Unweighted Genetic Risk Score Research Articles

Addressing causal relationship between drinking behavior and metabolic syndrome: one-sample Mendelian randomization analysis.

Alcohol drinking is associated with central obesity, hypertension, and hyperlipidemia, which further causes metabolic syndrome (MetS). However, prior epidemiological studies on such associations lack experimental evidence for a causal relationship. This study aims to explore the causal relationship between drinking behavior and MetS in Taiwan population by using Mendelian randomization (MR) analysis. A cross-sectional study was conducted using the Taiwan Biobank database, which comprised 50 640 Han Chinese who were 30-70years old without cancer from 2008 to 2020. In MR analysis, we constructed weighted and unweighted genetic risk scores by calculating SNP alleles significantly associated with alcohol drinking. We calculated odds ratios and 95% confidence interval (CI) by using a two-stage regression model. A total of 50 640 participants were included with a mean age of 49.5years (SD: 1.67years), 36.6% were men. The adjusted odds ratio (aOR) of MetS per 5% increase in the likelihood of genetic predisposition to drink based on weighted genetic risk score with adjustment was 1.11 (95% CI: 1.10, 1.12, P < .001). Analysis was also conducted by grouping the likelihood of genetic predisposition to drink based on quartiles with multivariate adjustment. Using Q1 as the reference group, the aORs of MetS for Q2, Q3, and Q4 were 1.19 (1.12, 1.27, p < .001), 1.31 (1.23, 1.40, p < .001), and 1.87 (1.75, 2.00, p < .001), respectively, for the weighted genetic risk score. This study shows a modest relationship between drinking behavior and MetS by using MR analysis.

Investigation of the interaction between genetic risk score (GRS) and fatty acid quality indices on metabolic syndrome among overweight and obese women

Background and aimMetabolic syndrome is one of the major public-health challenges, affecting one-quarter of the world population. Fatty acid quality indices are novel determinants of this disease and their interactions with genetic factors may have an impact on metabolic syndrome risk. Therefore, we aimed to investigate the interaction between genetic risk score (GRS) and fatty acid quality indices with metabolic syndrome (MetS) among overweight and obese women.MethodsIn the present cross-sectional study, 279 overweight and obese women (18–48 years old) were included. Several anthropometric measurements such as weight, height, body mass index (BMI), waist circumference (WC), and body fat percent (BF%) were measured. Also, systolic and diastolic blood pressure (SBP and DBP) were measured. Biochemical determination was performed for fasting blood glucose (FBS), triglyceride (TG), and high-density lipoprotein (HDL). MetS was determined according to National Cholesterol Education Program (NCEP ATP III) criteria. Dietary intake was evaluated by a validated and reliable 147-item semi-quantitative food frequency questionnaire. Cholesterol-saturated fat index (CSI) and the ratio of omega-6/omega-3 (ω-6/ω-3) essential fatty acids were considered as fat quality indices. The salting-out method was used to extract the total DNA. The unweighted GRS was calculated using the risk alleles of the three single nucleotide polymorphisms. The total average GRS value was 2 and the sum of the risk alleles of the 3 polymorphisms was 6.ResultThe results of our analysis showed that after controlling for age, energy intake, BMI, and physical activity, there was a positive interaction between T2 of GRS and T2 of N6/N3 ratio on WC (β = 7.95, 95%CI = 0.83,15.08, P = 0.029), T3 of GRS and T2 of N6/N3 ratio on DBP (β = 5.93, 95%CI= -0.76,12.63, P = 0.083), and FBS (β = 6.47, 95%CI = 0.59,13.53, P = 0.073), T3 of GRS and T3 of N6/N3 ratio on TG (β = 54.42, 95%CI = 1.76,107.08, P = 0.043), and T3 of GRS and T3 of CSI on BF% (β = 3.55, 95%CI= -0.35,7.45, P = 0.075). Also T2 of GRS in the interaction with T3 of CSI leads to an decrease − 8.35 mg/dl in HDL level after adjustment in (β= -8.35, 95%CI= -17.34,0.62, P = 0.068).ConclusionIt seems the interaction of GRS and fatty acid quality indices is positively associated with several components of metabolic syndrome such as WC, TG and BF%. Our findings are of importance to public health, considering the high consumption of foods that are high on fatty acids. Conflicting evidence of many previous studies regarding the effect of fat intake and obesity and cardiovascular diseases could be because of the gene-diet interactions and genetic heterogeneity across various ethnic groups. Hence, the synergism effect of genetic and dietay intakes should be considered in future studies.

