Number Of Risk Alleles Research Articles

Combining I148M and E167K variants to improve risk prediction for nonalcoholic fatty liver disease in Qingdao Han population, China

BackgroundPNPLA3 I148M variant and TM6SF2 E167K variant are recognized as the major genetic modifiers of nonalcoholic fatty liver disease (NAFLD). The present study sought to evaluate the potential additive effect of the two variants on the risk of NAFLD in Qingdao Han Population, China.MethodsWe genotyped PNPLA3 I148M variant and TM6SF2 E167K variant in a cohort of 512 unrelated NAFLD patients and 451 healthy controls by sequencing and polymerase chain reaction analysis. In addition, serum lipid profiles and liver enzymes were determined by standard clinical laboratory methods.ResultsThe minor allele frequencies were 45.48% for PNPLA3 148 locus G allele and 6.69% for TM6SF2 167 locus T allele. The PNPLA3 I148M variant was significantly associated with the risk of NAFLD in an additive model (CG, OR = 2.092, 95% CI: 1.551–2.820, P = 0.000; GG, OR = 4.566, 95% CI: 3.141–6.638, P = 0.000, respectively). And, our data suggested a strong link between the TM6SF2 E167K variant and the risk of NAFLD in a dominant model (CT + TT, OR = 2.327, 95% CI: 1.542–3.513, P = 0.000). In addition, the increasing of the number of risk alleles were associated with the risk of NAFLD (1 risk allele, OR = 1.687, P = 0.001; 2 risk alleles, OR = 4.326, P = 0.000; 3 risk alleles, OR = 6.018, P = 0.027, respectively).ConclusionsCombining the I148M and E167K variants in a manner of an additive effect could improve risk prediction for NAFLD in a Qingdao Han Population cohort.Trial registrationChinese Clinical Trial Register.gov: ChiCTR1800015426.

SU108 - ARE POLYGENIC RISK SCORES FOR MAJOR MENTAL DISORDERS ASSOCIATED WITH GENERAL OR SPECIFIC PSYCHOSIS SYMPTOM DIMENSIONS?

Background Psychotic symptoms can be conceptualised as dimensions of psychopathology cutting across diagnostic boundaries. Thus, they might be considered enhanced quantitative phenotypes to relate to genetic variants as summarised by Polygenic Risk Scores (PRSs) for Major Mental Disorders (MMDs), including Schizophrenia (SZ), Bipolar Disorder (BP), and Major Depressive Disorder (MDD). The objectives of this study were to: 1) identify the dimensional structure of symptoms at First Episode Psychosis (FEP), testing whether a bi-factor model statistically fits the conceptualization of psychosis as a single common construct (general psychosis factor) while also recognising multidimensionality (positive, negative, disorganized, manic, and depressive symptom factors); 2) examine the extent to which MMD PRSs indexed the phenotypic variance due to the general psychosis construct and to the specific symptom dimensions. Methods The sample included 1182 FEP patients recruited as part of the EUGEI study. The MRC Sociodemographic Schedule and the OPerational CRITeria (OPCRIT) were used to collect sociodemographic information and assess psychopathology. DNA was extracted from blood or saliva samples collected from 940 participants. The following analysis steps were performed: 1) OPCRIT psychopathology items were analysed using multidimensional item response modelling in Mplus to estimate unidimensional, multidimensional, and bi-factor models of psychosis. Models’ fit statistics were compared using Log-Likelihood, and Akaike and Bayesian Information Criteria. 2) SZ, BP, and MDD PRSs were built using the results from large mega-analyses from Working Groups of the Psychiatric Genomics Consortium. In PRSice, individuals’ number of risk alleles in the target sample was weighted by the log odds ratio from the discovery samples, and summed into the three PRSs. 3) For the best data fitting psychosis model, linear regressions were estimated to predict symptom dimensions as a continuous outcome from the three PRSs, accounting for population stratification. Results The best model fit statistics was observed for the bi-factor model including one general and five specific symptom factors compared with the other models. This indicated that there was a broad latent structure underlying the whole range of psychosis symptoms among five latent specific symptom dimensions. PRSs for SZ, BP, and MDD were calculated at the best model fitting P-value threshold. As expected, there was a substantial difference in discrimination of case-control status between SZ PRS and BP and MDD PRSs. A significant positive linear regression equation was observed for BP PRS and mania dimension severity (t(864)=2.74, p Discussion These results suggest that a) psychosis at illness onset can be conceptualised as being composed of one general factor and five specific symptom dimensions, b) there is an association between mania dimension score and BP PRS. Despite the need to both replicate these findings also using PGC new released GWAS to build better powered PRSs, psychosis symptom dimensions have clearly been shown to be a valid and a useful continuous quantitative phenotype across categorical disorders.

A Genetic Risk Score for Atrial Fibrillation Predicts the Response to Catheter Ablation.

