Assessing the performance of European-derived cardiometabolic polygenic risk scores in South-Asians and their interplay with family history

Background & aims We aimed to assess the performance of European-derived polygenic risk scores (PRSs) for common metabolic diseases such as coronary artery disease (CAD), obesity, and type 2 diabetes (T2D) in the South Asian (SAS) individuals in the UK Biobank. Additionally, we studied the interaction between PRS and family history (FH) in the same population. Methods To calculate the PRS, we used a previously published model derived from the EUR population and applied it to the individuals of SAS ancestry from the UKB study. Each PRS was adjusted according to an individual’s genotype location in the principal components (PC) space to derive an ancestry adjusted PRS (aPRS). We calculated the percentiles based on aPRS and stratified individuals into three aPRS categories: low, intermediate, and high. Considering the intermediate-aPRS percentile as a reference, we compared the low and high aPRS categories and generated the odds ratio (OR) estimates. Further, we measured the combined role of aPRS and first-degree family history (FH) in the SAS population. Results The risk of developing severe obesity for SAS individuals was almost twofold higher for individuals with high aPRS than for those with intermediate aPRS, with an OR of 1.95 (95% CI = 1.71–2.23, P < 0.01). At the same time, the risk of severe obesity was lower in the low-aPRS group (OR = 0.60, CI = 0.53–0.67, P < 0.01). Results in the same direction were found in the EUR data, where the low-PRS group had an OR of 0.53 (95% CI = 0.51–0.56, P < 0.01) and the high-PRS group had an OR of 2.06 (95% CI = 2.00-2.12, P < 0.01). We observed similar results for CAD and T2D. Further, we show that SAS individuals with a familial history of CAD and T2D with high-aPRS are associated with a higher risk of these diseases, implying a greater genetic predisposition. Conclusion Our findings suggest that CAD, obesity, and T2D GWAS summary statistics generated predominantly from the EUR population can be potentially used to derive aPRS in SAS individuals for risk stratification. With future GWAS recruiting more SAS participants and tailoring the PRSs towards SAS ancestry, the predictive power of PRS is likely to improve further

IDENTIFICATION AND FUNCTIONAL CHARACTERIZATION OF VPS41 AS A POTENTIAL GENETIC MODIFIER OF PENETRANCE IN P.G2019S LRRK2-ASSOCIATED PARKINSON’S DISEASE

peer reviewedTrait- or disease-associated genetic variants contribute to substantial variability and penetrance of complex traits and diseases in humans. While several causative genes and risk factors have been identified in familial forms of Parkinson’s disease (PD), it remains unclear how patient’s genomes shape the predisposition to develop PD. Mutations in LRRK2 are the most common autosomal dominantly inherited form of PD. The p.G2019S mutation displays incomplete penetrance and even within the group of affected individuals a broad range of age at disease onset (AAO) is observed. Through a whole genome sequencing approach in multiple families with p.G2019S LRRK2-associated PD, we have detected rare and common variants that might act as genetic modifiers of AAO. However, prioritizing disease-modifying variants and understanding their biological action remain a challenge. Using a new scoring system, we prioritized coding variants acting as modifiers of AAO in these families for functional in vitro validation. Among these modifiers we find GO term enrichment for genes with association to “neuron projection" but also Golgi apparatus associated vesicle and transport. From the candidates we selected the missense variant p.E432K in VPS41 (a member of the HOPS complex essential in lysosome/endosome trafficking), predicted by segregation analysis to confer protective effect on AAO in one of the families analysed. To this end, we assessed LRRK2 phenotypes in patient iPSC-derived dopaminergic neuron cultures. We found that VPS41 knockdown (KD) results in neurite outgrowth indistinguishable between p.G2019S and isogenic WT LRRK2 neurons. Lysosome and endosome morphology was altered upon VPS41 KD, but independent of LRRK2 status. The overexpression (OE) of WT and p.E432K VPS41 in HEK293T cells showed a differential starvation response, with increased localization of TFE3 to nuclei under baseline and starved conditions. In contrast, decreased TFE3 protein levels were previously reported in PD post-mortem substantia nigra compared to healthy controls. Through protein interaction assays we found that p.E432K VPS41 displays increased affinity to RAB7A indicating an increased interaction at the endosome/lysosome interface that is reported to be impaired in p.G2019S LRRK2 mutant neurons. Our findings lend support the concept of disease modifying variants incrementally contributing to the differential risk to develop PD in the context of LRRK2 mutations. We are currently further investigating how p.E432K VPS41 affects neurite outgrowth, endosome/lysosome morphology and autophagy in patient derived neurons and their controls.R-AGR-0592 - FNR - NCER-PD Phase II Coordination (01/06/2015 - 30/11/2023) - KRÜGER Rejk

