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

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.

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Association of polygenic risk score with the risk of chronic lymphocytic leukemia and monoclonal B-cell lymphocytosis

Blood ◽

10.1182/blood-2017-11-814608 ◽

2018 ◽

Vol 131 (23) ◽

pp. 2541-2551 ◽

Cited By ~ 9

Author(s):

Geffen Kleinstern ◽

Nicola J. Camp ◽

Lynn R. Goldin ◽

Celine M. Vachon ◽

Claire M. Vajdic ◽

...

Keyword(s):

Chronic Lymphocytic Leukemia ◽

B Cell ◽

Risk Score ◽

Clinical Impact ◽

Lymphocytic Leukemia ◽

Polygenic Risk Score ◽

Polygenic Risk ◽

Key Points ◽

High Discrimination

Key Points PRS, based on the known CLL loci, predicts CLL risk with high discrimination. This PRS predicts risk of monoclonal B-cell lymphocytosis, a precursor to CLL and a condition that has clinical impact beyond risk for CLL.

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Polygenic Risk Score and Risk of Chronic Lymphocytic Leukemia, Monoclonal B-Cell Lymphocytosis (MBL), and MBL Subtypes

Blood ◽

10.1182/blood-2020-136548 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 35-36

Author(s):

Geffen Kleinstern ◽

J. Brice Weinberg ◽

Sameer A. Parikh ◽

Esteban Braggio ◽

Dennis P. Robinson ◽

...

Keyword(s):

