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747 results on '"Blauwendraat, Cornelis"'

1. Association of CSF α‐synuclein seed amplification assay positivity with disease progression and cognitive decline: A longitudinal Alzheimer's Disease Neuroimaging Initiative study

Author

Tosun, Duygu, Hausle, Zachary, Thropp, Pamela, Concha‐Marambio, Luis, Lamoureux, Jennifer, Lebovitz, Russ, Shaw, Leslie M, Singleton, Andrew B, Weiner, Michael W, Initiative, the Alzheimer's Disease Neuroimaging, and Blauwendraat, Cornelis

Subjects
Biomedical and Clinical Sciences, Biological Psychology, Clinical Sciences, Neurosciences, Psychology, Dementia, Acquired Cognitive Impairment, Alzheimer's Disease, Aging, Neurodegenerative, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Brain Disorders, 4.1 Discovery and preclinical testing of markers and technologies, 2.1 Biological and endogenous factors, Neurological, Humans, Male, Female, Aged, Disease Progression, Alzheimer Disease, Longitudinal Studies, Amyloid beta-Peptides, tau Proteins, alpha-Synuclein, Biomarkers, Cross-Sectional Studies, Cognitive Dysfunction, Neuroimaging, Peptide Fragments, Aged, 80 and over, Middle Aged, Alzheimer's disease, cognitive decline, co-pathology, Lewy body, seed amplification assay, Alzheimer's Disease Neuroimaging Initiative, co‐pathology, Geriatrics, Clinical sciences, Biological psychology
Abstract

IntroductionCerebrospinal fluid (CSF) α-synuclein (α-syn) seed amplification assay (SAA) is a sensitive and specific tool for detecting Lewy body co-pathology in Alzheimer's disease.MethodsA total of 1637 cross-sectional and 407 longitudinal CSF samples from the Alzheimer's Disease Neuroimaging Initiative (ADNI) were tested with SAA. We examined longitudinal dynamics of amyloid beta (Aβ), α-syn seeds, and phosphorylated tau181 (p-tau181), along with global and domain-specific cognition in stable SAA+, stable SAA-, and those who converted to SAA+ from SAA-.ResultsSAA+ individuals had faster cognitive decline than SAA-, notably in mild cognitive impairment, and presented with earlier symptom onset. SAA+ conversion was associated with CSF Aβ42 positivity but did not impact the progression of either CSF Aβ42 or CSF p-tau181 status. CSF Aβ42, p-tau181, and α-syn SAA were all strong predictors of clinical progression, particularly CSF Aβ42. In vitro, CSF α-syn SAA kinetic parameters were associated with participant demographics, clinical profiles, and cognitive decline.DiscussionThese results highlight the interplay between amyloid and α-syn and their association with disease progression.HighlightsSeed amplification assay (SAA) positivity was associated with greater cognitive decline and earlier symptom onset. Thirty-four Alzheimer's Disease Neuroimaging Initiative (ADNI) individuals progressed from SAA- to SAA+, that is, ≈ 5% conversion. SAA conversion was associated with amyloid beta (Aβ) pathology and greater cognitive decline. SAA status did not impact the progression of either CSF Aβ42 or phosphorylated tau181 biomarkers. Change in clinical diagnosis was associated with both Alzheimer's disease biomarkers and SAA. SAA kinetic parameters were associated with clinical features and progression.

Published
2024

2. African ancestry neurodegeneration risk variant disrupts an intronic branchpoint in GBA1

Author

Álvarez Jerez, Pilar, Wild Crea, Peter, Ramos, Daniel M, Gustavsson, Emil K, Radefeldt, Mandy, Damianov, Andrey, Makarious, Mary B, Ojo, Oluwadamilola O, Billingsley, Kimberley J, Malik, Laksh, Daida, Kensuke, Bromberek, Sarah, Hu, Fangle, Schneider, Zachary, Surapaneni, Aditya L, Stadler, Julia, Rizig, Mie, Morris, Huw R, Pantazis, Caroline B, Leonard, Hampton L, Screven, Laurel, Qi, Yue A, Nalls, Mike A, Bandres-Ciga, Sara, Hardy, John, Houlden, Henry, Eng, Celeste, Burchard, Esteban González, Kachuri, Linda, Lin, Chia-Ho, Black, Douglas L, Singleton, Andrew B, Fischer, Steffen, Bauer, Peter, Reed, Xylena, Ryten, Mina, Beetz, Christian, Ward, Michael, Okubadejo, Njideka U, and Blauwendraat, Cornelis

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Genetics, Neurodegenerative, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Prevention, Biotechnology, Acquired Cognitive Impairment, Dementia, Aging, Brain Disorders, Neurosciences, Parkinson's Disease, 2.1 Biological and endogenous factors, Neurological, Glucosylceramidase, Humans, Introns, Parkinson Disease, Genetic Predisposition to Disease, Black People, Polymorphism, Single Nucleotide, RNA Splicing, Global Parkinson’s Genetics Program, Chemical Sciences, Medical and Health Sciences, Biophysics, Developmental Biology, Biological sciences, Biomedical and clinical sciences, Chemical sciences
Abstract

