Identification of Recessively Inherited Genetic Variants Potentially Linked to Pancreatic Cancer Risk

Although 21 pancreatic cancer susceptibility loci have been identified in individuals of European ancestry through genome-wide association studies (GWASs), much of the heritability of pancreatic cancer risk remains unidentified. A recessive genetic model could be a powerful tool for identifying additional risk variants. To discover recessively inherited pancreatic cancer risk loci, we performed a re-analysis of the largest pancreatic cancer GWAS, the Pancreatic Cancer Cohort Consortium (PanScan) and the Pancreatic Cancer Case-Control Consortium (PanC4), including 8,769 cases and 7,055 controls of European ancestry. Six single nucleotide polymorphisms (SNPs) showed associations with pancreatic cancer risk according to a recessive model of inheritance. We replicated these variants in 3,212 cases and 3,470 controls collected from the PANcreatic Disease ReseArch (PANDoRA) consortium. The results of the meta-analyses confirmed that rs4626538 (7q32.2), rs7008921 (8p23.2) and rs147904962 (17q21.31) showed specific recessive effects (p<10−5) compared with the additive effects (p>10−3), although none of the six SNPs reached the conventional threshold for genome-wide significance (p < 5×10−8). Additional bioinformatic analysis explored the functional annotations of the SNPs and indicated a possible relationship between rs36018702 and expression of the BCL2L11 and BUB1 genes, which are known to be involved in pancreatic biology. Our findings, while not conclusive, indicate the importance of considering non-additive genetic models when performing GWAS analysis. The SNPs associated with pancreatic cancer in this study could be used for further meta-analysis for recessive association of SNPs and pancreatic cancer risk and might be a useful addiction to improve the performance of polygenic risk scores.

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Performance of polygenic risk scores for cancer prediction in a racially diverse academic biobank

10.1101/2021.05.13.21256833 ◽

2021 ◽

Author(s):

Louise Wang ◽

Heena Desai ◽

Shefali S. Verma ◽

Anh Le ◽

Ryan Hausler ◽

...

Keyword(s):

Cancer Risk ◽

Genetic Factors ◽

Association Studies ◽

European Ancestry ◽

Risk Scores ◽

Genome Wide Association Studies ◽

Discriminatory Ability ◽

Polygenic Risk ◽

Genome Wide ◽

European Populations

Purpose: Genome-wide association studies (GWAS) have identified hundreds of single nucleotide polymorphisms (SNPs) significantly associated with several cancers, but the predictive ability of polygenic risk scores (PRS) derived from multiple variants is unclear for many cancers, especially among non-European populations. Methods: Genome wide genotype data was available for 20,079 individuals enrolled in an academic biobank. PRS were derived from significant DNA variants for 15 cancers. Logistic regression was used to determine the discriminatory accuracy of each cancer-specific PRS in patients of genetically determined African and European ancestry separately. Results: Among European individuals, four PRS were significantly associated with their respective cancers (breast, colon, melanoma, and prostate), with an OR ranging from 1.25-1.47. Among African individuals, PRS for breast, colon, and prostate were significantly associated with their respective cancers. The discriminatory ability of a model comprised of age, sex, and principal components was 0.617–0.709, and the AUC increased by 1-4% with the addition of the PRS in Europeans. AUC was overall higher in the full model including PRS (AUC 0.742-0.818) in African individuals, but the PRS increased the AUC by less than 1% in the majority of cancers in African individuals. Conclusion: PRS constructed from SNPs moderately increased discriminatory ability for cancer status over age, sex, and nonspecific genetic factors in individuals of European but not African ancestry. Further large-scale studies are needed to identify ancestry-specific genetic factors for cancer risk in non-European populations to incorporate PRS into cancer risk assessment.

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A Transcriptome-Wide Association Study Identifies Novel Candidate Susceptibility Genes for Pancreatic Cancer

JNCI Journal of the National Cancer Institute ◽

10.1093/jnci/djz246 ◽

2020 ◽

Vol 112 (10) ◽

pp. 1003-1012 ◽

Cited By ~ 5

Author(s):

Jun Zhong ◽

Ashley Jermusyk ◽

Lang Wu ◽

Jason W Hoskins ◽

Irene Collins ◽

...