Background and ObjectivesThe association of susceptibility loci for atrial fibrillation (AF) with AF recurrence after ablation has been reported, although with controversial results. In this prospective cohort analysis, we aimed to investigate whether a genetic risk score (GRS) can predict the rhythm outcomes after catheter ablation of AF.MethodsWe determined the association between 20 AF-susceptible single nucleotide polymorphisms (SNPs) and AF recurrence after catheter ablation in 746 patients (74% males; age, 59±11 years; 56% paroxysmal AF). A GRS was calculated by summing the unweighted numbers of risk alleles of selected SNPs. A Cox proportional hazard model was used to identify the association between the GRS and risk of AF recurrence after catheter ablation.ResultsAF recurrences after catheter ablation occurred in 168 (22.5%) subjects with a median follow-up of 23 months. The GRS was calculated using 5 SNPs (rs1448818, rs2200733, rs6843082, rs6838973 at chromosome 4q25 [PITX2] and rs2106261 at chromosome 16q22 [ZFHX3]), which showed modest associations with AF recurrence. The GRS was significantly associated with AF recurrence (hazard ratio [HR] per each score, 1.13; 95% confidence interval [CI], 1.03–1.24). Patients with intermediate (GRS 4–6) and high risks (GRS 7–10) showed HRs of 2.00 (95% CI, 0.99–4.04) and 2.66 (95% CI, 1.32–5.37), respectively, compared to patients with low risk (GRS 0–3).ConclusionsOur novel GRS using 5 AF-susceptible SNPs was strongly associated with AF recurrence after catheter ablation in Korean population, beyond clinical risk factors. Further efforts are warranted to construct a generalizable, robust genetic prediction model which can guide the optimal treatment strategies.

M34 - A GENETIC RISK SCORE, DEPRESSION AND OBESITY: EVIDENCE FROM THE SPANISH POPULATION STUDY PISMA-EP

Background Depression and obesity are highly prevalent diseases in the general population, responsible of disability burden worldwide. Both conditions are major risk factors for chronic physical diseases such as type 2 diabetes, cardiovascular disease and hypertension among others. The reason why obesity and depression cluster together is not totally understood and several mechanisms have been proposed. There are many factors driving this observation, such as individual lifestyle choices, socioeconomic factors, psychosocial stress, disparities in health care, medication, as well as biological and genetic factors. The aim of this study is to investigate whether a Genetic Risk Score (GRS) combining 85 candidate SNPs for depression and other major psychiatric disorders is associated with depression and predicts depression in individuals with obesity. Methods The sample consists of 743 community-based individuals from the PISMA-ep study. The PISMA-ep is a cross-sectional epidemiological study of mental disorders based on a representative sample of the adult population of Andalusia, Spain. A DSM-IV diagnosis of major depression was ascertained using the MINI interview. Height and weight data reported from each individual was used to calculate Body Mass Index (BMI), as a measure of obesity, using the formula: weight(kg)/height(m)2. All individuals have been genotyped for the 85 candidate polymorphisms using TaqMan® OpenArrayTM Genotyping System. These markers were selected according to genome location, function and previous evidence. Logistic regression models will be conducted to predict depression. We will calculate an unweighted GRS by summation of the number of risk alleles, and a weighted GRS as the sum of risk alleles at each locus multiplied by their effect sizes. Receiver Operating Characteristic (ROC) analysis will be used to compare the discriminatory ability of predictors of depression. Results We hope that both unweighted and weighted GRS will be associated with depression and explain a modest amount of variance. We also hope that adding ‘traditional’ risk factors to GRS will significantly improve the predictive ability with the area under the curve (AUC) in the ROC analysis. We further expect that the GRS will discriminate depression better in obese individuals compare to normal-weight subjects. Discussion The association between depression and obesity has repeatedly been reported in many studies. Given the high prevalence of both disorders, we expect that incorporating genetic information, traditional risk factors and obesity status may largely improve the predicting ability for depression. Addressing obesity in people with depression or vice versa is highly important as both disorders are associated with substantial personal and societal economic costs worldwide.

Independent and additive effects of PNPLA3 and TM6SF2 polymorphisms on the development of non-B, non-C hepatocellular carcinoma.

This study was aimed at evaluating the association between single nucleotide polymorphisms (SNPs) in the PNPLA3, NCAN, TM6SF2 and MBOAT7 and hepatocellular carcinoma (HCC) development in Thai patients according to underlying etiologies of liver disease. These SNPs were determined by allelic discrimination in blood samples of 105 healthy controls and 530 patients with HCC [270 with hepatitis B virus (HBV-HCC), 131 with hepatitis C virus (HCV-HCC), and 129 with non-B, non-C HCC (NBNC-HCC) matched for age and gender]. G allele of PNPLA3 rs738409 variant was significantly higher in NBNC-HCC (49%) compared to healthy controls (32%), HBV-HCC (32%) and HCV-HCC (31%) (P < 0.001). T allele of TM6SF2 rs58542926 was more prevalent in NBNC-HCC (24%) than in healthy controls (8%), HBV-HCC (10%) and HCV-HCC (12%) (P < 0.001). The distribution of NCAN (rs2228603) and MBOAT7 (rs641738) was not different between groups. In multivariate logistic regression analysis, PNPLA3 rs738409 (OR 2.06, 95% CI 1.24-3.43; P = 0.005) and TM6SF2 rs58542926 (OR 2.22, 95% CI 1.34-3.65; P = 0.002) were independently associated with NBNC-HCC compared to viral-related HCC (VR-HCC). The proportion of patients with NBNC-HCC increased significantly along with the increase of the number of risk alleles. There was no association between these SNPs and overall survival in patients with HCC. These data showed that PNPLA3 and TM6SF2 polymorphisms were independently linked to NBNC-HCC but not HBV- or HCV-HCC in Thai populations. In addition, the risk genotypes might interact with each other through tumor development in patients with NBNC-HCC.

