ORBi^lu Collection: Genetics & genetic processes

HLA in isolated REM sleep behavior disorder and Lewy body dementia

Title: HLA in isolated REM sleep behavior disorder and Lewy body dementia

Author, co-author: Yu, Eric; Krohn, Lynne; Ruskey, Jennifer A.; Asayesh, Farnaz; Spiegelman, Dan; Shah, Zalak; Chia, Ruth; Arnulf, Isabelle; Hu, Michele T. M.; Montplaisir, Jacques Y.; Gagnon, Jean-François; Desautels, Alex; Dauvilliers, Yves; Gigli, Gian Luigi; Valente, Mariarosaria; Janes, Francesco; Bernardini, Andrea; Högl, Birgit; Stefani, Ambra; Ibrahim, Abubaker; Heidbreder, Anna; Sonka, Karel; Dusek, Petr; Kemlink, David; Oertel, Wolfgang; Janzen, Annette; Plazzi, Giuseppe; Antelmi, Elena; Figorilli, Michela; Puligheddu, Monica; Mollenhauer, Brit; Trenkwalder, Claudia; Sixel-Döring, Friederike; Cochen De Cock, Valérie; Ferini-Strambi, Luigi; Dijkstra, Femke; Viaene, Mineke; Abril, Beatriz; Boeve, Bradley F.; Rouleau, Guy A.; Postuma, Ronald B.; May, Patrick; Krüger, Rejko; Consortium, The International L. B. D. Genomics; Scholz, Sonja W.; Gan-Or, Ziv

Abstract: Synucleinopathies-related disorders such as Lewy body dementia (LBD) and isolated/idiopathic REM sleep behavior disorder (iRBD) have been associated with neuroinflammation. In this study, we examined whether the human leukocyte antigen (HLA) locus plays a role in iRBD and LBD. In iRBD, HLA-DRB1*11:01 was the only allele passing FDR correction (OR = 1.57, 95 CI = 1.27–1.93, p = 2.70e-05). We also discovered associations between iRBD and HLA-DRB1 70D (OR = 1.26, 95\%CI = 1.12–1.41, p = 8.76e-05), 70Q (OR = 0.81, 95\%CI = 0.72–0.91, p = 3.65e-04) and 71R (OR = 1.21, 95\%CI = 1.08–1.35, p = 1.35e-03). Position 71 (pomnibus = 0.00102) and 70 (pomnibus = 0.00125) were associated with iRBD. Our results suggest that the HLA locus may have different roles across synucleinopathies.

GWAS meta-analysis of over 29,000 people with epilepsy identifies 26 risk loci and subtype-specific genetic architecture

Title: GWAS meta-analysis of over 29,000 people with epilepsy identifies 26 risk loci and subtype-specific genetic architecture

Author, co-author: Stevelink, Remi; Campbell, Ciarán; Chen, Siwei; Abou-Khalil, Bassel; Adesoji, Oluyomi M.; Afawi, Zaid; Amadori, Elisabetta; Anderson, Alison; Anderson, Joseph; Andrade, Danielle M.; Annesi, Grazia; Auce, Pauls; Avbersek, Andreja; Bahlo, Melanie; Baker, Mark D.; Balagura, Ganna; Balestrini, Simona; Barba, Carmen; Barboza, Karen; Bartolomei, Fabrice; Bast, Thomas; Baum, Larry; Baumgartner, Tobias; Baykan, Betül; Bebek, Nerses; Becker, Albert J.; Becker, Felicitas; Bennett, Caitlin A.; Berghuis, Bianca; Berkovic, Samuel F.; Beydoun, Ahmad; Bianchini, Claudia; Bisulli, Francesca; Blatt, Ilan; Bobbili, Dheeraj Reddy; Borggraefe, Ingo; Bosselmann, Christian; Braatz, Vera; Bradfield, Jonathan P.; Brockmann, Knut; Brody, Lawrence C.; Buono, Russell J.; Busch, Robyn M.; Caglayan, Hande; Campbell, Ellen; Canafoglia, Laura; Canavati, Christina; Cascino, Gregory D.; Castellotti, Barbara; Catarino, Claudia B.; Cavalleri, Gianpiero L.; Cerrato, Felecia; Chassoux, Francine; Cherny, Stacey S.; Cheung, Ching-Lung; Chinthapalli, Krishna; Chou, I.-Jun; Chung, Seo-Kyung; Churchhouse, Claire; Clark, Peggy O.; Cole, Andrew J.; Compston, Alastair; Coppola, Antonietta; Cosico, Mahgenn; Cossette, Patrick; Craig, John J.; Cusick, Caroline; Daly, Mark J.; Davis, Lea K.; de Haan, Gerrit-Jan; Delanty, Norman; Depondt, Chantal; Derambure, Philippe; Devinsky, Orrin; Di Vito, Lidia; Dlugos, Dennis J.; Doccini, Viola; Doherty, Colin P.; El-Naggar, Hany; Elger, Christian E.; Ellis, Colin A.; Eriksson, Johan G.; Faucon, Annika; Feng, Yen-Chen A.; Ferguson, Lisa; Ferraro, Thomas N.; Ferri, Lorenzo; Feucht, Martha; Fitzgerald, Mark; Fonferko-Shadrach, Beata; Fortunato, Francesco; Franceschetti, Silvana; Franke, Andre; French, Jacqueline A.; Freri, Elena; Gagliardi, Monica; Gambardella, Antonio; Geller, Eric B.; Giangregorio, Tania; Gjerstad, Leif; Glauser, Tracy; Goldberg, Ethan; Goldman, Alicia; Granata, Tiziana; Greenberg, David A.; Guerrini, Renzo; Gupta, Namrata; Haas, Kevin F.; Hakonarson, Hakon; Hallmann, Kerstin; Hassanin, Emadeldin Saeed Fathy Sayed; Hegde, Manu; Heinzen, Erin L.; Helbig, Ingo; Hengsbach, Christian; Heyne, Henrike O.; Hirose, Shinichi; Hirsch, Edouard; Hjalgrim, Helle; Howrigan, Daniel P.; Hucks, Donald; Hung, Po-Cheng; Iacomino, Michele; Imbach, Lukas L.; Inoue, Yushi; Ishii, Atsushi; Jamnadas-Khoda, Jennifer; Jehi, Lara; Johnson, Michael R.; Kälviäinen, Reetta; Kamatani, Yoichiro; Kanaan, Moien; Kanai, Masahiro; Kantanen, Anne-Mari; Kara, Bülent; Kariuki, Symon M.; Kasperavičiūte, Dalia; Kasteleijn-Nolst Trenite, Dorothee; Kato, Mitsuhiro; Kegele, Josua; Kesim, Yeşim; Khoueiry-Zgheib, Nathalie; King, Chontelle; Kirsch, Heidi E.; Klein, Karl M.; Kluger, Gerhard; Knake, Susanne; Knowlton, Robert C.; Koeleman, Bobby P. C.; Korczyn, Amos D.; Koupparis, Andreas; Kousiappa, Ioanna; Krause, Roland; Krenn, Martin; Krestel, Heinz; Krey, Ilona; Kunz, Wolfram S.; Kurki, Mitja I.; Kurlemann, Gerhard; Kuzniecky, Ruben; Kwan, Patrick; Labate, Angelo; Lacey, Austin; Lal, Dennis; Landoulsi, Zied; Lau, Yu-Lung; Lauxmann, Stephen; Leech, Stephanie L.; Lehesjoki, Anna-Elina; Lemke, Johannes R.; Lerche, Holger; Lesca, Gaetan; Leu, Costin; Lewin, Naomi; Lewis-Smith, David; Li, Gloria H.-Y.; Li, Qingqin S.; Licchetta, Laura; Lin, Kuang-Lin; Lindhout, Dick; Linnankivi, Tarja; Lopes-Cendes, Iscia; Lowenstein, Daniel H.; Lui, Colin H. T.; Madia, Francesca; Magnusson, Sigurdur; Marson, Anthony G.; May, Patrick; McGraw, Christopher M.; Mei, Davide; Mills, James L.; Minardi, Raffaella; Mirza, Nasir; Møller, Rikke S.; Molloy, Anne M.; Montomoli, Martino; Mostacci, Barbara; Muccioli, Lorenzo; Muhle, Hiltrud; Müller-Schlüter, Karen; Najm, Imad M.; Nasreddine, Wassim; Neale, Benjamin M.; Neubauer, Bernd; Newton, Charles R. J. C.; Nöthen, Markus M.; Nothnagel, Michael; Nürnberg, Peter; O’Brien, Terence J.; Okada, Yukinori; Ólafsson, Elías; Oliver, Karen L.; Özkara, Çiğdem; Palotie, Aarno; Pangilinan, Faith; Papacostas, Savvas S.; Parrini, Elena; Pato, Carlos N.; Pato, Michele T.; Pendziwiat, Manuela; Petrovski, Slavé; Pickrell, William O.; Pinsky, Rebecca; Pippucci, Tommaso; Poduri, Annapurna; Pondrelli, Federica; Powell, Rob H. W.; Privitera, Michael; Rademacher, Annika; Radtke, Rodney; Ragona, Francesca; Rau, Sarah; Rees, Mark I.; Regan, Brigid M.; Reif, Philipp S.; Rhelms, Sylvain; Riva, Antonella; Rosenow, Felix; Ryvlin, Philippe; Saarela, Anni; Sadleir, Lynette G.; Sander, Josemir W.; Sander, Thomas; Scala, Marcello; Scattergood, Theresa; Schachter, Steven C.; Schankin, Christoph J.; Scheffer, Ingrid E.; Schmitz, Bettina; Schoch, Susanne; Schubert-Bast, Susanne; Schulze-Bonhage, Andreas; Scudieri, Paolo; Sham, Pak; Sheidley, Beth R.; Shih, Jerry J.; Sills, Graeme J.; Sisodiya, Sanjay M.; Smith, Michael C.; Smith, Philip E.; Sonsma, Anja C. M.; Speed, Doug; Sperling, Michael R.; Stefansson, Hreinn; Stefansson, Kári; Steinhoff, Bernhard J.; Stephani, Ulrich; Stewart, William C.; Stipa, Carlotta; Striano, Pasquale; Stroink, Hans; Strzelczyk, Adam; Surges, Rainer; Suzuki, Toshimitsu; Tan, K. Meng; Taneja, R. S.; Tanteles, George A.; Taubøll, Erik; Thio, Liu Lin; Thomas, G. Neil; Thomas, Rhys H.; Timonen, Oskari; Tinuper, Paolo; Todaro, Marian; Topaloğlu, Pınar; Tozzi, Rossana; Tsai, Meng-Han; Tumiene, Birute; Turkdogan, Dilsad; Unnsteinsdóttir, Unnur; Utkus, Algirdas; Vaidiswaran, Priya; Valton, Luc; van Baalen, Andreas; Vetro, Annalisa; Vining, Eileen P. G.; Visscher, Frank; von Brauchitsch, Sophie; von Wrede, Randi; Epilepsies, International League Against Epilepsy Consortium On Complex

Abstract: Epilepsy is a highly heritable disorder affecting over 50 million people worldwide, of which about one-third are resistant to current treatments. Here we report a multi-ancestry genome-wide association study including 29,944 cases, stratified into three broad categories and seven subtypes of epilepsy, and 52,538 controls. We identify 26 genome-wide significant loci, 19 of which are specific to genetic generalized epilepsy (GGE). We implicate 29 likely causal genes underlying these 26 loci. SNP-based heritability analyses show that common variants explain between 39.6 and 90 of genetic risk for GGE and its subtypes. Subtype analysis revealed markedly different genetic architectures between focal and generalized epilepsies. Gene-set analyses of GGE signals implicate synaptic processes in both excitatory and inhibitory neurons in the brain. Prioritized candidate genes overlap with monogenic epilepsy genes and with targets of current antiseizure medications. Finally, we leverage our results to identify alternate drugs with predicted efficacy if repurposed for epilepsy treatment.