Recently, an African ancestry-specific Parkinson disease (PD) risk signal was identified at the gene encoding glucocerebrosidase (GBA1). This variant ( rs3115534 -G) is carried by ~50% of West African PD cases and imparts a dose-dependent increase in risk for disease. The risk variant has varied frequencies across African ancestry groups but is almost absent in European and Asian ancestry populations. GBA1 is a gene of high clinical and therapeutic interest. Damaging biallelic protein-coding variants cause Gaucher disease and monoallelic variants confer risk for PD and dementia with Lewy bodies, likely by reducing the function of glucocerebrosidase. Interestingly, the African ancestry-specific GBA1 risk variant is a noncoding variant, suggesting a different mechanism of action. Using full-length RNA transcript sequencing, we identified partial intron 8 expression in risk variant carriers (G) but not in nonvariant carriers (T). Antibodies targeting the N terminus of glucocerebrosidase showed that this intron-retained isoform is likely not protein coding and subsequent proteomics did not identify a shorter protein isoform, suggesting that the disease mechanism is RNA based. Clustered regularly interspaced short palindromic repeats editing of the reported index variant ( rs3115534 ) revealed that this is the sequence alteration responsible for driving the production of these transcripts containing intron 8. Follow-up analysis of this variant showed that it is in a key intronic branchpoint sequence and, therefore, has important implications in splicing and disease. In addition, when measuring glucocerebrosidase activity, we identified a dose-dependent reduction in risk variant carriers. Overall, we report the functional effect of a GBA1 noncoding risk variant, which acts by interfering with the splicing of functional GBA1 transcripts, resulting in reduced protein levels and reduced glucocerebrosidase activity. This understanding reveals a potential therapeutic target in an underserved and underrepresented population.

Published
2024

3. Assessing the lack of diversity in genetics research across neurodegenerative diseases: A systematic review of the GWAS Catalog and literature

Author

Jonson, Caroline, Levine, Kristin S, Lake, Julie, Hertslet, Linnea, Jones, Lietsel, Patel, Dhairya, Kim, Jeff, Bandres‐Ciga, Sara, Terry, Nancy, Mata, Ignacio F, Blauwendraat, Cornelis, Singleton, Andrew B, Nalls, Mike A, Yokoyama, Jennifer S, and Leonard, Hampton L

Subjects
Biomedical and Clinical Sciences, Biological Psychology, Clinical Sciences, Neurosciences, Psychology, Neurodegenerative, Aging, Human Genome, Health Disparities, Women's Health, Genetics, Minority Health, Good Health and Well Being, Humans, Genetic Predisposition to Disease, Genome-Wide Association Study, Neurodegenerative Diseases, White People, Alzheimer's disease, amyotrophic lateral sclerosis, ancestral diversity, genetic research disparities, genome-wide association study, multi-ancestry cohorts, neurodegenerative diseases, Parkinson's disease, population genetics, precision medicine, genome‐wide association study, multi‐ancestry cohorts, Geriatrics, Clinical sciences, Biological psychology
Abstract

The under-representation of non-European cohorts in neurodegenerative disease genome-wide association studies (GWAS) hampers precision medicine efforts. Despite the inherent genetic and phenotypic diversity in these diseases, GWAS research consistently exhibits a disproportionate emphasis on participants of European ancestry. This study reviews GWAS up to 2022, focusing on non-European or multi-ancestry neurodegeneration studies. We conducted a systematic review of GWAS results and publications up to 2022, focusing on non-European or multi-ancestry neurodegeneration studies. Rigorous article inclusion and quality assessment methods were employed. Of 123 neurodegenerative disease (NDD) GWAS reviewed, 82% predominantly featured European ancestry participants. A single European study identified over 90 risk loci, compared to a total of 50 novel loci in identified in all non-European or multi-ancestry studies. Notably, only six of the loci have been replicated. The significant under-representation of non-European ancestries in NDD GWAS hinders comprehensive genetic understanding. Prioritizing genomic diversity in future research is crucial for advancing NDD therapies and understanding. HIGHLIGHTS: Eighty-two percent of neurodegenerative genome-wide association studies (GWAS) focus on Europeans. Only 6 of 50 novel neurodegenerative disease (NDD) genetic loci have been replicated. Lack of diversity significantly hampers understanding of NDDs. Increasing diversity in NDD genetic research is urgently required. New initiatives are aiming to enhance diversity in NDD research.

