Lasse Pihlstrøm

• Harvey, Joshua; Imm, Jennifer; Kouhsar, Morteza; Smith, Adam R.; Creese, Byron & Smith, Rebecca G. [Show all 28 contributors for this article] (2026). Interrogating DNA methylation associated with Lewy body pathology in a cross brain-region and multi-cohort study. Nature Communications. 17(1). doi: 10.1038/s41467-026-77009-x. Full text in Research Archive Show summary

  Here, we conduct a large meta-analysis of DNA methylation across multiple cortical brain regions, in relation to increasing burden of Lewy body pathology. Utilizing a dataset of 1205 samples (832 unique donors), we identify 24 false discovery rate significant differentially methylated loci associated with Lewy body pathology, with loci located in UBASH3B and PTAFR, and an intergenic locus passing the genome-wide significance threshold. Ontological enrichment analysis highlights several neurologically relevant traits, including synaptic alterations. We compare methylation signatures between neurodegenerative pathologies and highlight a shared epigenetic profile across Lewy body, Alzheimer’s and Huntington’s diseases, although the top-ranked loci show disease specificity. Utilizing summary statistics from large-scale genome-wide association studies, we identify significant enrichment of DNA methylation differences with respect to increasing Lewy body pathology in the SNCA genomic region. We also identify specific relationships between genetic risk variants for Lewy body dementia and Parkinson’s disease to methylation quantitative trait loci in the SNCA 5’ region and expression of alternative transcript isoforms.

• Brakedal, Brage; Skeie, Geir Olve; Derad, Carlotta; Alstadhaug, Karl Bjørnar; Anundskås, Ingunn & Berven, Haakon [Show all 41 contributors for this article] (2026). Nicotinamide Riboside for Patients With Early-Stage Parkinson Disease: The NOPARK Randomized Clinical Trial. Journal of the American Medical Association (JAMA). ISSN 0098-7484. doi: 10.1001/jama.2026.18828. Full text in Research Archive Show summary

  Importance: Nicotinamide riboside, a nicotinamide adenine dinucleotide precursor, has been proposed as a potential disease-modifying therapy for Parkinson disease based on preclinical and early studies. Whether prolonged oral nicotinamide riboside improves clinical outcomes in Parkinson disease is unknown. Objective: To determine whether nicotinamide riboside improves clinical outcomes in Parkinson disease compared with placebo. Design, Setting, and Participants: Randomized, double-blind, placebo-controlled, phase 3 clinical trial conducted at 11 centers in Norway. Eligible participants were patients aged 35 years or older with Parkinson disease diagnosed within 2 years before enrollment, Hoehn and Yahr disease stage less than 3, abnormal dopamine transporter scintigraphy findings confirming dopaminergic nigrostriatal denervation, and stable dopaminergic treatment before enrollment. Of 537 screened individuals, 410 were randomized from May 6, 2020, to June 20, 2024, and 393 were included in the primary analysis. Final follow-up was completed on June 19, 2025. Interventions: Patients were randomized to receive oral nicotinamide riboside, 500 mg twice daily (n = 206), or matching placebo (n = 204) for 52 weeks. Main Outcomes and Measures: The primary outcome was change from baseline to week 52 in the Movement Disorder Society Unified Parkinson Disease Rating Scale total score (MDS-UPDRS parts I-III; range, 0-236, with higher scores indicating more severe disease; clinically important differences for improvement and worsening, 6.7 and 5.2 points, respectively), analyzed using a mixed model for repeated measures. The 5 key secondary outcomes were the individual parts I, II, and III of the MDS-UPDRS; dopamine transporter single-photon emission computed tomography brain imaging findings; and the Non-Motor Symptoms Scale score (NMSS; range, 0-360, with higher scores indicating greater nonmotor symptom burden). Results: Among the 393 participants in the primary analysis, the mean age was 65.6 (SD, 9.4) years and 133 (34%) were female. At week 52, the total MDS-UPDRS score increased by 2.45 (95% CI, 0.80-4.10) points with nicotinamide riboside and decreased by 0.27 (95% CI, −1.95 to 1.40) points with placebo, yielding an adjusted mean difference of 2.72 points (95% CI, 0.47-4.98 points; P  = .02), favoring placebo. Of the 5 prespecified key secondary outcomes, 4 showed no significant difference, but nonmotor symptom burden worsened more with nicotinamide riboside (NMSS score adjusted mean difference, 4.22 [95% CI, 1.07-7.37] points; P  = .009). Serious adverse events occurred in 17 (8.3%) of 205 participants receiving nicotinamide riboside and 29 (14.1%) of 205 receiving placebo in the safety population. Conclusions and Relevance: Among patients with early Parkinson disease, nicotinamide riboside treatment for 52 weeks did not improve clinical outcomes and was associated with worse clinical outcomes than placebo. These findings do not support nicotinamide riboside as a disease-modifying treatment for Parkinson disease. Trial Registration ClinicalTrials.gov Identifier: NCT03568968

• Kaddoura, Ahmad; Dalbro, Solveig Elisabeth Jacobsen; Walsem, Regina Marleen van & Pihlstrøm, Lasse (2026). Assessing the prognostic value of early oculomotor abnormalities in Huntington’s disease. Frontiers in Neurology. 17. doi: 10.3389/fneur.2026.1844433. Full text in Research Archive
• Lim, Kai Shi; Periñan, Maria Teresa; Chew, Elaine Guo Yan; Lee, Paul Suhwan; Akçimen, Fulya & Lim, Jia Lun [Show all 229 contributors for this article] (2026). Association of LRRK2 p.A419V with Parkinson’s Disease in East Asians and analysis of age at onset. NPJ Parkinson's Disease. 12(1). doi: 10.1038/s41531-026-01265-3. Full text in Research Archive Show summary

  Common and rare variants in LRRK2 influence Parkinson’s disease (PD) risk across diverse populations, and in this study, the rare p.A419V variant was investigated across multiple ancestry cohorts comprising over 200,000 PD cases and controls. In cases of East Asian (EAS) ancestry, p.A419V was significantly associated with increased risk of PD (OR = 2.9; 95% CI: 1.66–5.10; p = 0.0002), and was not in linkage disequilibrium with other LRRK2 coding variants. The variant was significantly associated with a lower age at PD onset in the study cohort, while a meta-analysis of the EAS cases indicated a similar, albeit non-significant trend. LRRK2 protein modelling prediction indicated that binding sites for RAB8A, RAB29 and RAB32 were in close proximity to the p.A419V variant within the ARM domain. Together, these findings confirm the p.A419V as a significant PD risk factor in EAS populations, as well as highlight disease-relevant variants in the ARM domain and the link with LRRK2-RAB signaling.

• Sosero, Yuri L.; Heilbron, Karl; Fontanillas, Pierre; Norcliffe-Kaufmann, Lucy; Yu, Eric & Rudakou, Uladzislau [Show all 31 contributors for this article] (2025). Genome-wide association study of REM sleep behavior disorder in Parkinson’s disease. NPJ Parkinson's Disease. 11(1). doi: 10.1038/s41531-025-01078-w. Full text in Research Archive Show summary

  Abstract REM sleep behavior disorder (RBD), is a prodromal synucleinopathy affecting a subset of Parkinson’s disease (PD) patients and associated with neuropsychiatric symptoms. This study compared the genetic profiles of 13,020 PD patients with probable RBD (PD + RBD) and 5403 without (PD-RBD) using genome-wide association study (GWAS). RBD was assessed by questionnaires or self-reporting. Potential genetic correlations between neuropsychiatric traits and PD + RBD were assessed using linkage disequilibrium score regression. The top variant in the SNCA locus was associated with PD + RBD (rs10005233-T, OR = 1.21, 95% CI = 1.16–1.27, p  = 1.81e−15). PD risk variants in SNCA (rs5019538-G, OR = 0.85, 95% CI = 0.81–0.89, p  = 2.46e−10; rs356182-G, OR = 0.89, 95% CI = 0.84–0.95, p  = 0.0001) and LRRK2 loci (rs34637584, OR = 0.41, 95% CI = 0.28–0.61, p  = 1.04e−5) were associated with reduced PD + RBD risk. A suggestive genetic correlation between attention deficit hyperactivity disorder and PD + RBD was observed but was not statistically significant after correction. These findings highlight genetic distinctions between PD + RBD and PD-RBD, offering insights into PD stratification and potential subtype-specific treatments.

• Udayar, Vinod; Gilormini, Pierre André; Bryois, Julien; Gehrlein, Alexandra; Chen, Xi & Sonea, Stephanie [Show all 18 contributors for this article] (2025). Enzyme Activity-Based Genome-wide Screening for Modifiers of Lysosomal Glucocerebrosidase Uncovers Candidate Risk Factors for Parkinson’s Disease. ACS Central Science. ISSN 2374-7943. 11(10), p. 1933–1945. doi: 10.1021/acscentsci.5c00240. Full text in Research Archive
• Lie, Ingeborg Haugesag; Maurtveten, Ellen Hoven; Andersen, Maren Stolp; Dalbro, Solveig Elisabeth Jacobsen; Tunold, Jon-Anders & Pihlstrøm, Lasse (2025). The Menstrual Cycle and Pregnancy Commonly Impact Symptoms of Women with Early-Onset Parkinson's Disease. Movement Disorders Clinical Practice. doi: 10.1002/mdc3.70438. Full text in Research Archive
• Sun, Wenhua; Schulte, Claudia; Gasser, Thomas; Tan, Manuela; Pihlstrøm, Lasse & Chana, Pedro [Show all 218 contributors for this article] (2025). TMEM175, SCARB2 and CTSB associations with Parkinson’s disease risk across populations. NPJ Parkinson's Disease. 11(1). doi: 10.1038/s41531-025-01180-z. Full text in Research Archive Show summary

  Genome-wide association study of Parkinson’s disease (PD) identified common variants associated with lysosomal mechanism, including TMEM175, SCARB2, and CTSB. We investigated the association between common and rare variants across populations using cohorts from the Global Parkinson’s Genetics Program (GP2) (33,733 cases and 18,703 controls from ten ancestries). In the European cohort, we confirmed significant associations with PD risk for all known genetic risk variants across the three genes and TMEM175 p. Met393Thr as an independent genome-wide significant signal. Additionally, a novel independent signal, SCARB2 rs11547135, was detected. The burden analysis linked PD to SCARB2 in African American, Ashkenazi Jewish and East Asian cohorts. Single variants-based tests identified rare missense variants in SCARB2 in several populations. Our study reinforces the association of lysosomal genetic variants with PD risk, revealing genetic heterogeneity across populations.

