Use Of Genetic Risk Score Research Articles

Use of PNPLA3, TM6SF2, and HSD17B13 for detection of fibrosis in MASLD in the general population

BackgroundGenetic testing can be used to evaluate disease risk. We evaluated if the use of three Single Nucleotide Polymorphisms (SNPs), alone or combined into a genetic risk score (GRS), can aid identify significant fibrosis in subjects with metabolic dysfunction-associated steatotic liver disease (MASLD). MethodsWe assessed three known risk variants: PNPLA3 rs738409, TM6SF2 rs58542926, and HSD17B13 rs72613567. The study included 414 adult individuals invited from the Danish population, who were defined as at-risk of MASLD due to elevated ALT and body mass index (BMI) >25 kg/m2. Participants were assessed clinically and by the Fibrosis-4 (FIB-4) index and Fibroscan. ResultsIn total, 17 participants (4.1 %) had alcohol-related liver disease, 79 (19.1 %) had no evidence of liver disease, and four (1.0 %) were diagnosed with other liver diseases, including malignant disease. The remaining 314 participants (75.8 %) were diagnosed with MASLD. Of the 27 who underwent a liver biopsy for suspected fibrosis, 15 had significant fibrosis (≥F2) and 12 had no/mild fibrosis (F0/F1). The GRS was not associated with significant fibrosis (p = 0.09) but PNPLA3 was with an odds ratio of 6.75 (95 % CI 1.29 – 50.7; p = 0.039) risk allele CG/GG versus CC. The diagnostic accuracy of PNPLA3 combined with an increased Fib-4 (>1.3) was excellent for detecting significant fibrosis with a sensitivity of 1.00 (95 % CI 0.72–1.00), but the specificity was no better than for FIB-4 alone. ConclusionsThis study found no evidence to support the use of GRS for diagnosing significant fibrosis in MASLD. However, the combination of PNPLA3 and Fib-4 increased sensitivity considerably. In addition, ALT remains a useful tool for screening diagnosing other liver diseases than MASLD.

Validation of genetic risk scores for obesity on a sample of the population of Russian regions

Aim. To validate and evaluate the accuracy of 15 genetic risk scores (GRSs) for obesity, created in populations of European origin in the sample of two European Russia regions. Material and methods. Genetic testing has been performed using next generation sequencing on a sample from the Russian population (n=1179). The study included 15 GRS associated with body mass index (BMI) or waist-to-hip ratio adjusted for BMI (WHRadjBMI).Results. The predictive power of 8 out of 9 GRSs for obesity based on BMI remains the same for the Russian population. The predictive power of 6 GRSs for obesity based on WHRadjBMI is lower in the Russian population than in the reference sample. GRS reproducibility increases with the size of initial samples and number of variants included in the GRS increase. The use of GRSs for obesity based on BMI in the Russian population created on European populations is justified.Conclusion. For the first time in Russia, 15 obesity GRSs developed in European populations have been validated. The data obtained on the effectiveness of the considered GRS can be used in the future to improve the obesity prediction and prevention in Russia.

Genetic risk scores: are they important for diabetes management? results from multiple cross-sectional studies

BackgroundSeveral genetic risk scores (GRS) for type 2 diabetes (T2DM) have been published, but not replicated. We aimed to 1) replicate previous findings on the association between GRS on prevalence of T2DM and 2) assess the association between GRS and T2DM management in a sample of community-dwelling people from Switzerland.MethodsFour waves from a prospective study conducted in Lausanne. Seven GRS related to T2DM were selected, and compared between participants with and without T2DM, and between controlled and uncontrolled participants treated for T2DM.ResultsData from 5426, 4017, 2873 and 2170 participants from the baseline, first, second and third follow-ups, respectively, was used. In all study periods, participants with T2DM scored higher than participants without T2DM in six out of seven GRS. Data from 367, 437, 285 and 207 participants with T2DM was used. In all study periods, approximately half of participants treated for T2DM did not achieve adequate fasting blood glucose or HbA1c levels, and no difference between controlled and uncontrolled participants was found for all seven GRS. Power analyses showed that most GRS needed a sample size above 1000 to consider the difference between controlled and uncontrolled participants as statistically significant at p = 0.05.ConclusionIn this study, we confirmed the association between most published GRS and diabetes. Conversely, no consistent association between GRS and diabetes control was found. Use of GRS to manage patients with T2DM in clinical practice is not justified.

