Table 1 Main characteristics of the included studies in the systematic review

Abe M, 2017 [22]

Case-control

Japanese

Derivation: 558 cases and 1116 controls; Replication: 547 cases and 547 controls.

11 SNPs (6 derived from GWASs in US/Europeans, 5 identified in GWASs in East Asians)

Unweighted GRS

Derivation study: 0.6392; Replication study: 0.5695

Balavarca Y, 2019 [23]

Case-control

German

236 non-advanced adenomas, 291 advanced CRC; 487 controls

39 SNPs

Unweighted GRS; Weighted GRS using weights derived from the same study

Gender, age, FH of CRC, smoking, alcohol intake, red meat consumption, use of NSAIDs, previous colonoscopy and polyps history

0.584 (0.545–0.622)

Unweighted GRS: 0.636 (0.599–0.672);

Weighted GRS: 0.616 (0.579–0.654)

Chandler PD, 2018 [24]

Cohort

US

23,294 individuals, 329 CRC cases

5 SNPs

Unweighted GRS

Cho YA, 2019 [25]

Case-control

Korean

632 cases 1295 controls

13 SNPs

Unweighted GRS; Weighted GRS using weights derived from the same study

BMI, physical activity, diet, smoking, alcohol consumption.

de Kort S, 2019 [26]

Case-cohort

Dutch

1907 CRC cases, 2729 subcohort members

18 SNPs

Unweighted GRS

Age, BMI, pant size, CRC first degree relative, smoking, nonoccupational physical activity, intake of: alcohol, meat, vegetables, fish, sweets, added sugar, saturated fats and fiber, total energy.

Dunlop MG, 2013 [27]

Case-control

European descendents

Genotypes alone: 39,266; In combination with other factors: 11,324; External validation case-control sets: 1563 Swedish cases and 1504 controls, 702 Finnish cases and 418 controls.

10 SNPs

Unweighted GRS

FH of CRC, age, gender.

Hiraki LT, 2013 [28]

Case-control

European descendants

10,061 cases and 12,768 controls

4 SNPs

Unweighted GRS

Age, gender, center, smoking, batch effects, FH of CRC, BMI, NSAIDs use, alcohol use, dietary calcium, folate and red meat intake, sedentary status, hormone replacement therapy when possible and according to the study.

Hosono S, 2016 [29]

Case-control

Japanese

Derivation set: 558 cases and 1116 controls Replication set: 547 cases and 547 controls

6 SNPs

Unweighted GRS

Age, smoke, alcohol consumption, folate intake, BMI, FH of CRC, physical activity.

Derivation study: 0.7009; Replication study: 0.5232

Derivation study: Genetic only risk score: 0.6046; Combined (genetic + traditional): 0.7167; Replication study: Genetic only: AUC 0.6391; Combined (genetic + traditional) AUC 0.6356

Hsu L, 2015 [30]

Case-control

European descendants

Training set: 5811 cases and 6302 controls; Validation set: 866 cases and 869 controls.

27 SNPs

Unweighted GRS; Weighted GRS using weights derived from literature (results not reported)

Age, gender, FH of CRC, history of endoscopic examinations

Men 0.51 (0.48–0.53); Women 0.52 (0.50–0.55)

Men: AUC 0.59 (0.54–0.64); Women: 0.56 (0.51–0.61)

Huyghe JR, 2019 [31]

Case-control

European descendants

1439 cases and 720 controls

95 SNPs

Weighted GRS using weights derived from the same study

Ibáñez-Sanz G, 2017 [32]

Case-control

Spanish

1336 cases and 2744 controls.

21 SNPs

Unweighted GRS; Weighted GRS using weights derived from literature and from the same study (results not reported)

Alcohol consumption, BMI, physical activity, red meat and vegetables intake, NSAIDs/aspirin use, FH of CRC

Environmental risk factors and family history: 0.61 (0.59–0.64)

0.63 (0.60–0.66)

Iwasaki M, 2017 [33]

Case-control

Japanese men

675 cases and 675 controls

6 SNPs

Weighted GRS using weights derived from the same study

Age, BMI, alcohol consumption, smoking.

0.60

0.66

Significant difference in the inclusive model with a GRS compared to the non-genetic model for the IDI (0.0052; 95% CI: 0.0023–0.0081), continuous NRI (0.36; 95% CI: 0.0023–0.71), and NRI (0.26; 95% CI: 0.0039–0.43).

Jenkins MA, 2019 [34]

Case-control

North American and Australian

1181 cases and 999 controls

45 SNPs

Weighted GRS using weights derived from literature

FH of CRC

Jeon J, 2018 [35]

case-control

European descendants

Training set: 4875 cases and 5291 controls Validation set: 4873 cases and 5299 controls.

