Disease Liability Research Articles

Genetic liability estimated from large-scale family data improves genetic prediction, risk score profiling, and gene mapping for major depression

Large biobank samples provide an opportunity to integrate broad phenotyping, familial records, and molecular genetics data to study complex traits and diseases. We introduce Pearson-Aitken Family Genetic Risk Scores (PA-FGRS), a method for estimating disease liability from patterns of diagnoses in extended, age-censored genealogical records. We then apply the method to study a paradigmatic complex disorder, major depressive disorder (MDD), using the iPSYCH2015 case-cohort study of 30,949 MDD cases, 39,655 random population controls, and more than 2 million relatives. We show that combining PA-FGRS liabilities estimated from family records with molecular genotypes of probands improves three lines of inquiry. Incorporating PA-FGRS liabilities improves classification of MDD over and above polygenic scores, identifies robust genetic contributions to clinical heterogeneity in MDD associated with comorbidity, recurrence, and severity and can improve the power of genome-wide association studies. Our method is flexible and easy to use, and our study approaches are generalizable to other datasets and other complex traits and diseases.

Population Performance and Individual Agreement of Coronary Artery Disease Polygenic Risk Scores.

Polygenic risk scores (PRSs) for coronary artery disease (CAD) are a growing clinical and commercial reality. Whether existing scores provide similar individual-level assessments of disease liability is a critical consideration for clinical implementation that remains uncharacterized. Characterize the reliability of CAD PRSs that perform equivalently at the population level at predicting individual-level risk. Cross-sectional Study. All of Us Research Program (AOU), Penn Medicine Biobank (PMBB), and UCLA ATLAS Precision Health Biobank. Volunteers of diverse genetic backgrounds enrolled in AOU, PMBB, and UCLA with available electronic health record and genotyping data. Polygenic risk for CAD from previously published PRSs and new PRSs developed separately from the testing cohorts. Sets of CAD PRSs that perform population prediction equivalently were identified by comparing calibration and discrimination (Brier score and AUROC) of generalized linear models of prevalent CAD using Bayesian analysis of variance. Among equivalently performing scores, individual-level agreement between risk estimates was tested with intraclass correlation (ICC) and Light's Kappa, measures of inter-rater reliability. 50 PRSs were calculated for 171,095 AOU participants. When included in a model of prevalent CAD, 48 scores had practically equivalent Brier scores and AUROCs (region of practical equivalence = 0.02). Across these scores, 84% of participants had at least one score in both the top and bottom risk quintile. Continuous agreement of individual risk predictions from the 48 scores was poor, with an ICC of 0.351 (95% CI; 0.349, 0.352). Agreement between two statistically equivalent scores was moderate, with an ICC of 0.649 (95% CI; 0.646, 0.652). Light's Kappa, used to evaluate consistency of assignment to high-risk thresholds, did not exceed 0.56 (interpreted as 'fair') across statistically and practically equivalent scores. Repeating the analysis among 41,193 PMBB and 50,748 UCLA participants yielded different sets of statistically and practically equivalent scores which also lacked strong individual agreement. Across three diverse biobanks, CAD PRSs that performed equivalently at the population level produced unreliable individual risk estimates. Approaches to clinical implementation of CAD PRSs must consider the potential for discordant individual risk estimates from otherwise indistinguishable scores.

NAD+ supplement relieved chronic sleep restriction (CSR)-induced microglial proinflammation in vivo and in vitro

