Genetic analysis in European ancestry individuals identifies 517 loci associated with liver enzymes

AbstractSerum concentration of hepatic enzymes are linked to liver dysfunction, metabolic and cardiovascular diseases. We perform genetic analysis on serum levels of alanine transaminase (ALT), alkaline phosphatase (ALP) and gamma-glutamyl transferase (GGT) using data on 437,438 UK Biobank participants. Replication in 315,572 individuals from European descent from the Million Veteran Program, Rotterdam Study and Lifeline study confirms 517 liver enzyme SNPs. Genetic risk score analysis using the identified SNPs is strongly associated with serum activity of liver enzymes in two independent European descent studies (The Airwave Health Monitoring study and the Northern Finland Birth Cohort 1966). Gene-set enrichment analysis using the identified SNPs highlights involvement in liver development and function, lipid metabolism, insulin resistance, and vascular formation. Mendelian randomization analysis shows association of liver enzyme variants with coronary heart disease and ischemic stroke. Genetic risk score for elevated serum activity of liver enzymes is associated with higher fat percentage of body, trunk, and liver and body mass index. Our study highlights the role of molecular pathways regulated by the liver in metabolic disorders and cardiovascular disease.

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Abstract P229: Genetic Risk Scores are Associated with Chronic Venous Disease Prevalence and Severity in a Multi-Ethnic Cohort: The San Diego Population Study (SDPS)

Circulation ◽

10.1161/circ.125.suppl_10.ap229 ◽

2012 ◽

Vol 125 (suppl_10) ◽

Author(s):

Christina L Wassel ◽

Laura J Rasmussen-Torvik ◽

Peter W Callas ◽

Julie O Denenberg ◽

Peter Durda ◽

...

Keyword(s):

Ethnic Group ◽

Risk Score ◽

Genetic Risk ◽

Genetic Risk Score ◽

Disease Prevalence ◽

Chronic Venous Disease ◽

Risk Scores ◽

Venous Disease ◽

European Descent ◽

The Difference

Background: Chronic venous disease is common, affecting up to 40% of the population, although estimates vary quite widely due to differing evaluation methods and definitions. Chronic venous disease shares some risk factors with venous thromboembolism (VTE). Several genetic loci have been recently discovered and replicated for VTE, mostly in populations of European descent. We tested associations of these loci, as well as a genetic risk score including these variants, with chronic venous disease prevalence and severity in a multi-ethnic cohort. Methods: The San Diego Population Study (SDPS) is a prospective cohort study that evaluated 2404 ethnically diverse men and women aged 29-91 for venous disease using duplex ultrasound. The current study includes 1229 participants from the baseline exam who were genotyped for 35 variants in 23 loci. Venous disease was defined as moderate or severe, as well as severe only. Logistic regression was used to examine the association of each variant with venous disease, stratified by ethnic group. A weighted genetic risk score, using the top 20% of variants and weighting by the beta coefficients, was generated for each ethnic group. Associations of this risk score with venous disease were examined stratified by ethnic group. Results: The mean ± standard deviation (SD) age was 60±11, with 64% female, and 62% White, 14% Hispanic, 11% African-American, and 12% Asian. The prevalence of moderate and severe venous disease was 41%, and severe venous disease alone was 25%. While some loci overlapped in the ethnic-specific genetic risk scores, others were exclusive to an ethnic group. In models adjusting for known venous disease risk factors, in Whites, Hispanics, African-Americans and Asians, respectively, each SD higher genetic risk score was associated with a 1.42-fold higher odds (95% CI (1.21, 1.66)), 2.06-fold higher odds (95% CI (1.44, 2.95)), a 2.25-fold higher odds (95% CI (1.38, 3.66)), and 2.45-fold higher odds (95% CI (1.57, 3.82)) for moderate or severe disease. The difference in c-statistics was statistically significant between the known venous risk factor model and this model adding the genetic risk factor for Hispanics, African-Americans, and Asians, with 0.67 vs. 0.75 (p=0.03), 0.69 vs. 0.77 (p=0.02), 0.63 vs. 0.74 (p=0.01), respectively. The difference was not significant for Whites, 0.64 vs. 0.66 (p=0.12). All results were similar for severe venous disease only. Conclusions: This ethnic-specific genetic risk score is strongly associated with chronic venous disease, and may be of greater importance for venous disease in those of non-European descent. Future work should focus on examining racial/ethnic group genetic architecture in relation to venous disease.

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1535-P: An Insulin Resistance Genetic Risk Score (IR_GRS) Is Associated with Mortality in Type 1 Diabetes (T1D)

Diabetes ◽

10.2337/db19-1535-p ◽

2019 ◽

Vol 68 (Supplement 1) ◽

pp. 1535-P

Author(s):

RACHEL G. MILLER ◽

TINA COSTACOU ◽

SUNA ONENGUT-GUMUSCU ◽

WEI-MIN CHEN ◽

STEPHEN S. RICH ◽

...

Keyword(s):

Insulin Resistance ◽

Type 1 Diabetes ◽

Risk Score ◽

Genetic Risk ◽

Genetic Risk Score

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Generalization of a genetic risk score for time to first albuminuria in children with sickle cell anaemia: SCCRIP cohort study results

British Journal of Haematology ◽

10.1111/bjh.17647 ◽

2021 ◽

Author(s):

Sara R. Rashkin ◽

Evadnie Rampersaud ◽

Guolian Kang ◽

Kenneth I. Ataga ◽

Jane S. Hankins ◽

...