63 SNPs

Weighted GRS using weights derived from the same study

Gender, height, body mass index, education, type 2 diabetes mellitus, smoking status, alcohol consumption, NSAID/aspirin use, regular use of postmenopausal hormones, gender- and study-specific quartiles of smoking pack-years and dietary factors, total-energy, and physical activity

Men: 0.60 (0.59–0.61); Women: 0.60 (0.59–0.61)

Men: 0.63 (0.62–0.64); Women: 0.62 (0.61–0.63)

Jo J, 2012 [36]

Case-control

Korean

187 cases and 976 controls

3 SNPs in men, 5 SNPs in women

Unweighted GRS; Weighted GRS using weights derived from the same study

FH of CRC, age.

Conventional risk factors alone, men: 0.692 (0.647–0.732); Conventional risk factors alone, women: 0.603 (0.569–0.637)

Counted GRS plus traditional risk factors, men: 0.729 (0.682–0.767); Weighted GRS plus traditional risk factors, men: 0.719 (0.677–0.761); Counted GRS plus traditional risk factors, women: 0.650 (0.615–0.680); Weighted GRS plus traditional risk factors: 0.646 (0.612–0.674)

Jung KJ, 2015 [37]

Case-cohort

Korean

173 cases and 1514 controls

7 SNPs

Unweighted GRS; Weighted GRS using weights derived from the same study

TRS: age, gender, smoking status, fasting serum glucose, FH of CRC

0.73 (0.69–0.78)

0.74 (0.70–0.78)

The NRI (95% CI) for a prediction model with GRS compared to the model with TRS alone was 0.17 (− 0.05–0.37) for colorectal cancer, − 0.17 (− 0.33–0.21) for colon cancer, and 0.41 (0.10–0.68) for rectal cancer.

Jung SY, 2019 [38]

Cohort

European ancestry (women only)

6539 individuals, 472 cases developed CRC

54 SNPs

Age and % calories from saturated fatty acid

Marshall KW, 2010 [39]

Case-control

North American

Training set: 112 CRC and 120 controls. Validation set: 202 CRC and 208 controls (only individuals aged ≥50 years).

7 genes

Training set: AUC 0.80 (0.74–0.85); Validation set: AUC 0.80 (0.76–0.84)

Prizment AE, 2013 [40]

Cohort

Caucasian

8657 individuals (205 cases)

20 SNPs

Weighted GRS using weights derived from literature

Rodriguez-Broadbent H, 2017 [41]

Case-control

European descendants

9254 cases and 18,386 controls

38 SNPs related to total cholesterol circulating levels, 14 SNPs related to triglyceride circulating levels, 9 SNPs related to LDL circulating levels, 43 SNPs related to HDL circulating levels

Schmit SL, 2019 [42]

Case-control

European descendants

Discovery stage: 36,948 cases and 30,864 controls; Replication set: 12,952 cases and 48,383 controls; Generalizability in East Asians, African Americans, and Hispanics: 12,085 cases and 22,083 controls.

76 SNPs: 67 previously published SNPs and 9 novel SNPs

Weighted GRS using weights derived from the same study

Shi Z, 2019 [43]

Case-control

Caucasian

387 cases and 13,427 controls

30 SNPs

Weighted GRS using weights derived from literature

Population-standardization

Smith T, 2018 [44]

Cohort

UK

Taylor model: 361,543 (1623 cases); Wells model: 286,877 (1294 cases)

41 SNPs

Weighted GRS using weights derived from literature

Taylor model: age-specific CRC rates and estimated RR for different degrees of FH of CRC. Wells model: age, diabetes, multi-vitamin usage, FH of CRC, education, BMI, alcohol use, physical activity, NSAIDs use, red meat intake, smoking and estrogen use (women only).

Taylor model: 0.67 (0.65–0.68); Wells model: 0.68 (0.67–69)

Taylor model:0.69 (0.67–0.70); Wells model: 0.69 (0.65–0.68)

Thrift AP, 2015 [45]

Case-control

European descendants

10,226 cases and 10,286 controls

696 SNPs

Weighted GRS using weights derived from literature

Thrift AP, 2015 [46]

Case-control

European descendants

10,226 cases and 10,286 controls

77 SNPs for BMI; 47 SNPs for waist-hip ratio (WHR)

Weighted GRS using weights derived from literature

Wang HM, 2013 [47]

Case-control

Taiwanese

218 cases and 385 controls

16 SNPs in the short model; 26 SNPs in the full model

16-SNPs model: 0.724; 26-SNPs model: 0.734

Wang K, 2018 [48]

Cohort

Chinese

64 CRC cases (172 digestive cancer cases, 9636 controls)

9 SNPs

AFP level: 0.523 (0.456–0.591); CA19–9 level:0.524 (0.451–0.597); CEA level: 0.568 (0.492–0.645); AFP, CA19–9, CEA level: 0.509 (0.439–0.579)