Genetic risk score in patients with the APOE2/E2 genotype as a predictor of familial dysbetalipoproteinemia

BackgroundFamilial dysbetalipoproteinemia (FD) is an autosomal recessive (rarely dominant) inherited disorder that is almost exclusively associated with the apolipoprotein E gene (APOE) variability. Nonetheless, only a small proportion of APOE2/E2 subjects develop the phenotype for mixed dyslipidemia; the context of other trigger metabolic or genetic factors remains unknown. MethodsOne hundred and one patients with FD and eighty controls (all APOE2/E2 homozygotes; rs429358) were screened for 18 single-nucleotide polymorphisms (SNPs) within the genes involved in triglyceride metabolism. ResultsTwo SNPs were significantly associated with the FD phenotype (rs439401 within APOE; P < 0.0005 and rs964184 within ZPR1/APOA5/A4/C3/A1 gene cluster; P < 0.0001). Unweighted genetic risk scores - from these two SNPs (GRS2), and, also, additional 13 SNPs with P-value below 0.9 (GRS15) - were created as an additional tool to improve the risk estimation of FD development in subjects with the APOE2/E2 genotype. Both GRS2 and GRS15 were significantly (P < 0.0001) increased in patients and both GRSs discriminated almost identically between the groups (P = 0.86). Subjects with an unweighted GRS2 of three or more had an almost four-fold higher risk of FD development than other individuals (odds ratio (OR) 3.58, 95% confidence interva (CI): 1.78–7.18, P < 0.0005). ConclusionsWe identified several SNPs that are individual additive factors influencing FD development. The use of unweighted GRS2 is a simple and clinically relevant tool that further improves the prediction of FD in APOE2/E2 homozygotes with corresponding biochemical characteristics.

Variants in transient receptor potential channels and toll-like receptors modify airway responses to allergen and air pollution: a randomized controlled response human exposure study

BackgroundEnvironmental co-exposure to allergen and traffic-related air pollution is common globally and contributes to the exacerbation of respiratory diseases. Individual responses to environmental insults remain variable due to gene-environment interactions.ObjectiveThis study examined whether single nucleotide polymorphisms (SNPs) in lung cell surface receptor genes modifies lung function change and immune cell recruitment in allergen-sensitized individuals exposed to diesel exhaust (DE) and allergen.MethodsIn this randomized, double-blinded, four-arm, crossover study, 13 allergen-sensitized participants underwent allergen inhalation challenge following a 2-hour exposure to DE, particle-depleted diesel exhaust (PDDE) or filtered air (FA). Lung function tests and bronchoscopic sample collection were performed up to 48 h after exposures. Transient receptor potential channel (TRPA1 and TRPV1) and toll-like receptor (TLR2 and TLR4) risk alleles were used to construct an unweighted genetic risk score (GRS). Exposure-by-GRS interactions were tested using mixed-effects models.ResultsIn participants with high GRS, allergen exposure was associated with an increase in airway hyperresponsiveness (AHR) when co-exposed to PDDE (p = 0.03) but not FA or DE. FA and PDDE also were associated with a relative increase in macrophages and decrease in lymphocytes in bronchoalveolar lavage.ConclusionsTRPs and TLRs variants are associated with increased AHR and altered immune cellularity in allergen-exposed individuals. This effect is blunted by DE exposure, suggesting greater influence of unmeasured gene variants as primary meditators of a particulate-rich co-exposure.Trial registrationThe study was registered with ClinicalTrials.gov on December 20, 2013 (NCT02017431).

A combination of strongly associated prothrombotic single nucleotide polymorphisms could efficiently predict venous thrombosis risk.