Accurate long-read sequencing identified GBA1 as major risk factor in the Luxembourgish Parkinson's study.

peer reviewedHeterozygous variants in the glucocerebrosidase GBA1 gene are an increasingly recognized risk factor for Parkinson's disease (PD). Due to the GBAP1 pseudogene, which shares 96% sequence homology with the GBA1 coding region, accurate variant calling by array-based or short-read sequencing methods remains a major challenge in understanding the genetic landscape of GBA1-associated PD. We analyzed 660 patients with PD, 100 patients with Parkinsonism and 808 healthy controls from the Luxembourg Parkinson's study, sequenced using amplicon-based long-read DNA sequencing technology. We found that 12.1% (77/637) of PD patients carried GBA1 variants, with 10.5% (67/637) of them carrying known pathogenic variants (including severe, mild, risk variants). In comparison, 5% (34/675) of the healthy controls carried GBA1 variants, and among them, 4.3% (29/675) were identified as pathogenic variant carriers. We found four GBA1 variants in patients with atypical parkinsonism. Pathogenic GBA1 variants were 2.6-fold more frequently observed in PD patients compared to controls (OR = 2.6; CI = [1.6,4.1]). Three novel variants of unknown significance (VUS) were identified. Using a structure-based approach, we defined a potential risk prediction method for VUS. This study describes the full landscape of GBA1-related parkinsonism in Luxembourg, showing a high prevalence of GBA1 variants as the major genetic risk for PD. Although the long-read DNA sequencing technique used in our study may be limited in its effectiveness to detect potential structural variants, our approach provides an important advancement for highly accurate GBA1 variant calling, which is essential for providing access to emerging causative therapies for GBA1 carriers.R-AGR-0592 - FNR - NCER-PD Phase II Coordination (01/06/2015 - 30/11/2023) - KRÜGER Rejko3. Good health and well-bein

Trans-ancestry polygenic models for the prediction of LDL blood levels: an analysis of the United Kingdom Biobank and Taiwan Biobank

peer reviewedPolygenic risk score (PRS) predictions often show bias toward the population of available genome-wide association studies (GWASs), which is typically of European ancestry. This study aimed to assess the performance differences of ancestry-specific PRS and test the implementation of multi-ancestry PRS to enhance the generalizability of low-density lipoprotein (LDL) cholesterol predictions in the East Asian (EAS) population. In this study, we computed ancestry-specific and multi-ancestry PRSs for LDL using data obtained from the Global Lipid Genetics Consortium, while accounting for population-specific linkage disequilibrium patterns using the PRS-CSx method in the United Kingdom Biobank dataset (UKB, n = 423,596) and Taiwan Biobank dataset (TWB, n = 68,978). Population-specific PRSs were able to predict LDL levels better within the target population, whereas multi-ancestry PRSs were more generalizable. In the TWB dataset, covariate-adjusted R2 values were 9.3% for ancestry-specific PRS, 6.7% for multi-ancestry PRS, and 4.5% for European-specific PRS. Similar trends (8.6%, 7.8%, and 6.2%) were observed in the smaller EAS population of the UKB (n = 1,480). Consistent with R2 values, PRS stratification in EAS regions (TWB) effectively captured a heterogenous variability in LDL blood cholesterol levels across PRS strata. The mean difference in LDL levels between the lowest and highest EAS-specific PRS (EAS_PRS) deciles was 0.82, compared to 0.59 for European-specific PRS (EUR_PRS) and 0.76 for multi-ancestry PRS. Notably, the mean LDL values in the top decile of multi-ancestry PRS were comparable to those of EAS_PRS (3.543 vs. 3.541, p = 0.86). Our analysis of the PRS prediction model for LDL cholesterol further supports the issue of PRS generalizability across populations. Our targeted analysis of the EAS population revealed that integrating non-European genotyping data with a powerful European-based GWAS can enhance the generalizability of LDL PRS.3. Good health and well-bein