Published
2024

4. A cross‐sectional study of α‐synuclein seed amplification assay in Alzheimer's disease neuroimaging initiative: Prevalence and associations with Alzheimer's disease biomarkers and cognitive function

Author

Tosun, Duygu, Hausle, Zachary, Iwaki, Hirotaka, Thropp, Pamela, Lamoureux, Jennifer, Lee, Edward B, MacLeod, Karen, McEvoy, Sean, Nalls, Michael, Perrin, Richard J, Saykin, Andrew J, Shaw, Leslie M, Singleton, Andrew B, Lebovitz, Russ, Weiner, Michael W, Blauwendraat, Cornelis, and Initiative, for the Alzheimer's Disease Neuroimaging

Subjects
Biomedical and Clinical Sciences, Biological Psychology, Clinical Sciences, Neurosciences, Psychology, Neurodegenerative, Dementia, Aging, Brain Disorders, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Alzheimer's Disease Related Dementias (ADRD), Acquired Cognitive Impairment, Alzheimer's Disease, Behavioral and Social Science, 2.1 Biological and endogenous factors, 4.1 Discovery and preclinical testing of markers and technologies, 4.2 Evaluation of markers and technologies, Neurological, Humans, Alzheimer Disease, alpha-Synuclein, Biomarkers, Male, Female, Aged, Cross-Sectional Studies, tau Proteins, Amyloid beta-Peptides, Neuroimaging, Aged, 80 and over, Prevalence, Lewy Bodies, Cognition, Sensitivity and Specificity, Brain, Cognitive Dysfunction, Alzheimer's disease, co-pathology, Lewy body, SAA, Alzheimer's Disease Neuroimaging Initiative, co‐pathology, Geriatrics, Clinical sciences, Biological psychology
Abstract

IntroductionAlzheimer's disease (AD) pathology is defined by β-amyloid (Aβ) plaques and neurofibrillary tau, but Lewy bodies (LBs; ?-synuclein aggregates) are a common co-pathology for which effective biomarkers are needed.MethodsA validated α-synuclein Seed Amplification Assay (SAA) was used on recent cerebrospinal fluid (CSF) samples from 1638 Alzheimer's Disease Neuroimaging Initiative (ADNI) participants, 78 with LB-pathology confirmation at autopsy. We compared SAA outcomes with neuropathology, Aβ and tau biomarkers, risk-factors, genetics, and cognitive trajectories.ResultsSAA showed 79% sensitivity and 97% specificity for LB pathology, with superior performance in identifying neocortical (100%) compared to limbic (57%) and amygdala-predominant (60%) LB-pathology. SAA+ rate was 22%, increasing with disease stage and age. Higher Aβ burden but lower CSF p-tau181 associated with higher SAA+ rates, especially in dementia. SAA+ affected cognitive impairment in MCI and Early-AD who were already AD biomarker positive.DiscussionSAA is a sensitive, specific marker for LB-pathology. Its increase in prevalence with age and AD stages, and its association with AD biomarkers, highlights the clinical importance of α-synuclein co-pathology in understanding AD's nature and progression.HighlightsSAA shows 79% sensitivity, 97% specificity for LB-pathology detection in AD. SAA positivity prevalence increases with disease stage and age. Higher Aβ burden, lower CSF p-tau181 linked with higher SAA+ rates in dementia. SAA+ impacts cognitive impairment in early disease stages. Study underpins need for wider LB-pathology screening in AD treatment.

Published
2024

5. Parkinsons disease variant detection and disclosure: PD GENEration, a North American study.

Author

Cook, Lola, Verbrugge, Jennifer, Schwantes-An, Tae-Hwi, Schulze, Jeanine, Foroud, Tatiana, Hall, Anne, Marder, Karen, Mata, Ignacio, Mencacci, Niccolò, Nance, Martha, Schwarzschild, Michael, Simuni, Tanya, Bressman, Susan, Wills, Anne-Marie, Fernandez, Hubert, Litvan, Irene, Lyons, Kelly, Shill, Holly, Singer, Carlos, Tropea, Thomas, Vanegas Arroyave, Nora, Carbonell, Janfreisy, Cruz Vicioso, Rossy, Katus, Linn, Quinn, Joseph, Hodges, Priscila, Meng, Yan, Strom, Samuel, Blauwendraat, Cornelis, Lohmann, Katja, Casaceli, Cynthia, Rao, Shilpa, Ghosh Galvelis, Kamalini, Naito, Anna, Beck, James, and Alcalay, Roy

Subjects
GBA1, LRRK2, Parkinson’s disease, clinical trials, genetic counselling, genetic testing, Humans, Parkinson Disease, Genetic Testing, Male, Female, Glucosylceramidase, Leucine-Rich Repeat Serine-Threonine Protein Kinase-2, alpha-Synuclein, Aged, Middle Aged, Ubiquitin-Protein Ligases, Protein Kinases, Protein Deglycase DJ-1, Vesicular Transport Proteins, North America, Genetic Variation, Genetic Predisposition to Disease, Adult, Disclosure, Genetic Counseling, Canada, United States
Abstract