Venous thrombosis (VT) is multifactorial trait that contributes to the global burden of cardiovascular diseases. Although abundant single nucleotide polymorphisms (SNPs) provoke the susceptibility of an individual to VT, research has found that the five most strongly associated SNPs, namely, rs6025 (F5 Leiden), rs2066865 (FGG), rs2036914 (F11), rs8176719 (ABO), and rs1799963 (F2), play the greatest role. Association and risk prediction models are rarely established by using merely the five strongly associated SNPs. This study aims to explore the combined VT risk predictability of the five SNPs and well-known non-genetic VT risk factors such as aging and obesity in the Hungarian population. SNPs were genotyped in the VT group (n = 298) and control group (n = 400). Associations were established using standard genetic models. Genetic risk scores (GRS) [unweighted GRS (unGRS), weighted GRS (wGRS)] were also computed. Correspondingly, the areas under the receiver operating characteristic curves (AUCs) for genetic and non-genetic risk factors were estimated to explore their VT risk predictability in the study population. rs6025 was the most prevalent VT risk allele in the Hungarian population. Its risk allele frequency was 3.52-fold higher in the VT group than that in the control group [adjusted odds ratio (AOR) = 3.52, 95% CI: 2.50-4.95]. Using all genetic models, we found that rs6025 and rs2036914 remained significantly associated with VT risk after multiple correction testing was performed. However, rs8176719 remained statistically significant only in the multiplicative (AOR = 1.33, 95% CI: 1.07-1.64) and genotypic models (AOR = 1.77, 95% CI: 1.14-2.73). In addition, rs2066865 lost its significant association with VT risk after multiple correction testing was performed. Conversely, the prothrombin mutation (rs1799963) did not show any significant association. The AUC of Leiden mutation (rs6025) showed better discriminative accuracy than that of other SNPs (AUC = 0.62, 95% CI: 0.57-0.66). The wGRS was a better predictor for VT than the unGRS (AUC = 0.67 vs. 0.65). Furthermore, combining genetic and non-genetic VT risk factors significantly increased the AUC to 0.89 with statistically significant differences (Z = 3.924, p < 0.0001). Our study revealed that the five strongly associated SNPs combined with non-genetic factors could efficiently predict individual VT risk susceptibility. The combined model was the best predictor of VT risk, so stratifying high-risk individuals based on their genetic profiling and well-known non-modifiable VT risk factors was important for the effective and efficient utilization of VT risk preventive and control measures. Furthermore, we urged further study that compares the VT risk predictability in the Hungarian population using the formerly discovered VT SNPs with the novel strongly associated VT SNPs.

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.

A study of genetic variants, genetic risk score and DNA methylation of PNPLA3 and TM6SF2 in alcohol liver cirrhosis.

Genetic and epigenetic factors are associated with thedevelopment of alcohol-associated liver disease (AALD). The single nucleotide polymorphisms (SNPs), rs738409 in Patatin-like phospholipase domain-containing protein (PNPLA3) and rs58542926 in Transmembrane 6 Superfamily Member 2 (TM6SF2) are strongly associated with AALD in different global populations, Hence, we analyzed the genetic risk score for these variants and deoxyribonucleic acid (DNA) methylation levels of the PNPLA3 and TM6SF2 genes among cases (alcohol liver cirrhosis) and controls (heavy drinkers without cirrhosis). We studied patients with alcohol use disorder (AUD) with cirrhosis (AUD-C + ve, n = 136) and without cirrhosis (AUD-C-ve, n = 107) drawn from the clinical services of St. John's Medical College Hospital (SJMCH) (Gastroenterology and Psychiatry) and Centre for Addiction Medicine (CAM),National Institute of Mental Health and Neurosciences, (NIMHANS). Genotype data was generated for rs738409 (PNPLA3) and rs58542926 (TM6SF2) and used to calculate unweighted genetic risk score (uGRS) and weighted genetic risk scores (wGRS). DNA methylation levels were estimated by pyrosequencing at PNPLA3 and TM6SF2 loci. Overall we observed a significantly higher genetic risk score (weighted genetic risk score, wGRS) in individuals with alcohol use disorder compared to control population (p = < 0.01). Further, uGRS and wGRS were associated with thediagnosis of cirrhosis, even after correcting for age of onset, quantity and frequency of drinking. We also found hypomethylation at CpG2 of TM6SF2 gene in AUD-C + ve compared to AUD-C-ve (P = 0.02). We found that a genetic risk score based on SNPs in the PNPLA3 and TM6SF2 genes was significantly associated with cirrhosis in patients with AUD, suggesting a potential utility in identifying patients at risk and providing pre-emptive interventions. These may include interventions that aim to alter DNA methylation, which may be one of the mechanisms through which elevated genetic risk may influence thedevelopment of cirrhosis.

A multilocus genetic risk score for obesity: Association with BMI and metabolic alterations in a cohort with severe obesity.