Sleep insufficiency is a significant health problem worldwide and can induce multiple neurodevelopmental disorders in the central nervous system (CNS). Sleep deprivation (SD), especially chronic SD, leads to cognition and memory loss and worsens neurodegenerative disease liability. Microglia are the main inflammation-dominant glia and play a crucial role in SD-induced neurological impairments. Nicotinamide adenine dinucleotide (NAD+) is a redox reaction coenzyme that exerts anti-inflammatory and mitochondria-protective effects in microglia. Whether NAD+ mitigated SD-induced neurological disorders by regulating microglial functions is still unknown. In the current study, we designed an in vivo and in vitro model to evaluate the neuroprotective effect of NAD+ on chronic sleep restriction (CSR) and further investigate the underlying mechanisms. Behavioral tests and immunofluorescence staining were applied to investigate the cognition impairments and microglial activation. Biochemical experiments were tested to analyze the oxidative status and possible mechanism. In vitro data were used to verify the in vivo data. Our results displayed that NAD+ supplement mitigated CSR-induced cognitive decline and microglial activation response by suppressing the expression of pro-inflammatory cytokines in vivo. NAD+ administration also decreased oxidative stress and mitochondrial impairments in microglia. In vitro results showed that NAD+ treatment inhibited ROS production and prompted M1 conversion to M2 phenotype. cGAS-STING/NF-κB pathways were significantly activated but down-regulated by NAD+ administration. H151, a STING antagonist, was applied to validate that NAD+ treatment alleviates neuroinflammation partially by regulating cGAS-STING pathways in microglia. Our findings suggest that NAD+ supplement is a promising therapy for sleep disorders-induced neurological problems, and cGAS-STING pathway may act as a critical regulator in microglial proinflammation.

Genetic association studies using disease liabilities from deep neural networks.

The case-control study is a widely used method for investigating the genetic underpinnings of binary traits. However, long-term, prospective cohort studies often grapple with absent or evolving health-related outcomes. Here, we propose two methods, liability and meta, for conducting genome-wide association study (GWAS) that leverage disease liabilities calculated from deep patient phenotyping. Analyzing 38 common traits in ~300,000 UK Biobank participants, we identified an increased number of loci compared to the conventional case-control approach, with high replication rates in larger external GWAS. Further analyses confirmed the disease-specificity of the genetic architecture with the meta method demonstrating higher robustness when phenotypes were imputed with low accuracy. Additionally, polygenic risk scores based on disease liabilities more effectively predicted newly diagnosed cases in the 2022 dataset, which were controls in the earlier 2019 dataset. Our findings demonstrate that integrating high-dimensional phenotypic data into deep neural networks enhances genetic association studies while capturing disease-relevant genetic architecture.

Role of miRNA Gene Variants (miR-22 and miR-155) as the Factors Affecting Susceptibility to Panic Disorder.

Variants within genes encoding microRNAs (miRNAs) may alter the expression of both miRNAs and their target genes, thus contributing to the etiology of psychiatric disorders. The involvement of miRNAs in neuronal differentiation and synaptic plasticity supported this hypothesis. We aimed to investigate the links between miR-155 rs767649/miR-22 rs8076112 and the risk of panic disorder (PD) in a sample of Turkish population. In this experimental study, 134 PD patients and 140 healthy controls were recruited. Genotyping was carried out using Polymerase Chain Reaction-Restriction Fragment Length Polymorphism (PCR-RFLP) method. To evaluate PD phenotypes, Panic Disorder Severity Scale (PDSS) was also administered to patients to clarify possible associations between the scale and risk variants analyzed. The genotype analysis of miR-155 rs767649 did not show an association with PD risk and it was not related to the disease severity. For miR-22 rs8076112 variant, a statistically significant association was determined; CC genotypes were lower in patients compared to controls. Logistic regression analysis proved the highly protective effect (80.4%) of CC genotype against PD (p = 0.041; OR = 0.196, 95% CI = 0.041-0.934). Though its significance in disease liability, miR-22 rs8076112 was not associated with the disease severity. Our findings firstly report the combined analysis of miR-155 rs767649 and miR-22 rs8076112 in PD in terms of both disease susceptibility and severity. These findings await replication in independent cohorts with enrichment of other miRNA gene variants. Thus, certain miRNAs and their target genes involved in the etiology and phenotypes of PD could be enlightened.

Longitudinal characterization of impulsivity phenotypes boosts signal for genomic correlates and heritability.