Variants in seven genes (LRRK2, GBA1, PRKN, SNCA, PINK1, PARK7 and VPS35) have been formally adjudicated as causal contributors to Parkinsons disease; however, individuals with Parkinsons disease are often unaware of their genetic status since clinical testing is infrequently offered. As a result, genetic information is not incorporated into clinical care, and variant-targeted precision medicine trials struggle to enrol people with Parkinsons disease. Understanding the yield of genetic testing using an established gene panel in a large, geographically diverse North American population would help patients, clinicians, clinical researchers, laboratories and insurers better understand the importance of genetics in approaching Parkinsons disease. PD GENEration is an ongoing multi-centre, observational study (NCT04057794, NCT04994015) offering genetic testing with results disclosure and genetic counselling to those in the US (including Puerto Rico), Canada and the Dominican Republic, through local clinical sites or remotely through self-enrolment. DNA samples are analysed by next-generation sequencing including deletion/duplication analysis (Fulgent Genetics) with targeted testing of seven major Parkinsons disease-related genes. Variants classified as pathogenic/likely pathogenic/risk variants are disclosed to all tested participants by either neurologists or genetic counsellors. Demographic and clinical features are collected at baseline visits. Between September 2019 and June 2023, the study enrolled 10 510 participants across >85 centres, with 8301 having received results. Participants were: 59% male; 86% White, 2% Asian, 4% Black/African American, 9% Hispanic/Latino; mean age 67.4 ± 10.8 years. Reportable genetic variants were observed in 13% of all participants, including 18% of participants with one or more high risk factors for a genetic aetiology: early onset (

Published
2024

6. Exome sequencing in Asian populations identifies low-frequency and rare coding variation influencing Parkinson’s disease risk

Author

Chew, Elaine GY, Liu, Zhehao, Li, Zheng, Chung, Sun Ju, Lian, Michelle M., Tandiono, Moses, Heng, Yue Jing, Ng, Ebonne Y., Tan, Louis CS, Chng, Wee Ling, Tan, Tiak Ju, Peh, Esther KL, Ho, Ying Swan, Chen, Xiao Yin, Lim, Erin YT, Chang, Chu Hua, Leong, Jonavan J., Peh, Ting Xuan, Chan, Ling Ling, Chao, Yinxia, Au, Wing-Lok, Prakash, Kumar M., Lim, Jia Lun, Tay, Yi Wen, Mok, Vincent, Chan, Anne YY, Lin, Juei-Jueng, Jeon, Beom S., Song, Kyuyoung, Tham, Clement C., Pang, Chi Pui, Ahn, Jeeyun, Park, Kyu Hyung, Wiggs, Janey L., Aung, Tin, Tan, Ai Huey, Ahmad Annuar, Azlina, Makarious, Mary B., Blauwendraat, Cornelis, Nalls, Mike A., Robak, Laurie A., Alcalay, Roy N., Gan-Or, Ziv, Reynolds, Richard, Lim, Shen-Yang, Xia, Yun, Khor, Chiea Chuen, Tan, Eng-King, Wang, Zhenxun, and Foo, Jia Nee

Published
2024
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7. Investigation of the genetic aetiology of Lewy body diseases with and without dementia

Author

Wu, Lesley Yue, Real, Raquel, Martinez-Carrasco, Alejandro, Chia, Ruth, Lawton, Michael A, Shoai, Maryam, Bresner, Catherine, Blauwendraat, Cornelis, Singleton, Andrew B, Ryten, Mina, Abramzon, Yevgeniya, Ahmed, Sarah, Alba, Camille, Albert, Marilyn S, Bacikova, Dagmar, Barrett, Matthew J, Beach, Thomas G, Bennett, David A, Besser, Lilah M, Bigio, Eileen H, Boeve, Bradley F, Bohannan, Ryan C, Caraway, Chad A, Palma, Jose-Alberto, Dalgard, Clifton L, Dickson, Dennis, Ding, Jinhui, Faber, Kelley, Ferman, Tanis, Ferrucci, Luigi, Flanagan, Margaret E, Foroud, Tatiana M, Ghetti, Bernardino, Gibbs, J Raphael, Goate, Alison, Goldstein, David, Graff-Radford, Neill R, Hu, Heng-Chen, Hupalo, Daniel, Kaiser, Scott M, Kaufmann, Horacio, Kim, Ronald C, Klein, Gregory, Kukull, Walter, Kuzma, Amanda, Leverenz, James, Lopez, Grisel, Mao, Qinwen, Martinez-McGrath, Elisa, Masliah, Eliezer, Monuki, Ed, Newell, Kathy L, Norcliffe-Kaufmann, Lucy, Perkins, Matthew, Pletnikova, Olga, Renton, Alan E, Resnick, Susan M, Ross, Owen A, Sabir, Marya S, Scherzer, Clemens R, Scholz, Sonja W, Serrano, Geidy, Shakkotai, Vikram, Sidransky, Ellen, Tanaka, Toshiko, Tayebi, Nahid, Traynor, Bryan J, Troncoso, Juan C, Viollet, Coralie, Walton, Ronald L, Woltjer, Randy, Wszolek, Zbigniew K, Black, Sandra E, Gan-Or, Ziv, Keith, Julia, Masellis, Mario, Rogaeva, Ekaterina, Aarsland, Dag, Al-Sarraj, Safa, Attems, Johannes, Ferrari, Raffaele, Gentleman, Steve, Hardy, John A, Hodges, Angela K, Love, Seth, McKeith, Ian, Morris, Christopher M, Morris, Huw R, Palmer, Laura, Pickering-Brown, Stuart, Reynolds, Regina H, Thomas, Alan J, Tilley, Bension S, Troakes, Claire, Brett, Francesca, Brice, Alexis, and Duyckaerts, Charles