Logistic Regression ◽

Chronic Lymphocytic Leukemia ◽

B Cell ◽

Board Of Directors ◽

Research Funding ◽

Lymphocytic Leukemia ◽

Polygenic Risk Score ◽

Advisory Committees ◽

Polygenic Risk ◽

C Statistic

Background MBL is a precursor to chronic lymphocytic leukemia (CLL) and is subclassified into low-count (LC) MBL (absolute B-cell count<0.5x109/L) and high-count (HC) MBL (absolute B-cell count between 0.5 and 5x109/L). We previously reported that a polygenic risk score (PRS) based on a weighted average of 41 CLL-susceptibility variants was associated with risk of both MBL and CLL among a cohort of individuals from CLL families. Here we evaluate this PRS in an independent cohort of MBL and CLL individuals of European ancestry (EA), all of whom were ascertained agnostic to CLL family-history status. We also evaluate the PRS by MBL subtype (LC/HC), and in African American (AA) CLL cases and controls. Methods We genotyped 535 EA MBLs (139 HC-MBL, 396 LC-MBLs), 735 CLLs (640 EA, 95 AA), and 2,866 controls (2,631 EA, 235 AA) from the Mayo Clinic CLL Resource, Duke University, and Weill Cornell Medical College. We computed the CLL-PRS for each individual and used logistic regression to estimate odds ratios (OR) and 95% confidence intervals, adjusting for age and sex. To assess discriminatory accuracy, we computed the c-statistic. Among EA individuals, we calculated a trend test among LC-MBL, HC-MBL, and CLL risk using the P-value for heterogeneity from a polytomous logistic regression analysis. Moreover, we plotted a boxplot for the PRS among controls, LC-MBL, HC-MBL, and EA CLL, as well as for AA CLL cases and controls, and tested the statistical difference using the Kruskal Wallis test and Mann-Whitney test, respectively. Results We found a significant association of PRS with overall MBL risk (OR=1.87, P=1.1x10-28) with good discrimination (c-statistic=0.72). Significant associations were also found for LC-MBL (OR=1.75, P=7.5x10-19, c-statistic=0.72), HC-MBL (OR=2.22, P=1.4x10-17, c-statistic=0.74), and CLL of EA (OR=2.60, P=1.2x10-62, c-statistic=0.78), with a significant difference among these cohorts (Figure 1.A) and a significant positive trend across these cohorts (Pheterogeneity=8.4x10-6). Although we observed a 33% increased risk of CLL in AA (c-statistic=0.57), the PRS was borderline significant (P=0.07, Figure 1.B). Conclusion The CLL-PRS is a strong prediction-tool for risk of CLL and MBL among individuals of EA. Future studies are needed to improve the PRS for AAs including performing GWAS of AA in order to identify CLL-susceptibility SNPs that are more representative within known CLL loci and to discover novel CLL loci that are unique for AAs. Disclosures Parikh: GlaxoSmithKline: Honoraria; Janssen: Honoraria, Research Funding; Ascentage Pharma: Research Funding; AbbVie: Honoraria, Research Funding; Merck: Research Funding; TG Therapeutics: Research Funding; Genentech: Honoraria; Pharmacyclics: Honoraria, Research Funding; MorphoSys: Research Funding; AstraZeneca: Honoraria, Research Funding; Verastem Oncology: Honoraria. Braggio:DASA: Consultancy; Bayer: Other: Stock Owner; Acerta Pharma: Research Funding. Brander:Genentech: Consultancy, Honoraria, Other, Research Funding; Juno/Celgene/BMS: Other, Research Funding; MEI Pharma: Other, Research Funding; Ascentage: Other, Research Funding; ArQule: Consultancy, Other, Research Funding; NCCN: Other; Teva: Consultancy, Honoraria; Tolero: Research Funding; AstraZeneca: Consultancy, Honoraria, Other, Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Honoraria, Other, Research Funding; Pfizer: Consultancy, Other; TG Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; Novartis: Consultancy, Other; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; Tolero: Research Funding; Teva: Consultancy, Honoraria; DTRM: Other, Research Funding; BeiGene: Other, Research Funding; Novartis: Consultancy, Other; NCCN: Other; Verastem: Consultancy, Honoraria, Other, Research Funding. Cerhan:NanoString: Research Funding; BMS/Celgene: Research Funding. Kay:Astra Zeneca: Membership on an entity's Board of Directors or advisory committees; Agios Pharma: Membership on an entity's Board of Directors or advisory committees; Sunesis: Research Funding; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Acerta Pharma: Research Funding; Juno Theraputics: Membership on an entity's Board of Directors or advisory committees; Morpho-sys: Membership on an entity's Board of Directors or advisory committees; Rigel: Membership on an entity's Board of Directors or advisory committees; Cytomx: Membership on an entity's Board of Directors or advisory committees; Tolero Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol Meyer Squib: Membership on an entity's Board of Directors or advisory committees, Research Funding; MEI Pharma: Research Funding; Abbvie: Research Funding; Oncotracker: Membership on an entity's Board of Directors or advisory committees; Dava Oncology: Membership on an entity's Board of Directors or advisory committees. Furman:Acerta: Consultancy; AstraZeneca: Consultancy, Research Funding; Beigene: Consultancy; Abbvie: Consultancy; Pharmacyclics: Consultancy; Sunesis: Consultancy; TG Therapeutics: Consultancy, Research Funding; Verastem: Consultancy; Incyte: Consultancy; Genentech: Consultancy; Janssen: Consultancy, Speakers Bureau; Loxo Oncology: Consultancy; Oncotarget: Consultancy. Shanafelt:Mayo Clinic: Patents & Royalties: and other intellectual property; Genentech, Pharmacyclics LLC, an AbbVie Company, AbbVie, GlaxoSmithKline, and Merck: Research Funding.

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

10.1158/1538-7755.disp21-po-163 ◽

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

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The undiagnosed disease burden associated with alpha-1 antitrypsin deficiency genotypes

European Respiratory Journal ◽

10.1183/13993003.01441-2020 ◽

2020 ◽

Vol 56 (6) ◽

pp. 2001441 ◽

Cited By ~ 1

Author(s):

Tomoko Nakanishi ◽

Vincenzo Forgetta ◽

Tomohiro Handa ◽

Toyohiro Hirai ◽

Vincent Mooser ◽

...

Keyword(s):