• Lange, Lara M.; Levine, Kristin; Fox, Susan H.; Marras, Connie; Ahmed, Nazish & Kuznetsov, Nicole [Show all 249 contributors for this article] (2025). The LRRK2 p.L1795F variant causes Parkinson’s disease in the European population. NPJ Parkinson's Disease. 11(1). doi: 10.1038/s41531-025-00896-2. Full text in Research Archive Show summary

  LRRK2-PD represents the most common form of autosomal dominant Parkinson’s disease. We identified the LRRK2 p.L1795F variant in three families and six additional unrelated cases using genetic data from over 50,000 individuals. Carriers with available genotyping data shared a common haplotype. The clinical presentation resembles other LRRK2-PD forms. Combined with published functional evidence showing strongly enhanced LRRK2 kinase activity, we provide evidence that LRRK2 p.L1795F is pathogenic.

• Lie, Ingeborg Haugesag; Tan, Manuela; Andersen, Maren Stolp; Toft, Mathias & Pihlstrøm, Lasse (2025). Epigenome-wide association study, meta-analysis, and multiscore profiling of whole blood in Parkinson's disease. Annals of clinical and translational neurology. 12(4), p. 701–713. doi: 10.1002/acn3.52292. Full text in Research Archive
• Saffie-Awad, Paula; Grant, Spencer M.; Makarious, Mary B.; Elsayed, Inas; Sanyaolu, Arinola O. & Crea, Peter Wild [Show all 297 contributors for this article] (2025). Insights into ancestral diversity in Parkinson’s disease risk: a comparative assessment of polygenic risk scores. NPJ Parkinson's Disease. 11(1). doi: 10.1038/s41531-025-00967-4. Full text in Research Archive Show summary

  Risk prediction models play a crucial role in advancing healthcare by enabling early detection and supporting personalized medicine. Nonetheless, polygenic risk scores (PRS) for Parkinson’s disease (PD) have not been extensively studied across diverse populations, contributing to health disparities. In this study, we constructed 105 PRS using individual-level data from seven ancestries and compared two different models. Model 1 was based on the cumulative effect of 90 known European PD risk variants, weighted by summary statistics from four independent ancestries (European, East Asian, Latino/Admixed American, and African/Admixed). Model 2 leveraged multi-ancestry summary statistics using a p-value thresholding approach to improve prediction across diverse populations. Our findings provide a comprehensive assessment of PRS performance across ancestries and highlight the limitations of a “one-size-fits-all” approach to genetic risk prediction. We observed variability in predictive performance between models, underscoring the need for larger sample sizes and ancestry-specific approaches to enhance accuracy. These results establish a foundation for future research aimed at improving generalizability in genetic risk prediction for PD.

• Domenighetti, Cloé; Sugier, Pierre-Emmanuel; Sreelatha, Ashwin Ashok Kumar; Schulte, Claudia; Grover, Sandeep & Portugal, Berta [Show all 77 contributors for this article] (2024). Association of Body Mass Index and Parkinson Disease A Bidirectional Mendelian Randomization Study. Neurology. ISSN 0028-3878. 103(3). doi: 10.1212/WNL.0000000000209620. Full text in Research Archive
• Tan, Manuela; Lawton, Michael A.; Pollard, Miriam I.; Brown, Emmeline; Real, Raquel & Carrasco, Alejandro Martinez [Show all 40 contributors for this article] (2024). Genome-wide determinants of mortality and motor progression in Parkinson’s disease. NPJ Parkinson's Disease. 10(1). doi: 10.1038/s41531-024-00729-8. Full text in Research Archive Show summary

  There are 90 independent genome-wide significant genetic risk variants for Parkinson’s disease (PD) but currently only five nominated loci for PD progression. The biology of PD progression is likely to be of central importance in defining mechanisms that can be used to develop new treatments. We studied 6766 PD patients, over 15,340 visits with a mean follow-up of between 4.2 and 15.7 years and carried out genome-wide survival studies for time to a motor progression endpoint, defined by reaching Hoehn and Yahr stage 3 or greater, and death (mortality). There was a robust effect of the APOE ε4 allele on mortality in PD. We also identified a locus within the TBXAS1 gene encoding thromboxane A synthase 1 associated with mortality in PD. We also report 4 independent loci associated with motor progression in or near MORN1, ASNS, PDE5A, and XPO1. Only the non-Gaucher disease causing GBA1 PD risk variant E326K, of the known PD risk variants, was associated with mortality in PD. Further work is needed to understand the links between these genomic variants and the underlying disease biology. However, these may represent new candidates for disease modification in PD.

• Faouzi, Johann; Tan, Manuela; Casse, Fanny; Lesage, Suzanne; Tesson, Christelle & Brice, Alexis [Show all 12 contributors for this article] (2024). Proxy-analysis of the genetics of cognitive decline in Parkinson’s disease through polygenic scores. NPJ Parkinson's Disease. 10(1). doi: 10.1038/s41531-023-00619-5. Full text in Research Archive Show summary

  Cognitive decline is common in Parkinson’s disease (PD) and its genetic risk factors are not well known to date, besides variants in the GBA and APOE genes. However, variation in complex traits is caused by numerous variants and is usually studied with genome-wide association studies (GWAS), requiring a large sample size, which is difficult to achieve for outcome measures in PD. Taking an alternative approach, we computed 100 polygenic scores (PGS) related to cognitive, dementia, stroke, and brain anatomical phenotypes and investigated their association with cognitive decline in six longitudinal cohorts. The analysis was adjusted for age, sex, genetic ancestry, follow-up duration, GBA and APOE status. Then, we meta-analyzed five of these cohorts, comprising a total of 1702 PD participants with 6156 visits, using the Montreal Cognitive Assessment as a cognitive outcome measure. After correction for multiple comparisons, we found four PGS significantly associated with cognitive decline: intelligence (p = 5.26e–13), cognitive performance (p = 1.46e–12), educational attainment (p = 8.52e–10), and reasoning (p = 3.58e–5). Survival analyses highlighted an offset of several years between the first and last quartiles of PGS, with significant differences for the PGS of cognitive performance (5 years) and educational attainment (7 years). In conclusion, we found four PGS associated with cognitive decline in PD, all associated with general cognitive phenotypes. This study highlights the common genetic factors between cognitive decline in PD and the general population, and the importance of the participant’s cognitive reserve for cognitive outcome in PD.

• Murthy, Megha; Fodder, Katherine; Miki, Yasuo; Rambarack, Naiomi; Fernandez, Eduardo De Pablo & Pihlstrøm, Lasse [Show all 10 contributors for this article] (2024). DNA methylation patterns in the frontal lobe white matter of multiple system atrophy, Parkinson’s disease, and progressive supranuclear palsy: a cross-comparative investigation. Acta Neuropathologica. ISSN 0001-6322. 148(1). doi: 10.1007/s00401-024-02764-4. Full text in Research Archive
• Wetering, Janna van; Geut, Hanne; Bol, John J.; Galis, Yvon; Timmermans, Evelien & Twisk, Jos W.R. [Show all 13 contributors for this article] (2024). Neuroinflammation is associated with Alzheimer’s disease co-pathology in dementia with Lewy bodies. Acta neuropathologica communications. 12(1). doi: 10.1186/s40478-024-01786-z. Full text in Research Archive
• Sugier, Pierre-Emmanuel; Lucotte, Elise A.; Domenighetti, Cloé; Law, Matthew H.; Iles, Mark M. & Brown, Kevin [Show all 94 contributors for this article] (2023). Investigation of Shared Genetic Risk Factors Between Parkinson's Disease and Cancers. Movement Disorders. ISSN 0885-3185. 38(4), p. 604–615. doi: 10.1002/mds.29337. Full text in Research Archive
• Kim, Jonggeol Jeffrey; Vitale, Dan; Otani, Diego Véliz; Lian, Michelle Mulan; Heilbron, Karl & Aslibekyan, Stella [Show all 299 contributors for this article] (2023). Multi-ancestry genome-wide association meta-analysis of Parkinson’s disease. Nature Genetics. ISSN 1061-4036. 56, p. 27–36. doi: 10.1038/s41588-023-01584-8. Full text in Research Archive Show summary

  Although over 90 independent risk variants have been identified for Parkinson’s disease using genome-wide association studies, most studies have been performed in just one population at a time. Here we performed a large-scale multi-ancestry meta-analysis of Parkinson’s disease with 49,049 cases, 18,785 proxy cases and 2,458,063 controls including individuals of European, East Asian, Latin American and African ancestry. In a meta-analysis, we identified 78 independent genome-wide significant loci, including 12 potentially novel loci (MTF2, PIK3CA, ADD1, SYBU, IRS2, USP8, PIGL, FASN, MYLK2, USP25, EP300 and PPP6R2) and fine-mapped 6 putative causal variants at 6 known PD loci. By combining our results with publicly available eQTL data, we identified 25 putative risk genes in these novel loci whose expression is associated with PD risk. This work lays the groundwork for future efforts aimed at identifying PD loci in non-European populations.

• Tunold, Jon-Anders; Tan, Manuela; Koga, Shunsuke; Geut, Hanneke; Rozemuller, Annemieke J. M & Valentino, Rebecca [Show all 16 contributors for this article] (2023). Lysosomal polygenic risk is associated with the severity of neuropathology in Lewy body disease. Brain. ISSN 0006-8950. 146(10), p. 4077–4087. doi: 10.1093/brain/awad183. Full text in Research Archive Show summary

  Abstract Intraneuronal accumulation of misfolded α-synuclein is the pathological hallmark of Parkinson’s disease and dementia with Lewy bodies, often co-occurring with variable degrees of Alzheimer’s disease related neuropathology. Genetic association studies have successfully identified common variants associated with disease risk and phenotypic traits in Lewy body disease, yet little is known about the genetic contribution to neuropathological heterogeneity. Using summary statistics from Parkinson’s disease and Alzheimer’s disease genome-wide association studies, we calculated polygenic risk scores and investigated the relationship with Lewy, amyloid-β and tau pathology. Associations were nominated in neuropathologically defined samples with Lewy body disease from the Netherlands Brain Bank (n = 217) and followed up in an independent sample series from the Mayo Clinic Brain Bank (n = 394). We also generated stratified polygenic risk scores based on single-nucleotide polymorphisms annotated to eight functional pathways or cell types previously implicated in Parkinson’s disease and assessed for association with Lewy pathology in subgroups with and without significant Alzheimer’s disease co-pathology. In an ordinal logistic regression model, the Alzheimer’s disease polygenic risk score was associated with concomitant amyloid-β and tau pathology in both cohorts. Moreover, both cohorts showed a significant association between lysosomal pathway polygenic risk and Lewy pathology, which was more consistent than the association with a general Parkinson’s disease risk score and specific to the subset of samples without significant concomitant Alzheimer’s disease related neuropathology. Our findings provide proof of principle that the specific risk alleles a patient carries for Parkinson’s and Alzheimer’s disease also influence key aspects of the underlying neuropathology in Lewy body disease. The interrelations between genetic architecture and neuropathology are complex, as our results implicate lysosomal risk loci specifically in the subset of samples without Alzheimer’s disease co-pathology. Our findings hold promise that genetic profiling may help predict the vulnerability to specific neuropathologies in Lewy body disease, with potential relevance for the further development of precision medicine in these disorders.