Genomic correlates of impulsivity have been identified in several genome-wide association studies (GWAS) using cross-sectional designs, but no studies have investigated the molecular genetic correlates of impulsivity phenotypes using longitudinally constructed traits. In 3860 unrelated European participants in the Avon Longitudinal Study of Parents and Children (ALSPAC), we constructed longitudinal phenotypes for delay discounting and impulsive personality traits (as measured by the UPPS-P impulsive behavior scales) via assessment at ages 24, 26, and 28. We conducted GWASs of impulsivity using both cross-sectional and longitudinal phenotypes, estimated heritability and their phenotypic and genetic correlations, and evaluated their association with recently-developed polygenic risk scores (PRSs) for the impulsivity indicators themselves and also related psychiatric conditions. Latent growth curve modeling revealed a stable intercept over time for all impulsivity phenotypes. High genetic correlation of cross-sectional measures over time suggested a stable genetic component for delay discounting (rg = 0.53-0.99) and sensation seeking (rg = 0.99). Heritability estimates of the stable longitudinal phenotypes substantively improved as compared to their cross-sectional counterparts, revealing a significant SNP-heritability for delay discounting (0.22; p = 0.03) and sensation seeking (0.35; p = 0.0007). Consistent with previous reports, GWAS and gene-based analyses revealed associations between specific longitudinal impulsivity indicators and CADM2 and NCAM1 genes. The PRSs for the impulsivity indicators and disorders related to self-regulation were also significantly associated with longitudinal impulsivity traits. Finally, we validated the associations between longitudinal impulsivity phenotypes and their PRSs in an independent 13-wave longitudinal study (n = 1019) and the benefit of longitudinal phenotypes in simulation studies. In this first longitudinal genetic study of impulsivity traits, the results revealed stable genomic correlates of delay discounting and sensation seeking over time and further validated the utility of recently-developed PRSs, both in relation to the observed traits and in connecting them to psychiatric disorders. More generally, these findings support using latent intercepts as novel longitudinal phenotypes to boost signal for heritability and genomic correlates of mechanisms contributing to psychiatric disease liability.

The Germanic Model of Liability for Diseases of Animals in Sale Transactions: Historical Heritage or the Dead Weight of Past Generations? Factors Affecting the Form of Legal Standards for Warranty.

The subject of the analysis is the Germanic model of liability for the physical defects of animals examined through examples in Europe. Methods of legal analysis and interpretation are used. Contemporary (Austria, Belgium, France, Luxembourg and Switzerland) and historical examples (Germany and Poland) are examined and described. The characteristics of this model and the historical conditions which shaped the current legal state are demonstrated. It is shown where particular civil law systems in Europe have maintained the Germanic model of warranty to this day, where other systems have replaced it with another model and what factors have influenced this. The analysis is comparative in regard to legal systems and oriented toward veterinary science.

Predictive Performance of an Updated Polygenic Risk Score for Age-Related Macular Degeneration

ObjectiveA recent genome-wide association study of age-related macular degeneration (AMD) has identified new AMD-associated risk variants. These variants can now be incorporated into an updated polygenic risk score (PRS). This study aimed to assess the performance of an updated polygenic risk score (PRS2023) in an independent cohort of older individuals with retinal imaging data, and compare performance with an older PRS (PRS2016). DesignCross-sectional study. ParticipantsA total of 4,175 participants of European ancestry aged ≥70 years with genotype and retinal imaging data from the ASPirin in Reducing Events in the Elderly trial. MethodsWe used logistic regression models and area under the curve (AUC) to assess the performance of the PRS2023 compared with PRS2016. AMD status and severity were graded using colour fundus photography. Main Outcome MeasuresAssociation of PRS2023 and PRS2016 with AMD risk at baseline. ResultsAt enrolment among 4,175 participants, 2,605 (62.4%) had no AMD, 853 (20.4%), 671 (16.1%) and 46 (1.1%) had early, intermediate and late-stage AMD, respectively. More than 27% of the participants with a high PRS2023 (top quartile) had intermediate or late-stage AMD, compared with <15% for those in the middle two quartiles and <13% for those in the lowest quartile. Both PRS2023 and PRS2016 were significantly associated with AMD after adjustment for age, sex, smoking status and lipid levels, with increasing odds ratios (OR) for worsening AMD grades. The PRS2023 outperformed PRS2016 (DeLong test comparing AUC, P=0.03 for all AMD, P=0.03 for late AMD). PRS2023 was associated with late-stage AMD with an adjusted OR of 5.05 [3.41-7.47] per standard deviation. Assuming a population prevalence of 10% for late-stage AMD, the PRS2023 explained 42.2% of disease liability. The AUC of a model containing conventional/non-genetic risk factors and the PRS2023 was 91% [87%-95%] for predicting late-stage AMD, which improved 12% over the model without the PRS (AUC=79%, P<0.001 for difference). ConclusionsA new PRS (PRS2023) for AMD outperforms a previous PRS, and predicts increasing risk for late-stage AMD (with stronger association for more severe imaging-confirmed AMD grades). Our findings have clinical implications for the improved prediction and risk stratification of AMD.