Risk Score ◽

Disease Burden ◽

Forced Expiratory Volume ◽

European Ancestry ◽

Polygenic Risk Score ◽

Uk Biobank ◽

Polygenic Risk ◽

Antitrypsin Deficiency ◽

Alpha 1 Antitrypsin Deficiency ◽

Alpha 1 Antitrypsin

Alpha-1 antitrypsin deficiency (AATD), mainly due to the PI*ZZ genotype in SERPINA1, is one of the most common inherited diseases. Since it is associated with a high disease burden and partially prevented by smoking cessation, identification of PI*ZZ individuals through genotyping could improve health outcomes.We examined the frequency of the PI*ZZ genotype in individuals with and without diagnosed AATD from UK Biobank, and assessed the associations of the genotypes with clinical outcomes and mortality. A phenome-wide association study (PheWAS) was conducted to reveal disease associations with genotypes. A polygenic risk score (PRS) for forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC) ratio was used to evaluate variable penetrance of PI*ZZ.Among 458 164 European-ancestry participants in UK Biobank, 140 had the PI*ZZ genotype and only nine (6.4%, 95% CI 3.4–11.7%) of them were diagnosed with AATD. Those with PI*ZZ had a substantially higher odds of COPD (OR 8.8, 95% CI 5.8–13.3), asthma (OR 2.0, 95% CI 1.4–3.0), bronchiectasis (OR 7.3, 95%CI 3.2–16.8), pneumonia (OR 2.7, 95% CI 1.5–4.9) and cirrhosis (OR 7.8, 95% CI 2.5–24.6) diagnoses and a higher hazard of mortality (2.4, 95% CI 1.2–4.6), compared to PI*MM (wildtype) (n=398 424). These associations were stronger among smokers. PheWAS demonstrated associations with increased odds of empyema, pneumothorax, cachexia, polycythaemia, aneurysm and pancreatitis. Polygenic risk score and PI*ZZ were independently associated with FEV1/FVC <0.7 (OR 1.4 per 1-sd change, 95% CI 1.4–1.5 and OR 4.5, 95% CI 3.0–6.9, respectively).The important underdiagnosis of AATD, whose outcomes are partially preventable through smoking cession, could be improved through genotype-guided diagnosis.

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Partial Support for an Interaction Between a Polygenic Risk Score for Major Depressive Disorder and Prenatal Maternal Depressive Symptoms on Infant Right Amygdalar Volumes

Cerebral Cortex ◽

10.1093/cercor/bhaa158 ◽

2020 ◽

Vol 30 (12) ◽

pp. 6121-6134 ◽

Cited By ~ 1

Author(s):

H Acosta ◽

K Kantojärvi ◽

N Hashempour ◽

J Pelto ◽

N M Scheinin ◽

...

Keyword(s):

Major Depressive Disorder ◽

Depressive Symptoms ◽

Depressive Disorder ◽

Risk Score ◽

European Ancestry ◽

Polygenic Risk Score ◽

Maternal Depressive Symptoms ◽

Major Depressive ◽

Polygenic Risk ◽

Asian Cohort

Abstract Psychiatric disease susceptibility partly originates prenatally and is shaped by an interplay of genetic and environmental risk factors. A recent study has provided preliminary evidence that an offspring polygenic risk score for major depressive disorder (PRS-MDD), based on European ancestry, interacts with prenatal maternal depressive symptoms (GxE) on neonatal right amygdalar (US and Asian cohort) and hippocampal volumes (Asian cohort). However, to date, this GxE interplay has only been addressed by one study and is yet unknown for a European ancestry sample. We investigated in 105 Finnish mother–infant dyads (44 female, 11–54 days old) how offspring PRS-MDD interacts with prenatal maternal depressive symptoms (Edinburgh Postnatal Depression Scale, gestational weeks 14, 24, 34) on infant amygdalar and hippocampal volumes. We found a GxE effect on right amygdalar volumes, significant in the main analysis, but nonsignificant after multiple comparison correction and some of the control analyses, whose direction paralleled the US cohort findings. Additional exploratory analyses suggested a sex-specific GxE effect on right hippocampal volumes. Our study is the first to provide support, though statistically weak, for an interplay of offspring PRS-MDD and prenatal maternal depressive symptoms on infant limbic brain volumes in a cohort matched to the PRS-MDD discovery sample.

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Evaluation of modifiable factors and polygenic risk score in thyroid cancer

Endocrine Related Cancer ◽

10.1530/erc-21-0078 ◽

2021 ◽

Author(s):

Tung Hoang ◽

Quy Nguyen Ngoc ◽

Jeonghee Lee ◽

Eun Kyung Lee ◽

Yul Hwangbo ◽

...

Keyword(s):