• Cappelletti, Chiara; Henriksen, Sandra Pilar; Geut, Hanneke; Rozemuller, Annemieke J. M.; Berg, Wilma D. J. van de & Pihlstrøm, Lasse [Show all 7 contributors for this article] (2023). Transcriptomic profiling of Parkinson's disease brains reveals disease stage specific gene expression changes. Acta Neuropathologica. ISSN 0001-6322. 146, p. 227–244. doi: 10.1007/s00401-023-02597-7. Full text in Research Archive Show summary

  Parkinson´s disease (PD) is a progressive neurodegenerative disorder characterized by both motor and non-motor symptoms. Aggravation of symptoms is mirrored by accumulation of protein aggregates mainly composed by alpha-synuclein in different brain regions, called Lewy bodies (LB). Previous studies have identifed several molecular mechanisms as autophagy and infammation playing a role in PD pathogenesis. Increased insights into mechanisms involved in early disease stages and driving the progression of the LB pathology are required for the development of disease-modifying strategies. Here, we aimed to elucidate disease stage-specifc transcriptomic changes in brain tissue of well-characterized PD and control donors. We collected frontal cortex samples from 84 donors and sequenced both the coding and non-coding RNAs. We categorized our samples into groups based on their degree of LB pathology aiming to recapitulate a central aspect of disease progression. Using an analytical pipeline that corrected for sex, age at death, RNA quality, cell composition and unknown sources of variation, we found major disease stage-specifc transcriptomic changes. Gene expression changes were most pronounced in donors at the disease stage when microscopic LB changes frst occur in the sampled brain region. Additionally, we identifed disease stage-specifc enrichment of brain specifc pathways and immune mechanisms. On the contrary, we showed that mitochondrial mechanisms are enriched throughout the disease course. Our data-driven approach also suggests a role for several poorly characterized lncRNAs in disease development and progression of PD. Finally, by combining genetic and epigenetic information, we highlighted two genes (MAP4K4 and PHYHIP) as candidate genes for future functional studies. Together our results indicate that transcriptomic dysregulation and associated functional changes are highly disease stagespecifc, which has major implications for the study of neurodegenerative disorders.

• Tunold, Jon-Anders; Tan, Manuela; Toft, Mathias; Ross, Owen; Berg, Wilma D.J. van de & Pihlstrøm, Lasse (2023). Lysosomal Polygenic Burden Drives Cognitive Decline in Parkinson's Disease with Low Alzheimer Risk. Movement Disorders. ISSN 0885-3185. doi: 10.1002/mds.29698. Full text in Research Archive Show summary

  Abstract Background Genetics influence cognitive progression in Parkinson's disease, possibly through mechanisms related to Lewy and Alzheimer's disease pathology. Lysosomal polygenic burden has recently been linked to more severe Lewy pathology post mortem. Objectives To assess the influence of lysosomal polygenic burden on cognitive progression in Parkinson's disease patients with low Alzheimer's disease risk. Methods Using Cox regression we assessed association between lysosomal polygenic scores and time to Montreal Cognitive Assessment score ≤ 21 in the Parkinson's Progression Markers Initiative cohort (n = 374), with replication in data from the Parkinson's Disease Biomarker Program (n = 777). Patients were stratified by Alzheimer's disease polygenic risk. Results The lysosomal polygenic score was associated with faster progression of cognitive decline in patients with low Alzheimer's disease risk in both datasets ( P  = 0.0032 and P  = 0.0054, respectively). Conclusion Our study supports complex interplay between genetics and neuropathology in Parkinson's disease‐related cognitive impairment, emphasizing the role of lysosomal polygenic burden. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

• Nordengen, Kaja; Cappelletti, Chiara; Bahrami, Shahram; Frei, Oleksandr; Pihlstrøm, Lasse & Henriksen, Sandra Pilar [Show all 11 contributors for this article] (2023). Pleiotropy with sex-specific traits reveals genetic aspects of sex differences in Parkinson’s disease. Brain. ISSN 0006-8950. 147(3), p. 858–870. doi: 10.1093/brain/awad297. Full text in Research Archive Show summary

  Parkinson’s disease is an age-related neurodegenerative disorder with a higher incidence in males than females. The causes for this sex difference are unknown. Genome-wide association studies (GWAS) have identified 90 Parkinson’s disease risk loci, but the genetic studies have not found sex-specific differences in allele frequency on autosomal chromosomes or sex chromosomes. Genetic variants, however, could exert sex-specific effects on gene function and regulation of gene expression. To identify genetic loci that might have sex-specific effects, we studied pleiotropy between Parkinson’s disease and sex-specific traits. Summary statistics from GWASs were acquired from large-scale consortia for Parkinson’s disease (n cases = 13 708; n controls = 95 282), age at menarche (n = 368 888 females) and age at menopause (n = 69 360 females). We applied the conditional/conjunctional false discovery rate (FDR) method to identify shared loci between Parkinson’s disease and these sex-specific traits. Next, we investigated sex-specific gene expression differences in the superior frontal cortex of both neuropathologically healthy individuals and Parkinson’s disease patients (n cases = 61; n controls = 23). To provide biological insights to the genetic pleiotropy, we performed sex-specific expression quantitative trait locus (eQTL) analysis and sex-specific age-related differential expression analysis for genes mapped to Parkinson’s disease risk loci. Through conditional/conjunctional FDR analysis we found 11 loci shared between Parkinson’s disease and the sex-specific traits age at menarche and age at menopause. Gene-set and pathway analysis of the genes mapped to these loci highlighted the importance of the immune response in determining an increased disease incidence in the male population. Moreover, we highlighted a total of nine genes whose expression or age-related expression in the human brain is influenced by genetic variants in a sex-specific manner. With these analyses we demonstrated that the lack of clear sex-specific differences in allele frequencies for Parkinson’s disease loci does not exclude a gen- etic contribution to differences in disease incidence. Moreover, further studies are needed to elucidate the role that the candidate genes identified here could have in determining a higher incidence of Parkinson’s disease in the male population.

• Andersen, Maren Stolp; Leikfoss, Ingvild Sørum; Brorson, Ina Skaara; Cappelletti, Chiara; Bettencourt, Conceicao & Toft, Mathias [Show all 7 contributors for this article] (2023). Epigenome-wide association study of peripheral immune cell populations in Parkinson’s disease. NPJ Parkinson's Disease. 9(1). doi: 10.1038/s41531-023-00594-x. Full text in Research Archive
• Pihlstrøm, Lasse; Shireby, Gemma; Geut, Hanneke; Henriksen, Sandra Pilar; Rozemuller, Annemieke J. M. & Tunold, Jon-Anders [Show all 13 contributors for this article] (2022). Epigenome-wide association study of human frontal cortex identifies differential methylation in Lewy body pathology. Nature Communications. 13, p. 1–10. doi: 10.1038/s41467-022-32619-z. Full text in Research Archive Show summary

  Abstract Parkinson’s disease (PD) and dementia with Lewy bodies (DLB) are closely related progressive disorders with no available disease-modifying therapy, neuropathologically characterized by intraneuronal aggregates of misfolded α-synuclein. To explore the role of DNA methylation changes in PD and DLB pathogenesis, we performed an epigenome-wide association study (EWAS) of 322 postmortem frontal cortex samples and replicated results in an independent set of 200 donors. We report novel differentially methylated replicating loci associated with Braak Lewy body stage near TMCC2 , SFMBT2 , AKAP6 and PHYHIP . Differentially methylated probes were independent of known PD genetic risk alleles. Meta-analysis provided suggestive evidence for a differentially methylated locus within the chromosomal region affected by the PD-associated 22q11.2 deletion. Our findings elucidate novel disease pathways in PD and DLB and generate hypotheses for future molecular studies of Lewy body pathology.

• Krohn, Lynne; Heilbron, Karl; Blauwendraat, Cornelis; Reynolds, Regina H.; Yu, Eric & Senkevich, Konstantin [Show all 106 contributors for this article] (2022). Genome-wide association study of REM sleep behavior disorder identifies polygenic risk and brain expression effects. Nature Communications. 13(7496), p. 1–16. doi: 10.1038/s41467-022-34732-5. Full text in Research Archive
• Domenighetti, Cloé; Sugier, Pierre-Emmanuel; Sreelatha, Ashwin Ashok Kumar; Schulte, Claudia; Grover, Sandeep & Mohamed, Océane [Show all 79 contributors for this article] (2022). Dairy Intake and Parkinson's Disease: A Mendelian Randomization Study. Movement Disorders. ISSN 0885-3185. 37(4), p. 857–864. doi: 10.1002/mds.28902. Full text in Research Archive Show summary

  Background Previous prospective studies highlighted dairy intake as a risk factor for Parkinson's disease (PD), particularly in men. It is unclear whether this association is causal or explained by reverse causation or confounding. Objective The aim is to examine the association between genetically predicted dairy intake and PD using two-sample Mendelian randomization (MR). Methods We genotyped a well-established instrumental variable for dairy intake located in the lactase gene (rs4988235) within the Courage-PD consortium (23 studies; 9823 patients and 8376 controls of European ancestry). Results Based on a dominant model, there was an association between genetic predisposition toward higher dairy intake and PD (odds ratio [OR] per one serving per day = 1.70, 95% confidence interval = 1.12–2.60, P = 0.013) that was restricted to men (OR = 2.50 [1.37–4.56], P = 0.003; P-difference with women = 0.029). Conclusions Using MR, our findings provide further support for a causal relationship between dairy intake and higher PD risk, not biased by confounding or reverse causation. Further studies are needed to elucidate the underlying mechanisms. © 2022 International Parkinson and Movement Disorder Society

• Pihlstrøm, Lasse (2022). Kavlipris til fire pionerer i nevrogenetikk. Tidsskrift for Den norske legeforening (Tidsskriftet). ISSN 0029-2001. 142(14). doi: 10.4045/tidsskr.22.0604. Full text in Research Archive
• Walsem, Marleen Regina Van; Frich, Jan C; Castaneda, Monica Gomez; Howe, Emilie; Pihlstrøm, Lasse & Andelic, Nada [Show all 7 contributors for this article] (2022). Health related quality of life, service utilization and costs for patients with Huntington’s disease in Norway. BMC Health Services Research. 22(1), p. 1–12. doi: 10.1186/s12913-022-08881-8. Full text in Research Archive Show summary

  Background Huntington’s disease (HD) is a progressive genetic neurodegenerative disease accompanied by mental and neurocognitive disabilities, which requires long-term and comprehensive treatment and care. Information on the health and economic burden of HD is scarce, but essential for conducting health economic analyses, in light of the prospect of new therapies for HD. In this study, we aim to identify values for Health-Related Quality of Life (HRQoL), describe service utilization and costs, and their associations with clinical and socio-demographic variables across all phases of HD. Methods A cross-sectional study including 86 patients across all phases of HD. Values of HRQoL were calculated based on EQ-5D-3L index scores. Additionally, health care and societal costs were estimated based on service utilization collected using the Client Service Receipt Inventory (CSRI) and data from the patients’ interviews. Total societal costs included costs of primary and secondary health care services, informal care and productivity loss of the patients. Multiple regression analyses were used to investigate associations between socio-demographic and clinical variables on HRQoL and costs. Results HRQoL values declined, while total costs increased across disease severity. Total six-month healthcare costs and total societal costs were € 18,538 and € 66,789 respectively. Healthcare and societal costs doubled from early to middle phase, and tripled from middle to advanced disease phase. Main six-month cost components for the three disease phases were informal care costs (€ 30,605) accounting for approximately half the total societal costs, and costs due to production loss (€ 18,907) being slightly higher than the total healthcare costs. Disease severity and gender were found to have the strongest effect on both values of HRQoL and costs. Conclusions Reported values of HRQoL and costs including costs for production loss may be used in modelling the cost-effectiveness of treatment for HD. Our results highlight the crucial role the informal caregivers play in the care provided to HD patients in all disease phases. Future research should focus on the estimation of productivity loss among informal caregivers.

