scholarly journals Novel Common Genetic Susceptibility Loci for Colorectal Cancer

2018 ◽  
Vol 111 (2) ◽  
pp. 146-157 ◽  
Author(s):  
Stephanie L Schmit ◽  
Christopher K Edlund ◽  
Fredrick R Schumacher ◽  
Jian Gong ◽  
Tabitha A Harrison ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Relative Risk ◽  
Risk Score ◽  
European Ancestry ◽  
Polygenic Risk Score ◽  
Susceptibility Loci ◽  
Polygenic Risk ◽  
Control Subjects ◽  
Genome Wide ◽  
Familial Relative Risk

Abstract Background Previous genome-wide association studies (GWAS) have identified 42 loci (P < 5 × 10−8) associated with risk of colorectal cancer (CRC). Expanded consortium efforts facilitating the discovery of additional susceptibility loci may capture unexplained familial risk. Methods We conducted a GWAS in European descent CRC cases and control subjects using a discovery–replication design, followed by examination of novel findings in a multiethnic sample (cumulative n = 163 315). In the discovery stage (36 948 case subjects/30 864 control subjects), we identified genetic variants with a minor allele frequency of 1% or greater associated with risk of CRC using logistic regression followed by a fixed-effects inverse variance weighted meta-analysis. All novel independent variants reaching genome-wide statistical significance (two-sided P < 5 × 10−8) were tested for replication in separate European ancestry samples (12 952 case subjects/48 383 control subjects). Next, we examined the generalizability of discovered variants in East Asians, African Americans, and Hispanics (12 085 case subjects/22 083 control subjects). Finally, we examined the contributions of novel risk variants to familial relative risk and examined the prediction capabilities of a polygenic risk score. All statistical tests were two-sided. Results The discovery GWAS identified 11 variants associated with CRC at P < 5 × 10−8, of which nine (at 4q22.2/5p15.33/5p13.1/6p21.31/6p12.1/10q11.23/12q24.21/16q24.1/20q13.13) independently replicated at a P value of less than .05. Multiethnic follow-up supported the generalizability of discovery findings. These results demonstrated a 14.7% increase in familial relative risk explained by common risk alleles from 10.3% (95% confidence interval [CI] = 7.9% to 13.7%; known variants) to 11.9% (95% CI = 9.2% to 15.5%; known and novel variants). A polygenic risk score identified 4.3% of the population at an odds ratio for developing CRC of at least 2.0. Conclusions This study provides insight into the architecture of common genetic variation contributing to CRC etiology and improves risk prediction for individualized screening.

Abstract 881: Benchmarking genome-wide polygenic risk score development techniques in colorectal cancer risk prediction

2021 ◽  
Author(s):  
Minta Thomas ◽  
Lori C Sakoda ◽  
Jeffrey K Lee ◽  
Mark A Jenkins ◽  
Andrea Burnett-Hartman ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cancer Risk ◽  
Risk Prediction ◽  
Risk Score ◽  
Colorectal Cancer Risk ◽  
Polygenic Risk Score ◽  
Polygenic Risk ◽  
Genome Wide

Abstract PO-163: Genome-wide polygenic risk score of prostate cancer in African and European ancestry men

2022 ◽  
Author(s):  
Burcu F. Darst ◽  
Ravi K Madduri ◽  
Alexis A. Rodriguez ◽  
Xin Sheng ◽  
Rosalind A. Eeles ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Risk Score ◽  
European Ancestry ◽  
Polygenic Risk Score ◽  
Polygenic Risk ◽  
Genome Wide

Genome-wide polygenic risk score for retinopathy of type 2 diabetes

2021 ◽  
Author(s):  
Iain S Forrest ◽  
Kumardeep Chaudhary ◽  
Ishan Paranjpe ◽  
Ha My T Vy ◽  
Carla Marquez-Luna ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Risk Score ◽  
Large Scale ◽  
European Ancestry ◽  
Polygenic Risk Score ◽  
Standard Deviation Increase ◽  
Polygenic Risk ◽  
Genome Wide ◽  
A Genome