Association between the Risk of Low/High-Count Monoclonal B-Cell Lymphocytosis (MBL) and the Chronic Lymphocytic Leukemia (CLL) Polygenic Risk Score (PRS)

BackgroundMBL is a precursor state to CLL, with a prevalence of ~5-8% in the general population and 15-18% in CLL families. To date, 41 single nucleotide polymorphisms (SNPs) have been found to be associated with CLL. We previously showed that a PRS of the weighted average of the number of risk alleles of these SNPs is associated with CLL risk using cases and controls from the International Lymphoma Epidemiology (InterLymph) Consortium. We validated this score in an independent sample of CLL cases and controls from the Genetic Epidemiology of CLL (GEC) Consortium, a cohort of families with ≥2 members with CLL. In the CLL families we also reported an association between the PRS and MBL risk, where 93% of MBLs were low-count MBL. Here we evaluate the PRS in an independent sample ascertained from the Mayo Clinic Biobank.MethodsThe Mayo Clinic Biobank is a large-scale bio-repository of adult patients assembled to provide a wide array of health-related research studies. Biobank participants (N=2530) were screened for MBL using a highly-sensitive, 8-color (CD38, CD45, Kappa, Lambda, CD19, CD23, CD5 and CD20) flow-cytometry assay on stored cryopreserved peripheral blood mononucleotide cells. Low-count and high-count MBL were defined as those individuals who had <85% and ≥85 clonal B-cells out of total B-cells, respectively. Individuals without MBL (“controls”) were frequency matched to MBLs based on age and sex, after excluding non-Caucasian and non-interpretable flow results. Participants were genotyped using the Illumina OmniExpress array. Standard genotyping quality-control metrics were applied. We computed the PRS as previously published and categorized it by quintiles based on values previously used with InterLymph controls. The middle quintile served as the reference category. We used logistic regression to estimate odds ratios (ORs) and 95% confidence intervals (CI), adjusting for age at consent, sex, and socioeconomic status. In addition, we compared the median PRS by low-count MBL and high count MBL using the Mann-Whitney U test.ResultsWe identified 276 MBLs overall and 2109 controls; 97% (N=267) of MBLs had low-count MBL and only 3% (N=9) had high-count MBL. We then selected 844 controls frequency matched to the MBL cases on age and sex. Family history of leukemia/lymphoma was 11.3% among MBLs overall and 8.8% among controls. The median PRS was 7.88 and 7.46 (Figure) among MBLs overall and controls, respectively. The continuous PRS had a 1.75-fold increased risk for MBL overall (CI:1.5-2.1, P=2.65x10-12). Compared to the middle quintile, the highest quintile had 2.2-fold increased risk for MBL overall (CI:1.5-3.3, P=1.46x10-4) and the lowest quintile had 0.6-fold decreased risk (CI:0.4-0.96, P=0.03). The median PRS for low-count and high count MBL were 7.86 and 8.04, respectively. The continuous PRS had a 1.75-fold increased risk for low-count MBL (CI:1.5-2.1, P=4.81x10-12) and a 1.89-fold increased risk for high-count MBL (CI:0.8-4.2, P=0.13), however, the effect is not statistically significant between high-count and low-count MBL (P=0.89).ConclusionIn this independent sample, we validated our previous findings that the CLL PRS is associated with MBL risk. Although the sample size of high-count MBL was limited (N=9), there is evidence of a weak trend towards a higher PRS compared to low-count MBL and controls Larger sample size of high-count MBL is warranted in order to stratify MBL risk by low-count and high-count MBL. These results may help identify individuals at higher risk of MBL including low-count and high-count MBL, beyond the risk associated with age and family history of CLL.Figure: Polygenic risk score distribution by control and MBL status DisclosuresParikh:Janssen: Research Funding; Pharmacyclics: Honoraria, Research Funding; Gilead: Honoraria; Abbvie: Honoraria, Research Funding; AstraZeneca: Honoraria, Research Funding; MorphoSys: Research Funding. Cerhan:Nanostring: Research Funding; Celgene: Research Funding; Jannsen: Other: Scientific Advisory Board. Kay:Janssen: Membership on an entity's Board of Directors or advisory committees; Acerta: Research Funding; Infinity Pharm: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Agios Pharm: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Cytomx Therapeutics: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Tolero Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Morpho-sys: Membership on an entity's Board of Directors or advisory committees. Shanafelt:Genentech: Research Funding; Pharmacyclics: Research Funding; GlaxoSmithKline: Research Funding; Jansen: Research Funding.

Risk prediction of recurrent venous thromboembolism: a multiple genetic risk model

A single genetic biomarker is unable to accurately predict the risk for venous thromboembolism (VTE) recurrence. We aimed to: (a) develop a multiple single nucleotide polymorphisms (SNPs) model to predict the risk of VTE recurrence and (b) validate a previously described genetic risk score (GRS) and compare its performance with the model developed in this study. Twenty-two SNPs, including established and putative SNPs associated with VTE risk, were genotyped in the Malmö thrombophilia study cohort (MATS; n = 1465, follow-up ~ 10 years) by using TaqMan PCR. Out of 22-SNPs, 12 had an association with the risk of VTE recurrence and were included for calculating GRSs. The risk of VTE recurrence was calculated by stratifying patients according to number of risk alleles. In 12-SNP GRS, patients with ≥ 7 risk alleles were associated with higher risk of VTE recurrence compared to patients having ≤ 6 risk alleles. In a simplified model (8-SNP GRS), the discriminative power of 8-SNP GRS was similar to that of 12-SNP GRS based on post-test probabilities (PP). Furthermore, 8-SNP GRS further improved the risk prediction of VTE recurrence in unprovoked VTE and male patients (PP% = 15.4 vs 8.3, 17.1 vs 7.2 and 19.0 vs 7.1 for high risk groups vs low risk groups in whole population, males and unprovoked VTE patients respectively). In addition, we also validated previously described 5-SNP GRS in our cohort and found that the 8-SNP GRS performed better than the 5-SNP GRS in terms of higher PP. Our results show that a multiple SNP GRS consisting of 8-SNPs may be an effective model for prediction of VTE recurrence, particularly in unprovoked VTE and male patients.