• Grover, Sandeep; Sreelatha, Ashwin Ashok Kumar; Pihlstrøm, Lasse; Domenighetti, Cloé; Schulte, Claudia & Sugier, Pierre-Emmanuel [Show all 83 contributors for this article] (2022). Genome-wide Association and Meta-analysis of Age at Onset in Parkinson Disease: Evidence from the COURAGE-PD Consortium. Neurology. ISSN 0028-3878. 99(7), p. E698–E710. doi: 10.1212/WNL.0000000000200699. Full text in Research Archive Show summary

  Background and Objectives Considerable heterogeneity exists in the literature concerning genetic determinants of the age at onset (AAO) of Parkinson disease (PD), which could be attributed to a lack of well-powered replication cohorts. The previous largest genome-wide association studies (GWAS) identified SNCA and TMEM175 loci on chromosome (Chr) 4 with a significant influence on the AAO of PD; these have not been independently replicated. This study aims to conduct a meta-analysis of GWAS of PD AAO and validate previously observed findings in worldwide populations. Methods A meta-analysis was performed on PD AAO GWAS of 30 populations of predominantly European ancestry from the Comprehensive Unbiased Risk Factor Assessment for Genetics and Environment in Parkinson's Disease (COURAGE-PD) Consortium. This was followed by combining our study with the largest publicly available European ancestry dataset compiled by the International Parkinson Disease Genomics Consortium (IPDGC). Results The COURAGE-PD Consortium included a cohort of 8,535 patients with PD (91.9%: Europeans and 9.1%: East Asians). The average AAO in the COURAGE-PD dataset was 58.9 years (SD = 11.6), with an underrepresentation of females (40.2%). The heritability estimate for AAO in COURAGE-PD was 0.083 (SE = 0.057). None of the loci reached genome-wide significance (p < 5 × 10−8). Nevertheless, the COURAGE-PD dataset confirmed the role of the previously published TMEM175 variant as a genetic determinant of the AAO of PD with Bonferroni-corrected nominal levels of significance (p < 0.025): (rs34311866: β(SE)COURAGE = 0.477(0.203), pCOURAGE = 0.0185). The subsequent meta-analysis of COURAGE-PD and IPDGC datasets (Ntotal = 25,950) led to the identification of 2 genome-wide significant association signals on Chr 4, including the previously reported SNCA locus (rs983361: β(SE)COURAGE+IPDGC = 0.720(0.122), pCOURAGE+IPDGC = 3.13 × 10−9) and a novel BST1 locus (rs4698412: β(SE)COURAGE+IPDGC = −0.526(0.096), pCOURAGE+IPDGC = 4.41 × 10−8). Discussion Our study further refines the genetic architecture of Chr 4 underlying the AAO of the PD phenotype through the identification of BST1 as a novel AAO PD locus. These findings open a new direction for the development of treatments to delay the onset of PD.

• Domenighetti, Cloé; Douillard, Venceslas; Sugier, Pierre-Emmanuel; Sreelatha, Ashwin Ashok Kumar; Schulte, Claudia & Grover, Sandeep [Show all 80 contributors for this article] (2022). The Interaction between HLA-DRB1 and Smoking in Parkinson's Disease Revisited. Movement Disorders. ISSN 0885-3185. 37(9), p. 1929–1937. doi: 10.1002/mds.29133. Full text in Research Archive
• Andersen, Maren Stolp; Tan, Manuela; Holtman, Inge R.; Hardy, John & Pihlstrøm, Lasse (2022). Dissecting the limited genetic overlap of Parkinson's and Alzheimer's disease. Annals of clinical and translational neurology. 9(8), p. 1289–1295. doi: 10.1002/acn3.51606. Full text in Research Archive Show summary

  Parkinson's disease and Alzheimer's disease show overlapping features both clinically and neuropathologically and elucidating shared mechanisms could have important implications for therapeutic strategies. Evidence for genetic overlap is limited, although enrichment of heritability in genomic regions relevant to microglia has been demonstrated in both disorders. Using summary statistics from genome-wide association studies, we assessed genetic covariance stratified by cell types and local genetic correlation between Parkinson's and Alzheimer's disease. Significant covariance was observed for neurons only (p = 0.00046), and local genetic correlation was significant only in the human leukocyte antigen region (p = 1.0e-05). Our findings support a minor genetic overlap between these two disorders.

• Motazedi, Ehsan; Cheng, Weiqiu; Thomassen, Jesper Qvist; Frei, Oleksandr; Rongve, Arvid & Athanasiu, Lavinia [Show all 30 contributors for this article] (2022). Using Polygenic Hazard Scores to Predict Age at Onset of Alzheimer's Disease in Nordic Populations. Journal of Alzheimer's Disease. ISSN 1387-2877. 88(4), p. 1533–1544. doi: 10.3233/JAD-220174. Full text in Research Archive Show summary

  Background: Polygenic hazard scores (PHS) estimate age-dependent genetic risk of late-onset Alzheimer’s disease (AD), but there is limited information about the performance of PHS on real-world data where the population of interest differs from the model development population and part of the model genotypes are missing or need to be imputed. Objective: The aim of this study was to estimate age-dependent risk of late-onset AD using polygenic predictors in Nordic populations. Methods: We used Desikan PHS model, based on Cox proportional hazards assumption, to obtain age-dependent hazard scores for AD from individual genotypes in the Norwegian DemGene cohort (n = 2,772). We assessed the risk discrimination and calibration of Desikan model and extended it by adding new genotype markers (the Desikan Nordic model). Finally, we evaluated both Desikan and Desikan Nordic models in two independent Danish cohorts: The Copenhagen City Heart Study (CCHS) cohort (n = 7,643) and The Copenhagen General Population Study (CGPS) cohort (n = 10,886). Results: We showed a robust prediction efficiency of Desikan model in stratifying AD risk groups in Nordic populations, even when some of the model SNPs were missing or imputed. We attempted to improve Desikan PHS model by adding new SNPs to it, but we still achieved similar risk discrimination and calibration with the extended model. Conclusion: PHS modeling has the potential to guide the timing of treatment initiation based on individual risk profiles and can help enrich clinical trials with people at high risk to AD in Nordic populations.

• Brolin, Kajsa; Bandres-Ciga, Sara; Leonard, Hampton; Makarious, Mary B.; Blauwendraat, Cornelis & Mata, Ignacio F [Show all 11 contributors for this article] (2022). RIC3 variants are not associated with Parkinson's disease in large European, Latin American, or East Asian cohorts. Neurobiology of Aging. ISSN 0197-4580. 109, p. 264–268. doi: 10.1016/j.neurobiolaging.2021.08.009. Full text in Research Archive
• Domenighetti, Cloé; Sugier, Pierre-Emmanuel; Sreelatha, Ashwin Ashok Kumar; Schulte, Claudia; Grover, Sandeep & Mohamed, Oceáne [Show all 79 contributors for this article] (2022). Mendelian Randomisation Study of Smoking, Alcohol, and Coffee Drinking in Relation to Parkinson's Disease. Journal of Parkinson's Disease. ISSN 1877-7171. 12(1), p. 267–282. doi: 10.3233/JPD-212851. Full text in Research Archive Show summary

  Background:Previous studies showed that lifestyle behaviors (cigarette smoking, alcohol, coffee) are inversely associated with Parkinson’s disease (PD). The prodromal phase of PD raises the possibility that these associations may be explained by reverse causation. Objective:To examine associations of lifestyle behaviors with PD using two-sample Mendelian randomisation (MR) and the potential for survival and incidence-prevalence biases. Methods:We used summary statistics from publicly available studies to estimate the association of genetic polymorphisms with lifestyle behaviors, and from Courage-PD (7,369 cases, 7,018 controls; European ancestry) to estimate the association of these variants with PD. We used the inverse-variance weighted method to compute odds ratios (ORIVW) of PD and 95%confidence intervals (CI). Significance was determined using a Bonferroni-corrected significance threshold (p = 0.017). Results:We found a significant inverse association between smoking initiation and PD (ORIVW per 1-SD increase in the prevalence of ever smoking = 0.74, 95%CI = 0.60–0.93, p = 0.009) without significant directional pleiotropy. Associations in participants ≤67 years old and cases with disease duration ≤7 years were of a similar size. No significant associations were observed for alcohol and coffee drinking. In reverse MR, genetic liability toward PD was not associated with smoking or coffee drinking but was positively associated with alcohol drinking. Conclusion:Our findings are in favor of an inverse association between smoking and PD that is not explained by reverse causation, confounding, and survival or incidence-prevalence biases. Genetic liability toward PD was positively associated with alcohol drinking. Conclusions on the association of alcohol and coffee drinking with PD are hampered by insufficient statistical power.

• Langmyhr, Margrete; Henriksen, Sandra Pilar; Cappelletti, Chiara; Berg, Wilma D. J. van de; Pihlstrøm, Lasse & Toft, Mathias (2021). Allele-specific expression of Parkinson’s disease susceptibility genes in human brain. Scientific Reports. 11(1). doi: 10.1038/s41598-020-79990-9. Full text in Research Archive Show summary

  Genome-wide association studies have identifed genetic variation in genomic loci associated with susceptibility to Parkinson’s disease (PD), the most common neurodegenerative movement disorder worldwide. We used allelic expression profling of genes located within PD-associated loci to identify cis-regulatory variation afecting gene expression. DNA and RNA were extracted from post-mortem superior frontal gyrus tissue and whole blood samples from PD patients and controls. The relative allelic expression of transcribed SNPs in 12 GWAS risk genes was analysed by real-time qPCR. Allele-specifc expression was identifed for 9 out of 12 genes tested (GBA, TMEM175, RAB7L1, NUCKS1, MCCC1, BCKDK, ZNF646, LZTS3, and WDHD1) in brain tissue samples. Three genes (GPNMB, STK39 and SIPA1L2) did not show signifcant allele-specifc efects. Allele-specifc efects were confrmed in whole blood for three genes (BCKDK, LZTS3 and MCCC1), whereas two genes (RAB7L1 and NUCKS1) showed brain-specifc allelic expression. Our study supports the hypothesis that changes to the cis-regulation of gene expression is a major mechanism behind a large proportion of genetic associations in PD. Interestingly, allele-specifc expression was also observed for coding variants believed to be causal variants (GBA and TMEM175), indicating that splicing and other regulatory mechanisms may be involved in disease development.