Abstract Diabetic retinopathy (DR) is a common consequence in type 2 diabetes (T2D) and a leading cause of blindness in working-age adults. Yet, its genetic predisposition is largely unknown. Here, we examined the polygenic architecture underlying DR by deriving and assessing a genome-wide polygenic risk score (PRS) for DR. We evaluated the PRS in 6079 individuals with T2D of European, Hispanic, African and other ancestries from a large-scale multi-ethnic biobank. Main outcomes were PRS association with DR diagnosis, symptoms and complications, and time to diagnosis, and transferability to non-European ancestries. We observed that PRS was significantly associated with DR. A standard deviation increase in PRS was accompanied by an adjusted odds ratio (OR) of 1.12 [95% confidence interval (CI) 1.04–1.20; P = 0.001] for DR diagnosis. When stratified by ancestry, PRS was associated with the highest OR in European ancestry (OR = 1.22, 95% CI 1.02–1.41; P = 0.049), followed by African (OR = 1.15, 95% CI 1.03–1.28; P = 0.028) and Hispanic ancestries (OR = 1.10, 95% CI 1.00–1.10; P = 0.050). Individuals in the top PRS decile had a 1.8-fold elevated risk for DR versus the bottom decile (P = 0.002). Among individuals without DR diagnosis, the top PRS decile had more DR symptoms than the bottom decile (P = 0.008). The PRS was associated with retinal hemorrhage (OR = 1.44, 95% CI 1.03–2.02; P = 0.03) and earlier DR presentation (10% probability of DR by 4 years in the top PRS decile versus 8 years in the bottom decile). These results establish the significant polygenic underpinnings of DR and indicate the need for more diverse ancestries in biobanks to develop multi-ancestral PRS.

scholarly journals Genome-wide Modeling of Polygenic Risk Score in Colorectal Cancer Risk

2020 ◽  
Vol 107 (3) ◽  
pp. 432-444
Author(s):  
Minta Thomas ◽  
Lori C. Sakoda ◽  
Michael Hoffmeister ◽  
Elisabeth A. Rosenthal ◽  
Jeffrey K. Lee ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cancer Risk ◽  
Risk Score ◽  
Colorectal Cancer Risk ◽  
Polygenic Risk Score ◽  
Polygenic Risk ◽  
Genome Wide

scholarly journals Polygenic risk score and risk of monoclonal B-cell lymphocytosis in caucasians and risk of chronic lymphocytic leukemia (CLL) in African Americans

Leukemia ◽  
2021 ◽  
Author(s):  
Geffen Kleinstern ◽  
J. Brice Weinberg ◽  
Sameer A. Parikh ◽  
Esteban Braggio ◽  
Sara J. Achenbach ◽  
...  
Keyword(s):  
Environmental Factors ◽  
B Cell ◽  
Risk Score ◽  
Genetic Factors ◽  
Strong Predictor ◽  
Lymphocytic Leukemia ◽  
European Ancestry ◽  
Polygenic Risk Score ◽  
Polygenic Risk ◽  
C Statistic

AbstractMonoclonal B-cell lymphocytosis (MBL) is a precursor to CLL. Other than age, sex, and CLL family-history, little is known about factors associated with MBL risk. A polygenic-risk-score (PRS) of 41 CLL-susceptibility variants has been found to be associated with CLL risk among individuals of European-ancestry(EA). Here, we evaluate these variants, the PRS, and environmental factors for MBL risk. We also evaluate these variants and the CLL-PRS among African-American (AA) and EA-CLL cases and controls. Our study included 560 EA MBLs, 869 CLLs (696 EA/173 AA), and 2866 controls (2631 EA/235 AA). We used logistic regression, adjusting for age and sex, to estimate odds ratios (OR) and 95% confidence intervals within each race. We found significant associations with MBL risk among 21 of 41 variants and with the CLL-PRS (OR = 1.86, P = 1.9 × 10−29, c-statistic = 0.72). Little evidence of any association between MBL risk and environmental factors was observed. We observed significant associations of the CLL-PRS with EA-CLL risk (OR = 2.53, P = 4.0 × 10−63, c-statistic = 0.77) and AA-CLL risk (OR = 1.76, P = 5.1 × 10−5, c-statistic = 0.62). Inherited genetic factors and not environmental are associated with MBL risk. In particular, the CLL-PRS is a strong predictor for both risk of MBL and EA-CLL, but less so for AA-CLL supporting the need for further work in this population.