Parental genetically predicted liability for coronary heart disease and risk of adverse pregnancy outcomes: a cohort study

BackgroundAdverse pregnancy outcomes (APO) may unmask or exacerbate a woman’s underlying risk for coronary heart disease (CHD). We estimated associations of maternal and paternal genetically predicted liability for CHD with lifelong risk of APOs. We hypothesized that associations would be found for women, but not their male partners (negative controls).MethodsWe studied up to 83,969‬ women (and up to 55,568‬ male partners) from the Norwegian Mother, Father and Child Cohort Study or the Trøndelag Health Study with genotyping data and lifetime history of any APO in their pregnancies (1967–2019) in the Medical Birth Registry of Norway (miscarriage, stillbirth, hypertensive disorders of pregnancy, gestational diabetes, small for gestational age, large for gestational age, and spontaneous preterm birth). Maternal and paternal genetic risk scores (GRS) for CHD were generated using 148 gene variants (p-value < 5 × 10−8, not in linkage disequilibrium). Associations between GRS for CHD and each APO were determined using logistic regression, adjusting for genomic principal components, in each cohort separately, and combined using fixed effects meta-analysis.ResultsOne standard deviation higher GRS for CHD in women was related to increased risk of any hypertensive disorders of pregnancy (odds ratio [OR] 1.08, 95% confidence interval [CI] 1.05–1.10), pre-eclampsia (OR 1.08, 95% CI 1.05–1.11), and small for gestational age (OR 1.04, 95% CI 1.01–1.06). Imprecise associations with lower odds of large for gestational age (OR 0.98, 95% CI 0.96–1.00) and higher odds of stillbirth (OR 1.04, 95% CI 0.98–1.11) were suggested. These findings remained consistent after adjusting for number of total pregnancies and the male partners’ GRS and restricting analyses to stable couples. Associations for other APOs were close to the null. There was weak evidence of an association of paternal genetically predicted liability for CHD with spontaneous preterm birth in female partners (OR 1.02, 95% CI 0.99–1.05), but not with other APOs.ConclusionsHypertensive disorders of pregnancy, small for gestational age, and stillbirth may unmask women with a genetically predicted propensity for CHD. The association of paternal genetically predicted CHD risk with spontaneous preterm birth in female partners needs further exploration.

Exploring the Causal Association between Brain Iron Accumulation and Alzheimer’s Disease: A Two‐Sample Univariable Mendelian Randomisation Analysis