Using a Genetic Risk Score Approach to Predict Headache Response to Triptans in Migraine Without Aura.

A large meta-analysis of genome-wide association studies has recently identified a number of risk loci for migraine without aura (MwoA). In this study, we tested the hypothesis that a genetic risk score based on single-nucleotide polymorphisms (SNPs), previously reported to be associated with MwoA at genome-wide significance, may influence headache response to triptans in patients with migraine without aura. Genotyping of rs9349379, rs2078371, rs6478241, rs11172113, rs1024905, and rs6724624 was conducted with a real-time PCR allelic discrimination assay in 172 MwoA patients, of whom 36.6% were inconsistent responders to triptans. Each genetic risk score model was constructed as an unweighted score, calculated by adding the number of risk alleles for MwoA across each SNP at selected loci. The association with headache response to triptans was evaluated by logistic regression analysis adjusted for triptan, and the P values were corrected for the false discovery rate. The genetic risk score including susceptibility risk alleles at TRPM8 rs6724624 and FGF6 rs1024905 was found to be inversely associated with risk of inconsistent response to triptans (OR, 0.62; 95%CI, 0.43-0.89; false discovery rate q value, 0.045). In addition, adding this genetic risk score to the triptan-adjusted logistic regression model significantly improved (P = .037) the discrimination accuracy, from 0.57 (95%CI, 0.50-0.65) to 0.64 (95%CI, 0.57-0.72). A modest but significant effect on risk of inconsistent response to triptans was identified for a genetic risk score model composed of 2 known risk alleles for MwoA, suggesting its potential utility in predicting headache response to triptan therapy.

Genome-wide association analysis of common genetic variants of resistant hypertension.

Resistant hypertension (RHTN), defined as uncontrolled blood pressure (BP) ≥ 140/90 using three or more drugs or controlled BP (<140/90) using four or more drugs, is associated with adverse outcomes, including decline in kidney function. We conducted a genome-wide association analysis in 1194 White and Hispanic participants with hypertension and coronary artery disease from the INternational VErapamil-SR Trandolapril STudy-GENEtic Substudy (INVEST-GENES). Top variants associated with RHTN at p < 10-4 were tested for replication in 585 White and Hispanic participants with hypertension and subcortical strokes from the Secondary Prevention of Subcortical Strokes GENEtic Substudy (SPS3-GENES). A genetic risk score for RHTN was created by summing the risk alleles of replicated RHTN signals. rs11749255 in MSX2 was associated with RHTN in INVEST (odds ratio (OR) (95% CI) = 1.50 (1.2-1.8), p = 7.3 × 10-5) and replicated in SPS3 (OR = 2.0 (1.4-2.8), p = 4.3 × 10-5), with genome-wide significance in meta-analysis (OR = 1.60 (1.3-1.9), p = 3.8 × 10-8). Other replicated signals were in IFLTD1 and PTPRD. IFLTD1 rs6487504 was associated with RHTN in INVEST (OR = 1.90 (1.4-2.5), p = 1.1 × 10-5) and SPS3 (OR = 1.70 (1.2-2.5), p = 4 × 10-3). PTPRD rs324498, a previously reported RHTN signal, was among the top signals in INVEST (OR = 1.60 (1.3-2.0), p = 3.4 × 10-5) and replicated in SPS3 (OR = 1.60 (1.1-2.4), one-sided p = 0.005). Participants with the highest number of risk alleles were at increased risk of RHTN compared to participants with a lower number (p-trend = 1.8 × 10-15). Overall, we identified and replicated associations with RHTN in the MSX2, IFLTD1, and PTPRD regions, and combined these associations to create a genetic risk score.

PNPLA3 p.I148M and TM6SF2 p.E167K variants do not predispose to liver injury in cholestatic liver diseases: A prospective analysis of 178 patients with PSC.