• Yu, Eric; Ambati, Aditya; Andersen, Maren Stolp; Krohn, Lynne; Estiar, Mehrdad A. & Saini, Prabhjyot [Show all 19 contributors for this article] (2021). Fine mapping of the HLA locus in Parkinson’s disease in Europeans. NPJ Parkinson's Disease. 7(84). doi: 10.1038/s41531-021-00231-5. Full text in Research Archive Show summary

  We fine mapped the leukocyte antigen (HLA) region in 13,770 Parkinson’s disease (PD) patients, 20,214 proxy-cases, and 490,861 controls of European origin. Four HLA types were associated with PD after correction for multiple comparisons, HLA-DQA1*03:01, HLA-DQB1*03:02, HLA-DRB1*04:01, and HLA-DRB1*04:04. Haplotype analyses followed by amino acid analysis and conditional analyses suggested that the association is protective and primarily driven by three specific amino acid polymorphisms present in most HLA-DRB1*04 subtypes—11V, 13H, and 33H (OR = 0.87, 95% CI: 0.83–0.90, p < 8.23 × 10−9 for all three variants). No other effects were present after adjustment for these amino acids. Our results suggest that specific HLA-DRB1 variants are associated with reduced risk of PD, providing additional evidence for the role of the immune system in PD. Although effect size is small and has no diagnostic significance, understanding the mechanism underlying this association may lead to the identification of new targets for therapeutics development.

• Alfradique-Dunham, Isabel; Al-Ouran, Rami; Coelln, Rainer Von; Blauwendraat, Cornelis; Hill, Emily & Luo, Lan [Show all 22 contributors for this article] (2021). Genome-Wide Association Study Meta-Analysis for Parkinson Disease Motor Subtypes. Neurology: Genetics. 7(2). doi: 10.1212/NXG.0000000000000557. Full text in Research Archive
• Berge-Seidl, Victoria; Pihlstrøm, Lasse & Toft, Mathias (2021). Integrative analysis identifies bHLH transcription factors as contributors to Parkinson’s disease risk mechanisms. Scientific Reports. 11:3502, p. 1–10. doi: 10.1038/s41598-021-83087-2. Full text in Research Archive Show summary

  Abstract Genome-wide association studies (GWAS) have identified multiple genetic risk signals for Parkinson’s disease (PD), however translation into underlying biological mechanisms remains scarce. Genomic functional annotations of neurons provide new resources that may be integrated into analyses of GWAS findings. Altered transcription factor binding plays an important role in human diseases. Insight into transcriptional networks involved in PD risk mechanisms may thus improve our understanding of pathogenesis. We analysed overlap between genome-wide association signals in PD and open chromatin in neurons across multiple brain regions, finding a significant enrichment in the superior temporal cortex. The involvement of transcriptional networks was explored in neurons of the superior temporal cortex based on the location of candidate transcription factor motifs identified by two de novo motif discovery methods. Analyses were performed in parallel, both finding that PD risk variants significantly overlap with open chromatin regions harboring motifs of basic Helix-Loop-Helix (bHLH) transcription factors. Our findings show that cortical neurons are likely mediators of genetic risk for PD. The concentration of PD risk variants at sites of open chromatin targeted by members of the bHLH transcription factor family points to an involvement of these transcriptional networks in PD risk mechanisms.

• Tunold, Jon-Anders; Geut, Hanneke; Rozemuller, J.M. Annemieke; Henriksen, Sandra Pilar; Toft, Mathias & Berg, Wilma D.J. van de [Show all 7 contributors for this article] (2021). APOE and MAPT are associated with dementia in neuropathologically confirmed Parkinson's disease. Frontiers in Neurology. 12:631145, p. 1–8. doi: 10.3389/fneur.2021.631145. Full text in Research Archive Show summary

  Introduction: Cognitive decline and dementia are common and debilitating non-motor phenotypic features of Parkinson's disease with a variable severity and time of onset. Common genetic variation of the Apolipoprotein E ( APOE ) and micro-tubule associated protein tau ( MAPT ) loci have been linked to cognitive decline and dementia in Parkinson's disease, although studies have yielded mixed results. To further elucidate the influence of APOE and MAPT variability on dementia in Parkinson's disease, we genotyped postmortem brain tissue samples of clinically and pathologically well-characterized Parkinson's donors and performed a survival analysis of time to dementia. Methods: We included a total of 152 neuropathologically confirmed Parkinson's disease donors with or without clinical dementia during life. We genotyped known risk variants tagging the APOE ε4 allele and MAPT H1/H2 inversion haplotype. Cox proportional hazards regression analyses adjusted for age at onset, sex and genetic principal components were performed to assess the association between the genetic variants and time from motor onset to onset of dementia. Results: We found that both the APOE ε4 allele (HR 1.82, 95 % CI 1.16–2.83, p = 0.009) and MAPT H1-haplotype (HR 1.71, 95 % CI 1.06–2.78, p = 0.03) were associated with earlier development of dementia in patients with Parkinson's disease. Conclusion: Our results provide further support for the importance of APOE ε4 and MAPT H1-haplotype in the etiology of Parkinson's disease dementia, with potential future relevance for risk stratification and patient selection for clinical trials of therapies targeting cognitive decline in Parkinson's disease.

• Andersen, Maren Stolp; Bandres-Ciga, Sara; Reynolds, Regina H.; Hardy, John; Ryten, Mina & Krohn, Lynne [Show all 9 contributors for this article] (2021). Heritability Enrichment Implicates Microglia in Parkinson's Disease Pathogenesis. Annals of Neurology. ISSN 0364-5134. 89(5), p. 942–951. doi: 10.1002/ana.26032. Full text in Research Archive
• Blauwendraat, Cornelis; Iwaki, Hirotaka; Makarious, Mary B.; Bandres-Ciga, Sara; Leonard, Hampton L. & Grenn, Francis P. [Show all 40 contributors for this article] (2021). Investigation of Autosomal Genetic Sex Differences in Parkinson's Disease. Annals of Neurology. ISSN 0364-5134. 90(1), p. 35–42. doi: 10.1002/ana.26090. Full text in Research Archive
• Pihlstrøm, Lasse; Fan, Chun Chieh; Frei, Oleksandr; Tan, Manuela; Karunamuni, Roshan A. & Blauwendraat, Cornelis [Show all 12 contributors for this article] (2021). Genetic Stratification of Age-Dependent Parkinson's Disease Risk by Polygenic Hazard Score. Movement Disorders. ISSN 0885-3185. doi: 10.1002/mds.28808. Full text in Research Archive Show summary

  Background Parkinson's disease (PD) is a highly age-related disorder, where common genetic risk variants affect both disease risk and age at onset. A statistical approach that integrates these effects across all common variants may be clinically useful for individual risk stratification. A polygenic hazard score methodology, leveraging a time-to-event framework, has recently been successfully applied in other age-related disorders. Objectives We aimed to develop and validate a polygenic hazard score model in sporadic PD. Methods Using a Cox regression framework, we modeled the polygenic hazard score in a training data set of 11,693 PD patients and 9841 controls. The score was then validated in an independent test data set of 5112 PD patients and 5372 controls and a small single-study sample of 360 patients and 160 controls. Results A polygenic hazard score predicts the onset of PD with a hazard ratio of 3.78 (95% confidence interval 3.49–4.10) when comparing the highest to the lowest risk decile. Combined with epidemiological data on incidence rate, we apply the score to estimate genetically stratified instantaneous PD risk across age groups. Conclusions We demonstrate the feasibility of a polygenic hazard approach in PD, integrating the genetic effects on disease risk and age at onset in a single model. In combination with other predictive biomarkers, the approach may hold promise for risk stratification in future clinical trials of disease-modifying therapies, which aim at postponing the onset of PD. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society

• Chen, Zhongbo; Zhang, David; Reynolds, Regina H.; Gustavsson, Emil Karl; García-Ruiz, Sonia & D’Sa, Karishma [Show all 154 contributors for this article] (2021). Human-lineage-specific genomic elements are associated with neurodegenerative disease and APOE transcript usage. Nature Communications. 12(1), p. 1–13. doi: 10.1038/s41467-021-22262-5. Full text in Research Archive
• Storm, Catherine S.; Kia, Demis A.; Almramhi, Mona M.; Bandres-Ciga, Sara; Finan, Chris & Noyce, Alastair J. [Show all 175 contributors for this article] (2021). Finding genetically-supported drug targets for Parkinson’s disease using Mendelian randomization of the druggable genome. Nature Communications. 12(1), p. 1–14. doi: 10.1038/s41467-021-26280-1. Full text in Research Archive
• Blauwendraat, Cornelis; Reed, Xylena; Krohn, Lynne; Heilbron, Karl; Bandres-Ciga, Sara & Tan, Manuela [Show all 62 contributors for this article] (2020). Genetic modifiers of risk and age at onset in GBA associated Parkinson's disease and Lewy body dementia. Brain. ISSN 0006-8950. 143(1), p. 234–248. doi: 10.1093/brain/awz350. Full text in Research Archive
• Guelfi, Sebastian; D’Sa, Karishma; Botía, Juan A.; Vandrovcova, Jana; Reynolds, Regina H. & Zhang, David [Show all 155 contributors for this article] (2020). Regulatory sites for splicing in human basal ganglia are enriched for disease-relevant information. Nature Communications. 11(1). doi: 10.1038/s41467-020-14483-x. Full text in Research Archive
• Bandres-Ciga, Sara; Saez-Atienzar, Sara; Kim, J. J.; Makarious, M. B.; Faghri, F. & Diez‑Fairen, M. [Show all 28 contributors for this article] (2020). Large‑scale pathway specific polygenic risk and transcriptomic community network analysis identifies novel functional pathways in Parkinson disease. Acta Neuropathologica. ISSN 0001-6322. 140, p. 341–358. doi: 10.1007/s00401-020-02181-3. Full text in Research Archive
• Krohn, Lynne; Wu, Richard Y. J.; Heilbron, Karl; Ruskey, Jennifer A.; Laurent, Sandra B. & Blauwendraat, Cornelis [Show all 50 contributors for this article] (2020). Fine-Mapping of SNCA in Rapid Eye Movement Sleep Behavior Disorder and Overt Synucleinopathies. Annals of Neurology. ISSN 0364-5134. 87(4), p. 584–598. doi: 10.1002/ana.25687. Full text in Research Archive
• Iwaki, Hirotaka; Blauwendraat, Cornelis; Leonard, Hampton; Makarious, Mary B.; Kim, Jonggeol J. & Liu, Ganqiang [Show all 48 contributors for this article] (2020). Differences in the presentation and progression of Parkinson's disease by sex. Movement Disorders. ISSN 0885-3185. p. 1–14. doi: 10.1002/mds.28312. Full text in Research Archive
• Smeland, Olav Bjerkehagen; Shadrin, Alexey A.; Bahrami, Shahram; Broce, Iris J.; Tesli, Martin Steen & Frei, Oleksandr [Show all 22 contributors for this article] (2020). Genome-wide Association Analysis of Parkinson’s Disease and Schizophrenia Reveals Shared Genetic Architecture and Identifies Novel Risk Loci. Biological Psychiatry. ISSN 0006-3223. 89(3), p. 227–235. doi: 10.1016/j.biopsych.2020.01.026. Full text in Research Archive Show summary