Genome wide association studies have identified numerous single nucleotide polymorphisms (SNPs) associated with obesity, yet effect sizes of individual SNPs are small. Therefore, the aim of our study was to investigate whether a genetic risk score (GRS) comprising risk alleles of SNPs identified in the GIANT consortium meta-analyses shows association with body mass index (BMI) and other BMI related metabolic alterations in a cohort with an extreme phenotype. Genotyping of 93 SNPs was performed in 314 obese individuals (mean BMI 40.5 ± 7.8 kg/m², aged 45 ± 12 years), participating in a standardized weight reduction program, and in 74 lean controls (mean BMI 24.6 ± 3.3 kg/m², aged 41.7 ± 13.4 years). Allele numbers of all 93 SNPs were added to a GRS. Anthropometric parameters, parameters of glucose/insulin and lipid metabolism were assessed standardized after a 12 hours fast. GRS was significantly different between controls and obese individuals (unweighted GRS: 86.6 vs 89.0, P = .002; weighted GRS: 84.9 vs 88.3, P = .005). Furthermore, linear regression analysis showed significant associations of GRS with BMI ( P < .0001), weight ( P = .0005), waist circumference ( P = .0039), fat mass ( P < .0001) and epicardial fat thickness ( P = .0032), yet with small effect sizes ( r ² < 0.06). In conclusion, in our study GRS could differentiate between extreme obese and lean individuals, and was associated with BMI and its related traits, yet with small effect sizes.

The Interactions between Maternal Iron Supplementation and Iron Metabolism-Related Genetic Polymorphisms on Birth Outcomes: A Prospective Study in Chinese

BackgroundThe effect of iron supplementation during pregnancy on birth outcomes may vary with maternal genetic background and needs more investigation. ObjectivesThis prospective study aimed to evaluate the interactions between maternal iron supplementation and iron metabolism-related genetic polymorphisms on birth outcomes. MethodsThis was a substudy from a community-based randomized control trial conducted in Northwest China, which included 860 women from the 2 micronutrient supplementation groups (folic acid [FA] and FA + iron group). Maternal peripheral blood, sociodemographic and health-related information, and neonatal birth outcomes were collected. Six single nucleotide polymorphisms in iron metabolism-related genes were genotyped. The alleles associated with decreased iron/hemoglobin status were used as the effect alleles. The genetic risk score (GRS) that reflected the genetic risk of low iron/hemoglobin status was estimated using the unweighted and weighted methods. Generalized estimating equations with small-sample corrections were applied to evaluate the interactions between iron supplementation and SNPs/GRS on birth outcomes. ResultsThere were significant interactions between maternal iron supplementation and rs7385804 (P = 0.009), rs149411 (P = 0.035), rs4820268 (P = 0.031), the unweighted GRS (P = 0.018), and the weighted GRS (P = 0.009) on birth weight. Compared with FA supplementation only, FA + iron supplementation significantly increased birth weight among women with more effect alleles in rs7385804 (β: 88.8 g, 95% CI: 9.2, 168.3) and the GRSs (the highest unweighted GRS, β: 135.5 g, 95% CI: 7.7, 263.4; the highest weighted GRS, β: 145.9 g, 95% CI: 43.4, 248.5); it had a trend of decreasing birth weight and increasing low birth weight risk among women with fewer effect alleles. ConclusionsIn our population, maternal genetic background related to iron metabolism plays a significant role in determining the efficacy of iron supplementation. Routine iron supplementation could be more beneficial to fetal weight growth among mothers with higher genetic risk for low iron/hemoglobin status.

Development of a genetic risk score to predict the risk of hypertension in European adolescents from the HELENA study.