Subjects
Biomedical and Clinical Sciences, Biological Psychology, Clinical Sciences, Neurosciences, Psychology, Human Genome, Genetics, Brain Disorders, Lewy Body Dementia, Alzheimer's Disease Related Dementias (ADRD), Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Parkinson's Disease, Neurodegenerative, Dementia, Aging, Prevention, Acquired Cognitive Impairment, Clinical Research, 2.1 Biological and endogenous factors, Neurological, International Lewy Body Dementia Genomics Consortium, APOE, Lewy body diseases, dementia, genome-wide association studies, Clinical sciences, Biological psychology
Abstract

Up to 80% of Parkinson's disease patients develop dementia, but time to dementia varies widely from motor symptom onset. Dementia with Lewy bodies presents with clinical features similar to Parkinson's disease dementia, but cognitive impairment precedes or coincides with motor onset. It remains controversial whether dementia with Lewy bodies and Parkinson's disease dementia are distinct conditions or represent part of a disease spectrum. The biological mechanisms underlying disease heterogeneity, in particular the development of dementia, remain poorly understood, but will likely be the key to understanding disease pathways and, ultimately, therapy development. Previous genome-wide association studies in Parkinson's disease and dementia with Lewy bodies/Parkinson's disease dementia have identified risk loci differentiating patients from controls. We collated data for 7804 patients of European ancestry from Tracking Parkinson's, The Oxford Discovery Cohort, and Accelerating Medicine Partnership-Parkinson's Disease Initiative. We conducted a discrete phenotype genome-wide association study comparing Lewy body diseases with and without dementia to decode disease heterogeneity by investigating the genetic drivers of dementia in Lewy body diseases. We found that risk allele rs429358 tagging APOEe4 increases the odds of developing dementia, and that rs7668531 near the MMRN1 and SNCA-AS1 genes and an intronic variant rs17442721 tagging LRRK2 G2019S on chromosome 12 are protective against dementia. These results should be validated in autopsy-confirmed cases in future studies.

Published
2024

9. The Black and African American Connections to Parkinson’s Disease (BLAAC PD) study protocol

Author

Chahine, Lana M., Louie, Naomi, Solle, J, Akçimen, Fulya, Ameri, Andrew, Augenbraun, Samantha, Avripas, Sabrina, Breaux, Sarah, Causey, Christopher, Chandra, Shivika, Dean, Marissa, Disbrow, Elizabeth A., Fanty, Lauren, Fernandez, Jessica, Foster, Erin R., Furr Stimming, Erin, Hall, Deborah, Hinson, Vanessa, Johnson-Turbes, Ashani, Jonas, Cabell, Kilbane, Camilla, Norris, Scott A., Nguyen, Bao-Tran, Padmanaban, Mahesh, Paquette, Kimberly, Parry, Carly, Pessoa Rocha, Natalia, Rawls, Ashley, Shamim, Ejaz A., Shulman, Lisa M., Sipma, Rebeka, Staisch, Julia, Traurig, Rami, von Coelln, Rainer, Wild Crea, Peter, Xie, Tao, Fang, Zih-Hua, O’Grady, Alyssa, Kopil, Catherine M., McGuire Kuhl, Maggie, Singleton, Andrew, Blauwendraat, Cornelis, and Bandres-Ciga, Sara

Published
2024
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10. Parkinson’s families project: a UK-wide study of early onset and familial Parkinson’s disease

Author

Towns, Clodagh, Fang, Zih-Hua, Tan, Manuela M. X., Jasaityte, Simona, Schmaderer, Theresa M., Stafford, Eleanor J., Pollard, Miriam, Tilney, Russel, Hodgson, Megan, Wu, Lesley, Labrum, Robyn, Hehir, Jason, Polke, James, Lange, Lara M., Schapira, Anthony H. V., Bhatia, Kailash P., Singleton, Andrew B., Blauwendraat, Cornelis, Klein, Christine, Houlden, Henry, Wood, Nicholas W., Jarman, Paul R., Morris, Huw R., and Real, Raquel

Published
2024
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12. Characterizing a complex CT-rich haplotype in intron 4 of SNCA using large-scale targeted amplicon long-read sequencing

Author

Alvarez Jerez, Pilar, Daida, Kensuke, Grenn, Francis P., Malik, Laksh, Miano-Burkhardt, Abigail, Makarious, Mary B., Ding, Jinhui, Gibbs, J. Raphael, Moore, Anni, Reed, Xylena, Nalls, Mike A., Shah, Syed, Mahmoud, Medhat, Sedlazeck, Fritz J., Dolzhenko, Egor, Park, Morgan, Iwaki, Hirotaka, Casey, Bradford, Ryten, Mina, Blauwendraat, Cornelis, Singleton, Andrew B., and Billingsley, Kimberley J.