AbstractBackgroundAlzheimer’s disease aetiology is complex and not fully understood. Brain iron has been increasingly implicated in the pathology of neurodegenerative diseases, and a myriad of epidemiological studies has supported a connection between brain iron accumulation and Alzheimer’s disease, but evidence remains inconsistent. Additionally, genetic studies have suggested that variations in genes that regulate brain iron metabolism may increase the risk of developing Alzheimer’s disease.MethodIn this study we conduct two‐sample univariable Mendelian randomisation analysis, leveraging the largest available summary statistic genetic data from genome‐wide associations studies on quantitative susceptibility mapping phenotypes to explore potentially causal associations between iron deposition measured in 18 brain structures and Alzheimer’s disease.ResultWe identified that higher genetically predicted brain iron accumulation in left putamen was associated with higher odds of Alzheimer’s disease (Odds ratio (OR) per standard deviation (SD) higher genetically predicted median susceptibility: 1.11, 95% confidence interval (CI): 1.03 to 1.20) and higher genetically predicted brain iron accumulation in right putamen was also associated with higher odds of Alzheimer’s disease (OR: 1.10, 95% CI: 1.01 to 1.20). However, genetic predisposition to higher Alzheimer’s disease liability was associated with lower brain iron deposition in right thalamus (beta per unit higher log‐odds of Alzheimer’s disease: ‐0.04, 95% CI: ‐0.08 to ‐0.01), left amygdala (beta: ‐0.04, 95% CI: ‐0.07 to ‐0.01), right amygdala (beta: ‐0.04, 95% CI: ‐0.07 to ‐0.01), left thalamus (beta: ‐0.03, 95% CI: ‐0.07 to ‐0.003) and left putamen (beta: ‐0.04, 95% CI: ‐0.08 to ‐0.002).ConclusionThis work provides a new layer of evidence using genetic association data that supports a potentially causal effect of iron accumulation in putamen on Alzheimer’s disease, which has been proposed in the literature. Iron can promote oxidative stress, which can contribute to neuronal damage and death in the putamen. Additionally, iron can disrupt the normal functioning of the basal ganglia, which in turn may lead to movement disorders, a symptom observed in Alzheimer’s disease. Therefore, despite the lack of evidence from clinical trials, iron‐targeted therapeutic strategies could be a beneficial approach for contributing to the treatment of Alzheimer’s disease.

Assortative mating and parental genetic relatedness contribute to the pathogenicity of variably expressive variants

We examined more than 97,000 families from four neurodevelopmental disease cohorts and the UK Biobank to identify phenotypic and genetic patterns in parents contributing to neurodevelopmental disease risk in children. We identified within- and cross-disorder correlations between six phenotypes in parents and children, such as obsessive-compulsive disorder (R= 0.32-0.38, p<10-126). We also found that measures of sub-clinical autism features in parents are associated with several autism severity measures in children, including biparental mean Social Responsiveness Scale scores and proband Repetitive Behaviors Scale scores (regression coefficient= 0.14, p=3.38×10-4). We further describe patterns of phenotypic similarity between spouses, where spouses show correlations for six neurological and psychiatric phenotypes, including a within-disorder correlation for depression (R= 0.24-0.68, p<0.001) and a cross-disorder correlation between anxiety and bipolar disorder (R= 0.09-0.22, p<10-92). Using a simulated population, we also found that assortative mating can lead to increases in disease liability over generations and the appearance of "genetic anticipation" in families carrying rare variants. We identified several families in a neurodevelopmental disease cohort where the proband inherited multiple rare variants in disease-associated genes from each of their affected parents. We further identified parental relatedness as a risk factor for neurodevelopmental disorders through its inverse relationship with variant pathogenicity and propose that parental relatedness modulates disease risk by increasing genome-wide homozygosity in children (R= 0.05-0.26, p<0.05). Our results highlight the utility of assessing parent phenotypes and genotypes toward predicting features in children who carry rare variably expressive variants and implicate assortative mating as a risk factor for increased disease severity in these families.