Keyword(s):

Gene Expression ◽

Pancreatic Cancer ◽

Cancer Risk ◽

Association Study ◽

Association Studies ◽

Tissue Expression ◽

Genome Wide Association ◽

Genome Wide Association Studies ◽

Pancreatic Cancer Risk ◽

Genome Wide

Abstract Background Although 20 pancreatic cancer susceptibility loci have been identified through genome-wide association studies in individuals of European ancestry, much of its heritability remains unexplained and the genes responsible largely unknown. Methods To discover novel pancreatic cancer risk loci and possible causal genes, we performed a pancreatic cancer transcriptome-wide association study in Europeans using three approaches: FUSION, MetaXcan, and Summary-MulTiXcan. We integrated genome-wide association studies summary statistics from 9040 pancreatic cancer cases and 12 496 controls, with gene expression prediction models built using transcriptome data from histologically normal pancreatic tissue samples (NCI Laboratory of Translational Genomics [n = 95] and Genotype-Tissue Expression v7 [n = 174] datasets) and data from 48 different tissues (Genotype-Tissue Expression v7, n = 74–421 samples). Results We identified 25 genes whose genetically predicted expression was statistically significantly associated with pancreatic cancer risk (false discovery rate < .05), including 14 candidate genes at 11 novel loci (1p36.12: CELA3B; 9q31.1: SMC2, SMC2-AS1; 10q23.31: RP11-80H5.9; 12q13.13: SMUG1; 14q32.33: BTBD6; 15q23: HEXA; 15q26.1: RCCD1; 17q12: PNMT, CDK12, PGAP3; 17q22: SUPT4H1; 18q11.22: RP11-888D10.3; and 19p13.11: PGPEP1) and 11 at six known risk loci (5p15.33: TERT, CLPTM1L, ZDHHC11B; 7p14.1: INHBA; 9q34.2: ABO; 13q12.2: PDX1; 13q22.1: KLF5; and 16q23.1: WDR59, CFDP1, BCAR1, TMEM170A). The association for 12 of these genes (CELA3B, SMC2, and PNMT at novel risk loci and TERT, CLPTM1L, INHBA, ABO, PDX1, KLF5, WDR59, CFDP1, and BCAR1 at known loci) remained statistically significant after Bonferroni correction. Conclusions By integrating gene expression and genotype data, we identified novel pancreatic cancer risk loci and candidate functional genes that warrant further investigation.

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Evaluating the Utility of Polygenic Risk Scores in Identifying High-Risk Individuals for Eight Common Cancers

JNCI Cancer Spectrum ◽

10.1093/jncics/pkaa021 ◽

2020 ◽

Vol 4 (3) ◽

Cited By ~ 3

Author(s):

Guochong Jia ◽

Yingchang Lu ◽

Wanqing Wen ◽

Jirong Long ◽

Ying Liu ◽

...

Keyword(s):