From genome wide association study (GWAS) a large number of single nucleotide polymorphisms (SNPs) have previously been associated with blood pressure (BP) levels. A combination of SNPs, forming a genetic risk score (GRS) could be considered as a useful genetic tool to identify individuals at risk of developing hypertension from early stages in life. Therefore, the aim of our study was to build a GRS being able to predict the genetic predisposition to hypertension (HTN) in European adolescents. Data were extracted from the Healthy Lifestyle in Europe by Nutrition in Adolescence (HELENA) cross-sectional study. A total of 869 adolescents (53% female), aged 12.5-17.5, with complete genetic and BP information were included. The sample was divided into altered (≥130 mmHg for systolic and/or ≥80 mmHg for diastolic) or normal BP. Based on the literature, a total of 1.534 SNPs from 57 candidate genes related with BP were selected from the HELENA GWAS database. From 1,534 SNPs available, An initial screening of SNPs univariately associated with HTN (p < 0.10) was established, to finally obtain a number of 16 SNPs significantly associated with HTN (p < 0.05) in the multivariate model. The unweighted GRS (uGRS) and weighted GRS (wGRS) were estimated. To validate the GRSs, the area under the curve (AUC) was explored using ten-fold internal cross-validation for uGRS (0.802) and wGRS (0.777). Further covariates of interest were added to the analyses, obtaining a higher predictive ability (AUC values of uGRS: 0.879; wGRS: 0.881 for BMI z-score). Furthermore, the differences between AUCs obtained with and without the addition of covariates were statistically significant (p < 0.05). Both GRSs, the uGRS and wGRS, could be useful to evaluate the predisposition to hypertension in European adolescents.

Associations of VEGF-A-Related Variants with Adolescent Cardiometabolic and Dietary Parameters.

Previous research has allowed the identification of variants related to the vascular endothelial growth factor-A (VEGF-A) and their association with anthropometric, lipidemic and glycemic indices. The present study examined potential relations between key VEGF-A-related single-nucleotide polymorphisms (SNPs), cardiometabolic parameters and dietary habits in an adolescent cohort. Cross-sectional analyses were conducted using baseline data from 766 participants of the Greek TEENAGE study. Eleven VEGF-A-related SNPs were examined for associations with cardiometabolic indices through multivariate linear regressions after adjusting for confounding factors. A 9-SNP unweighted genetic risk score (uGRS) for increased VEGF-A levels was constructed to examine associations and the effect of its interactions with previously extracted dietary patterns for the cohort. Two variants (rs4416670, rs7043199) displayed significant associations (p-values < 0.005) with the logarithms of systolic and diastolic blood pressure (logSBP and logDBP). The uGRS was significantly associated with higher values of the logarithm of Body Mass Index (logBMI) and logSBP (p-values < 0.05). Interactions between the uGRS and specific dietary patterns were related to higher logDBP and logGlucose (p-values < 0.01). The present analyses constitute the first-ever attempt to investigate the influence of VEGF-A-related variants on teenage cardiometabolic determinants, unveiling several associations and the modifying effect of diet.

Polygenic Risk of Hypertriglyceridemia Is Modified by BMI.

Background: Genetic risk scores (GRSs) have partially improved the understanding of the etiology of moderate hypertriglyceridemia (HTG), which until recently was mainly assessed by secondary predisposing causes. The main objective of this study was to assess whether this variability is due to the interaction between clinical variables and GRS. Methods: We analyzed 276 patients with suspected polygenic HTG. An unweighted GRS was developed with the following variants: c.724C > G (ZPR1 gene), c.56C > G (APOA5 gene), c.1337T > C (GCKR gene), g.19986711A > G (LPL gene), c.107 + 1647T > C (BAZ1B gene) and g.125478730A > T (TRIB gene). Interactions between the GRS and clinical variables (body mass index (BMI), diabetes mellitus, diet, physical activity, alcohol consumption, age and gender) were evaluated. Results: The GRS was associated with triglyceride (TG) concentrations. There was a significant interaction between BMI and GRS, with the intensity of the relationship between the number of alleles and the TG concentration being greater in individuals with a higher BMI. Conclusions: GRS is associated with plasma TG concentrations and is markedly influenced by BMI. This finding could improve the stratification of patients with a high genetic risk for HTG who could benefit from more intensive healthcare interventions.

Development of a genetic risk score for obesity predisposition evaluation.

Obesity is a major public health issue resulting from an interaction between genetic and environmental factors. Genetic risk scores (GRSs) are useful to summarize the effects of many genetic variants on obesity risk. In this study, we aimed to assess the association of previously well-studied genetic variants with obesity and develop a genetic risk score to anticipate the risk of obesity development in the Iranian population. Among 968 participants, 599 (61.88%) were obese, and 369 (38.12%) were considered control samples. After genotyping, an initial screening of 16 variants associated with body mass index (BMI) was performed utilizing a general linear model (p < 0.25), and seven genetic variants were selected. The association of these variants with obesity was examined using a multivariate logistic regression model (p < 0.05), and finally, five variants were found to be significantly associated with obesity. Two gene score models (weighted and unweighted), including these five loci, were constructed. To compare the discriminative power of the models, the area under the curve was calculated using tenfold internal cross-validation. Among the studied variants, ADRB3 rs4994, FTO rs9939609, ADRB2 rs1042714, IL6 rs1800795, and MTHFR rs1801133 polymorphisms were significantly associated with obesity in the Iranian population. Both of the constructed models were significantly associated with BMI (p < 0.05) and the area under the mean curve of the weighted GRS and unweighted GRS were 70.22% ± 0.05 and 70.19% ± 0.05, respectively. Both GRSs proved to predict obesity and could potentially be utilized as genetic tools to assess the obesity predisposition in the Iranian population. Also, among the studied variants, ADRB3 rs4994 and FTO rs9939609 polymorphisms have the highest impacts on the risk of obesity.