Association of ultra-rare coding variants with genetic generalized epilepsy : A case–control whole exome sequencing study

Publisher Copyright: © 2022 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.Objective: We aimed to identify genes associated with genetic generalized epilepsy (GGE) by combining large cohorts enriched with individuals with a positive family history. Secondarily, we set out to compare the association of genes independently with familial and sporadic GGE. Methods: We performed a case–control whole exome sequencing study in unrelated individuals of European descent diagnosed with GGE (previously recruited and sequenced through multiple international collaborations) and ancestry-matched controls. The association of ultra-rare variants (URVs; in 18 834 protein-coding genes) with epilepsy was examined in 1928 individuals with GGE (vs. 8578 controls), then separately in 945 individuals with familial GGE (vs. 8626 controls), and finally in 1005 individuals with sporadic GGE (vs. 8621 controls). We additionally examined the association of URVs with familial and sporadic GGE in two gene sets important for inhibitory signaling (19 genes encoding γ-aminobutyric acid type A [GABAA] receptors, 113 genes representing the GABAergic pathway). Results: GABRG2 was associated with GGE (p = 1.8 × 10−5), approaching study-wide significance in familial GGE (p = 3.0 × 10−6), whereas no gene approached a significant association with sporadic GGE. Deleterious URVs in the most intolerant subgenic regions in genes encoding GABAA receptors were associated with familial GGE (odds ratio [OR] = 3.9, 95% confidence interval [CI] = 1.9–7.8, false discovery rate [FDR]-adjusted p =.0024), whereas their association with sporadic GGE had marginally lower odds (OR = 3.1, 95% CI = 1.3–6.7, FDR-adjusted p =.022). URVs in GABAergic pathway genes were associated with familial GGE (OR = 1.8, 95% CI = 1.3–2.5, FDR-adjusted p =.0024) but not with sporadic GGE (OR = 1.3, 95% CI =.9–1.9, FDR-adjusted p =.19). Significance: URVs in GABRG2 are likely an important risk factor for familial GGE. The association of gene sets of GABAergic signaling with familial GGE is more prominent than with sporadic GGE.Peer reviewe

Functional validation of a mitochondria-specific polygenic risk score in patient-based models for stratification of idiopathic Parkinson's disease

peer reviewedBackground: A large body of evidence specifically points to mitochondrial dysfunction as a major cause of Parkinson’s disease (PD) pathogenesis. Given that only ~10% of PD cases can be attributed to monogenic causes, we hypothesize that a fraction of idiopathic PD (iPD) cases may harbour a pathogenic combination of common variants in mitochondrial genes ultimately resulting in mitochondrial dysfunction. Objectives: To gain essential knowledge on the contribution of genetic variability in nuclear-encoded mitochondrial genes to iPD pathogenesis. Starting from genomic data, we aim to functionally validate mitochondrial polygenic risk profiles in patient-based cellular models, thus defining mitochondrial pathways potentially involved in neurodegeneration in subgroups of iPD patients.R-AGR-0592 - FNR - NCER-PD Phase II Coordination (01/06/2015 - 30/11/2023) - KRÜGER Rejko3. Good health and well-bein