Cancer Risk ◽

Association Studies ◽

Elevated Risk ◽

Genome Wide Association ◽

Risk Scores ◽

Cancer Case ◽

Genome Wide Association Studies ◽

Polygenic Risk ◽

Risk Variants ◽

Genome Wide

Abstract Background Genome-wide association studies have identified common genetic risk variants in many loci associated with multiple cancers. We sought to systematically evaluate the utility of these risk variants in identifying high-risk individuals for eight common cancers. Methods We constructed polygenic risk scores (PRS) using genome-wide association studies–identified risk variants for each cancer. Using data from 400 812 participants of European descent in a population-based cohort study, UK Biobank, we estimated hazard ratios associated with PRS using Cox proportional hazard models and evaluated the performance of the PRS in cancer risk prediction and their ability to identify individuals at more than a twofold elevated risk, a risk level comparable to a moderate-penetrance mutation in known cancer predisposition genes. Results During a median follow-up of 5.8 years, 14 584 incident case patients of cancers were identified (ranging from 358 epithelial ovarian cancer case patients to 4430 prostate cancer case patients). Compared with those at an average risk, individuals among the highest 5% of the PRS had a two- to threefold elevated risk for cancer of the prostate, breast, pancreas, colorectal, or ovary, and an approximately 1.5-fold elevated risk of cancer of the lung, bladder, or kidney. The areas under the curve ranged from 0.567 to 0.662. Using PRS, 40.4% of the study participants can be classified as having more than a twofold elevated risk for at least one site-specific cancer. Conclusions A large proportion of the general population can be identified at an elevated cancer risk by PRS, supporting the potential clinical utility of PRS for personalized cancer risk prediction.

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Increasing Sample Diversity in Psychiatric Genetics – Introducing a new Cohort of Patients with Schizophrenia and Controls from Vietnam – Results from a Pilot Study

10.1101/2021.04.21.21255615 ◽

2021 ◽

Author(s):

VT Nguyen ◽

A Braun ◽

J Kraft ◽

TMT Ta ◽

GM Panagiotaropoulou ◽

...

Keyword(s):

Pilot Study ◽

Data Collection ◽

Predictive Power ◽

Association Studies ◽

East Asian ◽

Genetic Research ◽

European Ancestry ◽

Risk Scores ◽

Genome Wide Association Studies ◽

Genome Wide

AbstractObjectivesGenome-Wide Association Studies (GWAS) of Schizophrenia (SCZ) have provided new biological insights; however, most cohorts are of European ancestry. As a result, derived polygenic risk scores (PRS) show decreased predictive power when applied to populations of different ancestries. We aimed to assess the feasibility of a large-scale data collection in Hanoi, Vietnam, contribute to international efforts to diversify ancestry in SCZ genetic research and examine the transferability of SCZ-PRS to individuals of Vietnamese Kinh ancestry.MethodsIn a pilot study, 368 individuals (including 190 SCZ cases) were recruited at the Hanoi Medical University’s associated psychiatric hospitals and outpatient facilities. Data collection included sociodemographic data, baseline clinical data, clinical interviews assessing symptom severity and genome-wide SNP genotyping. SCZ-PRS were generated using different training data sets: i) European, ii) East-Asian and iii) trans-ancestry GWAS summary statistics from the latest SCZ GWAS meta-analysis.ResultsSCZ-PRS significantly predicted case status in Vietnamese individuals using mixed-ancestry (R2 liability=4.9%, p=6.83*10−8), East-Asian (R2 liability=4.5%, p=2.73*10−7) and European (R2 liability=3.8%, p = 1.79*10−6) discovery samples.DiscussionOur results corroborate previous findings of reduced PRS predictive power across populations, highlighting the importance of ancestral diversity in GWA studies.

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Polygenic transcriptome risk scores (PTRS) can improve portability of polygenic risk scores across ancestries

Genome Biology ◽

10.1186/s13059-021-02591-w ◽

2022 ◽

Vol 23 (1) ◽

Author(s):

Yanyu Liang ◽

Milton Pividori ◽

Ani Manichaikul ◽

Abraham A. Palmer ◽

Nancy J. Cox ◽

...

Keyword(s):

Association Studies ◽

Poor Performance ◽

Genome Wide Association ◽

European Ancestry ◽

Risk Scores ◽

Genome Wide Association Studies ◽

Uk Biobank ◽

Transcript Levels ◽

Polygenic Risk ◽

Genome Wide

Abstract Background Polygenic risk scores (PRS) are valuable to translate the results of genome-wide association studies (GWAS) into clinical practice. To date, most GWAS have been based on individuals of European-ancestry leading to poor performance in populations of non-European ancestry. Results We introduce the polygenic transcriptome risk score (PTRS), which is based on predicted transcript levels (rather than SNPs), and explore the portability of PTRS across populations using UK Biobank data. Conclusions We show that PTRS has a significantly higher portability (Wilcoxon p=0.013) in the African-descent samples where the loss of performance is most acute with better performance than PRS when used in combination.