BackgroundThe adiponutrin (PNPLA3) p.I148M and transmembrane 6 superfamily member 2 (TM6SF2) p.E167K variants represent major genetic risk factors for progressive liver injury in nonalcoholic fatty liver disease (NAFLD), alcoholic liver disease (ALD) and chronic viral hepatitis. The aim of this study was to find out whether these variants have a detrimental impact on the progression of chronic liver disease in patients with prolonged cholestasis induced by primary sclerosing cholangitis (PSC).MethodsWe prospectively recruited 178 PSC patients (112 male, age range 17–75 years, 55 with liver cirrhosis, 94 with ulcerative colitis, 48 transplanted during follow-up). PNPLA3 rs738409 and TM6SF2 rs58542926 polymorphisms were genotyped using dedicated TaqMan assays. Associations between genotypes, biochemical and clinical phenotypes were analyzed using contingency tables.ResultsAllele and genotype distribution of both variants were consistent with Hardy-Weinberg equilibrium. No significant differences in the genotype distribution of PNPLA3 (P = 0.90) or TM6SF2 (P = 0.72) were observed between patients with cirrhosis and patients without cirrhosis. Serum liver enzyme activities were not modified by the presence of PNPLA3 (ALT P = 0.88, AST P = 0.77) or TM6SF2 (ALT P = 0.92, AST P = 0.49) risk variants. Increasing number of risk alleles had no impact on serum liver enzyme activities, as demonstrated by a separate analysis of patients carrying 0 (n = 99), 1 (n = 64), 2 (n = 12) or 3 (n = 3) risk alleles (P>0.05). No impact of PNPLA3 or TM6SF2 risk variants was detectable in patients with PSC and ulcerative colitis, and none of the variants increased the odds of transplantation.ConclusionsNeither PNPLA3 nor TM6SF2 polymorphisms seem to contribute significantly towards an increased risk for deterioration of liver function in patients with PSC. These results underscore the divergent mechanisms of liver damage in cholestatic conditions as compared to metabolic and viral liver diseases.

Genetic Variants in pre-miR-146a, pre-miR-499, pre-miR-125a, pre-miR-605, and pri-miR-182 Are Associated with Breast Cancer Susceptibility in a South American Population.

Breast cancer (BC) is one of the most frequent tumors affecting women worldwide. microRNAs (miRNAs) single-nucleotide polymorphisms (SNPs) likely contribute to BC susceptibility. We evaluated the association of five SNPs with BC risk in non-carriers of the BRCA1/2-mutation from a South American population. The SNPs were genotyped in 440 Chilean BRCA1/2-negative BC cases and 1048 controls. Our data do not support an association between rs2910164:G>C or rs3746444:A>G and BC risk. The rs12975333:G>T is monomorphic in the Chilean population. The pre-miR-605 rs2043556-C allele was associated with a decreased risk of BC, both in patients with a strong family history of BC and in early-onset non-familial BC (Odds ratio (OR) = 0.5 [95% confidence interval (CI) 0.4–0.9] p = 0.006 and OR = 0.6 [95% CI 0.5–0.9] p = 0.02, respectively). The rs4541843-T allele is associated with increased risk of familial BC. This is the first association study on rs4541843 and BC risk. Previously, we showed that the TOX3-rs3803662:C>T was significantly associated with increased risk of familial BC. Given that TOX3 mRNA is a target of miR-182, and that both the TOX3 rs3803662-T and pri-miR-182 rs4541843-T alleles are associated with increased BC risk, we evaluated their combined effect. Risk of familial BC increased in a dose-dependent manner with the number of risk alleles (p-trend = 0.0005), indicating an additive effect.

Association between genetic variability of neuronal nitric oxide synthase and sensorimotor gating in humans

Research increasingly suggests that nitric oxide (NO) plays a role in the pathogenesis of schizophrenia. One important line of evidence comes from genetic studies, which have repeatedly detected an association between the neuronal isoform of nitric oxide synthase (nNOS or NOS1) and schizophrenia. However, the pathogenetic pathways linking nNOS, NO, and the disorder remain poorly understood. A deficit in sensorimotor gating is considered to importantly contribute to core schizophrenia symptoms such as psychotic disorganization and thought disturbance. We selected three candidate nNOS polymorphisms (Ex1f-VNTR, rs6490121 and rs41279104), associated with schizophrenia and cognition in previous studies, and tested their association with the efficiency of sensorimotor gating in healthy human adults. We found that risk variants of Ex1f-VNTR and rs6490121 (but not rs41279104) were associated with a weaker prepulse inhibition (PPI) of the acoustic startle reflex, a standard measure of sensorimotor gating. Furthermore, the effect of presence of risk variants in Ex1f-VNTR and rs6490121 was additive: PPI linearly decreased with increasing number of risk alleles, being highest in participants with no risk allele, while lowest in individuals who carry three risk alleles. Our findings indicate that NO is involved in the regulation of sensorimotor gating, and highlight one possible pathogenetic mechanism for NO playing a role in the development of schizophrenia psychosis.

Abstract 3257: Polygenic risk score, stage, and mode of detection in relation to breast cancer risk

Abstract Identification of increasing numbers of breast cancer risk variants holds promise to improve risk prediction and identify population subgroups that could benefit from targeted prevention and early detection. We aimed to examine whether women with increased polygenic risk are more likely to be diagnosed with symptomatic breast cancer. A case-control study including data collected from interviews, DNA from saliva, and cancer registry data collected between 2001-2007 (4,315 cases, 3,919 controls) was used to construct a polygenic risk score (PRS). Single nucleotide polymorphisms (SNPs, N=98) were selected from recently published genome-wide association studies of breast cancer and breast density, and comparative rat genome studies. Logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CI) associated with the SNPs. SNPs with p-values ≤0.10 (N=24) were used to construct quintiles of the PRS by multiplying the log-odds of the SNPs by the number of risk alleles; multivariable logistic regression models evaluated all women and strata of women defined by method of detection and stage at diagnosis. Odds ratios were adjusted for age, family history of breast cancer, age at menopause/menopausal status, body mass index, parity, and age at first birth. Overall, PRS quintile categories were associated with breast cancer risk in a dose response manner (Q1: OR=1, reference; Q2 OR=1.36, 95% CI 1.16-1.58; Q3 OR=1.66, 95% CI 1.43-1.93; Q4 OR=1.83, 95% CI 1.58-2.12; Q5 OR=2.58, 95% CI 2.23-2.98). Evaluated on a continuous scale, the PRS was associated with an OR=1.38 for a 1-unit change in the standard deviation (SD), 95% CI 1.32-1.45. Odds ratios were essentially unchanged when stratified by method of detection (p-value=0.40). The odds ratio of breast cancer associated with the continuous PRS was elevated among women diagnosed with advanced breast cancer: DCIS, OR=1.36, 95% CI 1.26-1.47 per 1 SD; localized OR=1.37, 95% CI 1.30-1.45 per 1 SD; regional OR=1.38, 95% CI 1.28-1.48 per 1 SD; and distant OR=1.82, 95% CI 1.39-2.40. These results suggest that polygenic risk scores are strongly related to breast cancer risk, that the association does not vary by method of breast cancer detection, but that the association is strongest for metastatic breast cancer. Citation Format: Amy Trentham-Dietz, John M. Hampton, Irene M. Ong, C David Page, Michael N. Gould, Jill D. Haag, Polly A. Newcomb, James D. Shull, Elizabeth S. Burnside. Polygenic risk score, stage, and mode of detection in relation to breast cancer risk [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3257.