Type 1 diabetes in diverse ancestries and the use of genetic risk scores

Type 1 diabetes in diverse ancestries and the use of genetic risk scores

The body mass index increases the genetic risk scores' ability to predict risk of hepatic damage in European adolescents: The HELENA study.

Hepatic disorders are often complex and multifactorial, modulated by genetic and environmental determinants. During the last years, the hepatic disease has been progressively established from early stages in life. The use of genetic risk scores (GRS) to predict the genetic susceptibility to a particular phenotype among youth has gained interest in recent years. Moreover, the alanine aminotransferase (ALT) blood biomarker is often considered as hepatic screening tool, in combination with imaging techniques. The aim of the present study was to develop an ALT-specific GRS to help in the evaluation of hepatic damage risk in European adolescents. A total of 972 adolescents (51.3% females), aged 12.5-17.5 years, from the Healthy Lifestyle in Europe by Nutrition in Adolescence study were included in the analyses. The sample incorporated adolescents in all body mass index (BMI) categories and was divided considering healthy/unhealthy ALT levels, using sex-specific cut-off points. From 1212 a priori ALT-related single nucleotide polymorphisms (SNPs) extracted from candidate gene selection, a first screening of 234 SNPs univariately associated was established, selecting seven significant SNPs (p < .05) in the multivariate model. An unweighted GRS (uGRS) was developed by summing the number of reference alleles, and a weighted GRS (wGRS), by multiplying each allele to its estimated coefficient. The uGRS and wGRS were significantly associated with ALT (p < .001). The area under curve was obtained integrating BMI as clinical factor, improving the predictive ability for uGRS (.7039) and wGRS (.7035), using 10-fold internal cross-validation. Considering BMI status, both GRSs could contribute as complementary tools to help in the early diagnosis of hepatic damage risk in European adolescents.

Genetic Risk Score Constructed from Polymorphisms in the VEGFA, TBX5, and SMAD7 Genes Provides Novel Insights into the Molecular Mechanisms of the Tetralogy of Fallot and Ventricular Septal Defect (Case-Control Study from the Pakistani Population)

Congenital heart defects are common and complex birth-defect malformations in developed and developing countries. It is a multifactorial disease that involves the interaction of either gene-gene or gene-environment. This comparative study was the first report on the genotypic-phenotypic correlation in the Pakistani population. The single nucleotide polymorphisms (SNPs) were further tested for association with maternal diabetes mellitus or hypertension. In addition, the cumulative genetic risk score (GRS) for low to moderately-associated SNPs was calculated for each study subject, which can ultimately guide us for better therapeutic options and prevention strategies. According to the predefined selection criteria, 376 subjects were recruited. The multiplex mini-sequencing genotyping technique opted for the cost-effective genotyping of selected loci. The association of variants with the disease was examined using logistic regression analysis. The statistical and graphical analysis was conducted using SPSS, Haploview, SNPStats, and GraphPad Prism. The results for all SNPs analysis suggested a nonsignificant association with overall congenital heart defect risk except rs3809923. However, interestingly on stratified analysis variants, rs3809923 and rs3809922 showed an association only with tetralogy of Fallot. The remaining risk factor analysis for maternal hypertension and diabetes mellitus association with SNPs were nonsignificant. The GRS was the first time constructed for this low to moderately-associated variants. Interestingly, the cumulative GRS was significantly different from the control group revealing the cumulative effect of these polymorphisms panel in patients. In conclusion, the use of GRS in the clinical setting can predict better risk association and patient outcomes.