AFP level -genetic corrected: 0.524 (0.458–0.591); CA19–genetic corrected CA19–9 level: 0.525 (0.452–0.597); CEA level-genetic corrected 0.572 (0.495–0.649); AFP, CA19–9, CEA level-genetic: 0.564 (0.487–0.641)

Weigl K, 2018 [49]

Case-control

German

Genotype: 294 advanced neoplasms, 249 non-advanced adenomas, 500 controls Replication: 462 controls, 140 advanced adenomas, 355 non-advanced adenomas

48 SNPs (replication analyses within the TCPS with a subset of 35 SNPs of the original GRS)

Unweighted GRS; Weighted GRS using weights derived from literature (results not reported)

Gender, age, previous colonoscopy, physical activity, BMI

Model adjusted for age and gender: 0.599; Model adjusted for age, gender, previous colonoscopy, physical activity: 0.607; Model adjusted for age, gender, previous colonoscopy, physical activity, BMI: 0.615

Model adjusted for age and gender: 0.653; Model adjusted for age, gender, previous colonoscopy, physical activity: 0.658; Model adjusted for age, gender, previous colonoscopy, physical activity, BMI: 0.665

The NRI and IDI of model including Genetic Risk Score were respectively of 0.29 (0.14–0.43) and 0.04 (0.03–0.05) when the model was adjusted for age and gender; 0.30 (0.15–0.44) and 0.04 (0.03–0.05) when adjusted for age, gender, previous colonoscopy, physical activity and 0.29 (0.14–0.43) and 0.04 (0.03–0.05) when the model was adjusted for age, gender, previous colonoscopy, physical activity, BMI.

Weigl K, 2018 [50]

Case-control

German

2363 cases and 2198 controls.

44 SNPs

Unweighted GRS; Weighted GRS using weights derived from literature (results not reported)

Gender, age, education, previous colonoscopy, smoking, hormone replacement therapy (women only), BMI, FH of CRC

Xin J, 2018 [51]

Case-control

Chinese

1316 cases and 2229 controls

14 SNPs

Unweighted GRS; Weighted GRS using weights derived from literature and from the same study

Smoking status

The highest quartile respect to the lower quartile showed an OR (95%CI) of: 2.70 (2.06–3.54) in the simple count GRS model, 2.74 (2.19–3.43) in the directed logistic regression GRS model, 2.56 (2.05–3.20) in the odds ratio weighted GRS model, 2.90 (2.32–3.63) in the explained variance weighted GRS model, 2.51 (2.01–3.14) in the explained variance weighted OR GRS model.

Model were compared among each other respect to NRI (95%CI; p-value) and IDI (95%CI; p-value): the simple-count-GRS vs. logistic regression weighted OR-GRS showed an NRI of − 0.082 (− 0.159, − 0.007; p value: 0.033) and an IDI of − 0.002 (− 0.004, − 2.33E− 04; 0.028); the simple-count-GRS vs. explained variance weighted OR-GRS showed an NRI of 0.017 (− 0.055, 0.090; 0.638) and an IDI of 2.80E− 04 (− 0.001, 0.001; 0.567); logistic regression weighted-GRS vs. explained variance weighted OR-GRS showed an NRI − 0.077 (− 0.153, − 0.001; 0.046) and an IDI of − 5.54E− 04 (− 0.001, − 3.17E− 05; 0.038). In addition, a model including only smoking factors was with a model including smoking factors and simple count GRS (SC-GRS), with an increased AUC, NRI and IDI in combined model of 0.084, 0.317 (0.225, 0.408) and 0.031 (0.023, 0.039)

Xin J, 2019 [52]

Case-control

Chinese

Chinese studies: 2248 cases and 3173 controls; GECCO study: 4461 cases and 4140 controls

Chinese studies: 19 SNPs vs. 58 SNPs; GECCO study: 19 SNPs vs. 75 SNPs

Weighted GRS using weights derived from the same study

Gender, age, first principal component

Chinese studies: 19 SNPs model of 0.597 (0.581–0.613), 58 SNPs model of 0.623 (0.604–0.642); GECCO study: 19 SNPs model of 0.575 (0.563–0.587), 58 SNPs model of 0.585 (0.573–0.597)

Yeh CC, 2007 [53]

Case-control

Taiwanese

727 cases and 736 controls

10 SNPs

Age, education, physical activity, coffee consumption, cigarette consumption, alcohol use, staple consumption, meat, vegetable/fruit and fish/shrimp intake.

Zhang L, 2017 [54]

Case-control

Chinese

369 cases and 929 controls

4 SNPs

Age, BMI, physical activity, emotion status, mental stress, cholesterol, drinking and smoking, vegetables and seafood consumption