  BACKGROUND:Parkinson’s disease (PD) and schizophrenia (SCZ) are heritable brain disorders that involvedysregulation of the dopaminergic system. Epidemiological studies have reported potential comorbidity between thedisorders, and movement disturbances are common in patients with SCZ before treatment with antipsychotic drugs.Despite this, little is known about shared genetic etiology between the disorders.METHODS:We analyzed recent large genome-wide association studies on patients with SCZ (N= 77,096) and PD(N= 417,508) using a conditional/conjunctional false discovery rate (FDR) approach to evaluate overlap incommon genetic variants and improve statistical power for genetic discovery. Using a variety of biologicalresources, we functionally characterized the identified genomic loci.RESULTS:We observed genetic enrichment in PD conditional onassociations with SCZ and vice versa, indicatingpolygenic overlap. We then leveraged this cross-trait enrichment using conditional FDR analysis and identified 9 novel PDrisk loci and 1 novel SCZ locus at conditional FDR,.01. Furthermore, we identified 9 genomic loci jointly associated withPD and SCZ at conjunctional FDR,.05. There was an even distribution of antagonistic and agonistic effect directionsamong the shared loci, in line with the insignificant genetic correlation between the disorders. Of 67 genes mapped to theshared loci, 65 are expressed in the human brain and show cell type–specific expression profiles.CONCLUSIONS:Altogether, the study increases understanding of the genetic architectures underlying SCZ and PD,indicating that common molecular genetic mechanisms may contribute to overlapping pathophysiological and clinicalfeatures between the disorders.

• Billingsley, Kimberley; Barbosa, Ines A.; Bandres-Ciga, Sara; Quinn, John; Bubb, Vivien & Deshpande, Charu [Show all 18 contributors for this article] (2019). Mitochondria function associated genes contribute to Parkinson’s Disease risk and later age at onset. NPJ Parkinson's Disease. 5(8). doi: 10.1038/s41531-019-0080-x. Full text in Research Archive
• Ligaard, Johanne; Sannæs, Julia Ryen & Pihlstrøm, Lasse (2019). Deep brain stimulation and genetic variability in Parkinson’s disease: a review of the literature. NPJ Parkinson's Disease. 5(18). doi: 10.1038/s41531-019-0091-7. Full text in Research Archive Show summary

  Deep brain stimulation is offered as symptomatic treatment in advanced Parkinson’s disease, depending on a clinical assessment of the individual patient’s risk-benefit profile. Genetics contribute to phenotypic variability in Parkinson’s disease, suggesting that genetic testing could have clinical relevance for personalized therapy. Aiming to review current evidence linking genetic variation to deep brain stimulation treatment and outcomes in Parkinson’s disease we performed systematic searches in the Embase and PubMed databases to identify relevant publications and summarized the findings. We identified 39 publications of interest. Genetic screening studies indicate that monogenic forms of Parkinson’s disease and high-risk variants of GBA may be more common in cohorts treated with deep brain stimulation. Studies assessing deep brain stimulation outcomes in patients carrying mutations in specific genes are limited in size. There are reports suggesting that the phenotype associated with parkin mutations could be suitable for early surgery. In patients with LRRK2 mutations, outcomes of deep brain stimulation seem at least as good as in mutation-negative patients, whereas less favorable outcomes are seen in patients carrying mutations in GBA. Careful assessment of clinical symptoms remains the primary basis for clinical decisions associated with deep brain stimulation surgery in Parkinson’s disease, although genetic information could arguably be taken into account in special cases. Current evidence is scarce, but highlights a promising development where genetic profiling may be increasingly relevant for clinicians tailoring personalized medical or surgical therapy to Parkinson’s disease patients.

• Reynolds, Regina H.; Botía, Juan A.; Nalls, Mike A.; Pihlstrøm, Lasse; Hardy, John & Taliun, Sarah A. Gagliano [Show all 7 contributors for this article] (2019). Moving beyond neurons: the role of cell type-specific gene regulation in Parkinson’s disease heritability. NPJ Parkinson's Disease. 5(6). doi: 10.1038/s41531-019-0076-6. Full text in Research Archive
• Iqbal, Zafar; Koht, Jeanette; Pihlstrøm, Lasse; Henriksen, Sandra Pilar; Cappelletti, Chiara & Russell, Michael Bjørn [Show all 9 contributors for this article] (2019). Missense mutations in DYT-TOR1A dystonia. Neurology: Genetics. 5:e343(4), p. 1–6. doi: 10.1212/NXG.0000000000000343. Full text in Research Archive Show summary

  DYT-TOR1A dystonia is caused by dominant mutations in the TOR1A gene, most frequently a heterozygous in-frame deletion in exon 5 (c.904_906delGAG; p.302/303delE).1 The most frequent phenotype has childhood onset in a limb, spreading to generalized dystonia within a few years. However, also mild focal forms and onset in the cervical and even cranial region have been described. Age at onset varies from 3 to 64 years,2 and penetrance is only 30%. Other in-frame deletions and point mutations in TOR1A have been associated with dystonia in a limited number of patients.3,4 Here, we report 2 new patients with missense mutations in TOR1A.

• Nalls, Mike A.; Blauwendraat, Cornelis; Vallerga, Costanza L.; Heilbron, Karl; Bandres-Ciga, Sara & Chang, Diana [Show all 51 contributors for this article] (2019). Identification of novel risk loci, causal insights, and heritable risk for Parkinson's disease: a meta-analysis of genome-wide association studies. Lancet Neurology. ISSN 1474-4422. 18(12), p. 1091–1102. doi: 10.1016/S1474-4422(19)30320-5. Full text in Research Archive
• Rongve, Arvid; Witoelar, Aree; Ruiz, Agustín; Athanasiu, Lavinia; Abdelnour, Carla & Clarimon, Jordi [Show all 40 contributors for this article] (2019). GBA and APOE ε4 associate with sporadic dementia with Lewy bodies in European genome wide association study. Scientific Reports. 9(7013). doi: 10.1038/s41598-019-43458-2. Full text in Research Archive Show summary

  Dementia with Lewy Bodies (DLB) is a common neurodegenerative disorder with poor prognosis and mainly unknown pathophysiology. Heritability estimates exceed 30% but few genetic risk variants have been identified. Here we investigated common genetic variants associated with DLB in a large European multisite sample. We performed a genome wide association study in Norwegian and European cohorts of 720 DLB cases and 6490 controls and included 19 top-associated single-nucleotide polymorphisms in an additional cohort of 108 DLB cases and 75545 controls from Iceland. Overall the study included 828 DLB cases and 82035 controls. Variants in the ASH1L/GBA (Chr1q22) and APOE ε4 (Chr19) loci were associated with DLB surpassing the genome-wide significance threshold (p < 5 × 10−8). One additional genetic locus previously linked to psychosis in Alzheimer’s disease, ZFPM1 (Chr16q24.2), showed suggestive association with DLB at p-value < 1 × 10−6. We report two susceptibility loci for DLB at genome-wide significance, providing insight into etiological factors. These findings highlight the complex relationship between the genetic architecture of DLB and other neurodegenerative disorders.

• Sabir, Marya S.; Blauwendraat, Cornelis; Ahmed, Sarah; Serrano, Geidy E.; Beach, Thomas G. & Perkins, Matthew [Show all 21 contributors for this article] (2019). Assessment of APOE in atypical parkinsonism syndromes. Neurobiology of Disease. ISSN 0969-9961. 127, p. 142–146. doi: 10.1016/j.nbd.2019.02.016. Full text in Research Archive
• Iwaki, Hirotaka; Blauwendraat, Cornelis; Leonard, Hampton L.; Kim, Jonggeol J.; Liu, Ganqiang & Maple-Grødem, Jodi [Show all 45 contributors for this article] (2019). Genomewide association study of Parkinson's disease clinical biomarkers in 12 longitudinal patients' cohorts. Movement Disorders. ISSN 0885-3185. 34(12), p. 1839–1850. doi: 10.1002/mds.27845. Full text in Research Archive
• Fernandez-Santiago, Ruben; Martín-Flores, Núria; Antonelli, Francesca; Cerquera, Catalina; Moreno, Verónica & Bandres-Ciga, Sara [Show all 15 contributors for this article] (2019). SNCA and mTOR Pathway Single Nucleotide Polymorphisms Interact to Modulate the Age at Onset of Parkinson’s Disease. Movement Disorders. ISSN 0885-3185. 34(9), p. 1333–1344. doi: 10.1002/mds.27770. Full text in Research Archive
• Blauwendraat, Cornelis; Heilbron, Karl; Vallerga, Costanza L; Bandres-Ciga, Sara; Coelln, Rainer von & Pihlstrøm, Lasse [Show all 42 contributors for this article] (2019). Parkinson's disease age at onset genome-wide association study: Defining heritability, genetic loci, and α‐synuclein mechanisms. Movement Disorders. ISSN 0885-3185. 34(6), p. 866–875. doi: 10.1002/mds.27659. Full text in Research Archive
• Iwaki, Hirotaka; Blauwendraat, Cornelis; Leonard, Hampton L.; Liu, Ganqiang; Maple-Grødem, Jodi & Corvol, Jean-Christophe [Show all 41 contributors for this article] (2019). Genetic risk of Parkinson disease and progression: An analysis of 13 longitudinal cohorts. Neurology: Genetics. 5(4), p. 1–14. doi: 10.1212/NXG.0000000000000348. Full text in Research Archive Show summary

  Objective: To determine if any association between previously identified alleles that confer risk for Parkinson disease and variables measuring disease progression. Methods: We evaluated the association between 31 risk variants and variables measuring disease progression. A total of 23,423 visits by 4,307 patients of European ancestry from 13 longitudinal cohorts in Europe, North America, and Australia were analyzed. Results: We confirmed the importance of GBA on phenotypes. GBA variants were associated with the development of daytime sleepiness (p.N370S: hazard ratio [HR] 3.28 [1.69–6.34]) and possible REM sleep behavior (p.T408M: odds ratio 6.48 [2.04–20.60]). We also replicated previously reported associations of GBA variants with motor/cognitive declines. The other genotype-phenotype associations include an intergenic variant near LRRK2 and the faster development of motor symptom (Hoehn and Yahr scale 3.0 HR 1.33 [1.16–1.52] for the C allele of rs76904798) and an intronic variant in PMVK and the development of wearing-off effects (HR 1.66 [1.19–2.31] for the C allele of rs114138760). Age at onset was associated with TMEM175 variant p.M393T (−0.72 [−1.21 to −0.23] in years), the C allele of rs199347 (intronic region of GPNMB, 0.70 [0.27–1.14]), and G allele of rs1106180 (intronic region of CCDC62, 0.62 [0.21–1.03]). Conclusions: This study provides evidence that alleles associated with Parkinson disease risk, in particular GBA variants, also contribute to the heterogeneity of multiple motor and nonmotor aspects. Accounting for genetic variability will be a useful factor in understanding disease course and in minimizing heterogeneity in clinical trials.