SLC6A1 variant pathogenicity, molecular function, and phenotype: a genetic and clinical analysis

Title: SLC6A1 variant pathogenicity, molecular function, and phenotype: a genetic and clinical analysis

Author, co-author: Stefanski, Arthur; Pérez-Palma, Eduardo; Brünger, Tobias; Montanucci, Ludovica; Gati, Cornelius; Klöckner, Chiara; Johannesen, Katrine M.; Goodspeed, Kimberly; Macnee, Marie; Deng, Alexander T.; Aledo-Serrano, Ángel; Borovikov, Artem; Kava, Maina; Bouman, Arjan M.; Hajianpour, M. J.; Pal, Deb K.; Engelen, Marc; Hagebeuk, Eveline E. O.; Shinawi, Marwan; Heidlebaugh, Alexis R.; Oetjens, Kathryn; Hoffman, Trevor L.; Striano, Pasquale; Freed, Amanda S.; Futtrup, Line; Balslev, Thomas; Abulí, Anna; Danvoye, Leslie; Lederer, Damien; Balci, Tugce; Nabavi Nouri, Maryam; Butler, Elizabeth; Drewes, Sarah; van Engelen, Kalene; Howell, Katherine B.; Khoury, Jean; May, Patrick; Trinidad, Marena; Froelich, Steven; Lemke, Johannes R.; Tiller, Jacob; Freed, Amber N.; Kang, Jing-Qiong; Wuster, Arthur; Møller, Rikke S.; Lal, Dennis

Abstract: Genetic variants in the SLC6A1 gene can cause a broad phenotypic disease spectrum by altering the protein function. Thus, systematically curated clinically relevant genotype-phenotype associations are needed to understand the disease mechanism and improve therapeutic decision-making. We aggregated genetic and clinical data from 172 individuals with likely pathogenic/pathogenic (lp/p) SLC6A1 variants and functional data for 184 variants (14.1% lp/p). Clinical and functional data were available for a subset of 126 individuals. We explored the potential associations of variant positions on the GAT1 3D structure with variant pathogenicity, altered molecular function, and phenotype severity using bioinformatic approaches. The GAT1 transmembrane domains 1, 6, and extracellular loop 4 (EL4) were enriched for patient over population variants. Across functionally tested missense variants (n = 156), the spatial proximity from the ligand was associated with loss-of-function in the GAT1 transporter activity. For variants with complete loss of in vitro GABA uptake, we found a 4.6-fold enrichment in patients having severe disease vs. non-severe disease (P = 2.9e-3, 95% CI: 1.5 - 15.3). In summary, we delineated associations between the 3D structure and variant pathogenicity, variant function, and phenotype in SLC6A1-related disorders. This knowledge supports biology-informed variant interpretation and research on GAT1 function. All our data can be interactively explored in the SLC6A1 Portal (https://slc6a1-portal.broadinstitute.org/).

Pathogenic paralogous variants can be used to apply the ACMG PS1 and PM5 variant interpretation criteria 2023.08.22.23294353

Title: Pathogenic paralogous variants can be used to apply the ACMG PS1 and PM5 variant interpretation criteria 2023.08.22.23294353

Author, co-author: Brünger, Tobias; Ivaniuk, Alina; Pérez-Palma, Eduardo; Montanucci, Ludovica; Cohen, Stacey; Smith, Lacey; Parthasarathy, Shridhar; Helbig, Ingo; Nothnagel, Michael; May, Patrick; Lal, Dennis

Abstract: Purpose The majority of missense variants in clinical genetic tests are classified as variants of uncertain significance. Broadening the evidence of the PS1 and PM5 criteria has the potential to increase conclusive variant interpretation. Methods We hypothesized that incorporation of pathogenic missense variants in conserved residues across paralogous genes can increase the number of variants where ACMG PS1/PM5 criteria can be applied. We mapped over 2.5 million pathogenic and general population variants from ClinVar, HGMD, and gnomAD databases onto 9,990 genes and aligned these by gene families. Subsequently, we developed a novel framework to extend PS1/PM5 by incorporating pathogenic paralogous variants annotations (para-PS1/PM5). Results We demonstrate that para-PS1/PM5 criteria increase the number of classifiable amino acids 3.6-fold compared to PS1 and PM5. Across all gene families with at least two disease-associated genes, the calculated likelihood ratios suggest moderate evidence for pathogenicity. Moreover, for 36 genes, the extended para-PS1/PM5 criteria reach strong evidence level. Conclusion We show that single pathogenic paralogous variants incorporation at paralogous protein positions increases the applicability of the PS1 and PM5 criteria, likely leading to a reduction of variants of uncertain significance across many monogenic disorders. Future iterations of the ACMG guidelines may consider para-PS1 and para-PM5.

Genome-wide identification and phenotypic characterization of seizure-associated copy number variations in 741,075 individuals.

Title: Genome-wide identification and phenotypic characterization of seizure-associated copy number variations in 741,075 individuals.

Author, co-author: Montanucci, Ludovica; Lewis-Smith, David; Collins, Ryan L.; Niestroj, Lisa-Marie; Parthasarathy, Shridhar; Xian, Julie; Ganesan, Shiva; Macnee, Marie; Brünger, Tobias; Thomas, Rhys H.; Talkowski, Michael; Krause, Roland; May, Patrick; Helbig, Ingo; Leu, Costin; Lal, Dennis

Abstract: Copy number variants (CNV) are established risk factors for neurodevelopmental disorders with seizures or epilepsy. With the hypothesis that seizure disorders share genetic risk factors, we pooled CNV data from 10,590 individuals with seizure disorders, 16,109 individuals with clinically validated epilepsy, and 492,324 population controls and identified 25 genome-wide significant loci, 22 of which are novel for seizure disorders, such as deletions at 1p36.33, 1q44, 2p21-p16.3, 3q29, 8p23.3-p23.2, 9p24.3, 10q26.3, 15q11.2, 15q12-q13.1, 16p12.2, 17q21.31, duplications at 2q13, 9q34.3, 16p13.3, 17q12, 19p13.3, 20q13.33, and reciprocal CNVs at 16p11.2, and 22q11.21. Using genetic data from additional 248,751 individuals with 23 neuropsychiatric phenotypes, we explored the pleiotropy of these 25 loci. Finally, in a subset of individuals with epilepsy and detailed clinical data available, we performed phenome-wide association analyses between individual CNVs and clinical annotations categorized through the Human Phenotype Ontology (HPO). For six CNVs, we identified 19 significant associations with specific HPO terms and generated, for all CNVs, phenotype signatures across 17 clinical categories relevant for epileptologists. This is the most comprehensive investigation of CNVs in epilepsy and related seizure disorders, with potential implications for clinical practice.

Epilepsies of presumed genetic etiology show enrichment of rare variants that occur in the general population

Title: Epilepsies of presumed genetic etiology show enrichment of rare variants that occur in the general population

Author, co-author: Bundalian, Linnaeus; Su, Yin-Yuan; Chen, Siwei; Velluva, Akhil; Kirstein, Anna Sophia; Garten, Antje; Biskup, Saskia; Battke, Florian; Lal, Dennis; Heyne, Henrike O.; Platzer, Konrad; Lin, Chen-Ching; Lemke, Johannes R.; Duc, Diana Le; Krause, Roland; May, Patrick; Consortium, Epi

Abstract: Previous studies suggested that severe epilepsies, e.g., developmental and epileptic encephalopathies (DEEs), are mainly caused by ultra-rare de novo genetic variants. For milder disease, rare genetic variants could contribute to the phenotype. To determine the importance of rare variants for different epilepsy types, we analyzed a whole-exome sequencing cohort of 9,170 epilepsy-affected individuals and 8,436 control individuals. Here, we separately analyzed three different groups of epilepsies: severe DEEs, genetic generalized epilepsy (GGE), and non-acquired focal epilepsy (NAFE). We required qualifying rare variants (QRVs) to occur in control individuals with an allele count R 1 and a minor allele frequency % 1:1,000, to be predicted as deleterious (CADD R 20), and to have an odds ratio in individuals with epilepsy R 2. We identified genes enriched with QRVs primarily in NAFE (n ¼ 72), followed by GGE (n ¼ 32) and DEE (n ¼ 21). This suggests that rare variants may play a more important role for causality of NAFE than for DEE. Moreover, we found that genes harboring QRVs, e.g., HSGP2, FLNA, or TNC, encode proteins that are involved in structuring the brain extracellular matrix. The present study confirms an involvement of rare variants for NAFE that occur also in the general population, while in DEE and GGE, the contribution of such variants appears more limited.

Bone Tissue and the Nervous System: What Do They Have in Common?

Title: Bone Tissue and the Nervous System: What Do They Have in Common?

Author, co-author: Minoia, A; Dalle Carbonare, L; Schwamborn, Jens Christian; Bolognin, Silvia; Valenti, MT

STUDYING THE IMPACT OF A53T α-SYNUCLEIN ON ASTROCYTIC FUNCTIONS AND ACTIVATION IN HUMAN IPSC-DERIVED CULTURES

Title: STUDYING THE IMPACT OF A53T α-SYNUCLEIN ON ASTROCYTIC FUNCTIONS AND ACTIVATION IN HUMAN IPSC-DERIVED CULTURES

Author, co-author: Mulica, Patrycja

Abstract: With its high prevalence among the elderly, the movement disorder Parkinson’s disease (PD) poses a major challenge for our society. Unfortunately, despite continuous efforts from the research community, we still lack the disease-modifying treatments for this condition. Therefore, it is of great importance to develop suitable models, which can be employed to better understand the molecular mechanisms underlying PD. In this context, iPSC technology offers a possibility to study the disease pathogenesis using patient-derived brain cells. In recent years, astrocytes have come into the spotlight as potential major contributors to PD development. Yet, there is a limited number of studies utilizing iPSC-derived models to examine PD-linked mutations at endogenous levels. This thesis aims to address the described gap by studying the effect of the A53T α-synuclein on the physiology of human iPSC-derived astrocytes. To identify a suitable model, we first compared two published protocols for the generation of iPSC astrocytes, referred to as Oksanen and Palm method, respectively. A transcriptomic analysis revealed higher maturation characteristics for Oksanen astrocytes. Furthermore, these astrocytes showed a higher similarity to their human postmortem counterparts. Applying the Oksanen protocol, we generated astrocytes derived from a healthy individual and a patient carrying the G209A mutation in SNCA, corresponding to p.A53T substitution in α-synuclein. The utilization of single-cell RNA sequencing allowed us to identify perturbed molecular mechanisms exclusively in pure astrocytic populations. We could demonstrate that astrocytes have a decreased capacity to differentiate. Furthermore, we observed a distinct response of the two cell lines to triggers of activation. Interestingly, activated patient astrocytes also showed changes in pathways related to mitochondrial homeostasis. Taken together, we show that A53T α-synuclein has a profound effect on the function of iPSC-derived astrocytes. In particular, we could demonstrate that patient astrocytes differ from healthy control cells in their activation status and with respect to mitochondrial biology. Further investigation will be required to elucidate the impact of the identified perturbations on the astrocyte-neuron interplay in the context of PD.