scholarly journals Non-Lynch Familial and Early-Onset Colorectal Cancer Explained by Accumulation of Low-Risk Genetic Variants

Cancers ◽  
2021 ◽  
Vol 13 (15) ◽  
pp. 3857
Author(s):  
Pilar Mur ◽  
Nuria Bonifaci ◽  
Anna Díez-Villanueva ◽  
Elisabet Munté ◽  
Maria Henar Alonso ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Risk Score ◽  
Early Onset ◽  
Low Risk ◽  
Polygenic Risk Score ◽  
Polygenic Risk ◽  
Pathogenic Variants ◽  
Predisposing Genes ◽  
The Mean ◽  
Early Onset Colorectal Cancer

A large proportion of familial and/or early-onset cancer patients do not carry pathogenic variants in known cancer predisposing genes. We aimed to assess the contribution of previously validated low-risk colorectal cancer (CRC) alleles to familial/early-onset CRC (fCRC) and to serrated polyposis. We estimated the association of CRC with a 92-variant-based weighted polygenic risk score (wPRS) using 417 fCRC patients, 80 serrated polyposis patients, 1077 hospital-based incident CRC patients, and 1642 controls. The mean wPRS was significantly higher in fCRC than in controls or sporadic CRC patients. fCRC patients in the highest (20th) wPRS quantile were at four-fold greater CRC risk than those in the middle quantile (10th). Compared to low-wPRS fCRC, a higher number of high-wPRS fCRC patients had developed multiple primary CRCs, had CRC family history, and were diagnosed at age ≥50. No association with wPRS was observed for serrated polyposis. In conclusion, a relevant proportion of mismatch repair (MMR)-proficient fCRC cases might be explained by the accumulation of low-risk CRC alleles. Validation in independent cohorts and development of predictive models that include polygenic risk score (PRS) data and other CRC predisposing factors will determine the implementation of PRS into genetic testing and counselling in familial and early-onset CRC.

scholarly journals Polygenic risk score, genome-wide association, and gene set analyses of cognitive domain deficits in schizophrenia

2018 ◽  
Vol 201 ◽  
pp. 393-399 ◽  
Author(s):  
Soichiro Nakahara ◽  
Sarah Medland ◽  
Jessica A. Turner ◽  
Vince D. Calhoun ◽  
Kelvin O. Lim ◽  
...  
Keyword(s):  
Risk Score ◽  
Genome Wide Association ◽  
Cognitive Domain ◽  
Polygenic Risk Score ◽  
Polygenic Risk ◽  
Gene Set ◽  
Genome Wide

scholarly journals P820 An easy and rapid targeted next generation sequencing-based genotyping assay for the validated IBD risk loci

2020 ◽  
Vol 14 (Supplement_1) ◽  
pp. S637-S638
Author(s):  
S Verstockt ◽  
L Hannes ◽  
S Deman ◽  
W J Wollants ◽  
E Souche ◽  
...  
Keyword(s):  
Risk Score ◽  
Performance Metrics ◽  
Genetic Risk Score ◽  
Cost Effective ◽  
Polygenic Risk Score ◽  
Call Rate ◽  
Susceptibility Loci ◽  
Polygenic Risk ◽  
Genotyping Assay ◽  
Genotyping Call Rate