Genetic and stress influences on the prevalence of hypertension among hispanics/latinos in the hispanic community health study/study of latinos (HCHS/SOL)

Purpose The current study examined the effects of chronic stress and a genetic risk score on the presence of hypertension and elevated systolic blood pressure and diastolic blood pressure among Hispanics/Latinos in the target population of Hispanic Community Health Study/Study of Latinos. Materials and Methods Of the participants (N = 11,623) assessed during two clinic visits (Visit 1 2008–2013 & Visit 2 2014–2018), we analysed data from 7,429 adults (50.4% female), aged 18–74, who were genotyped and responded to chronic stress questionnaires. We calculated an unweighted genetic risk score using blood pressure increasing single nucleotide polymorphisms (SNPs) found to be generalisable to Hispanics/Latinos (10 SNPs). Linear and logistic regression models were used to estimate associations between chronic stress and genetic risk score and their interaction, with prevalent Visit 2 SBP or DBP, and hypertension, respectively. Models accounted for sampling weights, stratification, and cluster design. Results Chronic stress (adjusted OR = 1.18, 95%CI:1.15,1.22) and hypertension genetic risk score (adjusted OR = 1.04, 95%CI:1.01,1.07) were significantly associated with prevalent hypertension, but there was no significant interaction between the chronic stress and genetic risk score on hypertension (p = .49). genetic risk score (b = .32, 95%CI:.08, .55, R 2 = .02) and chronic stress (b = .45, 95%CI:.19, .72, R 2 = .11) were related to DBP, with no significant interaction (p = .62). Genetic risk score (b = .42, 95%CI:.08, .76, R 2 = .01) and chronic stress (b = .80, 95%CI:.34,1.26, R 2 = .11) were also related to SBP, with no significant interaction (p = .51). Conclusion Results demonstrate the utility of a genetic risk score for blood pressure and are consistent with literature suggesting chronic stress has a strong, direct association with elevated blood pressure among U.S. Hispanics/Latinos.

Body mass index interacts with a genetic-risk score for depression increasing the risk of the disease in high-susceptibility individuals

Depression is strongly associated with obesity among other chronic physical diseases. The latest mega- and meta-analysis of genome-wide association studies have identified multiple risk loci robustly associated with depression. In this study, we aimed to investigate whether a genetic-risk score (GRS) combining multiple depression risk single nucleotide polymorphisms (SNPs) might have utility in the prediction of this disorder in individuals with obesity. A total of 30 depression-associated SNPs were included in a GRS to predict the risk of depression in a large case-control sample from the Spanish PredictD-CCRT study, a national multicentre, randomized controlled trial, which included 104 cases of depression and 1546 controls. An unweighted GRS was calculated as a summation of the number of risk alleles for depression and incorporated into several logistic regression models with depression status as the main outcome. Constructed models were trained and evaluated in the whole recruited sample. Non-genetic-risk factors were combined with the GRS in several ways across the five predictive models in order to improve predictive ability. An enrichment functional analysis was finally conducted with the aim of providing a general understanding of the biological pathways mapped by analyzed SNPs. We found that an unweighted GRS based on 30 risk loci was significantly associated with a higher risk of depression. Although the GRS itself explained a small amount of variance of depression, we found a significant improvement in the prediction of depression after including some non-genetic-risk factors into the models. The highest predictive ability for depression was achieved when the model included an interaction term between the GRS and the body mass index (BMI), apart from the inclusion of classical demographic information as marginal terms (AUC = 0.71, 95% CI = [0.65, 0.76]). Functional analyses on the 30 SNPs composing the GRS revealed an over-representation of the mapped genes in signaling pathways involved in processes such as extracellular remodeling, proinflammatory regulatory mechanisms, and circadian rhythm alterations. Although the GRS on its own explained a small amount of variance of depression, a significant novel feature of this study is that including non-genetic-risk factors such as BMI together with a GRS came close to the conventional threshold for clinical utility used in ROC analysis and improves the prediction of depression. In this study, the highest predictive ability was achieved by the model combining the GRS and the BMI under an interaction term. Particularly, BMI was identified as a trigger-like risk factor for depression acting in a concerted way with the GRS component. This is an interesting finding since it suggests the existence of a risk overlap between both diseases, and the need for individual depression genetics-risk evaluation in subjects with obesity. This research has therefore potential clinical implications and set the basis for future research directions in exploring the link between depression and obesity-associated disorders. While it is likely that future genome-wide studies with large samples will detect novel genetic variants associated with depression, it seems clear that a combination of genetics and non-genetic information (such is the case of obesity status and other depression comorbidities) will still be needed for the optimization prediction of depression in high-susceptibility individuals.