AGE- AND SEX-SPECIFIC TRANSCRIPTOME CHANGES IN THE MIDBRAIN OF PARK7-DEPLETED MICE

Title: AGE- AND SEX-SPECIFIC TRANSCRIPTOME CHANGES IN THE MIDBRAIN OF PARK7-DEPLETED MICE

Author, co-author: Helgueta Romero, Sergio

Abstract: To date, various functions have been reported for DJ-1 protein, encoded by PARK7 gene, mostly associated to maintenance of a balance between the reactive oxygen species (ROS) production and the antioxidant response. Indeed, DJ-1 has been related with several oxidative-stress associated diseases, either by its overexpression or by its absence. Loss-of-function mutations in PARK7 can lead to an early onset PD. PD is the second most common neurodegenerative disease that usually affects the population above the age of 65. PD is characterized by its motor symptoms, although prodromal non-motor symptoms can appear up to 20 years earlier and can have a major impact on quality of life for the patients. One of the most characteristic neuropathological hallmarks of PD is the progressive dopaminergic neuronal loss in the substantia nigra pars compacta (SNpc) of the midbrain, leading to striatal dopamine deficiency. One of the main drivers of the disease is oxidative stress caused by mitochondrial dysfunction. Sex-differences in the incidence, prevalence and severity of the disease are observed in PD, with males affected more than females. In mice, Park7 deletion leads to dopaminergic deficits during aging, and increased sensitivity to oxidative stress. However, the severity of the reported phenotypes varies, and the findings are often not separated by sex. In the present study, gene expression signatures of in vivo midbrain sections from male and female Park7 knock-out mice were investigated at different ages to understand the early, prodromal molecular changes upon loss of DJ-1. Interestingly, while at 3 months the transcriptomes of both male and female mice were unchanged compared to their wild type littermates, an extensive deregulation was observed specifically in 8-month-old males. The affected genes were enriched for processes such as focal adhesion, extracellular matrix (ECM) interaction, and epithelial-to-mesenchymal transition (EMT), while the most enriched transcription factor at the deregulated genes was nuclear factor erythroid 2-related factor 2 (NRF2). Among others, the EMT marker gene Cdh1 as well as antioxidant response genes were altered specifically in the midbrain, but not in the cortex, of male DJ-1 deficient mice. Moreover, many of the misregulated genes are known target genes of estradiol (E2) and all-trans-retinoic acid (ATRA) signaling and show sex-specific expression in wild type mice. In line with this, downregulation of the expression of Cyp1b1, encoding an enzyme involved in the metabolism of both E2 and ATRA was also observed only in the midbrain of male DJ-1 deficient mice. Depletion of DJ-1 or NRF2 in primary male astrocytes recapitulated many of the in vivo changes, including downregulation of Cyp1b1. Interestingly, knock-down of Cyp1b1 led to gene expression changes in focal adhesion and EMT in cultured male astrocytes. Moreover, iPSC-derived astrocytes from PD patient with loss-of-function PARK7 mutation showed changes in genes associated with EMT pathway and NRF2 signaling. Taken together, our data indicate that loss of Park7 leads to sex-specific gene expression changes specifically in males through astrocytic alterations in NRF2-CYP1B1 axis. In addition, since an extensive deregulation occurs in the midbrain of 8-month-old males, the single nuclei chromatin accessibility profile at this age and sex was also investigated, with the aim of identifying the upstream regulatory events that lead to the observed transcriptomic changes and the implication of each cell type on those changes. Despite the low number of recovered nuclei, the major brain cell types were successfully identified. Similar representation in terms of proportion of the total nuclei was observed between the genotypes for all identified cell type populations except for astrocytes, that showed lower numbers in Park7-/- mice in comparison to wild type mice. Moreover, the biggest differences in chromatin accessibility were observed in the astrocyte population that also showed the strongest overlap with the transcriptomic changes. Enrichment analysis performed over the genes showing both epigenomic and transcriptomic changes in astrocytes were consistent with pathways identified in the analysis of the entire midbrain sections. Further indicating the relevance of these changes and their association with astrocytes in the mouse midbrain with Park7 depletion at both chromatin and mRNA level. These findings provide new information about Park7-/- PD mouse model, showing specific changes during aging and suggesting higher sensitivity of males to loss of DJ-1, which might help to better understand variation in the reported phenotypes of Park7-/- mice. These results also point to astrocytes as the main cell population involved in the gene expression changes. Finally, this study gives an insight into the molecular changes that may occur in early stages of PD and help us to understand why males are more affected by PD than females.

Polygenic risk scores validated in patient-derived cells stratify for mitochondrial subtypes of Parkinson\textquoterights disease 2023.05.12.23289877

Title: Polygenic risk scores validated in patient-derived cells stratify for mitochondrial subtypes of Parkinson\textquoterights disease 2023.05.12.23289877

Author, co-author: Arena, Giuseppe; Landoulsi, Zied; Grossmann, Dajana; Vitali, Armelle; Delcambre, Sylvie; Baron, Alexandre; Antony, Paul; Boussaad, Ibrahim; Bobbili, Dheeraj Reddy; Sreelatha, Ashwin Ashok Kumar; Pavelka, Lukas; Klein, Christine; Seibler, Philip; Glaab, Enrico; Sharma, Manu; Krüger, Rejko; May, Patrick; Grünewald, Anne

Abstract: Background Parkinson's disease (PD) is the fastest growing neurodegenerative disorder, with affected individuals expected to double during the next 20 years. This raises the urgent need to better understand the genetic architecture and downstream cellular alterations underlying PD pathogenesis, in order to identify more focused therapeutic targets. While only ~10\% of PD cases can be clearly attributed to monogenic causes, there is mounting evidence that additional genetic factors could play a role in idiopathic PD (iPD). In particular, common variants with low to moderate effect size in multiple genes regulating key neuroprotective activities may act as risk factors for PD. In light of the well-established involvement of mitochondrial dysfunction in PD, we hypothesized that a fraction of iPD cases may harbour a pathogenic combination of common variants in nuclear-encoded mitochondrial genes, ultimately resulting in neurodegeneration.Methods: To capture this mitochondria-related 'missing heritability', we leveraged on existing data from previous genome-wide association studies (GWAS) i.e., the large PD GWAS from Nalls and colleagues. We then used computational approaches based on mitochondria-specific polygenic risk scores (mitoPRSs) for imputing the genotype data obtained from different iPD case-control datasets worldwide, including the Luxembourg Parkinson\textquoterights Study (412 iPD patients and 576 healthy controls) and the COURAGE-PD cohorts (7270 iPD cases and 6819 healthy controls).Results: Applying this approach to gene sets controlling mitochondrial pathways potentially relevant for neurodegeneration in PD, we demonstrated that common variants in genes regulating Oxidative Phosphorylation (OXPHOS-PRS) were significantly associated with a higher PD risk both in the Luxembourg Parkinson\textquoterights Study (odds ratio, OR=1.31[1.14-1.50], p=5.4e-04) and in COURAGE-PD (OR=1.23[1.18-1.27], p=1.5e-29). Functional analyses in primary skin fibroblasts and in the corresponding induced pluripotent stem cells-derived neuronal progenitor cells from Luxembourg Parkinson's Study iPD patients stratified according to the OXPHOS-PRS, revealed significant differences in mitochondrial respiration between high and low risk groups (p < 0.05). Finally, we also demonstrated that iPD patients with high OXPHOS-PRS have a significantly earlier age at disease onset compared to low-risk patients.Conclusions: Our findings suggest that OXPHOS-PRS may represent a promising strategy to stratify iPD patients into pathogenic subgroups in which the underlying neurodegeneration is due to a genetically defined mitochondrial burden potentially eligible for future, more tailored mitochondrially targeted treatments.

Genome-wide structural variant analysis identifies risk loci for non-Alzheimer’s dementias

Title: Genome-wide structural variant analysis identifies risk loci for non-Alzheimer’s dementias