Abstract 3007: Monogenic and polygenic associations with subsequent breast cancer risk in survivors of childhood cancer: The St. Jude Lifetime Cohort Study (SJLIFE)

Abstract The allelic spectrum of the genetic architecture of breast cancer (BC) susceptibility includes at least 172 common variants with small effect sizes (per-allele odds ratio range: 1.03-1.31), plus rare variants with high (BRCA1, BRCA2, CHD1, PTEN, STK11, TP53) or moderate penetrance (ATM, CHEK2, NBN, NF1, PALB2). While these common variants confer modest risk individually, their combined effect in the form of a polygenic risk score (PRS) may be substantial. The SJLIFE whole-genome sequencing (WGS) data provide a unique opportunity to evaluate common and rare sets of genetic variants jointly, along with treatment exposures, for their contributions to subsequent BC risk in adult survivors of childhood cancer. This analysis utilized WGS data from 1131 females of European ancestry [median age at last follow-up: 34.9 years (range: 6.2-68.6)] of whom 47 were diagnosed with a subsequent BC (median age at BC 40.3 years, range: 25.5-53.0). The PRS (mean, 10.1; range, 8.3-12.2) was calculated using a weighted sum of the number of risk alleles and their log per-allele odds ratio from Michailidou et al. (Nature, Nov. 2017). A total of 34 (3.0%) survivors were carriers of pathogenic or likely pathogenic (P/LP) variants in the 11 BC predisposition genes (listed above). The standardized incidence ratio (SIR) for BC was 6.7 (95% CI, 5.0-8.9) for survivors relative to the SEER population. The SIR varied from 3.7 (95% CI, 1.4-8.1) for survivors with PRS in the 1st quintile to 3.6 (95% CI, 1.2-8.3), 7.3 (95% CI, 3.8-12.7), 7.6 (95% CI, 3.6-14.0), and 11.4 (95% CI, 6.8-18.1) in the 2nd, 3rd, 4th, and 5th quintiles, respectively. In the multivariable model adjusting for age at diagnosis, chest irradiation, alkylating agents, anthracyclines, attained age, and significant genotype eigenvectors, the relative rates (RR) of BC were 16.5 (95% CI, 6.4 - 42.6), 11.5 (95% CI, 4.4-29.9), and 47.8 (95% CI, 8.2-278.3) for carriers vs. non-carriers of the P/LP variants among all survivors, and survivors with and without chest irradiation, respectively. The RR per one standard deviation of PRS were 1.5 (95% CI, 1.1-1.9), 1.6 (95% CI, 1.2-2.0) and 1.3 (95% CI, 0.7-2.2), respectively, for the same three groups. Importantly, PRS was significantly associated with the rate of subsequent BC under the age of 45 (RR, 1.7; 95% CI, 1.3-2.2) but not over 45 (RR, 0.9; 95% CI, 0.6-1.5). To our knowledge, this is the first assessment of the joint effects of rare and common genetic variations implicated in the etiology of BC in the general population, among long-term survivors of childhood cancer. Clinically, we anticipate that an individual genetic profile utilizing common susceptibility loci in combination with rare P/LP variants will inform an improved strategy for personalized BC risk stratification and management for childhood cancer survivors. Further replication studies are warranted to confirm and refine our findings. Citation Format: Zhaoming Wang, Carmen L. Wilson, Qi Liu, John Easton, Heather L. Mulder, Michael Rusch, Michael Edmonson, Shawn Levy, Aman Patel, Ying Shao, Ti-Cheng Chang, Stephen V. Rice, Yadav Sapkota, Russell J. Brooke, Wonjong Moon, Evadnie Rampersaud, Xiaotu Ma, Cynthia Pepper, Xin Zhou, Xiang Chen, Wenan Chen, Angela Jones, Braden Boone, Matthew J. Ehrhardt, Rebecca M. Howell, Nicholas Phillips, Courtney Lewis, Chimene A. Kesserwan, Gang Wu, Kim E. Nichols, James R. Downing, Melissa M. Hudson, Jinghui Zhang, Yutaka Yasui, Leslie L. Robison. Monogenic and polygenic associations with subsequent breast cancer risk in survivors of childhood cancer: The St. Jude Lifetime Cohort Study (SJLIFE) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3007.

Prediction of changes in bone mineral density in the elderly: contribution of "osteogenomic profile".