Keyword(s):

Cohort Study ◽

Sickle Cell ◽

Risk Score ◽

Genetic Risk ◽

Sickle Cell Anaemia ◽

Genetic Risk Score ◽

Study Results

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Genetic risk score predicts prostate cancer incidence and mortality

Nature Reviews Urology ◽

10.1038/s41585-021-00422-y ◽

2021 ◽

Author(s):

Tim Thomas

Keyword(s):

Prostate Cancer ◽

Risk Score ◽

Cancer Incidence ◽

Genetic Risk ◽

Genetic Risk Score ◽

Prostate Cancer Incidence ◽

Incidence And Mortality

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Identifying individuals with high risk of Alzheimer’s disease using polygenic risk scores

Nature Communications ◽

10.1038/s41467-021-24082-z ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Ganna Leonenko ◽

Emily Baker ◽

Joshua Stevenson-Hoare ◽

Annerieke Sierksma ◽

Mark Fiers ◽

...

Keyword(s):

High Risk ◽

Risk Score ◽

Genetic Risk ◽

Prediction Accuracy ◽

Genetic Risk Score ◽

Low Risk ◽

Risk Scores ◽

Sample Mean ◽

Polygenic Risk ◽

Reliable Identification

AbstractPolygenic Risk Scores (PRS) for AD offer unique possibilities for reliable identification of individuals at high and low risk of AD. However, there is little agreement in the field as to what approach should be used for genetic risk score calculations, how to model the effect of APOE, what the optimal p-value threshold (pT) for SNP selection is and how to compare scores between studies and methods. We show that the best prediction accuracy is achieved with a model with two predictors (APOE and PRS excluding APOE region) with pT<0.1 for SNP selection. Prediction accuracy in a sample across different PRS approaches is similar, but individuals’ scores and their associated ranking differ. We show that standardising PRS against the population mean, as opposed to the sample mean, makes the individuals’ scores comparable between studies. Our work highlights the best strategies for polygenic profiling when assessing individuals for AD risk.

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Association of a Genetic Risk Score With Body Mass Index

JAMA ◽

10.1001/jama.2016.14933 ◽

2016 ◽

Vol 316 (17) ◽

pp. 1825

Author(s):

Marcus R. Munafò ◽

Kate Tilling ◽

George Davey Smith

Keyword(s):

Body Mass Index ◽

Body Mass ◽

Risk Score ◽

Genetic Risk ◽

Genetic Risk Score

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243-OR: Integrating Genetic Risk Score and Islet Autoantibody Characteristics in the Predictive Model for Type 1 Diabetes in the TrialNet Study

Diabetes ◽

10.2337/db21-243-or ◽

2021 ◽

Vol 70 (Supplement 1) ◽

pp. 243-OR

Author(s):

LAURIC A. FERRAT ◽

ANDREA STECK ◽

HEMANG M. PARIKH ◽

LU YOU ◽

SUNA ONENGUT-GUMUSCU ◽

...

Keyword(s):

Type 1 Diabetes ◽

Predictive Model ◽

Risk Score ◽

Genetic Risk ◽

Genetic Risk Score ◽

Islet Autoantibody

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Mendelian Randomization Focused Analysis of Vitamin D on the Secondary Prevention of Ischemic Stroke

Stroke ◽

10.1161/strokeaha.120.032634 ◽

2021 ◽

Author(s):

Yap-Hang Chan ◽

C. Mary Schooling ◽

Jie Zhao ◽

Shiu-Lun Au Yeung ◽

Jo Jo Hai ◽

...

Keyword(s):

Myocardial Infarction ◽

Vitamin D ◽

Ischemic Stroke ◽

Risk Score ◽

Genetic Risk ◽

Odds Ratio ◽

Mendelian Randomization ◽

De Novo ◽

Genetic Risk Score ◽

Ischemic Disease

Background and Purpose: Experimental studies showed vitamin D (Vit-D) could promote vascular regeneration and repair. Prior randomized studies had focused mainly on primary prevention. Whether Vit-D protects against ischemic stroke and myocardial infarction recurrence among subjects with prior ischemic insults was unknown. Here, we dissected through Mendelian randomization any effect of Vit-D on the secondary prevention of recurrent ischemic stroke and myocardial infarction. Methods: Based on a genetic risk score for Vit-D constructed from a derivation cohort sample (n=5331, 45% Vit-D deficient, 89% genotyped) via high-throughput exome-chip screening of 12 prior genome-wide association study–identified genetic variants of Vit-D mechanistic pathways ( rs2060793 , rs4588 , and rs7041 ; F statistic, 73; P <0.001), we performed a focused analysis on prospective recurrence of myocardial infarction (MI) and ischemic stroke in an independent subsample with established ischemic disease (n=441, all with prior first ischemic event; follow-up duration, 41.6±14.3 years) under a 2-sample, individual-data, prospective Mendelian randomization approach. Results: In the ischemic disease subsample, 11.1% (n=49/441) had developed recurrent ischemic stroke or MI and 13.3% (n=58/441) had developed recurrent or de novo ischemic stroke/MI. Kaplan-Meier analyses showed that genetic risk score predicted improved event-free survival from recurrent ischemic stroke or MI (log-rank, 13.0; P =0.001). Cox regression revealed that genetic risk score independently predicted reduced risk of recurrent ischemic stroke or MI combined (hazards ratio, 0.62 [95% CI, 0.48–0.81]; P <0.001), after adjusted for potential confounders. Mendelian randomization supported that Vit-D is causally protective against the primary end points of recurrent ischemic stroke or MI (Wald estimate: odds ratio, 0.55 [95% CI, 0.35–0.81]) and any recurrent or de novo ischemic stroke/MI (odds ratio, 0.64 [95% CI, 0.42–0.91]) and recurrent MI alone (odds ratio, 0.52 [95% CI, 0.30–0.81]). Conclusions: Genetically predicted lowering in Vit-D level is causal for the recurrence of ischemic vascular events in persons with prior ischemic stroke or MI.

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