Author, co-author: Kaivola, Karri; Chia, Ruth; Ding, Jinhui; Rasheed, Memoona; Fujita, Masashi; Menon, Vilas; Walton, Ronald L.; Collins, Ryan L.; Billingsley, Kimberley; Brand, Harrison; Talkowski, Michael; Zhao, Xuefang; Dewan, Ramita; Stark, Ali; Ray, Anindita; Solaiman, Sultana; Alvarez Jerez, Pilar; Malik, Laksh; Dawson, Ted M.; Rosenthal, Liana S.; Albert, Marilyn S.; Pletnikova, Olga; Troncoso, Juan C.; Masellis, Mario; Keith, Julia; Black, Sandra E.; Ferrucci, Luigi; Resnick, Susan M.; Tanaka, Toshiko; Topol, Eric; Torkamani, Ali; Tienari, Pentti; Foroud, Tatiana M.; Ghetti, Bernardino; Landers, John E.; Ryten, Mina; Morris, Huw R.; Hardy, John A.; Mazzini, Letizia; D'Alfonso, Sandra; Moglia, Cristina; Calvo, Andrea; Serrano, Geidy E.; Beach, Thomas G.; Ferman, Tanis; Graff-Radford, Neill R.; Boeve, Bradley F.; Wszolek, Zbigniew K.; Dickson, Dennis W.; Chiò, Adriano; Bennett, David A.; De Jager, Philip L.; Ross, Owen A.; Dalgard, Clifton L.; Gibbs, J. Raphael; Traynor, Bryan J.; Scholz, Sonja W.; Soltis, Anthony R.; Viollet, Coralie; Sukumar, Gauthaman; Alba, Camille; Lott, Nathaniel; McGrath Martinez, Elisa; Tuck, Meila; Singh, Jatinder; Bacikova, Dagmar; Zhang, Xijun; Hupalo, Daniel N.; Adeleye, Adelani; Wilkerson, Matthew D.; Pollard, Harvey B.; Dalgard, Clifton L.; Black, Sandra E.; Gan-Or, Ziv; Keith, Julia; Masellis, Mario; Rogaeva, Ekaterina; Brice, Alexis; Lesage, Suzanne; Xiromerisiou, Georgia; Calvo, Andrea; Canosa, Antonio; Chio, Adriano; Logroscino, Giancarlo; Mora, Gabriele; Krüger, Rejko; May, Patrick; Alcolea, Daniel; Clarimon, Jordi; Fortea, Juan; Gonzalez-Aramburu, Isabel; Infante, Jon; Lage, Carmen; Lleó, Alberto; Pastor, Pau; Sanchez-Juan, Pascual; Brett, Francesca; Aarsland, Dag; Al-Sarraj, Safa; Attems, Johannes; Gentleman, Steve; Hardy, John A.; Hodges, Angela K.; Love, Seth; McKeith, Ian G.; Morris, Christopher M.; Morris, Huw R.; Palmer, Laura; Pickering-Brown, Stuart; Ryten, Mina; Thomas, Alan J.; Troakes, Claire; Albert, Marilyn S.; Barrett, Matthew J.; Beach, Thomas G.; Bekris, Lynn M.; Bennett, David A.; Boeve, Bradley F.; Dalgard, Clifton L.; Dawson, Ted M.; Dickson, Dennis W.; Faber, Kelley; Ferman, Tanis; Ferrucci, Luigi; Flanagan, Margaret E.; Foroud, Tatiana M.; Ghetti, Bernardino; Gibbs, J. Raphael; Goate, Alison; Goldstein, David S.; Graff-Radford, Neill R.; Kaufmann, Horacio; Kukull, Walter A.; Leverenz, James B.; Lopez, Grisel; Mao, Qinwen; Masliah, Eliezer; Monuki, Edwin; Newell, Kathy L.; Palma, Jose-Alberto; Perkins, Matthew; Pletnikova, Olga; Renton, Alan E.; Resnick, Susan M.; Rosenthal, Liana S.; Ross, Owen A.; Scherzer, Clemens R.; Serrano, Geidy E.; Shakkottai, Vikram G.; Sidransky, Ellen; Tanaka, Toshiko; Tayebi, Nahid; Topol, Eric; Torkamani, Ali; Troncoso, Juan C.; Woltjer, Randy; Wszolek, Zbigniew K.; Scholz, Sonja W.; Baloh, Robert H.; Bowser, Robert; Brice, Alexis; Broach, James; Camu, William; Chiò, Adriano; Cooper-Knock, John; Drepper, Carsten; Drory, Vivian E.; Dunckley, Travis L.; Feldman, Eva; Fratta, Pietro; Gerhard, Glenn; Gibson, Summer B.; Glass, Jonathan D.; Hardy, John A.; Harms, Matthew B.; Heiman-Patterson, Terry D.; Jansson, Lilja; Kirby, Janine; Kwan, Justin; Laaksovirta, Hannu; Landers, John E.; Landi, Francesco; Le Ber, Isabelle; Lumbroso, Serge; MacGowan, Daniel J. L.; Maragakis, Nicholas J.; Mouzat, Kevin; Myllykangas, Liisa; Orrell, Richard W.; Ostrow, Lyle W.; Pamphlett, Roger; Pioro, Erik; Pulst, Stefan M.; Ravits, John M.; Robberecht, Wim; Rogaeva, Ekaterina; Rothstein, Jeffrey D.; Sendtner, Michael; Shaw, Pamela J.; Sidle, Katie C.; Simmons, Zachary; Stein, Thor; Stone, David J.; Tienari, Pentti J.; Traynor, Bryan J.; Troncoso, Juan C.; Valori, Miko; Van Damme, Philip; Van Deerlin, Vivianna M.; Van Den Bosch, Ludo; Zinman, Lorne

Abstract: We characterized the role of structural variants, a largely unexplored type of genetic variation, in two non-Alzheimer’s dementias, namely Lewy body dementia (LBD) and frontotemporal dementia (FTD)/amyotrophic lateral sclerosis (ALS). To do this, we applied an advanced structural variant calling pipeline (GATK-SV) to short-read whole-genome sequence data from 5,213 European-ancestry cases and 4,132 controls. We discovered, replicated, and validated a deletion in TPCN1 as a novel risk locus for LBD and detected the known structural variants at the C9orf72 and MAPT loci as associated with FTD/ALS. We also identified rare pathogenic structural variants in both LBD and FTD/ALS. Finally, we assembled a catalog of structural variants that can be mined for new insights into the pathogenesis of these understudied forms of dementia.

Unravelling the early pathological mechanisms in Parkinson's Disease: Insights from alpha-synuclein dependent and independent models

Title: Unravelling the early pathological mechanisms in Parkinson's Disease: Insights from alpha-synuclein dependent and independent models

Author, co-author: Sciortino, Alessia

Abstract: Affecting over 10 million people worldwide, Parkinson’s disease is the second most common neurodegenerative disorder. With only 10% of cases having a known genetic cause, PD aetiology largely remains an enigma. Endogenous factors such as genetic predisposition, and exogenous factors such as exposure to toxins and lifestyle choices, interplay in the initiation and acceleration of the disease. Despite some common hallmarks such as nigrostriatal degeneration and Lewy bodies pathology, PD clinical picture largely varies across patients. Non-motor symptoms are common and thought to emerge up to 20 years prior to diagnosis, and they range from gastro-intestinal dysfunction to sleep disturbances to hallucinations. 90% of PD patients present at least one neuropsychiatric symptom, and about 30% of total patients develop dementia. Interventions aimed to prevent or slowdown disease progression require a better understanding of the early molecular events which foster neuronal dysfunction and death. Longitudinal studies which allow the investigation of early pathological stages are challenging to achieve on patients-based study only, thus largely rely on the use of animal models. Specifically, rodents have very similar anatomy, physiology, and genetics to humans, and a good set of genetic/molecular tools are available to generate pathological models. In the present thesis, we ventured into the investigation of alpha-synuclein dependent and independent models of PD, to unravel the early molecular events driving PD pathogenesis. Firstly, we investigated a genetic mouse model overexpressing the human, E46K mutated alpha-synuclein gene. We characterised neurodegeneration in the nigrostriatal pathway and motor deficits, detecting characteristics of an early-PD phenotype. Aiming to understand the molecular events driving neurodegeneration, we profiled the ventral midbrain transcriptome at different ages, uncovering that transcriptional changes are an early response to the alpha-synuclein challenge. Being the E46K mutation associated with dementia, we also profiled the hippocampus to investigate early transcriptional events linked with cognitive dysfunction in PD. We revealed that hippocampal dysfunction is mostly driven by the ageing process, operating over the interplay of genetic and gender predisposition. Secondly, we profiled transcriptomic changes in the midbrain of the alpha-synuclein independent, Park7-/- (DJ-1 KO) mouse model. Once again, we uncovered the interplay of sex and age in determining the susceptibility to the disease challenge, with males being more affected than females. Specifically, the response to DJ-1 loss of function appeared to be largely sex-specific, and to be mediated by the oestrogen pathway and the DJ-1/Nrf2/CYP1B1 axis. Even if sex-dimorphism has not been directly investigated in human Park7 PD cases due to their paucity, it has been reported in sporadic PD for several populations. Thus, our findings might significantly contribute to uncovering the reasons behind gender differences in PD. Thirdly, we investigated a moderate overexpressor of wild-type alpha-synuclein (Thy1-Syn14), aiming to reach a compromise between genetic and idiopathic PD modelling. To understand how endogenous and exogenous factors interplay in disease onset and progression, we exposed transgenic mice to the amyloidogenic protein Curli and to a fibre deprived diet. We uncovered that microbiome insults and diet act in combination to promote disease progression, and we provided supporting evidence to the concept of a gut-brain axis in PD. Our results underline the relevance of lifestyle adjustments in the management of PD patients. Finally, we investigated how different alpha-synuclein moieties and glutamate exposure might contribute to neurodegeneration. Even if these studies were left incomplete, we gained some preliminary indications which can represent a starting point for future research. We observed that both oligomers and fibrils are toxic forms of alpha-synuclein, and that a lack of standardisation in recombinant moieties production is a current issue that may halt reproducibility in alpha-synuclein research. We also reported a higher susceptibility of DJ-1 knock-down cells to glutamate excitotoxicity, potentially underlying an additional mechanism through which DJ-1 loss of function is responsible for PD development.

Embracing Monogenic Parkinson's Disease: The MJFF Global Genetic PD Cohort

Title: Embracing Monogenic Parkinson's Disease: The MJFF Global Genetic PD Cohort