The rate of longitudinal bone loss (ΔBMD) is a risk factor for fracture. The variation in ΔBMD is partly determined by genetic factors. This study sought to define the association between an osteogenomic profile and ΔBMD. The osteogenomic profile was created from 62 BMD-associated SNPs from genome-wide association studies (GWAS) that were genotyped in 1384 elderly men and women aged 60+ years. Weighted genetic risk scores (GRS) were constructed for each individual by summing the products of the number of risk alleles and the sex-specific regression coefficients [associated with BMD from GWAS]. ΔBMD, expressed as annual percent change-in-BMD, was determined by linear regression analysis for each individual who had had at least two femoral neck BMD measurements. The mean ΔBMD was - 0.65% (SD 1.64%) for women and - 0.57% (SD 1.40%) for men, and this difference was not statistically significant (P = 0.32). In women, each unit increase in GRS was associated with 0.21% (SE 0.10) higher ΔBMD at the femoral neck (P = 0.036), and this association was independent of baseline BMD and age. In logistic regression analysis, each unit increase of GRS was associated with 41% odds (95%CI: 1.07-1.87) of rapid bone loss (ΔBMD ≤ - 1.2%/year; mean of rapid loss group = - 2.2%/year). There was no statistically significant association between ΔBMD and GRS in men. We conclude that the osteogenomic profile constructed from BMD-associated genetic variants is modestly associated with long-term changes in femoral neck BMD in women, but not in men.

Increased variability of stimulus-driven cortical responses is associated with genetic variability in children with and without dyslexia

Individuals with dyslexia exhibit increased brainstem variability in response to sound. It is unknown as to whether increased variability extends to neocortical regions associated with audition and reading, extends to visual stimuli, and whether increased variability characterizes all children with dyslexia or, instead, a specific subset of children. We evaluated the consistency of stimulus-evoked neural responses in children with (N = 20) or without dyslexia (N = 12) as measured by magnetoencephalography (MEG). Approximately half of the children with dyslexia had significantly higher levels of variability in cortical responses to both auditory and visual stimuli in multiple nodes of the reading network. There was a significant and positive relationship between the number of risk alleles at rs6935076 in the dyslexia-susceptibility gene KIAA0319 and the degree of neural variability in primary auditory cortex across all participants. This gene has been linked with neural variability in rodents and in typical readers. These findings indicate that unstable representations of auditory and visual stimuli in auditory and other reading-related neocortical regions are present in a subset of children with dyslexia and support the link between the gene KIAA0319 and the auditory neural variability across children with or without dyslexia.

Abstract 469: APOL1 Genotypes and Risk of Heart Failure: an Additive Genetic Effect in the Elderly, but Not in the Young Adults in Patients with Chronic Kidney Disease

Objective: Apolipoprotein L1 (APOL1), the major protein component of HDL, is identified having an association with renal disease in African Americans (AA). We assessed the hypothesis that the genetic variations in APOL1 (G1 and G2 alleles) are associated with risk of heart failure (HF), and this effect is modified by age. Methods: Subjects aged 21-75, with an estimated GFR (eGFR) of 20 to 70 ml/min/1.73 m 2 at baseline recruitments (April 2003-Sept 2008), who were free of HF participating in the Chronic Renal Insufficiency Cohort (CRIC) Study and followed-up through March 2013 are analyzed (White: 1335, AA:1323). The associations of APOL1 risk genotype (assessed by either 1 of the G1 and G2, or 2 of their combinations, i.e., G1/G1, G1/G2 or G2/G2) with incident HF and mortality are examined using Cox’s regression models. Results: Within a mean 7-year (SD: 2.1) follow-up, AA had a significantly higher incidence of HF than White (2.62 vs. 1.67 per 100 person-year (PY), p=0.006) in those aged&lt;65, and 3.94 vs. 2.71 per 100 PY (p=0.026) in those aged≥65. Cox’s models, with adjusted age, sex, eGFR and HDL, indicate that compared to White, AA aged&lt;65 without or with 1 of either G1 or G2 had a significantly higher risk of HF [Hazard Ratio, HR: 2.15 (95%CI: 1.59-2.92, p&lt;.0001), followed by those with either 2 of G1/G1, G1/G2 or G2/G2 alleles (1.47, 0.88-2.48, p=0.15)]. However, a significant additive genetic effect of the number of risk alleles (i.e., 0,1,2) is observed in AA aged ≥65. The corresponding HRs (95%CI) are 1.73 (1.17-2.57, p=0.007) in those without or with either 1 of the G1 or G2, and 2.17 (1.20-3.94, p=0.011) in those with either 2 of the G1 and G2 combination. A significant interaction effect of age (≥65 vs. &lt;65) and the risk alleles (2 vs. 0/1) is observed (HR: 2.45, 95%CI: 1.14-5.28, p=0.02). Similar associations between APOL1 alleles and mortality from HF and all-cause are seen by the two age groups. Conclusion: African Americans with APOL1 risk alleles have significantly higher risk of HF and mortality than White. An additive genetic effect of the number of APOL1 risk alleles is shown among AA aged ≥65, but not in the younger adults. The modifying effect of age suggests that a possible 'different genetic-risk window' by ages warrants consideration in HF control and prevention.