• Bandres-Ciga, Sara; Saez-Atienzar, Sara; Bonet-Ponce, Luis; Billingsley, Kimberley; Vitale, Dan & Blauwendraat, Cornelis [Show all 12 contributors for this article] (2019). The endocytic membrane trafficking pathway plays a major role in the risk of Parkinson's disease. Movement Disorders. ISSN 0885-3185. 34(4), p. 460–468. doi: 10.1002/mds.27614. Full text in Research Archive
• Blauwendraat, Cornelis; Kia, Demis A.; Pihlstrøm, Lasse; Gan-Or, Ziv; Lesage, Suzanne & Gibbs, J. Raphael [Show all 22 contributors for this article] (2018). Insufficient evidence for pathogenicity of SNCA His50Gln (H50Q) in Parkinson's disease. Neurobiology of Aging. ISSN 0197-4580. 64, p. 159.e5–159.e8. doi: 10.1016/j.neurobiolaging.2017.12.012. Full text in Research Archive
• Bjørnaraa, Kari Anne; Pihlstrøm, Lasse; Dietrichs, Espen & Toft, Mathias (2018). Risk variants of the α-synuclein locus and REM sleep behavior disorder in Parkinson's disease: A genetic association study. BMC Neurology. 18(20), p. 1–5. doi: 10.1186/s12883-018-1023-6. Full text in Research Archive Show summary

  Background Parkinson’s disease is a heterogeneous disorder where genetic factors may underlie clinical variability. Rapid eye movement sleep behavior disorder (RBD) is a parasomnia strongly linked to synucleinopathies, including Parkinson’s disease. We hypothesized that SNCA variants conferring risk of Parkinson’s disease would also predispose to an RBD phenotype. Methods We assessed possible RBD (pRBD) status using the RBD screening questionnaire and investigated known susceptibility variants for Parkinson’s disease located in the α-synuclein (SNCA) and tau (MAPT) gene loci in 325 Parkinson’s disease patients. Associations between genetic risk variants and RBD were investigated by logistic regression, and an independent dataset of 382 patients from the Parkinson’s Progression Marker Initiative (PPMI) study was used for replication. Results pRBD was associated with rs3756063 located in the 5’ region of SNCA (two-sided p = 0.018, odds ratio 1.44). We replicated this finding in the PPMI dataset (one-sided p = 0.036, odds ratio 1.35) and meta-analyzed the results (two-sided p = 0.0032, odds ratio 1.40). The Parkinson’s disease risk variant in the 3′ region of SNCA and the MAPT variant showed no association with pRBD. Conclusions Our findings provide proof of principle that a largely stable, dichotomous clinical feature of Parkinson’s disease can be linked to a specific genetic susceptibility profile. Indirectly, it also supports the hypothesis of RBD as relevant marker for a distinct subtype of the disorder.

• Kristiansen, Madeleine; Maple-Grødem, Jodi; Alves, Guido Werner; Arepalli, Sampath; Hernandez, Dena G & Iwaki, Hirotaka [Show all 11 contributors for this article] (2018). A paradoxical relationship between family history, onset age, and genetic risk in Parkinson's disease. Movement Disorders. ISSN 0885-3185. 34(2), p. 298–299. doi: 10.1002/mds.27555. Full text in Research Archive
• Blauwendraat, Cornelis; Reed, Xylena; Kia, Demis A.; Gan-Or, Ziv; Lesage, Suzanne & Pihlstrøm, Lasse [Show all 29 contributors for this article] (2018). Frequency of loss of function variants in LRRK2 in Parkinson disease. JAMA Neurology. ISSN 2168-6149. 75(11), p. 1416–1422. doi: 10.1001/jamaneurol.2018.1885. Full text in Research Archive
• Berge-Seidl, Victoria; Pihlstrøm, Lasse; Wszolek, Zbigniew K.; Ross, Owen A. & Toft, Mathias (2018). No evidence for DNM3 as genetic modifier of age at onset in idiopathic Parkinson's disease. Neurobiology of Aging. ISSN 0197-4580. 74, p. 1–5. doi: 10.1016/j.neurobiolaging.2018.09.022. Full text in Research Archive
• Kishore, Asha; Sreelatha, Ashwin Ashok Kumar; Sturm, Marc; von-Zweydorf, Felix; Pihlstrøm, Lasse & Raimondi, Francesco [Show all 19 contributors for this article] (2018). Understanding the role of genetic variability in LRRK2 in Indian population. Movement Disorders. ISSN 0885-3185. p. 1–10. doi: 10.1002/mds.27558. Full text in Research Archive
• Pihlstrøm, Lasse; Blauwendraat, Cornelis; Cappelletti, Chiara; Berge-Seidl, Victoria; Langmyhr, Margrete & Henriksen, Sandra Pilar [Show all 12 contributors for this article] (2018). A comprehensive analysis of SNCA-related genetic risk in sporadic parkinson disease. Annals of Neurology. ISSN 0364-5134. 84(1), p. 117–129. doi: 10.1002/ana.25274. Full text in Research Archive
• Berge, Victoria; Pihlstrøm, Lasse; Maple-Grødem, Jodi; Forsgren, Lars; Linder, Jan & Larsen, Jan Petter [Show all 8 contributors for this article] (2017). The GBA variant E326K is associated with Parkinson's disease and explains a genome-wide association signal. Neuroscience Letters. ISSN 0304-3940. 658, p. 48–52. doi: 10.1016/j.neulet.2017.08.040. Full text in Research Archive Show summary

  Objective Coding variants in the GBA gene have been identified as the numerically most important genetic risk factors for Parkinson's disease (PD). In addition, genome-wide association studies (GWAS) have identified associations with PD in the SYT11-GBA region on chromosome 1q22, but the relationship to GBA coding variants have remained unclear. The aim of this study was to sequence the complete GBA gene in a clinical cohort and to investigate whether coding variants within the GBA gene may be driving reported association signals. Methods We analyzed high-throughput sequencing data of all coding exons of GBA in 366 patients with PD. The identified low-frequency coding variants were genotyped in three Scandinavian case-controls series (786 patients and 713 controls). Previously reported risk variants from two independent association signals within the SYT11-GBA locus on chromosome 1 were also genotyped in the same samples. We performed association analyses and evaluated linkage disequilibrium (LD) between the variants. Results We identified six rare mutations (1.6%) and two low-frequency coding variants in GBA. E326K (rs2230288) was significantly more frequent in PD patients compared to controls (OR 1.65, p = 0.03). There was no clear association of T369M (rs75548401) with disease (OR 1.43, p = 0.24). Genotyping the two GWAS hits rs35749011 and rs114138760 in the same sample set, we replicated the association between rs35749011 and disease status (OR 1.67, p = 0.03), while rs114138760 was found to have similar allele frequencies in patients and controls. Analyses revealed that E326K and rs35749011 are in very high LD (r2 0.95). Conclusions Our results confirm that the GBA variant E326K is a susceptibility allele for PD. The results suggest that E326K may fully account for the primary association signal observed at chromosome 1q22 in previous GWAS of PD.

• Chelban, Viorica; Manole, Andreea; Pihlstrøm, Lasse; Schottlaender, Lucia; Efthymiou, Stephanie & OConnor, Emer [Show all 9 contributors for this article] (2017). Analysis of the prion protein gene in multiple system atrophy. Neurobiology of Aging. ISSN 0197-4580. 49, p. 216.e15–216.e18. doi: 10.1016/j.neurobiolaging.2016.09.021. Full text in Research Archive
• Iqbal, Zafar; Rydning, Siri Lynne; Wedding, Iselin Marie; Koht, Jeanette; Pihlstrøm, Lasse & Rengmark, Aina Sylvia Haugen [Show all 9 contributors for this article] (2017). Targeted high throughput sequencing in hereditary ataxia and spastic paraplegia. PLOS ONE. 12:e0174667(3), p. 1–19. doi: 10.1371/journal.pone.0174667. Full text in Research Archive Show summary

  Hereditary ataxia and spastic paraplegia are heterogeneous monogenic neurodegenerative disorders. To date, a large number of individuals with such disorders remain undiagnosed. Here, we have assessed molecular diagnosis by gene panel sequencing in 105 early and late-onset hereditary ataxia and spastic paraplegia probands, in whom extensive previous investigations had failed to identify the genetic cause of disease. Pathogenic and likely-pathogenic variants were identified in 20 probands (19%) and variants of uncertain significance in ten probands (10%). Together these accounted for 30 probands (29%) and involved 18 different genes. Among several interesting findings, dominantly inherited KIF1A variants, p.(Val8Met) and p.(Ile27Thr) segregated in two independent families, both presenting with a pure spastic paraplegia phenotype. Two homozygous missense variants, p.(Gly4230Ser) and p.(Leu4221Val) were found in SACS in one consanguineous family, presenting with spastic ataxia and isolated cerebellar atrophy. The average disease duration in probands with pathogenic and likely-pathogenic variants was 31 years, ranging from 4 to 51 years. In conclusion, this study confirmed and expanded the clinical phenotypes associated with known disease genes. The results demonstrate that gene panel sequencing and similar sequencing approaches can serve as efficient diagnostic tools for different heterogeneous disorders. Early use of such strategies may help to reduce both costs and time of the diagnostic process.