Risk factor burden in familial hypercholesterolaemia with early onset coronary artery disease

Abstract Background Familial hypercholesterolaemia (FH) is considered a causal risk factor for premature coronary artery disease (CAD) with a priority placed on identifying index cases and their relatives for preventative interventions. However recent population sequencing studies have identified that not all FH mutation carriers develop CAD. We hypothesised that a significant burden of traditional risk factors is required in addition to genetic risk to develop CAD. Methods We interrogated the clinical registry of patients attending the CVD risk and Lipids clinic at St Bartholomew’s Hospital in London which serves a large multi-ethnic population. Patients were prioritized for genetic testing based on Simon Broome and Dutch Lipid criteria. A second cohort of patients from the clinic consisted of premature CAD patients without phenotypic FH. CAD was defined as &amp;gt; 50% stenosis in an epicardial vessel by invasive or non-invasive imaging. Results We identified 40 patients with genetically confirmed FH and CAD (FH+/CAD+) and 116 people with FH and without CAD (FH+/CAD-). Of 10 traditional risk factors evaluated, prevalence of each was higher in FH +/CAD+ compared to FH+/CAD- patients. Collectively, FH+/ CAD+ patients had a median number of risk factors of 5(4,6) compared to 4(3,5) for FH+/CAD- patients, (P&amp;lt;0.001). In non-FH patients, risk factors burden was higher in those with CAD (FH-/CAD+), compared to those without CAD: 5(4,6) V. 4(3,5) risk factors, respectively(P&amp;lt;0.001). Importantly, in patients who developed CAD, the traditional risk factor burden was greater in FH- patients than that of FH+ patients whereas, the genetic risk burden was greater in FH+ patients (Figure-1). The mean age of onset of CAD in both FH+ and FH- patients was comparable: 43± 10 V. 43± 12years. Patients with FH+/CAD+ were older (53± 11 V 49± 13 years, P=0.276) but had an earlier onset of CAD, when risk burden was greater (43± 8 years if ≥ 5 risk factors v 49± 15 years if &amp;lt; 5 risk factors, P=0.192). Conclusion In a selected population from a large specialist lipid clinic, we demonstrate that traditional risk factor burden is additive to genetic risk for the development and age of onset of CAD, supporting a disease liability threshold model in FH.Figure-1.Risk Burden in FH with CAD

Cognitive and neuropsychiatric endophenotypes in amyotrophic lateral sclerosis.

First- and second-degree relatives of people with amyotrophic lateral sclerosis report higher rates of neuropsychiatric disorders, indicating that risk genes may be pleiotropic, causing multiple phenotypes within kindreds. Such phenotypes may constitute a disease endophenotype that associates with disease liability. We have directly investigated cognitive functioning and neuropsychiatric traits among relatives of people with amyotrophic lateral sclerosis to identify potential endophenotypes of the disease. In a family-based, cross-sectional study design, first- and second-degree relatives of people with amyotrophic lateral sclerosis (n = 149) were compared to controls (n = 60) using an in-depth neuropsychological and neuropsychiatric assessment. Subgroup analyses examined the effect of family history and C9orf72 repeat expansion status (n = 16 positive carriers). Relatives of people with amyotrophic lateral sclerosis had lower scores on executive functioning, language and memory tasks compared to controls, with large effect sizes observed on object naming (d = 0.91, P = 0.00001) and phonemic verbal fluency (d = 0.81, P = 0.0003). Relatives also had higher autism quotient attention to detail traits (d = -0.52, P = 0.005), lower conscientiousness (d = 0.57, P = 0.003) and lower openness to experience personality traits (d = 0.54, P = 0.01) than controls. These effects were typically larger in relatives of people with familial, rather than sporadic, amyotrophic lateral sclerosis and were present in both gene carrier and non-carrier relatives of probands with a C9orf72 repeat expansion. Poorer phonemic fluency and object naming, along with autism and personality traits, are more frequent in relatives of people with amyotrophic lateral sclerosis. Among kindreds carrying the C9orf72 repeat expansion, these traits were identified in relatives regardless of their carrier status, suggesting the presence of a disease-associated endophenotype that is not exclusively mediated by the C9orf72 expansion.