A higher burden of multiple sclerosis genetic risk confers an earlier onset

Background: Age at onset of multiple sclerosis (MS) is an objective, influential predictor of the evolution of MS independent of disease duration. Objectives: Determine the influence of MS genetic predisposition on age of onset. Methods: We conducted a comprehensive investigation of MS risk variants and age at onset in 3495 non-Latinx white individuals, including for combinations of HLA-DRB1*15:01 alleles and quintiles of an unweighted genetic risk score (GRS) for 198 of 200 autosomal MS risk variants that reside outside the major histocompatibility complex. Results: The mean age at onset was 32 years, 29% were male, and 46% were HLA-DRB1*15:01 carriers. For those with the greatest genetic risk burden (the highest GRS quintile with two HLA-DRB1*15:01 alleles) were on average 5 years younger at onset (p = 0.002) than those with the lowest genetic risk burden (the lowest GRS quintile with no HLA-DRB1*15:01 alleles). There was a strong inverse relationship between the MS genetic risk burden and age at onset of MS (p < 5 × 10−8). Conclusion: We demonstrate a significant gradient between elevated MS genetic risk burden and an earlier onset of MS, suggesting that a higher MS genetic risk burden accelerates onset of the disease.

Interaction between dietary branched-chain amino acids and genetic risk score on the risk of type 2 diabetes in Chinese

Background and objectivesPrevious studies have found the important gene-diet interactions on type 2 diabetes (T2D) incident but have not followed branched-chain amino acids (BCAAs), even though they have shown heterogeneous effectiveness in diabetes-related factors. So in this study, we aim to investigate whether dietary BCAAs interact with the genetic predisposition in relation to T2D risk and fasting glucose in Chinese adults.MethodsIn a case-control study nested in the Harbin Cohort Study on Diet, Nutrition and Chronic Non-Communicable Diseases, we obtained data for 434 incident T2D cases and 434 controls matched by age and sex. An unweighted genetic risk score (GRS) was calculated for 25 T2D-related single nucleotide polymorphisms by summation of the number of risk alleles for T2D. Multivariate logistic regression models and general linear regression models were used to assess the interaction between dietary BCAAs and GRS on T2D risk and fasting glucose.ResultsSignificant interactions were found between GRS and dietary BCAAs on T2D risk and fasting glucose (p for interaction = 0.001 and 0.004, respectively). Comparing with low GRS, the odds ratio of T2D in high GRS were 2.98 (95% CI 1.54–5.76) among those with the highest tertile of total BCAA intake but were non-significant among those with the lowest intake, corresponding to 0.39 (0.12) mmol/L versus − 0.07 (0.10) mmol/L fasting glucose elevation per tertile. Viewed differently, comparing extreme tertiles of dietary BCAAs, the odds ratio (95% CIs) of T2D risk were 0.46 (0.22–0.95), 2.22 (1.15–4.31), and 2.90 (1.54–5.47) (fasting glucose elevation per tertile: − 0.23 (0.10), 0.18 (0.10), and 0.26 (0.13) mmol/L) among participants with low, intermediate, and high genetic risk, respectively.ConclusionsThis study indicated that dietary BCAAs could amplify the genetic association with T2D risk and fasting glucose. Moreover, higher BCAA intake showed positive association with T2D when genetic predisposition was also high but changed to negative when genetic predisposition was low.

Thyroid function, sex hormones and sexual function: a Mendelian randomization study.