Published
2024
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13. Genome-wide determinants of mortality and motor progression in Parkinson’s disease

Author

Tan, Manuela M. X., Lawton, Michael A., Pollard, Miriam I., Brown, Emmeline, Real, Raquel, Carrasco, Alejandro Martinez, Bekadar, Samir, Jabbari, Edwin, Reynolds, Regina H., Iwaki, Hirotaka, Blauwendraat, Cornelis, Kanavou, Sofia, Hubbard, Leon, Malek, Naveed, Grosset, Katherine A., Bajaj, Nin, Barker, Roger A., Burn, David J., Bresner, Catherine, Foltynie, Thomas, Wood, Nicholas W., Williams-Gray, Caroline H., Andreassen, Ole A., Toft, Mathias, Elbaz, Alexis, Artaud, Fanny, Brice, Alexis, Corvol, Jean-Christophe, Aasly, Jan, Farrer, Matthew J., Nalls, Michael A., Singleton, Andrew B., Williams, Nigel M., Ben-Shlomo, Yoav, Hardy, John, Hu, Michele T. M., Grosset, Donald G., Shoai, Maryam, Pihlstrøm, Lasse, and Morris, Huw R.

Published
2024
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14. Profiling complex repeat expansions in RFC1 in Parkinson’s disease

Author

Alvarez Jerez, Pilar, Daida, Kensuke, Miano-Burkhardt, Abigail, Iwaki, Hirotaka, Malik, Laksh, Cogan, Guillaume, Makarious, Mary B., Sullivan, Roisin, Vandrovcova, Jana, Ding, Jinhui, Gibbs, J. Raphael, Markham, Androo, Nalls, Mike A., Kesharwani, Rupesh K., Sedlazeck, Fritz J., Casey, Bradford, Hardy, John, Houlden, Henry, Blauwendraat, Cornelis, Singleton, Andrew B., and Billingsley, Kimberley J.

Published
2024
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16. Scalable Nanopore sequencing of human genomes provides a comprehensive view of haplotype-resolved variation and methylation

Author

Kolmogorov, Mikhail, Billingsley, Kimberley J, Mastoras, Mira, Meredith, Melissa, Monlong, Jean, Lorig-Roach, Ryan, Asri, Mobin, Alvarez Jerez, Pilar, Malik, Laksh, Dewan, Ramita, Reed, Xylena, Genner, Rylee M, Daida, Kensuke, Behera, Sairam, Shafin, Kishwar, Pesout, Trevor, Prabakaran, Jeshuwin, Carnevali, Paolo, Yang, Jianzhi, Rhie, Arang, Scholz, Sonja W, Traynor, Bryan J, Miga, Karen H, Jain, Miten, Timp, Winston, Phillippy, Adam M, Chaisson, Mark, Sedlazeck, Fritz J, Blauwendraat, Cornelis, and Paten, Benedict

Subjects
Biological Sciences, Bioinformatics and Computational Biology, Genetics, Neurodegenerative, Bioengineering, Human Genome, Neurosciences, Brain Disorders, Nanotechnology, Humans, Sequence Analysis, DNA, Haplotypes, Genome, Human, Nanopore Sequencing, Methylation, Pilot Projects, High-Throughput Nucleotide Sequencing, Technology, Medical and Health Sciences, Developmental Biology, Biological sciences
Abstract

Long-read sequencing technologies substantially overcome the limitations of short-reads but have not been considered as a feasible replacement for population-scale projects, being a combination of too expensive, not scalable enough or too error-prone. Here we develop an efficient and scalable wet lab and computational protocol, Napu, for Oxford Nanopore Technologies long-read sequencing that seeks to address those limitations. We applied our protocol to cell lines and brain tissue samples as part of a pilot project for the National Institutes of Health Center for Alzheimer's and Related Dementias. Using a single PromethION flow cell, we can detect single nucleotide polymorphisms with F1-score comparable to Illumina short-read sequencing. Small indel calling remains difficult within homopolymers and tandem repeats, but achieves good concordance to Illumina indel calls elsewhere. Further, we can discover structural variants with F1-score on par with state-of-the-art de novo assembly methods. Our protocol phases small and structural variants at megabase scales and produces highly accurate, haplotype-specific methylation calls.