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Interaction between Genetic Risk Scores for reduced pulmonary function and smoking, asthma and endotoxin

Thorax ◽

10.1136/thoraxjnl-2020-215624 ◽

2021 ◽

pp. thoraxjnl-2020-215624

Author(s):

Sinjini Sikdar ◽

Annah B Wyss ◽

Mi Kyeong Lee ◽

Thanh T Hoang ◽

Marie Richards ◽

...

Keyword(s):

Pulmonary Function ◽

Genetic Risk ◽

Association Studies ◽

European Ancestry ◽

Risk Scores ◽

P Value ◽

Genome Wide Association Studies ◽

Inverse Association ◽

Genetic Risk Scores ◽

Genome Wide

RationaleGenome-wide association studies (GWASs) have identified numerous loci associated with lower pulmonary function. Pulmonary function is strongly related to smoking and has also been associated with asthma and dust endotoxin. At the individual SNP level, genome-wide analyses of pulmonary function have not identified appreciable evidence for gene by environment interactions. Genetic Risk Scores (GRSs) may enhance power to identify gene–environment interactions, but studies are few.MethodsWe analysed 2844 individuals of European ancestry with 1000 Genomes imputed GWAS data from a case–control study of adult asthma nested within a US agricultural cohort. Pulmonary function traits were FEV1, FVC and FEV1/FVC. Using data from a recent large meta-analysis of GWAS, we constructed a weighted GRS for each trait by combining the top (p value<5×10−9) genetic variants, after clumping based on distance (±250 kb) and linkage disequilibrium (r2=0.5). We used linear regression, adjusting for relevant covariates, to estimate associations of each trait with its GRS and to assess interactions.ResultsEach trait was highly significantly associated with its GRS (all three p values<8.9×10−8). The inverse association of the GRS with FEV1/FVC was stronger for current smokers (pinteraction=0.017) or former smokers (pinteraction=0.064) when compared with never smokers and among asthmatics compared with non-asthmatics (pinteraction=0.053). No significant interactions were observed between any GRS and house dust endotoxin.ConclusionsEvaluation of interactions using GRSs supports a greater impact of increased genetic susceptibility on reduced pulmonary function in the presence of smoking or asthma.

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Genetic loci associated with heart rate variability and their effects on cardiac disease risk

Nature Communications ◽

10.1038/ncomms15805 ◽

2017 ◽

Vol 8 (1) ◽

Cited By ~ 30

Author(s):

Ilja M. Nolte ◽

M. Loretto Munoz ◽

Vinicius Tragante ◽

Azmeraw T. Amare ◽

Rick Jansen ◽

...

Keyword(s):

Heart Rate ◽

Heart Rate Variability ◽

Disease Risk ◽

Association Studies ◽

European Ancestry ◽

Risk Scores ◽

Genome Wide Association Studies ◽

Heritable Variation ◽

Membrane Hyperpolarization ◽

Genome Wide

Abstract Reduced cardiac vagal control reflected in low heart rate variability (HRV) is associated with greater risks for cardiac morbidity and mortality. In two-stage meta-analyses of genome-wide association studies for three HRV traits in up to 53,174 individuals of European ancestry, we detect 17 genome-wide significant SNPs in eight loci. HRV SNPs tag non-synonymous SNPs (in NDUFA11 and KIAA1755), expression quantitative trait loci (eQTLs) (influencing GNG11, RGS6 and NEO1), or are located in genes preferentially expressed in the sinoatrial node (GNG11, RGS6 and HCN4). Genetic risk scores account for 0.9 to 2.6% of the HRV variance. Significant genetic correlation is found for HRV with heart rate (−0.74<r g <−0.55) and blood pressure (−0.35<r g <−0.20). These findings provide clinically relevant biological insight into heritable variation in vagal heart rhythm regulation, with a key role for genetic variants (GNG11, RGS6) that influence G-protein heterotrimer action in GIRK-channel induced pacemaker membrane hyperpolarization.

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