Multi-ancestry polygenic risk scores for venous thromboembolism.

Venous thromboembolism (VTE) is a significant contributor to morbidity and mortality, with large disparities in incidence rates between Black and White Americans. Polygenic risk scores (PRSs) limited to variants discovered in genome-wide association studies in European-ancestry samples can identify European-ancestry individuals at high risk of VTE. However, there is limited evidence on whether high-dimensional PRS constructed using more sophisticated methods and more diverse training data can enhance the predictive ability and their utility across diverse populations. We developed PRSs for VTE using summary statistics from the International Network against Venous Thrombosis (INVENT) consortium GWAS meta-analyses of European- (71,771 cases and 1,059,740 controls) and African-ancestry samples (7,482 cases and 129,975 controls). We used LDpred2 and PRSCSx to construct ancestry-specific and multi-ancestry PRSs and evaluated their performance in an independent European- (6,261 cases and 88,238 controls) and African-ancestry sample (1,385 cases and 12,569 controls). Multi-ancestry PRSs with weights tuned in European- and African-ancestry samples, respectively, outperformed ancestry-specific PRSs in European- (PRSCSXEUR: AUC=0.61 (0.60, 0.61), PRSCSX_combinedEUR: AUC=0.61 (0.60, 0.62)) and African-ancestry test samples (PRSCSXAFR: AUC=0.58 (0.57, 0.6), PRSCSX_combined AFR: AUC=0.59 (0.57, 0.60)). The highest fifth percentile of the best-performing PRS was associated with 1.9-fold and 1.68-fold increased risk for VTE among European- and African-ancestry subjects, respectively, relative to those in the middle stratum. These findings suggest that the multi-ancestry PRS may be used to identify individuals at highest risk for VTE and provide guidance for the most effective treatment strategy across diverse populations.

Polygenic risk scores for prediction of breast cancer in Korean women.

BACKGROUND: Polygenic risk scores (PRSs) for breast cancer, developed using European and Asian genome-wide association studies (GWAS), have been shown to have good discrimination in Asian women. However, prospective calibration of absolute risk prediction models, based on a PRS or PRS combined with lifestyle, clinical and environmental factors, in Asian women is limited. METHODS: We consider several PRSs trained using European and/or Asian GWAS. For each PRS, we evaluate the discrimination and calibration of three absolute risk models among 41 031 women from the Korean Cancer Prevention Study (KCPS)-II Biobank: (i) a model using incidence, mortality and risk factor distributions (reference inputs) among US women and European relative risks; (ii) a recalibrated model, using Korean reference but European relative risks; and (iii) a fully Korean-based model using Korean reference and relative risk estimates from KCPS. RESULTS: All Asian and European PRS improved discrimination over lifestyle, clinical and environmental (Qx) factors in Korean women. US-based absolute risk models overestimated the risks for women aged ≥50 years, and this overestimation was larger for models that only included PRS (expected-to-observed ratio E/O = 1.2 for women <50, E/O = 2.7 for women ≥50). Recalibrated and Korean-based risk models had better calibration in the large, although the risk in the highest decile was consistently overestimated. Absolute risk projections suggest that risk-reducing lifestyle changes would lead to larger absolute risk reductions among women at higher PRS. CONCLUSIONS: Absolute risk models incorporating PRS trained in European and Asian GWAS and population-appropriate average age-specific incidences may be useful for risk-stratified interventions in Korean women.

Family History of Prostate and Breast Cancer Integrated with a Polygenic Risk Score Identifies Men at Highest Risk of Dying from Prostate Cancer before Age 75 Years.

PURPOSE: Family history of prostate cancer is one of the few universally accepted risk factors for prostate cancer. How much an assessment of inherited polygenic risk for prostate cancer adds to lifetime risk stratification beyond family history is unknown. EXPERIMENTAL DESIGN: We followed 10,120 men in the Health Professionals Follow-up Study with existing genotype data for risk of prostate cancer and prostate cancer-specific death. We assessed to what extent family history of prostate or breast cancer, combined with a validated polygenic risk score (PRS) including 269 prostate cancer risk variants, identifies men at risk of prostate cancer and prostate cancer death across the age span. RESULTS: During 20 years of follow-up, 1,915 prostate cancer and 166 fatal prostate cancer events were observed. Men in the top PRS quartile with a family history of prostate or breast cancer had the highest rate of both prostate cancer and prostate cancer-specific death. Compared with men at lowest genetic risk (bottom PRS quartile and no family history), the HR was 6.95 [95% confidence interval (CI), 5.57-8.66] for prostate cancer and 4.84 (95% CI, 2.59-9.03) for prostate cancer death. Men in the two upper PRS quartiles (50%-100%) or with a family history of prostate or breast cancer (61.8% of the population) accounted for 97.5% of prostate cancer deaths by age 75 years. CONCLUSIONS: Our study shows that prostate cancer risk stratification on the basis of family history and inherited polygenic risk can identify men at highest risk of dying from prostate cancer before age 75 years.