Author, co-author: Vollstedt, Eva-Juliane; Schaake, Susen; Lohmann, Katja; Padmanabhan, Shalini; Brice, Alexis; Lesage, Suzanne; Tesson, Christelle; Vidailhet, Marie; Wurster, Isabel; Hentati, Faycel; Mirelman, Anat; Giladi, Nir; Karen, Marder; Waters, Cheryl; Fahn, Stanley; Kasten, Meike; Brüggemann, Norbert; Borsche, Max; Foroud, Tatiana; Tolosa, Eduardo; Garrido, Alicia; Annesi, Grazia; Gagliardi, Monica; Bozi, Maria; Stefanis, Leonidas; Ferreira, Joaquim J.; Correia Guedes, Leonor; Avenali, Micol; Petrucci, Simona; Clark, Lorraine; Fedotova, Ekaterina Y.; Abramycheva, Natalya Y.; Alvarez, Victoria; Menéndez-González, Manuel; Jesús Maestre, Silvia; Gómez-Garre, Pilar; Mir, Pablo; Belin, Andrea Carmine; Ran, Caroline; Lin, Chin-Hsien; Kuo, Ming-Che; Crosiers, David; Wszolek, Zbigniew K.; Ross, Owen A.; Jankovic, Joseph; Nishioka, Kenya; Funayama, Manabu; Clarimon, Jordi; Williams-Gray, Caroline H.; Camacho, Marta; Cornejo-Olivas, Mario; Torres-Ramirez, Luis; Wu, Yih-Ru; Lee-Chen, Guey-Jen; Morgadinho, Ana; Pulkes, Teeratorn; Termsarasab, Pichet; Berg, Daniela; Gregor, Kuhlenbäumer; Kühn, Andrea A.; Borngräber, Friederike; de Michele, Giuseppe; De Rosa, Anna; Zimprich, Alexander; Puschmann, Andreas; Mellick, George D.; Jolanta, Dorszewska; Carr, Jonathan; Ferese, Rosangela; Stefano, Gambardella; Chase, Bruce; Markopoulou, Katerina; Wataru, Satake; Toda, Tatsushi; Rossi, Malco; Merello, Marcelo; Lynch, Timothy; Olszewska, Diana A.; Lim, Shen-Yang; Ahmad-Annuar, Azlina; Tan, Ai Huey; Al-Mubarak, Bashayer; Hanagasi, Hasmet; Koziorowski, Dariusz; Ertan, Sibel; Gen c, Gen Cer; de Carvalho Aguiar, Patricia; Barkhuizen, Melinda; Pimentel, Marcia M. G.; Saunders-Pullman, Rachel; van de Warrenburg, Bart; Bressman, Susan; Toft, Mathias; Appel-Cresswell, Silke; Lang, Anthony E.; Skorvanek, Matej; Boon, Agnita J. W.; Krüger, Rejko; Sammler, Esther M.; Tumas, Vitor; Zhang, Bao-Rong; Garraux, Gaetan; Chung, Sun Ju; Joong, Kim Yun; Winkelmann, Juliane; Sue, Carolyn M.; Eng-King, Tan; Damásio, Joana; Klivényi, Péter; Kostic, Vladimir S.; Arkadir, David; Martikainen, Mika; Borges, Vanderci; Hertz, Jens Michael; Brighina, Laura; Spitz, Mariana; Suchowersky, Oksana; Riess, Olaf; Parimal, Das; Mollenhauer, Brit; Gatto, Emilia M.; Skaalum, Petersen Maria; Wu, Ruey-Meei; Illarioshkin, Sergey N.; Valente, Enza Maria; Aasly, Jan O.; Aasly, Anna; N, Alcalay Roy; Thaler, Avner; Farrer, Matthew J.; Kathrin, Brockmann; Corvol, Jean-Christophe; Klein, Christine; Aasly, Anna; Aasly, Jan O.; Abramycheva, Natalya Y.; Ahmad-Annuar, Azlina; Albanese, Alberto; Alcalay, Roy N.; Aldakheel, Amaal; Alkhairallah, Thamer; Bashayer, Al-Mubarak; Al-Tassan, Nada; Alvarez, Victoria; Paolo, Amami; Annesi, Grazia; Appel-Cresswell, Silke; Araujo, Leite Marco Antonio; Arkadir, David; Avenali, Micol; Ferraz, Henrique Ballalai; Bardien, Soraya; Melinda, Barkhuizen; Barrett, Matthew J.; Ba sak, A. Nazl I; Berg, Daniela; Bilgic, Basar; Bloem, Bastiaan R.; Bonifati, Vincenzo; Boon, Agnita J. W.; Borges, Vanderci; Borngräber, Friederike; Borsche, Max; Bozi, Maria; Bressman, Susan; Brice, Alexis; Brighina, Laura; Brockmann, Kathrin; Brüggemann, Norbert; Camacho, Marta; Belin, Andrea Carmine; Carr, Jonathan; Cesarini, Martin Emiliano; Cornejo-Olivas, Mario; Chase, Bruce; Ju, Chung Sun; Guedes, Leonor Correia; Clarimon, Jordi; Lorraine, Clark; Corvol, Jean-Christophe; Crosiers, David; Parimal, Das; de Carvalho Aguiar, Patricia; Damásio, Joana; de Michele, Giuseppe; De Rosa, Anna; Dieguez, Elena; Dorszewska, Jolanta; Ertan, Sibel; Fahn, Stanley; Farrer, Matthew J.; Fedotova, Ekaterina Y.; Ferese, Rosangela; Ferreira, Joaquim J.; Foroud, Tatiana; Funayama, Manabu; Fung, Victor S. C.; Gagliardi, Monica; Stefano, Gambardella; Garraux, Gaetan; Garrido, Alicia; Gatto, Emilia M.; Gen c, Gen Cer; Giladi, Nir; Pilar, Gómez-Garre; Hanagasi, Hasmet; Hattori, Nobutaka; Faycel, Hentati; Hertz, Jens Michael; Illarioshkin, Sergey N.; Jankovic, Joseph; Januario, Cristina; Maestre, Silvia Jesús; Kaasinen, Valtteri; Kasten, Meike; Hiroshi, Kataoka; Kievit, Anneke A.; Kim, Yun Joong; Christine, Klein; Klivényi, Péter; Kostic, Vladimir S.; Koziorowski, Dariusz; Krüger, Rejko; Kühn, Andrea A.; Kuhlenbäumer, Gregor; Kuo, Ming-Che; Lang, Anthony E.; Lee-Chen, Guey-Jen; Lesage, Suzanne; Lim, Jia Lun; Lim, Shen-Yang; Lin, Chin-Hsien; Lohmann, Katja; Timothy, Lynch; Marder, Karen; Markopoulou, Katerina; Martikainen, Mika; May, Patrick; McCarthy, Allan; Mellick, George D.; Menéndez-González, Manuel; Merello, Marcelo; Mir, Pablo; Mirelman, Anat; Mollenhauer, Brit; Briceno, Hugo Morales; Morgadinho, Ana; Morris, Huw; Mosejova, Alexandra; Nishioka, Kenya; Cakmak, Özgür Öztop; Olszewska, Diana A.; Orr-Urtreger, Avi; Pachchek, Sinthuja; Padmanabhan, Shalini; Periñ\'an, Maria Teresa; Petrucci, Simona; Pimentel, Marcia M. G.; Procopio, Radha; Pulkes, Teeratorn; Puschmann, Andreas; Ran, Caroline; Riess, Olaf; Ross, Owen A.; Rossi, Malco; Ruiz-Martinez, Javier; Sammler, Esther M.; Pereira, João Santos; Satake, Wataru; Saunders-Pullman, Rachel; Schaake, Susen; Skaalum, Petersen Maria; Skorvanek, Matej; Stefanis, Leonidas; Soto-Beasley, Alexandra I.; Sousa, Mário; Spitz, Mariana; Suchowersky, Oksana; Sue, Carolyn M.; Tan, Ai Huey; Tan, Eng-King; Thaler, Avner; Tepge c, Fatih; Termsarasab, Pichet; Tesson, Christelle; Toda, Tatsushi; Toft, Mathias; Tolosa, Eduardo; Torres-Ramirez, Luis; Tumas, Vitor; Uyguner, Oya; Valente, Enza Maria; van de Warrenburg, Bart; Vidailhet, Marie; Vollstedt, Eva-Juliane; Walton, Ronald L.; Waters, Cheryl; H, Williams-Gray Caroline; Winkelmann, Juliane; Wu, Yih-Ru; Isabel, Wurster; Wszolek, Zbigniew K.; Wu, Ruey-Meei; Bao-Rong, Zhang; Zimprich, Alexander

Abstract: BACKGROUND: As gene-targeted therapies are increasingly being developed for Parkinson's disease (PD), identifying and characterizing carriers of specific genetic pathogenic variants is imperative. Only a small fraction of the estimated number of subjects with monogenic PD worldwide are currently represented in the literature and availability of clinical data and clinical trial-ready cohorts is limited. OBJECTIVE: The objectives are to (1) establish an international cohort of affected and unaffected individuals with PD-linked variants; (2) provide harmonized and quality-controlled clinical characterization data for each included individual; and (3) further promote collaboration of researchers in the field of monogenic PD. METHODS: We conducted a worldwide, systematic online survey to collect individual-level data on individuals with PD-linked variants in SNCA, LRRK2 VPS35, PRKN, PINK1, DJ-1, as well as selected pathogenic and risk variants in GBA and corresponding demographic, clinical, and genetic data. All registered cases underwent thorough quality checks, and pathogenicity scoring of the variants and genotype-phenotype relationships were analyzed. RESULTS: We collected 3888 variant carriers for our analyses, reported by 92 centers (42 countries) worldwide. Of the included individuals 3185 had a diagnosis of PD (ie, 1306 LRRK2, 115 SNCA, 23 VPS35 429 PRKN, 75 PINK1, 13 DJ-1, and 1224 GBA) and 703 were unaffected (ie, 328 LRRK2, 32 SNCA, 3 VPS35, 1 PRKN, 1 PINK1, and 338 GBA). In total, we identified 269 different pathogenic variants; 1322 individuals in our cohort (34\%) were indicated as not previously published. CONCLUSIONS: Within the MJFF Global Genetic PD Study Group, we (1) established the largest international cohort of affected and unaffected individuals carrying PD-linked variants; (2) provide harmonized and quality-controlled clinical and genetic data for each included individual; (3) promote collaboration in the field of genetic PD with a view toward clinical and genetic stratification of patients for gene-targeted clinical trials. 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Accurate long-read sequencing identified GBA variants as a major genetic risk factor in the Luxembourg Parkinson\textquoterights study 2023.03.29.23287880

Title: Accurate long-read sequencing identified GBA variants as a major genetic risk factor in the Luxembourg Parkinson\textquoterights study 2023.03.29.23287880

Author, co-author: Peiris, Sinthuja; Landoulsi, Zied; Pavelka, Lukas; Schulte, Claudia; Buena-Atienza, Elena; Gross, Caspar; Hauser, Ann-Kathrin; Bobbili, Dheeraj Reddy; Casadei, Nicolas; May, Patrick; Krüger, Rejko; Consortium, The NCER-PD

Abstract: Heterozygous variants in the glucocerebrosidase GBA gene are an increasingly recognized risk factor for Parkinson's disease (PD). Due to the pseudogene GBAP1 that shares 96\% sequence homology with the GBA coding region, accurate variant calling by array-based or short-read sequencing methods remains a major challenge in understanding the genetic landscape of GBA-related PD. We established a novel long-read sequencing technology for assessing the full length of the GBA gene. We used subsequent regression models for genotype-phenotype analyses. We sequenced 752 patients with parkinsonism and 806 healthy controls of the Luxembourg Parkinson's study. All GBA variants identified showed a 100% true positive rate by Sanger validation. We found 12% of unrelated PD patients carrying GBA variants. 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 GBA-related parkinsonism in Luxembourg, showing a high prevalence of GBA variants as the major genetic risk for PD. Our approach provides an important advancement for highly accurate GBA variant calling, which is essential for providing access to emerging causative therapies for GBA carriers.

Transferability of European-derived cardiometabolic polygenic risk scores in the South Asians and their interplay with family history 2023.03.20.23287470

Title: Transferability of European-derived cardiometabolic polygenic risk scores in the South Asians and their interplay with family history 2023.03.20.23287470

Author, co-author: Hassanin, Emadeldin Saeed Fathy Sayed; Maj, Carlo; Krawitz, Peter; May, Patrick; Bobbili, Dheeraj Reddy

Abstract: Background & Aims We aimed to investigate the effect of polygenic risk scores (PRSs) derived from individuals of European (EUR) ancestry on common diseases among individuals of South Asian (SAS) ancestry in the UK Biobank (UKB). 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 panel of SNPs derived from the EUR population and applied it to the individuals of SAS ancestry from the UKB study. We applied the PRS using summary statistics from genome-wide association studies (GWAS) for cardiometabolic and lifestyle diseases such as coronary artery disease (CAD), obesity, and type 2 diabetes (T2D). Each PRS was adjusted according to an individual\textquoterights predicted genetic ancestry to derive an adjusted PRS (aPRS). We calculated the percentiles based on aPRS and divided them according to the percentiles into three 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.Results The risk of developing severe obesity for individuals of SAS ancestry was almost threefold higher for individuals with high aPRS than for those with intermediate aPRS, with an OR of 3.67 (95% CI = 2.47-5.48, P < 0.01). While the risk of severe obesity was lower in the low-aPRS group (OR = 0.19, CI = 0.05\textendash0.52, P < 0.01). Comparable results were found in the EUR data, where the low-PRS group had an OR of 0.26 (95% CI= 0.24-0.3, P < 0.01) and the high-PRS group had an OR of 3.2 (95% CI = 3.1-3.3, 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 exhibit further higher risk to these diseases, thereby implying a greater genetic predisposition to these conditions.Conclusion Our findings suggest that using CAD, obesity, and T2D GWAS summary statistics predominantly from the EUR population have sufficient power to identify SAS individuals with higher genetic risk. With future GWAS recruiting more SAS participants and tailoring the PRSs towards SAS ancestry, we believe that the predictive power of PRS would improve.