Genetic Risk Score for Prediction of Coronary Heart Disease in the Korean Genome and Epidemiology Study.

Using a genetic risk score (GRS) to predict coronary heart disease (CHD) may detect disease earlier. The current study aims to assess whether GRS is associated with CHD incidence and whether it is clinically useful for improving prediction using traditional risk factors (TRFs) as well as family history. Data from a total of 48,941 participants in the Korean Genome and Epidemiology Study were analyzed in the current study. The weighted GRS was constructed using 55 single-nucleotide polymorphisms based on published genome-wide association studies. The association of GRS with incident CHD was analyzed using Cox proportional hazard model. Discrimination and reclassification were assessed to demonstrate the clinical utility of GRS. The analyses were performed separately by sex. After adjusting for family history and TRFs, GRS was significantly associated with CHD incidence in men; compared to the low GRS group, men in the high GRS group had a 2.07-fold increased risk of CHD (95% confidence interval [CI]: 1.51-2.85). In men, the combination of TRFs, family history, and GRS had better performance than TRFs alone (C statistics for TRF-only model, 0.66, 95% CI, 0.64-0.69; C statistics for combination model, 0.68, 95% CI, 0.65-0.71; category-free reclassification index, 15%). In women, however, there was no significant association between GRS and CHD and no improvement between models. GRS was associated with CHD incidence and contributed to a small improvement of CHD prediction in men. The potential clinical use of GRS may not outweigh the value of family history.

Association of clinical and genetic risk factors with management of dyslipidaemia: analysis of repeated cross-sectional studies in the general population of Lausanne, Switzerland

ObjectivesTo assess the importance of clinical and genetic factors in management of dyslipidaemia in the general population.DesignRepeated cross-sectional studies (2003–2006; 2009–2012 and 2014–2017) from a population-based cohort.SettingSingle centre in Lausanne,...

Diagnostic Test Accuracy of Genetic Tests in Diagnosing Psoriasis: A Systematic Review.

The pathogenesis of psoriasis involves the interaction of several environmental and genetic factors. Predicting the disease risk cannot depend on individual genetic alleles. Consequently, some studies have evaluated the use of genetic risk scores that combine several psoriasis susceptibility loci to increase the accuracy of predicting/diagnosing the disease. This meta-analysis summarizes the evidence regarding using genetic risk scores (GRS) in the diagnosis or prediction of psoriasis. A search of MEDLINE/PubMed, the Latin American Caribbean Health Sciences Literature (LILACS) database, Cochrane Library, Scopus, Web of Science, and ProQuest was conducted in July 2022. The primary objective was to record the area under the curve (AUC) for GRS of psoriasis. Secondary objectives included characteristics of studies and patients. The risk of bias (ROB) was assessed using the PROBAST tool. Five studies fulfilled the eligibility criteria of this review. None of the studies described the clinical criteria (reference standard) that were employed to diagnose psoriasis. The AUCs of the 11 GRS models ranged from 0.6029-0.8583 (median: 0.75). Marked heterogeneity was detected (Cochran Q: 1250.051, p < 0.001, and I2 index: 99.2%). So, pooling of the results of the included studies was not performed. The ROB was high for all studies and clinical application was not described. Genetic risk scores are promising tools for the prediction of psoriasis with fair to good accuracy. However, further research is required to identify the most accurate combination of loci and to validate the scores in variable ethnicities.

Association between genetic risk of high SBP and hypertension control: the CoLaus|PsyColaus study.