Associating broad and clinically defined polygenic scores for depression with depression-related phenotypes

Twin studies indicate that 30–40% of the disease liability for depression can be attributed to genetic differences. Here, we assess the explanatory ability of polygenic scores (PGS) based on broad- (PGSBD) and clinical- (PGSMDD) depression summary statistics from the UK Biobank in an independent sample of adults (N = 210; 100% European Ancestry) who were extensively phenotyped for depression and related neurocognitive traits (e.g., rumination, emotion regulation, anhedonia, and resting frontal alpha asymmetry). The UK Biobank-derived PGSBD had small associations with MDD, depression severity, anhedonia, cognitive reappraisal, brooding, and suicidal ideation but only the association with suicidal ideation remained statistically significant after correcting for multiple comparisons. Similarly small associations were observed for the PGSMDD but none remained significant after correcting for multiple comparisons. These findings provide important initial guidance about the expected effect sizes between current UKB PGSs for depression and depression-related neurocognitive phenotypes.

A simulation study for multifactorial genetic disorders to quantify the impact of polygenic risk scores on critical illness insurance

AbstractWith advances in genetic research, the understanding of the genetic structure of disease and the ability to predict disease risk have been enhanced. Polygenic risk scores (PRS) have been developed to assess a person’s risk of developing any heritable disease. PRS has two primary utilities that make it particularly relevant for insurers: the ability to identify high-risk groups when using PRS independently or in combination with standard risk factors; and the ability to inform early interventions that may alter future morbidity and mortality. Using heart disease as a case study, a simulation-based model is designed that introduces polygenic risk scoring into the actuarial analysis framework and then quantifies the adverse selection due to information asymmetry introduced by PRS. Individual and parental disease liability as well as PRS were simulated under a liability threshold model. A series of validations were conducted to confirm the utility of our simulated data sets. We explored three scenarios describing how insurance applicants use their PRS results to guide their insurance purchasing decisions and calculated the increased premiums that insurers would need to change to counteract this. The accuracy of PRS has the most significant impact on premiums and the proportion of individuals who know their PRS also has a substantial impact.

Polygenic Scores in the Direct-to-Consumer Setting: Challenges and Opportunities for a New Era in Consumer Genetic Testing.

Direct-to-consumer (DTC) genetic tests have generated considerable scholarly attention and public intrigue. Although the current consumer genetic testing regime relies on the reporting of individual variants of interest to consumers, there has recently been interest in the possibility of integrating polygenic scores (PGS), which aggregate genetic liability for disease across the entire genome. While PGS have thus far been extensively explored as clinical and public health tools, the use of PGS in consumer genetic testing has not yet received systematic attention, even though they are already in use for some consumer genetic tests. In this narrative review, we highlight the ethical, legal, and social implications of the use of PGS in DTC genetic tests and synthesize existing solutions to these concerns. We organize these concerns into three domains: (1) industry variation; (2) privacy and commercialization; and (3) patient safety and risk. While previously expressed concerns in these domains will remain relevant, the emergence of PGS-based DTC genetic tests raises challenges that will require novel approaches.

Personalized medicine: Function of CFTR variant p.Arg334Trp is rescued by currently available CFTR modulators.

Most of the 2,100 CFTR gene variants reported to date are still unknown in terms of their disease liability in Cystic Fibrosis (CF) and their molecular and cellular mechanism that leads to CFTR dysfunction. Since some rare variants may respond to currently approved modulators, characterizing their defect and response to these drugs is essential for effective treatment of people with CF (pwCF) not eligible for the current treatment. Here, we assessed how the rare variant, p.Arg334Trp, impacts on CFTR traffic and function and its response to existing CFTR modulators. To this end, we performed the forskolin-induced swelling (FIS) assay on intestinal organoids from 10 pwCF bearing the p.Arg334Trp variant in one or both alleles of the CFTR gene. In parallel, a novel p.Arg334Trp-CFTR expressing CFBE cell line was generated to characterize the variant individually. Results show that p.Arg334Trp-CFTR does not significantly affect the plasma membrane traffic of CFTR and evidences residual CFTR function. This CFTR variant is rescued by currently available CFTR modulators independently of the variant in the second allele. The study, predicting clinical benefit for CFTR modulators in pwCF with at least one p.Arg334Trp variant, demonstrates the high potential of personalized medicine through theranostics to extend the label of approved drugs for pwCF carrying rare CFTR variants. We recommend that this personalized approach should be considered for drug reimbursement policies by health insurance systems/national health services.