Abstract Background Inflammatory bowel diseases (IBD) are complex genetic diseases for which 242 susceptibility loci have been identified thus far. For translational or functional follow-up studies it can be of interest to know the genotype of specific variants. For other studies a composite genetic risk score–the polygenic risk score–is of value. There currently is a gap in technology to genotype a few hundred variants in a flexible and cost-effective way. We therefore developed a genotyping assay for the 242 validated IBD susceptibility loci. Methods Using MIPgen v.1.1, we designed molecular inversion probes (MIPs) covering 269 independent variants from the 242 IBD loci. MIP libraries were prepared according to Neveling et al. (Clin Chem. 2017), followed by paired-end sequencing using a MiSeq® System (Illumina). In the pilot studies, 16 IBD patients were genotyped, and results were compared with available immunochip (ichip) data. Genotypes for the covered variants were obtained using an in-house developed pipeline, and performance metrics were assessed (incl. genotyping call rate, percentage off-target reads and concordance with ichip-based genotypes). After optimisation, we genotyped 279 individuals (168 IBD patients and 111 non-IBD controls). We also calculated a weighted IBD polygenic risk score (PRSice 2.0) for these. Results Despite a genotyping call rate of 94.3%, the first pilot run suffered from a high rate of off-target reads (52.5%). After redesigning poorly-performing MIPs, off-target reads dropped to 9.4%, and the genotyping call rate increased to 97.5%. Concordance with genotypes previously obtained from ichip was 99.3%. When applying the optimised design on a larger scale (i.e. on the 279 individuals), we obtained similar performance metrics, with 8.0% off-target reads and a genotyping call rate of 97.3%. Moreover, upscaling resulted in a turnaround time of 2.5 working days/96 samples and a cost of €14/sample. The calculated IBD polygenic risk scores showed higher scores in patients as compared with controls (5.5E−03 vs. 4.0E−03, p = 8.80E−10; R² IBD polygenic risk score = 0.15, p = 1.28E−07), however with a large overlap between both groups. Quartile analysis showed that individuals within the highest quartile had an 8.1-fold (95% CI: 3.7–17.5) increase in risk towards IBD compared with individuals in the first quartile. Conclusion We developed a cost-effective genotyping assay for currently known IBD risk loci, with an integrated bioinformatics pipeline from raw sequencing data to individual genotypes and calculation of a polygenic risk score. Furthermore, this assay enables genotyping of individuals on a large scale while remaining flexible to implement newly identified genetic variants.

Genome-wide association study (GWAS) of chemotherapy-induced Raynaud's phenomenon (RP) to reveal shared pathways with cardiovascular disease (CVD).

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e18162-e18162
Author(s):  
Omar El Charif ◽  
Heather E. Wheeler ◽  
Matthew Trendowski ◽  
Eric R Gamazon ◽  
Shirin Ardeshirrouhanifard ◽  
...  
Keyword(s):  
Risk Score ◽  
Cellular Response ◽  
Genome Wide Association Study ◽  
Significant Snps ◽  
Case Control ◽  
Gene Set Enrichment Analysis ◽  
Polygenic Risk Score ◽  
Polygenic Risk ◽  
Genome Wide ◽  
Patient Reported

e18162 Background: RP is an adverse drug reaction characterized by reduced blood flow to the extremities causing pain and sensations of cold. Few studies have examined the genetic basis for RP, although family studies suggest a heritable component to primary RP. Methods: Eligible testicular cancer survivors (TCS) were < 55 y at diagnosis, treated with first line cisplatin-based chemotherapy, and completed questionnaires. Genotyping with standard quality control and imputation were performed. A case-control RP phenotype was derived from patient-reported outcomes and associations were computed by logistic regression. GWAS used cumulative bleomycin dose and 10 genetic principal components as covariates. Gene set enrichment analysis (GSEA) utilized genes ranked by the most significant GWAS SNP in/within 20 kilobases. A polygenic risk score for CVD derived from four prior independent GWAS (Khera et al. NEJM 2016) was assessed for association with RP. Results: Of 749 patients (median age 38 y, median time since chemotherapy 5 y), 38% reported RP. Bleomycin dose was the most significant predictor of RP (OR100 mg/m2 = 1.25, p < 0.0001). Number of years smoking also correlated with RP (ORyear = 1.05, p = 0.002). Age and hypertension showed no significant correlation with RP. GSEA revealed several significant pathways (FDR q < 0.1), including “ cellular response to VEGF stimulus” (q = 0.05) and “ cardiac muscle cell action potential” (q = 0.09). We hypothesized that RP may share genetic architecture with CVD. Deriving a polygenic risk score from genome-wide significant SNPs in prior CVD GWAS (n = 4260-22,389), we showed nearly significant case-control differences in CVD polygenic risk score (two-tailed t-test, p = 0.053). RP frequency significantly increased with polygenic risk score quartile (OR = 1.19, p = 0.008). Conclusions: Over one third of TCS report RP, with greater frequency among bleomycin-treated patients and smokers. Implicated genetic pathways include ones established in CVD. Although shared genetic risk between chemotherapy-induced RP and CVD may be possible, further investigation is required. Primary RP has been inconsistently linked with CVD.

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