Hypothyroidism and hyperthyroidism are observationally associated with sex hormone concentrations and sexual dysfunction, but causality is unclear. We investigated whether TSH, fT4, hypo- and hyperthyroidism are causally associated with sex hormones and sexual function. We used publicly available summary statistics from genome-wide association studies on TSH and fT4 and hypo- and hyperthyroidism from the ThyroidOmics Consortium (N ≤ 54,288). Outcomes from UK Biobank (women ≤ 194,174/men ≤ 167,020) and ReproGen (women ≤ 252,514) were sex hormones (sex hormone binding globulin [SHBG], testosterone, estradiol, free androgen index [FAI]) and sexual function (ovulatory function in women: duration of menstrual period, age at menarche and menopause, reproductive lifespan, and erectile dysfunction in men). We performed two-sample Mendelian randomization (MR) analyses on summary level, and unweighted genetic risk score (GRS) analysis on individual level data. One SD increase in TSH was associated with a 1.332nmol/L lower (95% CI: - 0.717,- 1.946; p = 2 × 10-5) SHBG and a 0.103nmol/l lower (- 0.051,V0.154; p = 9 × 10-5) testosterone in two-sample MR, supported by the GRS approach. Genetic predisposition to hypothyroidism was associated with decreased and genetic predisposition to hyperthyroidism with increased SHBG and testosterone in both approaches. The GRS for fT4 was associated with increased testosterone and estradiol in women only. The GRS for TSH and hypothyroidism were associated with increased and the GRS for hyperthyroidism with decreased FAI in men only. While genetically predicted thyroid function was associated with sex hormones, we found no association with sexual function.

Development of a Genetic Risk Score to predict the risk of overweight and obesity in European adolescents from the HELENA study

Obesity is the result of interactions between genes and environmental factors. Since monogenic etiology is only known in some obesity-related genes, a genetic risk score (GRS) could be useful to determine the genetic predisposition to obesity. Therefore, the aim of our study was to build a GRS able to predict genetic predisposition to overweight and obesity in European adolescents. A total of 1069 adolescents (51.3% female), aged 11–19 years participating in the Healthy Lifestyle in Europe by Nutrition in Adolescence (HELENA) cross-sectional study were genotyped. The sample was divided in non-overweight (non-OW) and overweight/obesity (OW/OB). From 611 single nucleotide polymorphisms (SNP) available, a first screening of 104 SNPs univariately associated with obesity (p < 0.20) was established selecting 21 significant SNPs (p < 0.05) in the multivariate model. Unweighted GRS (uGRS) was calculated by summing the number of risk alleles and weighted GRS (wGRS) by multiplying the risk alleles to each estimated coefficient. The area under curve (AUC) was calculated in uGRS (0.723) and wGRS (0.734) using tenfold internal cross-validation. Both uGRS and wGRS were significantly associated with body mass index (BMI) (p < .001). Both GRSs could potentially be considered as useful genetic tools to evaluate individual’s predisposition to overweight/obesity in European adolescents.

Identification of genetic features associated with fine particulate matter (PM2.5) modulated DNA damage using improved random forest analysis.

Recent studies have found multiple single nucleotide variants (SNVs) associated with DNA damage. However, previous association analysis may ignore the potential interaction effects between SNVs. Therefore, we used an improved random forest (RF) analysis to identify the SNVs related to personal DNA damage in exon-focused genome-wide association study (GWAS). A total of 301 subjects from three independent centers (Zhuhai, Wuhan, and Tianjin) were retained for analysis. An improved RF procedure was used to systematically screen key SNVs associated with DNA damage. Furthermore, we used genetic risk score (GRS) and mediation analysis to investigate the integrative effect and potential mechanism of these genetic variants on DNA damage. Besides, gene set enrichment analysis was conducted to identify the pathways enriched by key SNVs using the Data-driven Expression Prioritized Integration for Complex Traits (DEPICT). Finally, a set of 24 SNVs with the lowest mean square errors (MSE) were identified by improved RF analysis. Both weighted and unweighted GRSs were associated with increased DNA damage levels (Pweight<0.001 and Punweight<0.001). Gene set enrichment analysis indicated that these loci were significantly enriched in several biological features associated with DNA damage. These findings suggested the role of SNVs in modifying DNA damage levels. It may be convincing that this improved RF analysis can effectively identify SNVs associated with DNA damage levels.