Stroke genetics informs drug discovery and risk prediction across ancestries.

Previous genome-wide association studies (GWASs) of stroke - the second leading cause of death worldwide - were conducted predominantly in populations of European ancestry1,2. Here, in cross-ancestry GWAS meta-analyses of 110,182 patients who have had a stroke (five ancestries, 33% non-European) and 1,503,898 control individuals, we identify association signals for stroke and its subtypes at 89 (61 new) independent loci: 60 in primary inverse-variance-weighted analyses and 29 in secondary meta-regression and multitrait analyses. On the basis of internal cross-ancestry validation and an independent follow-up in 89,084 additional cases of stroke (30% non-European) and 1,013,843 control individuals, 87% of the primary stroke risk loci and 60% of the secondary stroke risk loci were replicated (P < 0.05). Effect sizes were highly correlated across ancestries. Cross-ancestry fine-mapping, in silico mutagenesis analysis3, and transcriptome-wide and proteome-wide association analyses revealed putative causal genes (such as SH3PXD2A and FURIN) and variants (such as at GRK5 and NOS3). Using a three-pronged approach4, we provide genetic evidence for putative drug effects, highlighting F11, KLKB1, PROC, GP1BA, LAMC2 and VCAM1 as possible targets, with drugs already under investigation for stroke for F11 and PROC. A polygenic score integrating cross-ancestry and ancestry-specific stroke GWASs with vascular-risk factor GWASs (integrative polygenic scores) strongly predicted ischaemic stroke in populations of European, East Asian and African ancestry5. Stroke genetic risk scores were predictive of ischaemic stroke independent of clinical risk factors in 52,600 clinical-trial participants with cardiometabolic disease. Our results provide insights to inform biology, reveal potential drug targets and derive genetic risk prediction tools across ancestries.

Polygenic risk scores for prediction of breast cancer risk in Asian populations.

PURPOSE: Non-European populations are under-represented in genetics studies, hindering clinical implementation of breast cancer polygenic risk scores (PRSs). We aimed to develop PRSs using the largest available studies of Asian ancestry and to assess the transferability of PRS across ethnic subgroups. METHODS: The development data set comprised 138,309 women from 17 case-control studies. PRSs were generated using a clumping and thresholding method, lasso penalized regression, an Empirical Bayes approach, a Bayesian polygenic prediction approach, or linear combinations of multiple PRSs. These PRSs were evaluated in 89,898 women from 3 prospective studies (1592 incident cases). RESULTS: The best performing PRS (genome-wide set of single-nucleotide variations [formerly single-nucleotide polymorphism]) had a hazard ratio per unit SD of 1.62 (95% CI = 1.46-1.80) and an area under the receiver operating curve of 0.635 (95% CI = 0.622-0.649). Combined Asian and European PRSs (333 single-nucleotide variations) had a hazard ratio per SD of 1.53 (95% CI = 1.37-1.71) and an area under the receiver operating curve of 0.621 (95% CI = 0.608-0.635). The distribution of the latter PRS was different across ethnic subgroups, confirming the importance of population-specific calibration for valid estimation of breast cancer risk. CONCLUSION: PRSs developed in this study, from association data from multiple ancestries, can enhance risk stratification for women of Asian ancestry.

Validating Breast Cancer Risk Prediction Models in the Korean Cancer Prevention Study-II Biobank.

BACKGROUND: Risk prediction models may be useful for precision breast cancer screening. We aimed to evaluate the performance of breast cancer risk models developed in European-ancestry studies in a Korean population. METHODS: We compared discrimination and calibration of three multivariable risk models in a cohort of 77,457 women from the Korean Cancer Prevention Study (KCPS)-II. The first incorporated U.S. breast cancer incidence and mortality rates, U.S. risk factor distributions, and RR estimates from European-ancestry studies. The second recalibrated the first by using Korean incidence and mortality rates and Korean risk factor distributions, while retaining the European-ancestry RR estimates. Finally, we derived a Korea-specific model incorporating the RR estimates from KCPS. RESULTS: The U.S. European-ancestry breast cancer risk model was well calibrated among Korean women <50 years [expected/observed = 1.124 (0.989, 1.278)] but markedly overestimated the risk for those ≥50 years [E/O = 2.472 (2.005, 3.049)]. Recalibrating absolute risk estimates using Korean breast cancer rates and risk distributions markedly improved the calibration in women ≥50 [E/O = 1.018 (0.825, 1.255)]. The model incorporating Korean-based RRs had similar but not clearly improved performance relative to the recalibrated model. CONCLUSIONS: The poor performance of the U.S. European-ancestry breast cancer risk model among older Korean women highlights the importance of tailoring absolute risk models to specific populations. Recalibrating the model using Korean incidence and mortality rates and risk factor distributions greatly improved performance. IMPACT: The data will provide valuable information to plan and evaluate actions against breast cancer focused on primary prevention and early detection in Korean women.