To assess whether a genetic risk score (GRS) for high SBP is associated with poor control of hypertension. Data from the four waves of a population-based, prospective study conducted in Lausanne, Switzerland. Control of hypertension was defined based on SBP less than 140 mmHg and DBP less than 90 mmHg. A weighted GRS was computed from 362 SNPs. Overall, 1097 (51% men, mean age 61 years), 1126 (53% men, age 65 years), 1020 (52% men, age 69 years) and 809 (50% men, age 71 years) participants treated for hypertension were selected from the baseline (2003-2006), first (2009-2012), second (2014-2017) and third (2018-2021) surveys. Hypertension control rates were 50, 58, 52 and 59% for the baseline, first, second and third surveys, respectively. No association was found between GRS and hypertension control: multivariate-adjusted mean ± standard error for controlled vs. uncontrolled participants: 9.30 ± 0.09 vs. 9.50 ± 0.09 ( P = 0.12); 9.32 ± 0.08 vs. 9.53 ± 0.10 ( P = 0.10); 9.17 ± 0.08 vs. 9.34 ± 0.11 ( P = 0.22), and 9.18 ± 0.09 vs. 9.46 ± 0.11 ( P = 0.07) for the baseline, first, second and third surveys, respectively. Power analysis showed that a minimum of 3410 people treated for hypertension would be necessary to detect an association between the GRS and hypertension control rates. Notably, positive associations between the GRS and SBP levels were found among participants not treated for hypertension, with Spearman correlations ranging between 0.05 and 0.09 (all P < 0.05). Using a GRS associated with SBP levels is not predictive of hypertension control. The use of GRS for hypertension management is not warranted in clinical practice.

Local genetic variation of inflammatory bowel disease in Basque population and its effect in risk prediction

Inflammatory bowel disease (IBD) is characterised by chronic inflammation of the gastrointestinal tract. Although its aetiology remains unknown, environmental and genetic factors are involved in its development. Regarding genetics, more than 200 loci have been associated with IBD but the transferability of those signals to the Basque population living in Northern Spain, a population with distinctive genetic background, remains unknown. We have analysed 5,411,568 SNPs in 498 IBD cases and 935 controls from the Basque population. We found 33 suggestive loci (p < 5 × 10−6) in IBD and its subtypes, namely Crohn’s Disease (CD) and Ulcerative Colitis (UC), detecting a genome-wide significant locus located in HLA region in patients with UC. Those loci contain previously associated genes with IBD (IL23R, JAK2 or HLA genes) and new genes that could be involved in its development (AGT, BZW2 or FSTL1). The overall genetic correlation between European populations and Basque population was high in IBD and CD, while in UC was lower. Finally, the use of genetic risk scores based on previous GWAS findings reached area under the curves > 0.68. In conclusion, we report on the genetic architecture of IBD in the Basque population, and explore the performance of European-descent genetic risk scores in this population.

From biobanking to personalized prevention of obesity, diabetes and metabolic syndrome

The growing prevalence of metabolic disorders creates an increasing demand for novel approaches to their prevention and therapy. Novel genetic diagnostic technologies are developed every year, which makes it possible to identify people who are at the highest genetic risk of diabetes, non-alcoholic fatty liver disease, and metabolic syndrome. Early intervention strategies can be used to prevent metabolic disorders in this group of people. Genetic risk scores (GRSs) are a powerful tool to identify people with a high genetic risk. Millions of genetic variants are analyzed in genome-wide association studies in order to combine them into GRSs. It has become possible to store and process such huge amounts of data with the help of biobanks, where biological samples are stored according to international standards. Genetic studies include more and more people every year that increases the predictive power of GRSs. It has already been demonstrated that the use of GRSs makes future preventive measures more effective. In the near future, GRSs are likely to become part of clinical guidelines so that they can be widely used to identify people at high risk for metabolic syndrome and its components.

Polygenic contribution for familial hypercholesterolemia (FH).