Published
2023

17. Multi-ancestry meta-analysis and fine-mapping in Alzheimer’s disease

Author

Lake, Julie, Warly Solsberg, Caroline, Kim, Jonggeol Jeffrey, Acosta-Uribe, Juliana, Makarious, Mary B, Li, Zizheng, Levine, Kristin, Heutink, Peter, Alvarado, Chelsea X, Vitale, Dan, Kang, Sarang, Gim, Jungsoo, Lee, Kun Ho, Pina-Escudero, Stefanie D, Ferrucci, Luigi, Singleton, Andrew B, Blauwendraat, Cornelis, Nalls, Mike A, Yokoyama, Jennifer S, and Leonard, Hampton L

Subjects
Biomedical and Clinical Sciences, Biological Psychology, Clinical and Health Psychology, Clinical Sciences, Psychology, Dementia, Health Disparities, Neurodegenerative, Prevention, Acquired Cognitive Impairment, Alzheimer's Disease, Human Genome, Neurosciences, Minority Health, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Genetics, Brain Disorders, Aging, 2.1 Biological and endogenous factors, Humans, Alzheimer Disease, Black or African American, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Polymorphism, Single Nucleotide, East Asian People, European People, Caribbean People, Hispanic or Latino, South American People, Biological Sciences, Medical and Health Sciences, Psychology and Cognitive Sciences, Psychiatry, Clinical sciences, Biological psychology, Clinical and health psychology
Abstract

Genome-wide association studies (GWAS) of Alzheimer's disease are predominantly carried out in European ancestry individuals despite the known variation in genetic architecture and disease prevalence across global populations. We leveraged published GWAS summary statistics from European, East Asian, and African American populations, and an additional GWAS from a Caribbean Hispanic population using previously reported genotype data to perform the largest multi-ancestry GWAS meta-analysis of Alzheimer's disease and related dementias to date. This method allowed us to identify two independent novel disease-associated loci on chromosome 3. We also leveraged diverse haplotype structures to fine-map nine loci with a posterior probability >0.8 and globally assessed the heterogeneity of known risk factors across populations. Additionally, we compared the generalizability of multi-ancestry- and single-ancestry-derived polygenic risk scores in a three-way admixed Colombian population. Our findings highlight the importance of multi-ancestry representation in uncovering and understanding putative factors that contribute to risk of Alzheimer's disease and related dementias.

Published
2023

18. Impact of the Dopamine System on Long‐Term Cognitive Impairment in Parkinson Disease: An Exploratory Study

Author

Weintraub, Daniel, Picillo, Marina, Cho, Hyunkeun Ryan, Caspell‐Garcia, Chelsea, Blauwendraat, Cornelis, Brown, Ethan G, Chahine, Lana M, Coffey, Christopher S, Dobkin, Roseanne D, Foroud, Tatiana, Galasko, Doug, Kieburtz, Karl, Marek, Kenneth, Merchant, Kalpana, Mollenhauer, Brit, Poston, Kathleen L, Simuni, Tanya, Siderowf, Andrew, Singleton, Andrew, Seibyl, John, Tanner, Caroline M, and Initiative, the Parkinson's Progression Markers

Subjects
Pharmacology and Pharmaceutical Sciences, Biomedical and Clinical Sciences, Mental Health, Neurosciences, Neurodegenerative, Parkinson's Disease, Aging, Prevention, Dementia, Behavioral and Social Science, Clinical Research, Brain Disorders, Acquired Cognitive Impairment, Aetiology, 2.3 Psychological, social and economic factors, Neurological, Mental health, dopamine, cognition, Parkinson's disease, Parkinson's Progression Markers Initiative, Clinical sciences
Abstract

BackgroundLittle is known about the impact of the dopamine system on development of cognitive impairment (CI) in Parkinson disease (PD).ObjectivesWe used data from a multi-site, international, prospective cohort study to explore the impact of dopamine system-related biomarkers on CI in PD.MethodsPD participants were assessed annually from disease onset out to 7 years, and CI determined by applying cut-offs to four measures: (1) Montreal Cognitive Assessment; (2) detailed neuropsychological test battery; (3) Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) cognition score; and (4) site investigator diagnosis of CI (mild cognitive impairment or dementia). The dopamine system was assessed by serial Iodine-123 Ioflupane dopamine transporter (DAT) imaging, genotyping, and levodopa equivalent daily dose (LEDD) recorded at each assessment. Multivariate longitudinal analyses, with adjustment for multiple comparisons, determined the association between dopamine system-related biomarkers and CI, including persistent impairment.ResultsDemographic and clinical variables associated with CI were higher age, male sex, lower education, non-White race, higher depression and anxiety scores and higher MDS-UPDRS motor score. For the dopamine system, lower baseline mean striatum dopamine transporter values (P range 0.003-0.005) and higher LEDD over time (P range

Published
2023

19. The Foundational Data Initiative for Parkinson Disease: Enabling efficient translation from genetic maps to mechanism