Twist exome capture allows for lower average sequence coverage in clinical exome sequencing

Title: Twist exome capture allows for lower average sequence coverage in clinical exome sequencing

Author, co-author: Yaldiz, Burcu; Kucuk, Erdi; Hampstead, Juliet; Hofste, Tom; Pfundt, Rolph; Corominas Galbany, Jordi; Rinne, Tuula; Yntema, Helger G.; Hoischen, Alexander; Nelen, Marcel; Gilissen, Christian; consortium, Solve-R. D.; Riess, Olaf; Haack, Tobias B.; Graessner, Holm; Zurek, Birte; Ellwanger, Kornelia; Ossowski, Stephan; Demidov, German; Sturm, Marc; Schulze-Hentrich, Julia M.; Schüle, Rebecca; Xu, Jishu; Kessler, Christoph; Wayand, Melanie; Synofzik, Matthis; Wilke, Carlo; Traschütz, Andreas; Schöls, Ludger; Hengel, Holger; Lerche, Holger; Kegele, Josua; Heutink, Peter; Brunner, Han; Scheffer, Hans; Hoogerbrugge, Nicoline; Hoischen, Alexander; Hoen, Peter A. C. T; Vissers, Lisenka E. L. M.; Gilissen, Christian; Steyaert, Wouter; Sablauskas, Karolis; de Voer, Richarda M.; Kamsteeg, Erik-Jan; van de Warrenburg, Bart; van Os, Nienke; te Paske, Iris; Janssen, Erik; de Boer, Elke; Steehouwer, Marloes; Yaldiz, Burcu; Kleefstra, Tjitske; Brookes, Anthony J.; Veal, Colin; Gibson, Spencer; Maddi, Vatsalya; Mehtarizadeh, Mehdi; Riaz, Umar; Warren, Greg; Dizjikan, Farid Yavari; Shorter, Thomas; Töpf, Ana; Straub, Volker; Bettolo, Chiara Marini; Manera, Jordi Diaz; Hambleton, Sophie; Engelhardt, Karin; Clayton-Smith, Jill; Banka, Siddharth; Alexander, Elizabeth; Jackson, Adam; Faivre, Laurence; Thauvin, Christel; Vitobello, Antonio; Denommé-Pichon, Anne-Sophie; Duffourd, Yannis; Bruel, Ange-Line; Peyron, Christine; Pélissier, Aurore; Beltran, Sergi; Gut, Ivo Glynne; Laurie, Steven; Piscia, Davide; Matalonga, Leslie; Papakonstantinou, Anastasios; Bullich, Gemma; Corvo, Alberto; Fernandez-Callejo, Marcos; Hernández, Carles; Picó, Daniel; Paramonov, Ida; Lochmüller, Hanns; Gumus, Gulcin; Bros-Facer, Virginie; Rath, Ana; Hanauer, Marc; Lagorce, David; Hongnat, Oscar; Chahdil, Maroua; Lebreton, Emeline; Stevanin, Giovanni; Durr, Alexandra; Davoine, Claire-Sophie; Guillot-Noel, Léna; Heinzmann, Anna; Coarelli, Giulia; Bonne, Gisèle; Evangelista, Teresinha; Allamand, Valérie; Nelson, Isabelle; Yaou, Rabah Ben; Metay, Corinne; Eymard, Bruno; Cohen, Enzo; Atalaia, Antonio; Stojkovic, Tanya; Macek, Milan; Turnovec, Marek; Thomasová, Dana; Kremliková, Radka Pourová; Franková, Vera; Havlovicová, Markéta; Lišková, Petra; Doležalová, Pavla; Parkinson, Helen; Keane, Thomas; Freeberg, Mallory; Thomas, Coline; Spalding, Dylan; Robinson, Peter; Danis, Daniel; Robert, Glenn; Costa, Alessia; Patch, Christine; Hanna, Mike; Houlden, Henry; Reilly, Mary; Vandrovcova, Jana; Efthymiou, Stephanie; Morsy, Heba; Cali, Elisa; Magrinelli, Francesca; Sisodiya, Sanjay M.; Rohrer, Jonathan; Muntoni, Francesco; Zaharieva, Irina; Sarkozy, Anna; Timmerman, Vincent; Baets, Jonathan; de Vries, Geert; De Winter, Jonathan; Beijer, Danique; de Jonghe, Peter; Van de Vondel, Liedewei; De Ridder, Willem; Weckhuysen, Sarah; Nigro, Vincenzo; Mutarelli, Margherita; Morleo, Manuela; Pinelli, Michele; Varavallo, Alessandra; Banfi, Sandro; Torella, Annalaura; Musacchia, Francesco; Piluso, Giulio; Ferlini, Alessandra; Selvatici, Rita; Gualandi, Francesca; Bigoni, Stefania; Rossi, Rachele; Neri, Marcella; Aretz, Stefan; Spier, Isabel; Sommer, Anna Katharina; Peters, Sophia; Oliveira, Carla; Pelaez, Jose Garcia; Matos, Ana Rita; José, Celina São; Ferreira, Marta; Gullo, Irene; Fernandes, Susana; Garrido, Luzia; Ferreira, Pedro; Carneiro, Fátima; Swertz, Morris A.; Johansson, Lennart; van der Velde, Joeri K.; van der Vries, Gerben; Neerincx, Pieter B.; Ruvolo, David; Abbott, Kristin M.; Frederikse, Wilhemina Skerstjens; Zonneveld-Huijssoon, Eveline; Roelofs-Prins, Dieuwke; van Gijn, Marielle; Köhler, Sebastian; Metcalfe, Alison; Verloes, Alain; Drunat, Séverine; Heron, Delphine; Mignot, Cyril; Keren, Boris; de Sainte Agathe, Jean-Madeleine; Rooryck, Caroline; Lacombe, Didier; Trimouille, Aurelien; De la Paz, Manuel Posada; Sánchez, Eva Bermejo; Martín, Estrella López; Delgado, Beatriz Martínez; de la Rosa, F. Javier Alonso García; Ciolfi, Andrea; Dallapiccola, Bruno; Pizzi, Simone; Radio, Francesca Clementina; Tartaglia, Marco; Renieri, Alessandra; Furini, Simone; Fallerini, Chiara; Benetti, Elisa; Balicza, Peter; Molnar, Maria Judit; Maver, Ales; Peterlin, Borut; Münchau, Alexander; Lohmann, Katja; Herzog, Rebecca; Pauly, Martje; Macaya, Alfons; Cazurro-Gutiérrez, Ana; Pérez-Dueñas, Belén; Munell, Francina; Jarava, Clara Franco; Masó, Laura Batlle; Marcé-Grau, Anna; Colobran, Roger; Osorio, Andrés Nascimento; de Benito, Daniel Natera; Lochmüller, Hanns; Thompson, Rachel; Polavarapu, Kiran; Grimbacher, Bodo; Beeson, David; Cossins, Judith; Hackman, Peter; Johari, Mridul; Savarese, Marco; Udd, Bjarne; Horvath, Rita; Chinnery, Patrick F.; Ratnaike, Thiloka; Gao, Fei; Schon, Katherine; Capella, Gabriel; Valle, Laura; Holinski-Feder, Elke; Laner, Andreas; Steinke-Lange, Verena; Schröck, Evelin; Rump, Andreas; Başak, Ayşe Nazlı; Hemelsoet, Dimitri; Dermaut, Bart; Schuermans, Nika; Poppe, Bruce; Verdin, Hannah; Mei, Davide; Vetro, Annalisa; Balestrini, Simona; Guerrini, Renzo; Claeys, Kristl; Santen, Gijs W. E.; Bijlsma, Emilia K.; Hoffer, Mariette J. V.; Ruivenkamp, Claudia A. L.; Boztug, Kaan; Haimel, Matthias; Maystadt, Isabelle; Cordts, Isabelle; Deschauer, Marcus; Zaganas, Ioannis; Kokosali, Evgenia; Lambros, Mathioudakis; Evangeliou, Athanasios; Spilioti, Martha; Kapaki, Elisabeth; Bourbouli, Mara; Striano, Pasquale; Zara, Federico; Riva, Antonella; Iacomino, Michele; Uva, Paolo; Scala, Marcello; Scudieri, Paolo; Cilio, Maria-Roberta; Carpancea, Evelina; Depondt, Chantal; Lederer, Damien; Sznajer, Yves; Duerinckx, Sarah; Mary, Sandrine; Depienne, Christel; Roos, Andreas; May, Patrick

Abstract: Background Exome and genome sequencing are the predominant techniques in the diagnosis and research of genetic disorders. Sufficient, uniform and reproducible/consistent sequence coverage is a main determinant for the sensitivity to detect single-nucleotide (SNVs) and copy number variants (CNVs). Here we compared the ability to obtain comprehensive exome coverage for recent exome capture kits and genome sequencing techniques. Results We compared three different widely used enrichment kits (Agilent SureSelect Human All Exon V5, Agilent SureSelect Human All Exon V7 and Twist Bioscience) as well as short-read and long-read WGS. We show that the Twist exome capture significantly improves complete coverage and coverage uniformity across coding regions compared to other exome capture kits. Twist performance is comparable to that of both short- and long-read whole genome sequencing. Additionally, we show that even at a reduced average coverage of 70× there is only minimal loss in sensitivity for SNV and CNV detection. Conclusion We conclude that exome sequencing with Twist represents a significant improvement and could be performed at lower sequence coverage compared to other exome capture techniques.