Causal effect of alcohol consumption on hyperuricemia using a Mendelian randomization design.

AIM: We used a Mendelian randomization analysis to assess the causal effect of alcohol consumption on hyperuricemia in Koreans. METHODS: The Korean Cancer Prevention Study-II (KCPS-II) Biobank cohort consisted of 156 701 healthy Korean aged 20 years or older. Clinical data including serum uric acid, alcohol consumption, and other related confounding variables were collected at baseline. The 27 single nucleotide polymorphisms (SNP) including rs671 in aldehyde dehydrogenase 2 (ALDH2) were obtained from a genome-wide association study of alcohol consumption in the KCPS-II Biobank among 11 678 men and women in 2017. Both unweighted and weighted genetic risk score (wGRS) were calculated using 10 SNPs selected based on linkage disequilibrium. RESULTS: As strong instrumental variables, both rs671 and wGRS were associated with an increased amount of alcohol drinking in men and women. Alcohol consumption was also positively associated with hyperuricemia risk in men (P < .001) and women (P = .014). Both rs671 major G allele and wGRS were not associated with hyperuricemia. In Mendelian randomization analysis, the causal relationship between any alcohol consumption and hyperuricemia was found only in men, albeit non-significant after correction for multiple testing. The associations did not change after excluding heavy drinkers or the elderly. CONCLUSIONS: These results provide evidence that alcohol consumption is causally associated with risk of hyperuricemia in Korean men and support its role as a risk determinant.

Cohort study on the effects of depression on atherosclerotic cardiovascular disease risk in Korea.

OBJECTIVES: Depression has been reported to be a risk factor of cardiovascular disease in the western world, but the association has not yet been studied among Asian populations. The aim of this study was to investigate whether depression increases the risk of developing atherosclerotic cardiovascular disease (ASCVD) in a large Korean cohort study. DESIGN: Population based cohort study. SETTING: Database of National Health Insurance System, Republic of Korea. PARTICIPANTS: 481 355 Koreans (260 695 men and 220 660 women) aged 40-80 years who had a biennial health check-up between 2002 and 2005. MAIN OUTCOME MEASURE: The main outcome in this study was the first ASCVD event (hospital admission or death). RESULTS: Depression increased the risk of developing ASCVD by 41% for men and 48% for women. In men, 3-4 outpatient visits for depression increased the risk of angina pectoris by 2.12 times (95% CI 1.55 to 2.90) and acute myocardial infarction by 2.29 times (95% CI 1.33 to 3.95). Depression was also associated with stroke in men (HR 1.29, 95% CI 1.19 to 1.39) and in women (HR 1.37, 95% CI 1.29 to 1.46). However, no increased risk of ASCVD was found for men who received 10 or more depressive treatments, compared with those without any outpatient visit for depression. CONCLUSIONS: In this cohort, depressed people were at increased risk of ASCVD incidence. Therefore, individuals with depression may need routine monitoring of heart health that may prevent their future CVD risk.

Bilirubin and Stroke Risk Using a Mendelian Randomization Design.

BACKGROUND AND PURPOSE: Circulating bilirubin, a natural antioxidant, is associated with decreased risk of stroke. However, the nature of the relationship between the two remains unknown. We used a Mendelian randomization analysis to assess the causal effect of serum bilirubin on stroke risk in Koreans. METHODS: The 14 single-nucleotide polymorphisms (SNPs) (<10-7) including rs6742078 of uridine diphosphoglucuronyl-transferase were selected from genome-wide association study of bilirubin level in the KCPS-II (Korean Cancer Prevention Study-II) Biobank subcohort consisting of 4793 healthy Korean and 806 stroke cases. Weighted genetic risk score was calculated using 14 SNPs selected from the top SNPs. RESULTS: Both rs6742078 (F statistics=138) and weighted genetic risk score with 14 SNPs (F statistics=187) were strongly associated with bilirubin levels. Simultaneously, serum bilirubin level was associated with decreased risk of stroke in an ordinary least-squares analysis. However, in 2-stage least-squares Mendelian randomization analysis, no causal relationship between serum bilirubin and stroke risk was found. CONCLUSIONS: There is no evidence that bilirubin level is causally associated with risk of stroke in Koreans. Therefore, bilirubin level is not a risk determinant of stroke.