The present review summarizes different polygenic risk scores associated with hypercholesterolemia applied to cohorts with a genetic diagnosis of familial hypercholesterolemia (FH). Several single-nucleotide polymorphisms associated with increased levels of LDL-C or Lp(a) have been genotyped in population cohorts with FH phenotype, to identify the cause of hypercholesterolemia in mutation negative individuals. In different studies, a large proportion of individuals without a monogenic causative variant (in low density lipoprotein receptor gene (LDLR), apolipoprotein B gene (APOB) or proprotein convertase subtilisin/kexin type 9 gene (PCSK9 genes) was considered to have a hypercholesterolemia with a polygenic basis. The heterogeneity in the phenotype of monogenic FH may also be explained by polygenic contributions to LDL-C. The elevated LDL-C genetic risk score (GRS) has been associated with increased risk of atherosclerotic cardiovascular disease in individuals with monogenic FH. Moreover, a poorer response to lipid lowering therapy has been associated with monogenic FH when compared to a polygenic basis. The reason why Lp(a) concentrations are raised in individuals with clinical FH is unclear, but it could be caused by a genetic variation in Lipoprotein(A) gene as a polygenic contribution. Polygenic risk scores have revealed to be important tools to define the cause of hypercholesterolemia in FH mutation-negative individuals and should be included in FH diagnosis strategies, although there is still space for more specific LDL-C GRS to be developed. The use of GRS may be used to refine cardiovascular risk prediction in FH patients and could lead to a personalized approach to therapy. The identification of the genetic status of an individual with FH phenotype (monogenic or polygenic) may have implications on their risk stratification, cascade screening of relatives, disease management and therapeutic measures.

Genetics of Cardiovascular Disease: How Far Are We from Personalized CVD Risk Prediction and Management?

Despite the rapid progress in diagnosis and treatment of cardiovascular disease (CVD), this disease remains a major cause of mortality and morbidity. Recent progress over the last two decades in the field of molecular genetics, especially with new tools such as genome-wide association studies, has helped to identify new genes and their variants, which can be used for calculations of risk, prediction of treatment efficacy, or detection of subjects prone to drug side effects. Although the use of genetic risk scores further improves CVD prediction, the significance is not unambiguous, and some subjects at risk remain undetected. Further research directions should focus on the “second level” of genetic information, namely, regulatory molecules (miRNAs) and epigenetic changes, predominantly DNA methylation and gene-environment interactions.

Genetic risk scores for cardiometabolic traits in sub-Saharan African populations.

There is growing support for the use of genetic risk scores (GRS) in routine clinical settings. Due to the limited diversity of current genomic discovery samples, there are concerns that the predictive power of GRS will be limited in non-European ancestry populations. GRS for cardiometabolic traits were evaluated in sub-Saharan Africans in comparison with African Americans and European Americans. We evaluated the predictive utility of GRS for 12 cardiometabolic traits in sub-Saharan Africans (AF; n = 5200), African Americans (AA; n = 9139) and European Americans (EUR; n = 9594). GRS were constructed as weighted sums of the number of risk alleles. Predictive utility was assessed using the additional phenotypic variance explained and the increase in discriminatory ability over traditional risk factors [age, sex and body mass index (BMI)], with adjustment for ancestry-derived principal components. Across all traits, GRS showed up to a 5-fold and 20-fold greater predictive utility in EUR relative to AA and AF, respectively. Predictive utility was most consistent for lipid traits, with percentage increase in explained variation attributable to GRS ranging from 10.6% to 127.1% among EUR, 26.6% to 65.8% among AA and 2.4% to 37.5% among AF. These differences were recapitulated in the discriminatory power, whereby the predictive utility of GRS was 4-fold greater in EUR relative to AA and up to 44-fold greater in EUR relative to AF. Obesity and blood pressure traits showed a similar pattern of greater predictive utility among EUR. This work demonstrates the poorer performance of GRS in AF and highlights the need to improve representation of multiple ethnic populations in genomic studies to ensure equitable clinical translation of GRS.