A Solve-RD ClinVar-based reanalysis of 1522 index cases from ERN-ITHACA reveals common pitfalls and misinterpretations in exome sequencing

Title: A Solve-RD ClinVar-based reanalysis of 1522 index cases from ERN-ITHACA reveals common pitfalls and misinterpretations in exome sequencing

Author, co-author: Denommé-Pichon, Anne-Sophie; Matalonga, Leslie; de Boer, Elke; Jackson, Adam; Benetti, Elisa; Banka, Siddharth; Bruel, Ange-Line; Ciolfi, Andrea; Clayton-Smith, Jill; Dallapiccola, Bruno; Duffourd, Yannis; Ellwanger, Kornelia; Fallerini, Chiara; Gilissen, Christian; Graessner, Holm; Haack, Tobias B.; Havlovicova, Marketa; Hoischen, Alexander; Jean-Marçais, Nolwenn; Kleefstra, Tjitske; López-Martín, Estrella; Macek, Milan; Mencarelli, Maria Antonietta; Moutton, Sébastien; Pfundt, Rolph; Pizzi, Simone; Posada, Manuel; Radio, Francesca Clementina; Renieri, Alessandra; Rooryck, Caroline; Ryba, Lukas; Safraou, Hana; Schwarz, Martin; Tartaglia, Marco; Thauvin-Robinet, Christel; Thevenon, Julien; Tran Mau-Them, Frédéric; Trimouille, Aurélien; Votypka, Pavel; de Vries, Bert B. A.; Willemsen, Marjolein H.; Zurek, Birte; Verloes, Alain; Philippe, Christophe; Abbott, Kristin M.; Faivre, Laurence; Kerstjens, Mieke; Martín, Estrella López; Macek Jr., Milan; Maystadt, Isabelle; Morleo, Manuela; Nigro, Vicenzo; Pinelli, Michele; Radio, Francesca C.; Riess, Olaf; Agathe, Jean-Madeleine De Sainte; Santen, Gijs W. E.; Thauvin, Christel; Torella, Annalaura; Vissers, Lisenka; Vitobello, Antonio; Zguro, Kristina; Boer, Elke De; Cohen, Enzo; Danis, Daniel; Gao, Fei; Horvath, Rita; Johari, Mridul; Johanson, Lennart; Li, Shuang; Morsy, Heba; Nelson, Isabelle; Paramonov, Ida; te Paske, Iris B. A. W.; Robinson, Peter; Savarese, Marco; Steyaert, Wouter; Töpf, Ana; van der Velde, Joeri K.; Vandrovcova, Jana; Ossowski, Stephan; Demidov, German; Sturm, Marc; Schulze-Hentrich, Julia M.; Schüle, Rebecca; Xu, Jishu; Kessler, Christoph; Wayand, Melanie; Synofzik, Matthis; Wilke, Carlo; Traschütz, Andreas; Schöls, Ludger; Hengel, Holger; Lerche, Holger; Kegele, Josua; Heutink, Peter; Brunner, Han; Scheffer, Hans; Hoogerbrugge, Nicoline; `t Hoen, Peter A. C.; Vissers, Lisenka E. L. M.; Sablauskas, Karolis; de Voer, Richarda M.; Kamsteeg, Erik-Jan; van de Warrenburg, Bart; van Os, Nienke; Paske, Iris Te; Janssen, Erik; Steehouwer, Marloes; Yaldiz, Burcu; Brookes, Anthony J.; Veal, Colin; Gibson, Spencer; Maddi, Vatsalya; Mehtarizadeh, Mehdi; Riaz, Umar; Warren, Greg; Dizjikan, Farid Yavari; Shorter, Thomas; Straub, Volker; Bettolo, Chiara Marini; Manera, Jordi Diaz; Hambleton, Sophie; Engelhardt, Karin; Alexander, Elizabeth; Peyron, Christine; Pélissier, Aurore; Beltran, Sergi; Gut, Ivo Glynne; Laurie, Steven; Piscia, Davide; Papakonstantinou, Anastasios; Bullich, Gemma; Corvo, Alberto; Fernandez-Callejo, Marcos; Hernández, Carles; Picó, Daniel; Lochmüller, Hanns; Gumus, Gulcin; Bros-Facer, Virginie; Rath, Ana; Hanauer, Marc; Lagorce, David; Hongnat, Oscar; Chahdil, Maroua; Lebreton, Emeline; Stevanin, Giovanni; Durr, Alexandra; Davoine, Claire-Sophie; Guillot-Noel, Léna; Heinzmann, Anna; Coarelli, Giulia; Bonne, Gisèle; Evangelista, Teresinha; Allamand, Valérie; Ben Yaou, Rabah; Metay, Corinne; Eymard, Bruno; Atalaia, Antonio; Stojkovic, Tanya; Turnovec, Marek; Thomasová, Dana; Kremliková, Radka Pourová; Franková, Vera; Havlovicová, Markéta; Li\vsková, Petra; Dole\vzalová, Pavla; Parkinson, Helen; Keane, Thomas; Freeberg, Mallory; Thomas, Coline; Spalding, Dylan; Robert, Glenn; Costa, Alessia; Patch, Christine; Hanna, Mike; Houlden, Henry; Reilly, Mary; Efthymiou, Stephanie; Cali, Elisa; Magrinelli, Francesca; Sisodiya, Sanjay M.; Rohrer, Jonathan; Muntoni, Francesco; Zaharieva, Irina; Sarkozy, Anna; Timmerman, Vincent; Baets, Jonathan; de Vries, Geert; De Winter, Jonathan; Beijer, Danique; de Jonghe, Peter; Van de Vondel, Liedewei; De Ridder, Willem; Weckhuysen, Sarah; Nigro, Vincenzo; Mutarelli, Margherita; Varavallo, Alessandra; Banfi, Sandro; Musacchia, Francesco; Piluso, Giulio; Ferlini, Alessandra; Selvatici, Rita; Gualandi, Francesca; Bigoni, Stefania; Rossi, Rachele; Neri, Marcella; Aretz, Stefan; Spier, Isabel; Sommer, Anna Katharina; Peters, Sophia; Oliveira, Carla; Pelaez, Jose Garcia; Matos, Ana Rita; José, Celina São; Ferreira, Marta; Gullo, Irene; Fernandes, Susana; Garrido, Luzia; Ferreira, Pedro; Carneiro, Fátima; Swertz, Morris A.; Johansson, Lennart; van der Vries, Gerben; Neerincx, Pieter B.; Ruvolo, David; Kerstjens Frederikse, Wilhemina S.; Zonneveld-Huijssoon, Eveline; Roelofs-Prins, Dieuwke; van Gijn, Marielle; Köhler, Sebastian; Metcalfe, Alison; Drunat, Séverine; Heron, Delphine; Mignot, Cyril; Keren, Boris; Lacombe, Didier; Trimouille, Aurelien; Capella, Gabriel; Valle, Laura; Holinski-Feder, Elke; Laner, Andreas; Steinke-Lange, Verena; Cilio, Maria-Roberta; Carpancea, Evelina; Depondt, Chantal; Lederer, Damien; Sznajer, Yves; Duerinckx, Sarah; Mary, Sandrine; Macaya, Alfons; Cazurro-Gutiérrez, Ana; Pérez-Dueñas, Belén; Munell, Francina; Jarava, Clara Franco; Masó, Laura Batlle; Marcé-Grau, Anna; Colobran, Roger; Hackman, Peter; Udd, Bjarne; Hemelsoet, Dimitri; Dermaut, Bart; Schuermans, Nika; Poppe, Bruce; Verdin, Hannah; Osorio, Andrés Nascimento; Depienne, Christel; Roos, Andreas; Cordts, Isabell; Deschauer, Marcus; Striano, Pasquale; Zara, Federico; Riva, Antonella; Iacomino, Michele; Uva, Paolo; Scala, Marcello; Scudieri, Paolo; Claeys, Kristl; Boztug, Kaan; Haimel, Matthias; W.E, Gijs; Ruivenkamp, Claudia A. L.; Natera de Benito, Daniel; Thompson, Rachel; Polavarapu, Kiran; Grimbacher, Bodo; Zaganas, Ioannis; Kokosali, Evgenia; Lambros, Mathioudakis; Evangeliou, Athanasios; Spilioti, Martha; Kapaki, Elisabeth; Bourbouli, Mara; Balicza, Peter; Molnar, Maria Judit; De la Paz, Manuel Posada; Sánchez, Eva Bermejo; Delgado, Beatriz Martínez; Alonso García de la Rosa, F. Javier; Schröck, Evelin; Rump, Andreas; Mei, Davide; Vetro, Annalisa; Balestrini, Simona; Guerrini, Renzo; Chinnery, Patrick F.; Ratnaike, Thiloka; Schon, Katherine; Maver, Ales; Peterlin, Borut; Münchau, Alexander; Lohmann, Katja; Herzog, Rebecca; Pauly, Martje; May, Patrick; Beeson, David; Cossins, Judith; Furini, Simone; Afenjar, Alexandra; Goldenberg, Alice; Masurel, Alice; Phan, Alice; Dieux-Coeslier, Anne; Fargeot, Anne; Guerrot, Anne-Marie; Toutain, Annick; Molin, Arnaud; Sorlin, Arthur; Putoux, Audrey; Jouret, Béatrice; Laudier, Béatrice; Demeer, Bénédicte; Doray, Bérénice; Bonniaud, Bertille; Isidor, Bertrand; Gilbert-Dussardier, Brigitte; Leheup, Bruno; Reversade, Bruno; Paul, Carle; Vincent-Delorme, Catherine; Neiva, Cecilia; Poirsier, Céline; Quélin, Chloé; Chiaverini, Christine; Coubes, Christine; Francannet, Christine; Colson, Cindy; Desplantes, Claire; Wells, Constance; Goizet, Cyril; Sanlaville, Damien; Amram, Daniel; Lehalle, Daphné; Geneviève, David; Gaillard, Dominique; Zivi, Einat; Sarrazin, Elisabeth; Steichen, Elisabeth; Schaefer, Élise; Lacaze, Elodie; Jacquemin, Emmanuel; Bongers, Ernie; Kilic, Esra; Colin, Estelle; Giuliano, Fabienne; Prieur, Fabienne; Laffargue, Fanny; Morice-Picard, Fanny; Petit, Florence; Cartault, François; Feillet, François; Baujat, Geneviève; Morin, Gilles; Diene, Gwenaëlle; Journel, Hubert; Perthus, Isabelle; Lespinasse, James; Alessandri, Jean-Luc; Amiel, Jeanne; Martinovic, Jelena; Delanne, Julian; Albuisson, Juliette; Lambert, Laëtitia; Perrin, Laurence; Ousager, Lilian Bomme; Van Maldergem, Lionel; Pinson, Lucile; Ruaud, Lyse; Samimi, Mahtab; Bournez, Marie; Bonnet-Dupeyron, Marie Noëlle; Vincent, Marie; Jacquemont, Marie-Line; Cordier-Alex, Marie-Pierre; Gérard-Blanluet, Marion; Willems, Marjolaine; Spodenkiewicz, Marta; Doco-Fenzy, Martine; Rossi, Massimiliano; Renaud, Mathilde; Fradin, Mélanie; Mathieu, Michèle; Holder-Espinasse, Muriel H.; Houcinat, Nada; Hanna, Nadine; Leperrier, Nathalie; Chassaing, Nicolas; Philip, Nicole; Boute, Odile; Van Kien, Philippe Khau; Parent, Philippe; Bitoun, Pierre; Sarda, Pierre; Vabres, Pierre; Jouk, Pierre-Simon; Touraine, Renaud; El Chehadeh, Salima; Whalen, Sandra; Marlin, Sandrine; Passemard, Sandrine; Grotto, Sarah; Bellanger, Séverine Audebert; Blesson, Sophie; Nambot, Sophie; Naudion, Sophie; Lyonnet, Stanislas; Odent, Sylvie; Attie-Bitach, Tania; Busa, Tiffany; Drouin-Garraud, Valérie; Layet, Valérie; Bizaoui, Varoona; Cusin, Véronica; Capri, Yline; Alembik, Yves

