayush, Graff, Mariaelisa, Guo, Xiuqing, Hendricks, Audrey E, Karaderi, Tugce, Lempradl, Adelheid, Locke, Adam E, Mahajan, Anubha, Marouli, Eirini, Sivapalaratnam, Suthesh, Young, Kristin L, Alfred, Tamuno, Feitosa, Mary F, Masca, Nicholas GD, Manning, Alisa K, Medina-Gomez, Carolina, Mudgal, Poorva, Ng, Maggie CY, Reiner, Alex P, Vedantam, Sailaja, Willems, Sara M, Winkler, Thomas W, Abecasis, Gonçalo, Aben, Katja K, Alam, Dewan S, Alharthi, Sameer E, Allison, Matthew, Amouyel, Philippe, Asselbergs, Folkert W, Auer, Paul L, Balkau, Beverley, Bang, Lia E, Barroso, Inês, Bastarache, Lisa, Benn, Marianne, Bergmann, Sven, Bielak, Lawrence F, Blüher, Matthias, Boehnke, Michael, Boeing, Heiner, Boerwinkle, Eric, Böger, Carsten A, Bork-Jensen, Jette, Bots, Michiel L, Bottinger, Erwin P, Bowden, Donald W, Brandslund, Ivan, Breen, Gerome, Brilliant, Murray H, Broer, Linda, Brumat, Marco, Burt, Amber A, Butterworth, Adam S, Campbell, Peter T, Cappellani, Stefania, Carey, David J, Catamo, Eulalia, Caulfield, Mark J, Chambers, John C, Chasman, Daniel I, Chen, Yii-Der I, Chowdhury, Rajiv, Christensen, Cramer, Chu, Audrey Y, Cocca, Massimiliano, Collins, Francis S, Cook, James P, Corley, Janie, Corominas Galbany, Jordi, Cox, Amanda J, Crosslin, David S, Cuellar-Partida, Gabriel, D'Eustacchio, Angela, Danesh, John, Davies, Gail, Bakker, Paul IW, Groot, Mark CH, Mutsert, Renée, Deary, Ian J, Dedoussis, George, Demerath, Ellen W, Heijer, Martin, Hollander, Anneke I, Ruijter, Hester M, Dennis, Joe G, Denny, Josh C, Di Angelantonio, Emanuele, Drenos, Fotios, Du, Mengmeng, Dubé, Marie-Pierre, Dunning, Alison M, Easton, Douglas F, Edwards, Todd L, Ellinghaus, David, Ellinor, Patrick T, Elliott, Paul, Evangelou, Evangelos, Farmaki, Aliki-Eleni, Farooqi, I Sadaf, Faul, Jessica D, Fauser, Sascha, Feng, Shuang, Ferrannini, Ele, Ferrieres, Jean, Florez, Jose C, Ford, Ian, Fornage, Myriam, Franco, Oscar H, Franke, Andre, Franks, Paul W, Friedrich, Nele, Frikke-Schmidt, Ruth, Galesloot, Tessel E, Gan, Wei, Gandin, Ilaria, Gasparini, Paolo, Gibson, Jane, Giedraitis, Vilmantas, Gjesing, Anette P, Gordon-Larsen, Penny, Gorski, Mathias, Grabe, Hans-Jörgen, Grant, Struan FA, Grarup, Niels, Griffiths, Helen L, Grove, Megan L, Gudnason, Vilmundur, Gustafsson, Stefan, Haessler, Jeff, Hakonarson, Hakon, Hammerschlag, Anke R, Hansen, Torben, Harris, Kathleen Mullan, Harris, Tamara B, Hattersley, Andrew T, Have, Christian T, Hayward, Caroline, He, Liang, Heard-Costa, Nancy L, Heath, Andrew C, Heid, Iris M, Helgeland, Øyvind, Hernesniemi, Jussi, Hewitt, Alex W, Holmen, Oddgeir L, Hovingh, G Kees, Howson, Joanna MM, Hu, Yao, Huang, Paul L, Huffman, Jennifer E, Ikram, M Arfan, Ingelsson, Erik, Jackson, Anne U, Jansson, Jan-Håkan, Jarvik, Gail P, Jensen, Gorm B, Jia, Yucheng, Johansson, Stefan, Jørgensen, Marit E, Jørgensen, Torben, Jukema, J Wouter, Kahali, Bratati, Kahn, René