Thyroid Cancer ◽

Alcohol Consumption ◽

Risk Score ◽

Tobacco Smoking ◽

Cumulative Effect ◽

European Ancestry ◽

Polygenic Risk Score ◽

Regular Exercise ◽

Polygenic Risk ◽

Modifiable Factors

The cumulative effect of single-nucleotide polymorphisms (SNPs) on thyroid cancer has been adequately defined in individuals of European ancestry; however, similar evidence in the Korean population is limited. This study aimed to investigate the influence of modifiable factors and the polygenic risk score (PRS) and their interactive and combined effects on thyroid cancer. Using data from the Cancer Screenee Cohort, this study included 759 thyroid cancer cases and 759 age- and sex-matched controls. We examined the effects of tobacco smoking, alcohol consumption, and regular exercise habits, body mass index (BMI), and the PRS of 6 SNPs on thyroid cancer. Odds ratios (ORs) and 95% confidence intervals (CIs) for the associations were obtained using a conditional logistic regression model. The results indicated that family history, obesity, and the unweighted and weighted PRS were independently associated with susceptibility to thyroid cancer, with ORs (95% CIs) of 2.96 (1.63-5.36), 1.72 (1.20-2.48), 1.46 (1.10-1.93), and 1.56 (1.19-2.03), respectively, whereas the effect of smoking, drinking, and regular exercise was not significant. The contribution of the PRS remained after stratifying participants with healthy behaviours, such as nonsmokers/nondrinkers, and regular exercise. Although the PRS did not significantly contribute to the risk for thyroid cancer when participants were stratified according to BMI, BMI and the PRS had a cumulative effect on thyroid cancer risk. The combined effect of genetic polymorphisms on predisposition to thyroid cancer may differ based on tobacco smoking, alcohol consumption, regular exercise behaviours and cumulative BMI. Larger population-based studies are needed to validate these findings.

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Non-linear interaction between physical activity and polygenic risk score of body mass index in Danish and Russian populations

PLoS ONE ◽

10.1371/journal.pone.0258748 ◽

2021 ◽

Vol 16 (10) ◽

pp. e0258748

Author(s):

Dmitrii Borisevich ◽

Theresia M. Schnurr ◽

Line Engelbrechtsen ◽

Alexander Rakitko ◽

Lars Ängquist ◽

...

Keyword(s):

Physical Activity ◽

Body Mass Index ◽

Environmental Factors ◽

Body Mass ◽

Risk Score ◽

Polygenic Risk Score ◽

Environment Interaction ◽

Linear Interaction ◽

Polygenic Risk ◽

Non Linear

Body mass index (BMI) is a highly heritable polygenic trait. It is also affected by various environmental and behavioral risk factors. We used a BMI polygenic risk score (PRS) to study the interplay between the genetic and environmental factors defining BMI. First, we generated a BMI PRS that explained more variance than a BMI genetic risk score (GRS), which was using only genome-wide significant BMI-associated variants (R2 = 13.1% compared to 6.1%). Second, we analyzed interactions between BMI PRS and seven environmental factors. We found a significant interaction between physical activity and BMI PRS, even when the well-known effect of the FTO region was excluded from the PRS, using a small dataset of 6,179 samples. Third, we stratified the study population into two risk groups using BMI PRS. The top 22% of the studied populations were included in a high PRS risk group. Engagement in self-reported physical activity was associated with a 1.66 kg/m2 decrease in BMI in this group, compared to a 0.84 kg/m2 decrease in BMI in the rest of the population. Our results (i) confirm that genetic background strongly affects adult BMI in the general population, (ii) show a non-linear interaction between BMI genetics and physical activity, and (iii) provide a standardized framework for future gene-environment interaction analyses.

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Development and Implementation of Polygenic Risk Score in Vietnamese Population

Research and Development on Information and Communication Technology ◽

10.32913/mic-ict-research.v2019.n2.893 ◽

2019 ◽

Vol 2019 (2) ◽

pp. 75-83

Author(s):

Nguyễn Trần Thế Hùng ◽

Lê Đức Hậu

Keyword(s):

Risk Score ◽

Prediction Models ◽

European Ancestry ◽

Polygenic Risk Score ◽

Clinical Settings ◽

Nucleotide Polymorphisms ◽

Single Nucleotide ◽

Polygenic Risk ◽

Vietnamese Population ◽

Artery Disease

Recent technological advancements and availability of genetic databases have facilitated the integration of genetic factors into risk prediction models. A Polygenic Risk Score (PRS) combines the effect of many Single Nucleotide Polymorphisms (SNP) into a single score. This score has lately been shown to have a clinically predictive value in various common diseases. Some clinical interpretations of PRS are summarized in this review for coronary artery disease, breast cancer, prostate cancer, diabetes mellitus, and Alzheimer’s disease. While these findings gave support to the implementation of PRS in clinical settings, the populations of interest were derived mainly from European ancestry. Therefore, applying these findings to non-European ancestry (Vietnamese in this context) requires many efforts and cautions. This review aims to articulate the evidence supporting the clinical use of PRS, the concepts behind the validity of PRS, approach to implement PRS in Vietnamese population, and cautions in selecting methods and thresholds to develop an appropriate PRS.

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Effect of APOE and a polygenic risk score on incident dementia and cognitive decline in a healthy older population

10.1101/2020.10.11.20210963 ◽

2020 ◽

Author(s):

Moeen Riaz ◽

Aamira Huq ◽

Joanne Ryan ◽

Suzanne G Orchard ◽

Jane Tiller ◽

...