Abstract: Purpose Within the Solve-RD project (https://solve-rd.eu/), the European Reference Network for Intellectual disability, TeleHealth, Autism and Congenital Anomalies aimed to investigate whether a reanalysis of exomes from unsolved cases based on ClinVar annotations could establish additional diagnoses. We present the results of the “ClinVar low-hanging fruit” reanalysis, reasons for the failure of previous analyses, and lessons learned. Methods Data from the first 3576 exomes (1522 probands and 2054 relatives) collected from European Reference Network for Intellectual disability, TeleHealth, Autism and Congenital Anomalies was reanalyzed by the Solve-RD consortium by evaluating for the presence of single-nucleotide variant, and small insertions and deletions already reported as (likely) pathogenic in ClinVar. Variants were filtered according to frequency, genotype, and mode of inheritance and reinterpreted. Results We identified causal variants in 59 cases (3.9%), 50 of them also raised by other approaches and 9 leading to new diagnoses, highlighting interpretation challenges: variants in genes not known to be involved in human disease at the time of the first analysis, misleading genotypes, or variants undetected by local pipelines (variants in off-target regions, low quality filters, low allelic balance, or high frequency). Conclusion The “ClinVar low-hanging fruit” analysis represents an effective, fast, and easy approach to recover causal variants from exome sequencing data, herewith contributing to the reduction of the diagnostic deadlock.

CNV-ClinViewer: Enhancing the clinical interpretation of large copy-number variants online

Title: CNV-ClinViewer: Enhancing the clinical interpretation of large copy-number variants online

Author, co-author: Macnee, Marie; Pérez-Palma, Eduardo; Brünger, Tobias; Klöckner, Chiara; Platzer, Konrad; Stefanski, Arthur; Montanucci, Ludovica; Bayat, Allan; Radtke, Maximilian; Collins, Ryan L.; Talkowski, Michael; Blankenberg, Daniel; Møller, Rikke S.; Lemke, Johannes R.; Nothnagel, Michael; May, Patrick; Lal, Dennis

Abstract: Pathogenic copy number variants (CNVs) can cause a heterogeneous spectrum of rare and severe disorders. However, most CNVs are benign and are part of natural variation in human genomes. CNV pathogenicity classification, genotype-phenotype analyses, and therapeutic target identification are challenging and time-consuming tasks that require the integration and analysis of information from multiple scattered sources by experts.Here, we introduce the CNV-ClinViewer, an open-source web-application for clinical evaluation and visual exploration of CNVs. The application enables real-time interactive exploration of large CNV datasets in a user-friendly designed interface and facilitates semi-automated clinical CNV interpretation following the ACMG guidelines by integrating the ClassifCNV tool. In combination with clinical judgment the application enables clinicians and researchers to formulate novel hypotheses and guide their decision-making process. Subsequently, the CNV-ClinViewer enhances for clinical investigators patient care and for basic scientists translational genomic research.The web-application is freely available at https://cnv-ClinViewer.broadinstitute.org and the open-source code can be found at https://github.com/LalResearchGroup/CNV-clinviewer.Supplementary data are available at Bioinformatics online.

Clinically relevant combined effect of polygenic background, rare pathogenic germline variants, and family history on colorectal cancer incidence

Title: Clinically relevant combined effect of polygenic background, rare pathogenic germline variants, and family history on colorectal cancer incidence

Author, co-author: Hassanin, Emadeldin Saeed Fathy Sayed; Spier, Isabel; Bobbili, Dheeraj Reddy; Aldisi, Rana; Klinkhammer, Hannah; David, Friederike; Dueñas, Nuria; Hüneburg, Robert; Perne, Claudia; Brunet, Joan; Capella, Gabriel; Nöthen, Markus M.; Forstner, Andreas J.; Mayr, Andreas; Krawitz, Peter; May, Patrick; Aretz, Stefan; Maj, Carlo

Abstract: Background and aims: Summarised in polygenic risk scores (PRS), the effect of common, low penetrant genetic variants associated with colorectal cancer (CRC), can be used for risk stratification. Methods: To assess the combined impact of the PRS and other main factors on CRC risk, 163,516 individuals from the UK Biobank were stratified as follows: 1. carriers status for germline pathogenic variants (PV) in CRC susceptibility genes ( APC, MLH1, MSH2, MSH6, PMS2) , 2. low (\textless 20\%), intermediate (20–80\%), or high PRS (\textgreater 80\%), and 3. family history (FH) of CRC. Multivariable logistic regression and Cox proportional hazards models were applied to compare odds ratios and to compute the lifetime incidence, respectively. Results: Depending on the PRS, the CRC lifetime incidence for non-carriers ranges between 6 and 22\%, compared to 40 and 74 for carriers. A suspicious FH is associated with a further increase of the cumulative incidence reaching 26 for non-carriers and 98 for carriers. In non-carriers without FH, but high PRS, the CRC risk is doubled, whereas a low PRS even in the context of a FH results in a decreased risk. The full model including PRS, carrier status, and FH improved the area under the curve in risk prediction (0.704). Conclusion: The findings demonstrate that CRC risks are strongly influenced by the PRS for both a sporadic and monogenic background. FH, PV, and common variants complementary contribute to CRC risk. The implementation of PRS in routine care will likely improve personalized risk stratification, which will in turn guide tailored preventive surveillance strategies in high, intermediate, and low risk groups.

Investigation of Shared Genetic Risk Factors Between Parkinson's Disease and Cancers

Title: Investigation of Shared Genetic Risk Factors Between Parkinson's Disease and Cancers

Author, co-author: Sugier, Pierre-Emmanuel; Lucotte, Elise A.; Domenighetti, Cloé; Law, Matthew H.; Iles, Mark M.; Brown, Kevin; Amos, Christopher; McKay, James D.; Hung, Rayjean J.; Karimi, Mojgan; Bacq-Daian, Delphine; Boland-Augé, Anne; Olaso, Robert; Deleuze, Jean-François; Lesueur, Fabienne; Ostroumova, Evgenia; Kesminiene, Ausrele; de Vathaire, Florent; Guénel, Pascal; consortium, The Epithyr; Sreelatha, Ashwin Ashok Kumar; Schulte, Claudia; Grover, Sandeep; May, Patrick; Bobbili, Dheeraj Reddy; Radivojkov-Blagojevic, Milena; Lichtner, Peter; Singleton, Andrew B.; Hernandez, Dena G.; Edsall, Connor; Mellick, George D.; Zimprich, Alexander; Pirker, Walter; Rogaeva, Ekaterina; Lang, Anthony E.; Koks, Sulev; Taba, Pille; Lesage, Suzanne; Brice, Alexis; Corvol, Jean-Christophe; Chartier-Harlin, Marie-Christine; Mutez, Eugénie; Brockmann, Kathrin; Deutschländer, Angela B.; Hadjigeorgiou, Georges M.; Dardiotis, Efthimios; Stefanis, Leonidas; Simitsi, Athina Maria; Valente, Enza Maria; Petrucci, Simona; Straniero, Letizia; Zecchinelli, Anna; Pezzoli, Gianni; Brighina, Laura; Ferrarese, Carlo; Annesi, Grazia; Quattrone, Andrea; Gagliardi, Monica; Matsuo, Hirotaka; Nakayama, Akiyoshi; Hattori, Nobutaka; Nishioka, Kenya; Chung, Sun Ju; Kim, Yun Joong; Kolber, Pierre; van de Warrenburg, Bart P. C.; Bloem, Bastiaan R.; Aasly, Jan; Toft, Mathias; Pihlstrøm, Lasse; Guedes, Leonor Correia; Ferreira, Joaquim J.; Bardien, Soraya; Carr, Jonathan; Tolosa, Eduardo; Ezquerra, Mario; Pastor, Pau; Diez-Fairen, Monica; Wirdefeldt, Karin; Pedersen, Nancy; Ran, Caroline; Belin, Andrea C.; Puschmann, Andreas; Rödström, Emil Ygland; Clarke, Carl E.; Morrison, Karen E.; Tan, Manuela; Krainc, Dimitri; Burbulla, Lena F.; Farrer, Matt J.; Krüger, Rejko; Gasser, Thomas; Sharma, Manu; Landoulsi, Zied; consortium, Courage-PD; Truong, Thérèse; Elbaz, Ales

Abstract: Abstract Background Epidemiological studies that examined the association between Parkinson's disease (PD) and cancers led to inconsistent results, but they face a number of methodological difficulties. Objective We used results from genome-wide association studies (GWASs) to study the genetic correlation between PD and different cancers to identify common genetic risk factors. Methods We used individual data for participants of European ancestry from the Courage-PD (Comprehensive Unbiased Risk Factor Assessment for Genetics and Environment in Parkinson's Disease; PD, N = 16,519) and EPITHYR (differentiated thyroid cancer, N = 3527) consortia and summary statistics of GWASs from iPDGC (International Parkinson Disease Genomics Consortium; PD, N = 482,730), Melanoma Meta-Analysis Consortium (MMAC), Breast Cancer Association Consortium (breast cancer), the Prostate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome (prostate cancer), International Lung Cancer Consortium (lung cancer), and Ovarian Cancer Association Consortium (ovarian cancer) (N comprised between 36,017 and 228,951 for cancer GWASs). We estimated the genetic correlation between PD and cancers using linkage disequilibrium score regression. We studied the association between PD and polymorphisms associated with cancers, and vice versa, using cross-phenotypes polygenic risk score (PRS) analyses. Results We confirmed a previously reported positive genetic correlation of PD with melanoma (Gcorr = 0.16 [0.04; 0.28]) and reported an additional significant positive correlation of PD with prostate cancer (Gcorr = 0.11 [0.03; 0.19]). There was a significant inverse association between the PRS for ovarian cancer and PD (odds ratio [OR] = 0.89 [0.84; 0.94]). Conversely, the PRS of PD was positively associated with breast cancer (OR = 1.08 [1.06; 1.10]) and inversely associated with ovarian cancer (OR = 0.95 [0.91; 0.99]). The association between PD and ovarian cancer was mostly driven by rs183211 located in an intron of the NSF gene (17q21.31). Conclusions We show evidence in favor of a contribution of pleiotropic genes to the association between PD and specific cancers. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.

ORBilu Collection: Genetics & genetic processes