Cost-Effectiveness of Polygenic Risk Profiling for Primary Open-Angle Glaucoma in the United Kingdom and Australia

Background: Primary open-angle glaucoma (POAG) is the most common subtype of glaucoma worldwide. We evaluate the cost-effectiveness of polygenic risk score (PRS) profiling as a screening tool for POAG. Methods: We used a Markov cohort model to evaluate the cost-effectiveness of implementing PRS screening in the UK and Australia, conducted from the healthcare payer’s perspective. We used published data to calculate prevalence, transition probabilities, utility and other parameters for each health state and age group. Our main outcome measure was the incremental cost-effectiveness ratio (ICER) and secondary outcomes were years of blindness avoided and a ‘Blindness ICER’. We did one-way as well as two-way deterministic and probabilistic sensitivity analyses. Results: Our proposed genetic screening programme for POAG in Australia is predicted to result in ICER of AU$34,252 (95% CI AU$21,324-95,497) and would avoid 1 year of blindness at ICER of AU$13,359 (95% CI: AU$8,143-37,448). In the UK, this screening is predicted to result in ICER of £24,783 (13,373-66,960) and would avoid 1 year of blindness at ICER of £10,095 (95%CI: £5,513-27,656). Findings were robust in all sensitivity analyses. Using the willingness to pay thresholds of $54,808 and £30,000, the proposed screening model is 79.2% likely to be cost-effective in Australia and is 60.2% likely to be cost-effective in the UK, respectively. Interpretation: We describe and model the cost-efficacy of incorporating a polygenic risk score for POAG screening in Australia and the UK for the first time and results indicated this is a promising cost-effectiveness strategy. Funding Statement: We had funding from a NHMRC Program grant (1150144), Partnership grant (1132454) and a Centre for Research Excellence grant (1116360). Declaration of Interests: S.M., J.E.C., and A.W.H. are listed as co-inventors on a patent application (WO2019241844A1) for the use of genetic risk scores to determine risk and guide treatment for glaucoma.

Genomic Diversity in Sporadic Breast Cancer in a Latin American Population.

Among Latin American women, breast cancer incidences vary across populations. Uruguay and Argentina have the highest rates in South America, which are mainly attributed to strong, genetic European contributions. Most genetic variants associated with breast cancer were described in European populations. However, the vast majority of genetic contributors to breast cancer risk remain unknown. Here, we report the results of a candidate gene association study of sporadic breast cancer in 176 cases and 183 controls in the Uruguayan population. We analyzed 141 variants from 98 loci that have been associated with overall breast cancer risk in European populations. We found weak evidence for the association of risk variants rs294174 (ESR1), rs16886165 (MAP3K1), rs2214681 (CNTNAP2), rs4237855 (VDR), rs9594579 (RANKL), rs8183919 (PTGIS), rs2981582 (FGFR2), and rs1799950 (BRCA1) with sporadic breast cancer. These results provide useful insight into the genetic susceptibility to sporadic breast cancer in the Uruguayan population and support the use of genetic risk scores for individualized screening and prevention.

The Role of Genetics in Cardiovascular Risk Reduction: Findings From a Single Lipid Clinic and Review of the Literature.

Genetic information is not routinely obtained in the management of most lipid disorders or in primary or secondary prevention of cardiovascular disease (CVD). We sought to determine the prevalence of pathogenic variants associated with lipoprotein metabolism or coronary artery disease (CAD) in a single lipid clinic and discuss the future use of genetic information in CVD prevention. Genetic testing was offered to patients with hypertriglyceridemia (defined as pre-treatment fasting triglycerides ≥150 mg/dL), elevated LDL-C (defined as pre-treatment ≥190 mg/dL), low HDL-C (defined as ≤40 mg/dL), elevated lipoprotein (a) (defined as ≥50 mg/dL or 100 nmol/L) or premature CAD (defined as an acute coronary syndrome or revascularization before age 40 years in men and 50 years in women) using next-generation DNA sequencing of 327 exons and selected variants in 129 genes known or suspected to be associated with lipoprotein metabolism or CAD. 82 of 84 patients (97.6%) were found to have a variant associated with abnormal lipid metabolism or CAD. The most common pathogenic or likely pathogenic variants included those of the LDL receptor (15 patients) and lipoprotein lipase (9 patients). Other common variants included those of apolipoprotein A5 (14 patients) and variants associated with elevated lipoprotein (a) (25 patients). The majority of patients presenting to a single lipid clinic were found to have at least one variant associated with abnormal lipoprotein metabolism or CAD. Incorporating genetic information, including the use of genetic risk scores, is anticipated in the future care of lipid disorders and CVD prevention.