Abstract P389: Sex-Specific Genetic Interrogation of Cardiovascular Disease Drug Targets

Investigating sex-specific effects of genetically-proxied drug target inhibition on cardiovascular disease (CVD) liability may improve the understanding of CVD pathophysiology and therapeutic intervention, to enhance the formulation of sex-specific treatment in clinical practice. We aimed to investigate sex-specific associations between genetic variation at CVD drug targets and CVD risk factors in the UK Biobank for anti-hypertensive, lipid-lowering and anti-inflammatory drug targets. Firstly, we conducted genome-wide association studies (GWAS) for systolic blood pressure (SBP), C-reactive protein (CRP), low density lipoprotein (LDL)-cholesterol for 488,226 women and men in the UK Biobank. We then performed genetic colocalization analyses to identify shared or differential genetic loci for CVD risk factors in males and females. Our findings highlight that females and males share potentially causal variants for SBP at the ADRB1, CACNA1D, CACNB2, CACNB3 and SLC12A3 drug targets, for LDL-cholesterol at PCSK9, HMGCR, and for CRP at IL6R . Notably, we highlight heterogeneous effects of SBP in men and women at ACE, CACNA1S, CACNA1C . This is the first comprehensive genetic interrogation of sex-specific effects on drug targets, suggesting physiological differences in hypertension-mediated CVD between men and women and potential differential response to anti-hypertensive medication. Whether this has viable clinical implications is yet to be formally tested in further sex-specific analyses in genetic association studies and clinical trials.

New insight into the causal relationship between Graves' disease liability and drug eruption: a Mendelian randomization study.

Graves' disease (GD) and drug eruption are closely associated and frequently observed in the clinical setting. However, it remains unclear whether a causal relationship exists between these two conditions. The aim of the study is to investigate whether GD is causal to drug eruptions using two-sample Mendelian randomization. We launched a two-sample MR to investigate whether GD is causal to drug eruption using Genome-wide association study (GWAS) summary data from Biobank Japan and FinnGen. Genetic variants were used as instrumental variables to avoid confounding bias. Statistical methods including inverse variance weighted (IVW), weighted median, MR-Egger, and MR-PRESSO were conducted to identify the robustness of the causal effect. Genetically predicted GD may increase the risk of drug eruption by 30.3% (OR=1.303, 95% CI 1.119-1.516, p<0.001) in the Asian population. In European populations, GD may increase the generalized drug eruption by 15.9% (OR=1.159, 95%CI 0.982-1.367, p=0.080). We found GD is potentially causal to drug eruption. This finding expanded the view of the frequently observed co-existence of GD and adverse drug reactions involving the skin. The mechanism remains for further investigation.

Portability of Polygenic Risk Scores for Sleep Duration, Insomnia and Chronotype in 33,493 Individuals.

Polygenic risk scores (PRSs) estimate genetic liability for diseases and traits. However, the portability of PRSs in sleep traits has remained elusive. We generated PRSs for self-reported insomnia, chronotype and sleep duration using summary data from genome-wide association studies (GWASs) performed in 350,000 to 697,000 European-ancestry individuals. We then projected the scores in two independent Finnish population cohorts (N = 33,493) and tested whether the PRSs were associated with their respective sleep traits. We observed that all the generated PRSs were associated with their corresponding traits (p < 0.05 in all cases). Furthermore, we found that there was a 22.2 min difference in reported sleep between the 5% tails of the PRS for sleep duration (p < 0.001). Our findings indicate that sleep-related PRSs show portability across cohorts. The findings also demonstrate that sleep measures using PRSs for sleep behaviors may provide useful instruments for testing disease and trait associations in cohorts where direct sleep parameters have not yet been measured.