Genetic variants in ATM, H2AFX and MRE11 genes and susceptibility to breast cancer in the polish population

BackgroundDNA damage repair is a complex process, which can trigger the development of cancer if disturbed. In this study, we hypothesize a role of variants in the ATM, H2AFX and MRE11 genes in determining breast cancer (BC) susceptibility.MethodsWe examined the whole sequence of the ATM kinase domain and estimated the frequency of founder mutations in the ATM gene (c.5932G > T, c.6095G > A, and c.7630-2A > C) and single nucleotide polymorphisms (SNPs) in H2AFX (rs643788, rs8551, rs7759, and rs2509049) and MRE11 (rs1061956 and rs2155209) among 315 breast cancer patients and 515 controls. The analysis was performed using high-resolution melting for new variants and the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method for recurrent ATM mutations. H2AFX and MRE11 polymorphisms were analyzed using TaqMan assays. The cumulative genetic risk scores (CGRS) were calculated using unweighted and weighted approaches.ResultsWe identified four mutations (c.6067G > A, c.8314G > A, c.8187A > T, and c.6095G > A) in the ATM gene in three BC cases and two control subjects. We observed a statistically significant association of H2AFX variants with BC. Risk alleles (the G of rs7759 and the T of rs8551 and rs2509049) were observed more frequently in BC cases compared to the control group, with P values, odds ratios (OR) and 95% confidence intervals (CIs) of 0.0018, 1.47 (1.19 to 1.82); 0.018, 1.33 (1.09 to 1.64); and 0.024, 1.3 (1.06 to 1.59), respectively. Haplotype-based tests identified a significant association of the H2AFX CACT haplotype with BC (P < 0.0001, OR = 27.29, 95% CI 3.56 to 209.5). The risk of BC increased with the growing number of risk alleles. The OR (95% CI) for carriers of ≥ four risk alleles was 1.71 (1.11 to 2.62) for the CGRS.ConclusionsThis study confirms that H2AFX variants are associated with an increased risk of BC. The above-reported sequence variants of MRE11 genes may not constitute a risk factor of breast cancer in the Polish population. The contribution of mutations detected in the ATM gene to the development of breast cancer needs further detailed study.

GWAS implicated risk variants in different genes contribute additively to increase the risk of coronary artery disease (CAD) in the Pakistani subjects

BackgroundCoronary artery disease (CAD) remains the single most important cause of mortality worldwide. Many candidate and GWAS genetic variants have been identified in the recent years. In the current study, we selected six SNPs from various genes that have originally been identified in GWAS studies and examined the association of SNPs individually and as a genetic risk score (GRS) with CAD and blood lipid levels in the Pakistani subjects.MethodsSix hundred twenty-four (404 cases and 219 controls) subjects were genotyped for variants rs10757274 in CDKN2A gene, rs17465637 in MIA3 gene, rs7025486 in DAB2IP gene, rs17228212 in SMAD3 gene, rs981887 in MRAS gene and rs1746048 in CXCL12 gene, by TaqMan and KASPar allele discrimination techniques. Serum lipid parameters were measured using commercially available kits. Statistical analyses were done using SPSS version 22.ResultsIndividually, the single SNPs were not associated with CAD (p < 0.05). However, the combined GRS of 6 SNPs was significantly higher in cases than controls (4.89 ± 0.11 vs 4.58 ± 0.08, p = 0.024). Among blood lipids, GRS showed significant positive association with serum triglycerides levels (p = 0.022).ConclusionThe GRS was quantitatively associated with CAD risk and showed association with serum triglycerides levels, suggesting that the mechanism of these variants is likely to be in part at least through creating an atherogenic lipid profile in subjects carrying high numbers of risk alleles.

CYP2E1 and GSTM1 gene polymorphisms, environmental factors, and the susceptibility to lung cancer.

To investigate the relationships between the CYP2E1 RsaI polymorphism, GSTM1 polymorphism, and the susceptibility to lung cancer, along with the interactions between environmental factors and these genes. A case-control study was carried out to explore the independent effect of gene polymorphisms on risk of lung cancer, and the combined effects of gene loci. The stratification analysis of age, sex, smoking, and drinking combined with positive loci was also analyzed, and any interaction was identified. The logistic regression analysis showed that there were statistical relationships between the CYP2E1 RsaI TT genotype and lung cancer, GSTM1 (-) and lung cancer. The combined effect's analysis of these 2 loci showed that, with an increase in the number of risk alleles, the risk of lung cancer also increased (supposing 0 risk allele as the reference group). Subjects carrying 3 risk alleles had the highest risk of developing lung cancer with an adjusted OR=10.38 (95% CI 2.10-51.35). Stratified analysis showed that, in women, nonsmoking subjects, or nondrinking subjects, the combined effects could increase the risk of lung cancer; no heterogeneity was found between these layers except sex. The interaction analysis showed that, supposing the male, GSTM1 (+) genotype as the reference, the female, GSTM1 (-) genotype had a significantly increased risk of lung cancer (OR=2.17 [1.01-4.70]); when the non-smoking, GSTM1 (+) genotype subjects was the reference group, smoking, GSTM1 (+) genotype subjects and smoking, GSTM1 (-) genotype subjects had significantly higher risk of lung cancer (OR=2.00 [1.01-3.96], OR=2.89 [1.28-6.54]). CYP2E1 RsaI TT genotype was a protective factor against the development of lung cancer, while GSTM1 (-) genotype was a risk factor for lung cancer. Increases in the number of the risk alleles also increased lung cancer risk. GSTM1 (-) genotype, sex, and smoking status might interact in the incidence of lung cancer.