Keyword(s):

Relative Risk ◽

Cognitive Decline ◽

Risk Score ◽

Cumulative Incidence ◽

Genetic Factors ◽

Polygenic Risk Score ◽

Older Individuals ◽

Polygenic Risk ◽

Increased Risk ◽

Incidence Of Dementia

AbstractImportanceFew studies have measured the effect of genetic factors on dementia and cognitive decline in a population of healthy older individuals followed prospectively.ObjectiveTo examine the effect of Apolipoprotein E (APOE) genotypes and a polygenic risk score (PRS) on incident dementia and cognitive decline in a longitudinal cohort of healthy older people.Design, Setting and ParticipantsPost-hoc genetic analysis of a randomized clinical trial population - the ASPirin in Reducing Events in the Elderly (ASPREE) trial. At enrollment, participants had no history of diagnosed dementia, atherothrombotic cardiovascular disease, or permanent physical disability and were without cognitive impairment.Main Outcomes and MeasuresDementia (adjudicated trial endpoint) and cognitive decline, defined as a >1.5 standard deviation decline in test score for either global cognition, episodic memory, language/executive function or psychomotor speed, versus baseline scores. Cumulative incidence curves for all-cause dementia and cognitive decline were calculated with mortality as a competing event, stratified by APOE genotypes and tertiles of a PRS based on 23 common non-APOE variants.Results12,978 participants with European ancestry were included; 54.8% were female, and average age at baseline was 75 years (range 70 to 96). During a median 4.5 years of follow-up, 324 (2.5%) participants developed dementia and 503 (3.8%) died. Cumulative incidence of dementia to age 85 years was estimated to be 7.4% in all participants, 12.6% in APOE ε4 heterozygotes, 26.6% in ε4 homozygotes, 9.6% in the high PRS tertile, and 7.3% in the low PRS tertile. APOE ε4 heterozygosity/homozygosity was associated with a 2.5/6.3-fold increased risk of dementia and a 1.4/1.8-fold increased risk of cognitive decline, versus ε3/ε3 (P<0.001 for both). A high PRS (top tertile) was associated with a 1.4-fold increase risk of dementia, versus the low tertile (CI 1.04-1.76, P=0.02), but was not associated with cognitive decline risk (CI 0.96-1.22, P = 0.18).Conclusions and RelevanceIncidence of dementia among healthy older individuals is low across all genotypes; however, APOE ε4 and high PRS increase relative risk. APOE ε4 is associated with cognitive decline, but PRS is not.KEY POINTSQuestionHow do genetic factors influence the risk of dementia and cognitive decline among healthy older individuals?FindingsWe studied cumulative incidence of dementia and cognitive decline in 12,978 healthy older individuals without cardiovascular disease or cognitive impairment at enrollment, stratified by APOE genotype and a polygenic risk score (PRS). APOE ε4 and PRS increased the relative risk of dementia, but cumulative incidence was low across all genotypes. APOE genotypes were associated with cognitive decline, but PRS was not.MeaningIncidence of dementia is low among healthy older individuals; however, genetic factors still increase relative risk.

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Capturing additional genetic risk from family history for improved polygenic risk prediction

10.1101/2022.01.06.22268853 ◽

2022 ◽

Author(s):

Tianyuan Lu ◽

Vincenzo Forgetta ◽

J Brent Richards ◽

Celia MT Greenwood

Keyword(s):

Family History ◽

Risk Prediction ◽

Risk Score ◽

Genetic Risk ◽

Adult Height ◽

Prediction Models ◽

European Ancestry ◽

Polygenic Risk Score ◽

Parental History ◽

Polygenic Risk

Family history of complex traits may reflect transmitted rare pathogenic variants, intrafamilial shared exposures to environmental and lifestyle factors, as well as a common genetic predisposition. We developed a latent factor model to quantify trait heritability in excess of that captured by a common variant-based polygenic risk score, but inferable from family history. We applied our model to predict adult height for 941 children in the Avon Longitudinal Study of Parents and Children cohort as well as 11 complex diseases for ~400,000 European ancestry participants in the UK Biobank. Parental history brought consistent significant improvements in the predictive power of polygenic risk prediction. For instance, a joint predictor was able to explain ~55% of the total variance in sex-adjusted adult height z-scores, close to the estimated heritability. Our work showcases an innovative paradigm for risk calculation, and supports incorporation of family history into polygenic risk score-based genetic risk prediction models.

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