S, Kähönen, Mika, Kamstrup, Pia R, Kanoni, Stavroula, Kaprio, Jaakko, Karaleftheri, Maria, Kardia, Sharon LR, Karpe, Fredrik, Kathiresan, Sekar, Kee, Frank, Kiemeney, Lambertus A, Kim, Eric, Kitajima, Hidetoshi, Komulainen, Pirjo, Kooner, Jaspal S, Kooperberg, Charles, Korhonen, Tellervo, Kovacs, Peter, Kuivaniemi, Helena, Kutalik, Zoltán, Kuulasmaa, Kari, Kuusisto, Johanna, Laakso, Markku, Lakka, Timo A, Lamparter, David, Lange, Ethan M, Lange, Leslie A, Langenberg, Claudia, Larson, Eric B, Lee, Nanette R, Lehtimäki, Terho, Lewis, Cora E, Li, Huaixing, Li, Jin, Li-Gao, Ruifang, Lin, Honghuang, Lin, Keng-Hung, Lin, Li-An, Lin, Xu, Lind, Lars, Lindström, Jaana, Linneberg, Allan, Liu, Ching-Ti, Liu, Dajiang J, Liu, Yongmei, Lo, Ken S, Lophatananon, Artitaya, Lotery, Andrew J, Loukola, Anu, Luan, Jian'an, Lubitz, Steven A, Lyytikäinen, Leo-Pekka, Männistö, Satu, Marenne, Gaëlle, Mazul, Angela L, McCarthy, Mark I, McKean-Cowdin, Roberta, Medland, Sarah E, Meidtner, Karina, Milani, Lili, Mistry, Vanisha, Mitchell, Paul, Mohlke, Karen L, Moilanen, Leena, Moitry, Marie, Montgomery, Grant W, Mook-Kanamori, Dennis O, Moore, Carmel, Mori, Trevor A, Morris, Andrew D, Morris, Andrew P, Müller-Nurasyid, Martina, Munroe, Patricia B, Nalls, Mike A, Narisu, Narisu, Nelson, Christopher P, Neville, Matt, Nielsen, Sune F, Nikus, Kjell, Njølstad, Pål R, Nordestgaard, Børge G, Nyholt, Dale R, O'Connel, Jeffrey R, O'Donoghue, Michelle L, Olde Loohuis, Loes M, Ophoff, Roel A, Owen, Katharine R, Packard, Chris J, Padmanabhan, Sandosh, Palmer, Colin NA, Palmer, Nicholette D, Pasterkamp, Gerard, Patel, Aniruddh P, Pattie, Alison, Pedersen, Oluf, Peissig, Peggy L, Peloso, Gina M, Pennell, Craig E, Perola, Markus, Perry, James A, Perry, John RB, Pers, Tune H, Person, Thomas N, Peters, Annette, Petersen, Eva RB, Peyser, Patricia A, Pirie, Ailith, Polasek, Ozren, Polderman, Tinca J, Puolijoki, Hannu, Raitakari, Olli T, Rasheed, Asif, Rauramaa, Rainer, Reilly, Dermot F, Renström, Frida, Rheinberger, Myriam, Ridker, Paul M, Rioux, John D, Rivas, Manuel A, Roberts, David J, Robertson, Neil R, Robino, Antonietta, Rolandsson, Olov, Rudan, Igor, Ruth, Katherine S, Saleheen, Danish, Salomaa, Veikko, Samani, Nilesh J, Sapkota, Yadav, Sattar, Naveed, Schoen, Robert E, Schreiner, Pamela J, Schulze, Matthias B, Scott, Robert A, Segura-Lepe, Marcelo P, Shah, Svati H, Sheu, Wayne H-H, Sim, Xueling, Slater, Andrew J, Small, Kerrin S, Smith, Albert V, Southam, Lorraine, Spector, Timothy D, Speliotes, Elizabeth K, Starr, John M, Stefansson, Kari, Steinthorsdottir, Valgerdur, Stirrups, Kathleen E, Strauch, Konstantin, Stringham, Heather M, Stumvoll, Michael, Sun, Liang, Surendran, Praveen, Swift, Amy J, Tada, Hayato, Tansey, Katherine E, Tardif, Jean-Claude, Taylor, Kent D, Teumer, Alexander, Thompson, Deborah J, Thorleifsson, Gudmar, Thorsteinsdottir, Unnur, Thuesen, Betina