Genetic Architecture of Primary Open-Angle Glaucoma in Individuals of African Descent: The African Descent and Glaucoma Evaluation Study III

To find genetic contributions to glaucoma in African Americans. Cross-sectional, case-control study. One thousand eight hundred seventy-five primary open-angle glaucoma (POAG) patients and 1709 controls, self-identified as being of African descent (AD), from the African Descent and Glaucoma Evaluation Study (ADAGES) III and Wake Forest School of Medicine. MegaChip genotypes were imputed to Thousand Genomes data. Association of single nucleotide polymorphisms (SNPs) with POAG and advanced POAG was tested by linear mixed model correcting for relatedness and population stratification. Genetic risk scores were tested by receiver operator characteristic curves (ROC-AUCs). Primary open-angle glaucoma defined by visual field loss without other nonocular conditions (n= 1875). Advanced POAG was defined by age-based mean deviation of visual field (n= 946). Eighteen million two hundred eighty-one thousand nine hundred twenty SNPs met imputation quality of r2 > 0.7 and minor allele frequency > 0.005. Association of a novel locus, EN04, was observed for advanced POAG (rs185815146 β, 0.36; standard error, 0.065; P < 3×10-8). For POAG, an AD signal was observed at the 9p21 European descent (ED) POAG signal (rs79721419; P < 6.5×10-5) independent of the previously observed 9p21 ED signal (rs2383204; P < 2.3×10-5) by conditional analyses. An association with POAG in FNDC3B (rs111698934; P < 3.9×10-5) was observed, not in linkage disequilibrium (LD) with the previously reported ED SNP. Additional previously identified loci associated with POAG in persons of AD were: 8q22, AFAP1, and TMC01. An AUC of 0.62 was observed with an unweighted genetic risk score comprising 11 SNPs in candidate genes. Two additional risk scores were studied by using a penalized matrix decomposition with cross-validation; risk scores of 50 and 400 SNPs were identified with ROC of AUC = 0.74 and AUC = 0.94, respectively. A novel association with advanced POAG in the EN04 locus was identified putatively in persons of AD. In addition to this finding, this genome-wide association study in POAG patients of AD contributes to POAG genetics by identification of novel signals in prior loci (9p21), as well as advancing the fine mapping of regions because of shorter average LD (FNDC3B). Although not useful without confirmation and clinical trials, the use of genetic risk scores demonstrated that considerable AD-specific genetic information remains in these data.

Genetic stratification for primary prevention of coronary artery disease.

To review the literature showing genetic risk variants is a reliable means of stratifying for risk of CAD for primary prevention. Over 90 genetic risk variants have been discovered that predispose to CAD. Results of several studies show that these risk variants effectively stratify for risk of CAD in asymptomatic individuals. The total individual genetic risk can be summarized into a single number referred to as the genetic risk score (GRS). The GRS unlike the Framingham Risk Score is not dependent on age and independent of conventional risk factors. As DNA does not change during one's lifetime the GRS can be calculated at birth or any time thereafter. Furthermore, the GRS has been shown to provide superior discriminatory power in selecting individuals who will benefit most from lifestyle changes or statin therapy. A prospective study showed individuals with high GRS and a favorable lifestyle was associated with significant reduction of cardiac events compared with an unfavorable lifestyle. Furthermore, the study shows inherited risk can be reduced analogous to reduction of risk form acquired and environmental factors. The use of GRS to stratify for risk of CAD in asymptomatic individuals could transform primary prevention worldwide.