Metabolic Risk Score and Vascular Mortality Among Korean Adults.

Metabolic syndrome (MetS) is a cluster of cardiovascular risk factors. However, rather than using a dichotomous scale, a continuous metabolic syndrome (cMetS) score has been proposed to evaluate MetS because current MetS criteria do not function well in identifying those at high risk of cardiovascular mortality. The objective of this study was to examine the association between cMetS score and vascular mortality among Korean population. We included 441 411 individuals who visited health promotion centers and were given a medical examination from 1994 to 2004. MetS status, sum of MetS components, and cMetS score were calculated. The individuals with MetS had a higher hazard ratio (HR) for mortality from atherosclerotic vascular disease (HR = 1.54, 95% CI = 1.42-1.67), ischemic heart disease (HR = 1.74, 95% CI = 1.51-2.01), and total stroke (HR = 1.44, 95% CI = 1.28-1.62) when compared with those without MetS. Graded, strong associations between cMetS score and vascular mortality, particularly from ischemic heart disease and ischemic stroke, were observed. Subjects with a cMetS score ≥30 were at about 64 times greater risk for vascular mortality than those with a cMetS score below 0. cMetS score can be used to predict the risk of vascular death and provides a useful guideline to identify individuals at high risk for metabolic syndrome among Koreans.

Decreases in Smoking-Related Cancer Mortality Rates Are Associated with Birth Cohort Effects in Korean Men.

Background: This study aimed to examine trends in smoking-related cancer mortality rates and to investigate the effect birth cohort on smoking-related cancer mortality in Korean men. Methods: The number of smoking-related cancer deaths and corresponding population numbers were obtained from Statistics Korea for the period 1984-2013. Joinpoint regression analysis was used to detect changes in trends in age-standardized mortality rates. Birth-cohort specific mortality rates were illustrated by 5 year age groups. Results: The age-standardized mortality rates for oropharyngeal decreased from 2003 to 2013 (annual percent change (APC): -3.1 (95% CI, -4.6 to -1.6)) and lung cancers decreased from 2002 to 2013 (APC -2.4 (95% CI -2.7 to -2.2)). The mortality rates for esophageal declined from 1994 to 2002 (APC -2.5 (95% CI -4.1 to -0.8)) and from 2002 to 2013 (APC -5.2 (95% CI -5.7 to -4.7)) and laryngeal cancer declined from 1995 to 2013 (average annual percent change (AAPC): -3.3 (95% CI -4.7 to -1.8)). By the age group, the trends for the smoking-related cancer mortality except for oropharyngeal cancer have changed earlier to decrease in the younger age group. The birth-cohort specific mortality rates and age-period-cohort analysis consistently showed that all birth cohorts born after 1930 showed reduced mortality of smoking-related cancers. Conclusions: In Korean men, smoking-related cancer mortality rates have decreased. Our findings also indicate that current decreases in smoking-related cancer mortality rates have mainly been due to a decrease in the birth cohort effect, which suggest that decrease in smoking rates.

Alcohol Intake and Serum Glucose Levels from the Perspective of a Mendelian Randomization Design: The KCPS-II Biobank.

BACKGROUND: Previous studies have suggested that alcohol intake is associated with increased fasting serum glucose (FSG), but the nature of the relationship remains unknown. We used Mendelian randomization analysis to assess the causal effect of alcohol intake on FSG in a middle-aged Korean population. METHODS: Clinical data including FSG and alcohol intake were collected from 156,386 Koreans aged 20 years or older who took part in the Korean Cancer Prevention Study-II (KCPS-II) Biobank Cohort. The single nucleotide polymorphism rs671 in ALDH2 was genotyped among 2,993 men and 1,374 women in 2016. This was a randomly selected subcohort of KCPS-II Biobank participants. RESULTS: Alcohol consumption was positively associated with FSG level in men, but not in women. The rs671 major G allele was associated with increased alcohol intake (F-statistic = 302.62) and an increase in FSG in men. Using Mendelian randomization analysis, alcohol intake increased FSG by 1.78 mg/dL per alcohol unit (10 g ethanol) per day (95% CI: 0.97-2.59) in men. The associations became stronger when we excluded heavy drinkers and the elderly. However, in women, no significant association between rs671 and alcohol or serum glucose was found. CONCLUSION: Using Mendelian randomization analysis, we suggest a causal relationship between alcohol intake and FSG among Korean men. Moreover, we found that the ALDH2 variant rs671 was not associated with FSG among Korean women.