Polygenic Resilience Modulates the Penetrance of Parkinson Disease Genetic Risk Factors

peer reviewedObjective: The aim of the current study is to understand why some individuals avoid developing Parkinson disease (PD) despite being at relatively high genetic risk, using the largest datasets of individual-level genetic data available. Methods: We calculated polygenic risk score to identify controls and matched PD cases with the highest burden of genetic risk for PD in the discovery cohort (International Parkinson's Disease Genomics Consortium, 7,204 PD cases and 9,412 controls) and validation cohorts (Comprehensive Unbiased Risk Factor Assessment for Genetics and Environment in Parkinson's Disease, 8,968 cases and 7,598 controls; UK Biobank, 2,639 PD cases and 14,301 controls; Accelerating Medicines Partnership–Parkinson's Disease Initiative, 2,248 cases and 2,817 controls). A genome-wide association study meta-analysis was performed on these individuals to understand genetic variation associated with resistance to disease. We further constructed a polygenic resilience score, and performed multimarker analysis of genomic annotation (MAGMA) gene-based analyses and functional enrichment analyses. Results: A higher polygenic resilience score was associated with a lower risk for PD (β = −0.054, standard error [SE] = 0.022, p = 0.013). Although no single locus reached genome-wide significance, MAGMA gene-based analyses nominated TBCA as a putative gene. Furthermore, we estimated the narrow-sense heritability associated with resilience to PD (h2 = 0.081, SE = 0.035, p = 0.0003). Subsequent functional enrichment analysis highlighted histone methylation as a potential pathway harboring resilience alleles that could mitigate the effects of PD risk loci. Interpretation: The present study represents a novel and comprehensive assessment of heritable genetic variation contributing to PD resistance. We show that a genetic resilience score can modify the penetrance of PD genetic risk factors and therefore protect individuals carrying a high-risk genetic burden from developing PD. ANN NEUROL 202

A pharmacogenomic assessment of psychiatric adverse drug reactions to levetiracetam

OBJECTIVE: Levetiracetam (LEV) is an effective anti-seizure medicine, but 10-20% of people treated with LEV report psychiatric side-effects and up to 1% may have psychotic episodes. Pharmacogenomic predictors of these adverse drug reactions (ADRs) have yet to be identified. We sought to determine the contribution of both common and rare genetic variation to psychiatric and behavioural ADRs associated with LEV. METHODS: This case-control study compared cases of LEV-associated behavioural disorder (n=149) or psychotic reaction (n=37) to LEV-exposed people with no history of psychiatric ADRs (n=920). All samples were of European ancestry. We performed GWAS analysis comparing those with LEV ADRs to controls. We estimated the polygenic risk scores (PRS) for schizophrenia and compared cases with LEV-associated psychotic reaction to controls. Rare variant burden analysis was performed using exome sequence data of cases with psychotic reactions (n=18) and controls (n=122). RESULTS: Univariate GWAS found no significant associations with either LEV-ADR. PRS analysis showed that cases of LEV-associated psychotic reaction had an increased PRS for schizophrenia relative to controls (p = 0.0097, estimate = 0.4886). The rare-variant analysis found no evidence of an increased burden of rare genetic variants in people who had experienced LEV-associated psychotic reaction relative to controls. SIGNIFICANCE: The polygenic burden for schizophrenia is a risk factor for LEV-associated psychotic reaction. To assess the clinical utility of PRS as a predictor, it should be tested in an independent and ideally prospective cohort. Larger sample sizes are required for the identification of significant univariate common genetic signals or rare genetic signals associated with psychiatric LEV-ADRs

A rare loss-of-function variant of ADAM17 is associated with late-onset familial Alzheimer disease

Common variants of about 20 genes contributing to AD risk have so far been identified through genome-wide association studies (GWAS). However, there is still a large proportion of heritability that might be explained by rare but functionally important variants. One of the so far identified genes with rare AD causing variants is ADAM10. Using whole-genome sequencing we now identified a single rare nonsynonymous variant (SNV) rs142946965 [p.R215I] in ADAM17 co-segregating with an autosomal-dominant pattern of late-onset AD in one family. Subsequent genotyping and analysis of available whole-exome sequencing data of additional case/control samples from Germany, UK, and USA identified five variant carriers among AD patients only. The mutation inhibits pro-protein cleavage and the formation of the active enzyme, thus leading to loss-of-function of ADAM17 alpha-secretase. Further, we identified a strong negative correlation between ADAM17 and APP gene expression in human brain and present in vitro evidence that ADAM17 negatively controls the expression of APP. As a consequence, p.R215I mutation of ADAM17 leads to elevated Aß formation in vitro. Together our data supports a causative association of the identified ADAM17 variant in the pathogenesis of AD