• Fagan, Emma Sveipe & Pihlstrøm, Lasse (2017). Genetic risk factors for cognitive decline in Parkinson's disease: a review of the literature. European Journal of Neurology. ISSN 1351-5101. 24(4), p. 561–574. doi: 10.1111/ene.13258. Full text in Research Archive
• Ezat, Beriwan; Pihlstrøm, Lasse; Aasly, Jan; Tysnes, Ole-Bjørn; Egge, Arild & Dietrichs, Espen (2017). Bruk av avansert behandling ved Parkinsons sykdom i Norge. Tidsskrift for Den norske legeforening (Tidsskriftet). ISSN 0029-2001. 137(9), p. 619–623. doi: 10.4045/tidsskr.16.0711. Full text in Research Archive
• Blauwendraat, Cornelis; Faghri, Faraz; Pihlstrøm, Lasse; Geiger, Joshua T.; Elbaz, Alexis & Lesage, Suzanne [Show all 41 contributors for this article] (2017). NeuroChip, an updated version of the NeuroX genotyping platform to rapidly screen for variants associated with neurological diseases. Neurobiology of Aging. ISSN 0197-4580. 57, p. 247.e9–247.e13. doi: 10.1016/j.neurobiolaging.2017.05.009. Full text in Research Archive
• Rengmark, Aina Sylvia Haugen; Pihlstrøm, Lasse; Linder, Jan; Forsgren, Lars & Toft, Mathias (2016). Low frequency of GCH1 and TH mutations in Parkinson's disease. Parkinsonism & Related Disorders. ISSN 1353-8020. 29, p. 109–111. doi: 10.1016/j.parkreldis.2016.05.010. Full text in Research Archive
• Pihlstrøm, Lasse; Morset, Kristina Rebekka; Grimstad, Espen; Vitelli, Valeria & Toft, Mathias (2016). A cumulative genetic risk score predicts progression in Parkinson's disease. Movement Disorders. ISSN 0885-3185. 31(4), p. 487–490. doi: 10.1002/mds.26505. Full text in Research Archive
• Pihlstrøm, Lasse; Berge, Victoria; Rengmark, Aina Sylvia Haugen & Toft, Mathias (2015). Parkinson's disease correlates with promoter methylation in the α-synuclein gene. Movement Disorders. ISSN 0885-3185. 30(4), p. 577–580. doi: 10.1002/mds.26073. Full text in Research Archive
• Pihlstrøm, Lasse; Rengmark, Aina Sylvia Haugen; Bjørnarå, Kari Anne; Dizdar, Nil; Fardell, Camilla & Forsgren, Lars [Show all 13 contributors for this article] (2015). Fine mapping and resequencing of the PARK16 locus in Parkinson's disease. Journal of Human Genetics. ISSN 1434-5161. 60(7), p. 357–362. doi: 10.1038/jhg.2015.34. Full text in Research Archive
• Lill, Christina M.; Rengmark, Aina Sylvia Haugen; Pihlstrøm, Lasse; Fogh, Isabella; Shatunov, Aleksey & Sleiman, Patrick M. [Show all 51 contributors for this article] (2015). The role of TREM2 R47H as a risk factor for Alzheimer’s disease, frontotemporal lobar degeneration, amyotrophic lateral sclerosis, and Parkinson’s disease. Alzheimer's & Dementia. ISSN 1552-5260. 11(12), p. 1407–1416. doi: 10.1016/j.jalz.2014.12.009. Full text in Research Archive
• Wang, Lisa; Aasly, Jan; Annesi, Grazia; Bardien, Soraya; Bozi, Maria & Brice, Alexis [Show all 55 contributors for this article] (2015). Large-scale assessment of polyglutamine repeat expansions in Parkinson disease. Neurology. ISSN 0028-3878. 85(15), p. 1283–1292. doi: 10.1212/WNL.0000000000002016. Full text in Research Archive
• Pihlstrøm, Lasse; Rengmark, Aina Sylvia Haugen; Bjørnarå, Kari Anne & Toft, Mathias (2014). Effective variant detection by targeted deep sequencing of DNA pools: An example from parkinson's disease. Annals of Human Genetics. ISSN 0003-4800. 78(3), p. 243–252. doi: 10.1111/ahg.12060. Full text in Research Archive
• Pihlstrøm, Lasse; Axelsson, Gunnar; Bjørnarå, Kari Anne; Dizdar, Nil; Fardell, Camilla & Forsgren, Lars [Show all 14 contributors for this article] (2013). Supportive evidence for 11 loci from genome-wide association studies in Parkinson's disease. Neurobiology of Aging. ISSN 0197-4580. 34(6). doi: 10.1016/j.neurobiolaging.2012.10.019. Full text in Research Archive
• Pihlstrøm, Lasse & Toft, Mathias (2011). Parkinson’s Disease: What Remains of the ‘‘Missing Heritability’’? Movement Disorders. ISSN 0885-3185. 26(11), p. 1971–1973. doi: 10.1002/mds.23898. Full text in Research Archive
• Pihlstrøm, Lasse & Toft, Mathias (2011). Genetic variability in SNCA and Parkinson's disease. Neurogenetics. ISSN 1364-6745. 12(4), p. 283–293. doi: 10.1007/s10048-011-0292-7. Full text in Research Archive Show summary

  Over the last decades, increasing knowledge about the genetic architecture of Parkinson's disease has provided novel insights into the pathogenesis of the disorder, generating hypotheses for further research. Characterizing the role of SNCA, encoding the alpha-synuclein protein, has been a particularly important aspect of this development. The identification of SNCA as the first gene implicated in monogenic parkinsonism led to the recognition of alpha-synuclein as a key protein in the pathogenesis and a major component of pathological hallmark lesions. An association between common variants in SNCA and risk of sporadic Parkinson's disease has been established through numerous studies. We review our current understanding of SNCA variability contributing to Parkinson's disease, highlighting the characterization of functionally relevant susceptibility alleles as a major future challenge. We argue that new strategies will be needed to pinpoint the variants that are ultimately responsible for the signals detected in association studies, where targeted resequencing may represent an attractive initial approach.

View all works in NVA

• Towns, Clodagh; Richer, Madeleine; Jasaityte, Simona; Stafford, Eleanor J.; Joubert, Julie & Antar, Tarek [Show all 243 contributors for this article] (2023). Defining the causes of sporadic Parkinson’s disease in the global Parkinson’s genetics program (GP2). NPJ Parkinson's Disease. 9(1). doi: 10.1038/s41531-023-00533-w. Full text in Research Archive Show summary

  The Global Parkinson’s Genetics Program (GP2) will genotype over 150,000 participants from around the world, and integrate genetic and clinical data for use in large-scale analyses to dramatically expand our understanding of the genetic architecture of PD. This report details the workflow for cohort integration into the complex arm of GP2, and together with our outline of the monogenic hub in a companion paper, provides a generalizable blueprint for establishing large scale collaborative research consortia.

• Lange, Lara M.; Avenali, Micol; Ellis, Melina; Illarionova, Anastasia; Sarmiento, Ignacio J. Keller & Tan, Ai-Huey [Show all 254 contributors for this article] (2023). Author Correction: Elucidating causative gene variants in hereditary Parkinson’s disease in the Global Parkinson’s Genetics Program (GP2) (npj Parkinson's Disease, (2023), 9, 1, (100), 10.1038/s41531-023-00526-9). NPJ Parkinson's Disease. 9(1). doi: 10.1038/s41531-023-00560-7. Full text in Research Archive
• Bandres-Ciga, Sara; Saez-Atienzar, Sara; Kim, J.J.; Makarious, M.B.; Faghri, Faraz & Diez-Fairen, Monica [Show all 28 contributors for this article] (2021). Correction to: Large‑scale pathway specific polygenic risk and transcriptomic community network analysis identifies novel functional pathways in Parkinson disease (Acta Neuropathologica, (2020), 140, 3, (341-358), 10.1007/s00401-020-02181-3). Acta Neuropathologica. ISSN 0001-6322. 142(1), p. 223–224. doi: 10.1007/s00401-021-02309-z. Full text in Research Archive
• Makarious, Mary B.; Diez-Fairen, Monica; Krohn, Lynne; Blauwendraat, Cornelis; Bandres-Ciga, Sara & Ding, Jinhui [Show all 10 contributors for this article] (2019). ARSA variants in a-synucleinopathies. Brain. ISSN 0006-8950. 142(12), p. e70–e70. doi: 10.1093/brain/awz340. Full text in Research Archive
• Rongve, Arvid; Witoelar, Aree Widya; Ruiz, Agustín; Athanasiu, Lavinia; Abdelnour, Carla & Clarimon, Jordi [Show all 40 contributors for this article] (2019). Author Correction: GBA and APOE ε4 associate with sporadic dementia with Lewy bodies in European genome wide association study (Scientific Reports, (2019), 9, 1, (7013), 10.1038/s41598-019-43458-2). Scientific Reports. 9(1). doi: 10.1038/s41598-019-51827-0. Full text in Research Archive
• Pihlstrøm, Lasse; Schottlaender, Lucia; Chelban, Viorica; Meissner, Wassilios G.; Federoff, Monica & Singleton, Andy [Show all 7 contributors for this article] (2018). Lysosomal storage disorder gene variants in multiple system atrophy. Brain. ISSN 0006-8950. 141(7), p. e53–e53. doi: 10.1093/brain/awy124. Full text in Research Archive
• Pihlstrøm, Lasse; Schottlaender, Lucia; Chelban, Viorica & Houlden, Henry (2018). LRP10 in α-synucleinopathies. Lancet Neurology. ISSN 1474-4422. 17(12), p. 1033–1034. doi: 10.1016/S1474-4422(18)30407-1. Full text in Research Archive
• Faiz, Kashif Waqar & Pihlstrøm, Lasse (2017). Parkinsons sykdom og parkinsonisme. Tidsskrift for Den norske legeforening (Tidsskriftet). ISSN 0029-2001. 137(4), p. 298–298. Full text in Research Archive
• Iqbal, Zafar; Pihlstrøm, Lasse; Rengmark, Aina Sylvia Haugen; Henriksen, Sandra Pilar; Linder, Jan & Forsgren, Lars [Show all 7 contributors for this article] (2016). Rare variants in dementia genes and Parkinson's disease. European Journal of Human Genetics. ISSN 1018-4813. 24(12), p. 1661–1662. doi: 10.1038/ejhg.2016.79. Full text in Research Archive
• Pihlstrøm, Lasse & Toft, Mathias (2015). Cumulative genetic risk and age at onset in Parkinson's disease. Movement Disorders. ISSN 0885-3185. 30(12), p. 1712–1713. doi: 10.1002/mds.26366. Full text in Research Archive
• Pihlstrøm, Lasse (2014). Re: Affeksjon for affeksjon :. Tidsskrift for Den norske legeforening (Tidsskriftet). ISSN 0029-2001. 134(20), p. 1920–1920. doi: 10.4045/tidsskr.14.1211. Full text in Research Archive
• Pihlstrøm, Lasse; Bjornara, KA; Dizdar, N; Fardell, C; Forsgren, L & Holmberg, B [Show all 12 contributors for this article] (2012). A Scandinavian multi-centre study replicates 11 susceptibility loci from genome-wide association studies in Parkinson's disease. European Journal of Neurology. ISSN 1351-5101. 19, p. 40–40. Full text in Research Archive

View all works in NVA