Effect of obesity on the association between MYL2 (rs3782889) and high-density lipoprotein cholesterol among Korean men.

High-density lipoprotein (HDL) cholesterol levels are associated with a decreased risk of coronary artery disease. Several genome-wide association studies that have examined HDL cholesterol levels have implicated myosin light chain 2 regulatory cardiac slow (MYL2) as a possible causal factor. Herein, the association between the rs3782889 single-nucleotide polymorphism (SNP) in the MYL2 gene and HDL cholesterol levels was tested in the Korean population. A total of 4294 individuals were included in a replication study with MYL2 SNP rs3782889. SNP rs3782889 in the MYL2 gene was associated with mean HDL cholesterol level (effect per allele, -1.055 mg dl(-1), P=0.0005). Subjects with the CT/CC genotype had a 1.43-fold (range 1.19-1.73-fold) higher risk of an abnormal HDL cholesterol level (<40 mg dl(-1)) than subjects with the TT genotype. When analyzed by sex, the MYL2 association was stronger in men than that in women. When analyzed by body mass index (BMI), the MYL2 association was much stronger in male subjects with BMI ⩾26.44 kg m(-2) (odds ratio (OR)=2.68; 95% confidence interval (CI)=1.87-3.84; P<0.0001) than that in male subjects with BMI <26.44 kg m(-2). When compared with subjects having the TT genotype and BMI <26.44 kg m(-2), ORs (95% CI) were 3.30 (2.41-4.50) in subjects having the CT/CC genotype and BMI ⩾26.44 kg m(-2) (P for interaction <0.0001). Our results clearly demonstrate that genetic variants in MYL2 influence HDL cholesterol levels in Korean obese male subjects.

Age-period-cohort analysis of the suicide rate in Korea.

BACKGROUND: The suicide rate has been increasing in Korea, and the country now has the highest rank in the world. This study aimed to present the long-term trends in Korea's suicide rate using Joinpoint analysis and age-period-cohort (APC) modeling. METHODS: The population and the number of suicides for each five-year age group were obtained from the National Statistical Office for the period 1984-2013 for Koreans aged 10 years and older. We determined the changes in the trends in age-standardized mortality rates using Joinpoint. APC modeling was performed to describe the trends in the suicide rate using the intrinsic estimator method. RESULTS: The age-standardized suicide rate in men rapidly increased from 1989 to 2004, and slightly increased thereafter, whereas the suicide rate in women increased from 1989 to 2009 and then decreased thereafter. Within the same period, the suicide rate was higher among the older age groups than in the younger groups. Within the same birth cohort, the suicide rate of the older groups was also higher than that in the younger groups. Within the same age group, the suicide rate of the younger cohorts was higher than it was in the older cohorts. In the APC modeling, old age, recent period, and having been born before 1924 were associated with higher suicide rates. LIMITATIONS: The accuracy and completeness of the suicide rate data may lead to bias. CONCLUSIONS: This study showed an increasing trend in the suicide rates for men and women after 1989. These trends may be mainly attributed to cohort effects.

Age-Period-Cohort Analysis of Liver Cancer Mortality in Korea.

BACKGROUND: Liver cancer is one of the most common causes of death in the world. In Korea, hepatitis B virus (HBV) is a major risk factor for liver cancer but infection rates have been declining since the implementation of the national vaccination program. In this study, we examined the secular trends in liver cancer mortality to distinguish the effects of age, time period, and birth cohort. MATERIALS AND METHODS: Data for the annual number of liver cancer deaths in Korean adults (30 years and older) were obtained from the Korean Statistical Information Service for the period from 1984-2013. Joinpoint regression analysis was used to study the shapes of and to detect the changes in mortality trends. Also, an age-period-cohort model was designed to study the effect of each age, period, and birth cohort on liver cancer mortality. RESULTS: For both men and women, the age-standardized mortality rate for liver cancer increased from 1984 to 1993 and decreased thereafter. The highest liver cancer mortality rate has shifted to an older age group in recent years. Within the same birth cohort group, the mortality rate of older age groups has been higher than in the younger age groups. Age-period-cohort analysis showed an association with a high mortality rate in the older age group and in recent years, whereas a decreasing mortality rate were observed in the younger birth cohort. CONCLUSIONS: This study confirmed a decreasing trend in liver cancer mortality among Korean men and women after 1993. The trends in mortality rate may be mainly attributed to cohort effects.