H, Tönjes, Anke, Tromp, Gerard, Trompet, Stella, Tsafantakis, Emmanouil, Tuomilehto, Jaakko, Tybjaerg-Hansen, Anne, Tyrer, Jonathan P, Uher, Rudolf, Uitterlinden, André G, Uusitupa, Matti, Laan, Sander W, Duijn, Cornelia M, Leeuwen, Nienke, Van Setten, Jessica, Vanhala, Mauno, Varbo, Anette, Varga, Tibor V, Varma, Rohit, Velez Edwards, Digna R, Vermeulen, Sita H, Veronesi, Giovanni, Vestergaard, Henrik, Vitart, Veronique, Vogt, Thomas F, Völker, Uwe, Vuckovic, Dragana, Wagenknecht, Lynne E, Walker, Mark, Wallentin, Lars, Wang, Feijie, Wang, Carol A, Wang, Shuai, Wang, Yiqin, Ware, Erin B, Wareham, Nicholas J, Warren, Helen R, Waterworth, Dawn M, Wessel, Jennifer, White, Harvey D, Willer, Cristen J, Wilson, James G, Witte, Daniel R, Wood, Andrew R, Wu, Ying, Yaghootkar, Hanieh, Yao, Jie, Yao, Pang, Yerges-Armstrong, Laura M, Young, Robin, Zeggini, Eleftheria, Zhan, Xiaowei, Zhang, Weihua, Zhao, Jing Hua, Zhao, Wei, Zhou, Wei, Zondervan, Krina T, CHD Exome+ Consortium, EPIC-CVD Consortium, ExomeBP Consortium, Global Lipids Genetic Consortium, GoT2D Genes Consortium, EPIC InterAct Consortium, INTERVAL Study, ReproGen Consortium, T2D-Genes Consortium, MAGIC Investigators, Understanding Society Scientific Group, Rotter, Jerome I, Pospisilik, John A, Rivadeneira, Fernando, Borecki, Ingrid B, Deloukas, Panos, Frayling, Timothy M, Lettre, Guillaume, North, Kari E, Lindgren, Cecilia M, Hirschhorn, Joel N, and Loos, Ruth JF

Subjects
2. Zero hunger, Adult, Male, Genetic Variation, Proteins, Syndrome, Body Mass Index, Gene Frequency, Animals, Humans, Drosophila, Female, Obesity, Energy Intake, Energy Metabolism
Abstract

Genome-wide association studies (GWAS) have identified >250 loci for body mass index (BMI), implicating pathways related to neuronal biology. Most GWAS loci represent clusters of common, noncoding variants from which pinpointing causal genes remains challenging. Here we combined data from 718,734 individuals to discover rare and low-frequency (minor allele frequency (MAF) < 5%) coding variants associated with BMI. We identified 14 coding variants in 13 genes, of which 8 variants were in genes (ZBTB7B, ACHE, RAPGEF3, RAB21, ZFHX3, ENTPD6, ZFR2 and ZNF169) newly implicated in human obesity, 2 variants were in genes (MC4R and KSR2) previously observed to be mutated in extreme obesity and 2 variants were in GIPR. The effect sizes of rare variants are ~10 times larger than those of common variants, with the largest effect observed in carriers of an MC4R mutation introducing a stop codon (p.Tyr35Ter, MAF = 0.01%), who weighed ~7 kg more than non-carriers. Pathway analyses based on the variants associated with BMI confirm enrichment of neuronal genes and provide new evidence for adipocyte and energy expenditure biology, widening the potential of genetically supported therapeutic targets in obesity.

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