Author

Bressan, Elisangela, Reed, Xylena, Bansal, Vikas, Hutchins, Elizabeth, Cobb, Melanie M, Webb, Michelle G, Alsop, Eric, Grenn, Francis P, Illarionova, Anastasia, Savytska, Natalia, Violich, Ivo, Broeer, Stefanie, Fernandes, Noémia, Sivakumar, Ramiyapriya, Beilina, Alexandra, Billingsley, Kimberley J, Berghausen, Joos, Pantazis, Caroline B, Pitz, Vanessa, Patel, Dhairya, Daida, Kensuke, Meechoovet, Bessie, Reiman, Rebecca, Courtright-Lim, Amanda, Logemann, Amber, Antone, Jerry, Barch, Mariya, Kitchen, Robert, Li, Yan, Dalgard, Clifton L, Center, The American Genome, Rizzu, Patrizia, Hernandez, Dena G, Hjelm, Brooke E, Nalls, Mike, Gibbs, J Raphael, Finkbeiner, Steven, Cookson, Mark R, Van Keuren-Jensen, Kendall, Craig, David W, Singleton, Andrew B, Heutink, Peter, and Blauwendraat, Cornelis

Subjects
Biological Sciences, Genetics, Stem Cell Research - Induced Pluripotent Stem Cell - Human, Stem Cell Research - Induced Pluripotent Stem Cell, Neurosciences, Stem Cell Research, Aging, Parkinson's Disease, Neurodegenerative, Brain Disorders, Human Genome, Aetiology, 2.1 Biological and endogenous factors, Neurological, American Genome Center, Parkinson disease, dopaminergic neurons, genetic risk, induced pluripotent stem cell, omics single-cell RNA sequencing single-cell ATAC sequencing SNCA LRRK2 GBA1
Abstract

The Foundational Data Initiative for Parkinson Disease (FOUNDIN-PD) is an international collaboration producing fundamental resources for Parkinson disease (PD). FOUNDIN-PD generated a multi-layered molecular dataset in a cohort of induced pluripotent stem cell (iPSC) lines differentiated to dopaminergic (DA) neurons, a major affected cell type in PD. The lines were derived from the Parkinson's Progression Markers Initiative study, which included participants with PD carrying monogenic PD variants, variants with intermediate effects, and variants identified by genome-wide association studies and unaffected individuals. We generated genetic, epigenetic, regulatory, transcriptomic, and longitudinal cellular imaging data from iPSC-derived DA neurons to understand molecular relationships between disease-associated genetic variation and proximate molecular events. These data reveal that iPSC-derived DA neurons provide a valuable cellular context and foundational atlas for modeling PD genetic risk. We have integrated these data into a FOUNDIN-PD data browser as a resource for understanding the molecular pathogenesis of PD.

Published
2023

20. A reference human induced pluripotent stem cell line for large-scale collaborative studies.

Author

Pantazis, Caroline, Yang, Andrian, Lara, Erika, McDonough, Justin, Blauwendraat, Cornelis, Peng, Lirong, Oguro, Hideyuki, Kanaujiya, Jitendra, Zou, Jizhong, Sebesta, David, Pratt, Gretchen, Cross, Erin, Blockwick, Jeffrey, Buxton, Philip, Kinner-Bibeau, Lauren, Medura, Constance, Tompkins, Christopher, Hughes, Stephen, Santiana, Marianita, Faghri, Faraz, Nalls, Mike, Vitale, Daniel, Ballard, Shannon, Qi, Yue, Ramos, Daniel, Anderson, Kailyn, Stadler, Julia, Narayan, Priyanka, Papademetriou, Jason, Reilly, Luke, Nelson, Matthew, Aggarwal, Sanya, Rosen, Leah, Kirwan, Peter, Pisupati, Venkat, Coon, Steven, Scholz, Sonja, Priebe, Theresa, Öttl, Miriam, Dong, Jian, Meijer, Marieke, Janssen, Lara, Lourenco, Vanessa, van der Kant, Rik, Crusius, Dennis, Paquet, Dominik, Raulin, Ana-Caroline, Bu, Guojun, Held, Aaron, Wainger, Brian, Gabriele, Rebecca, Casey, Jackie, Wray, Selina, Abu-Bonsrah, Dad, Parish, Clare, Beccari, Melinda, Cleveland, Don, Li, Emmy, Rose, Indigo, Kampmann, Martin, Calatayud Aristoy, Carles, Verstreken, Patrik, Heinrich, Laurin, Chen, Max, Schüle, Birgitt, Dou, Dan, Holzbaur, Erika, Zanellati, Maria, Basundra, Richa, Deshmukh, Mohanish, Cohen, Sarah, Khanna, Richa, Raman, Malavika, Nevin, Zachary, Matia, Madeline, Van Lent, Jonas, Timmerman, Vincent, Conklin, Bruce, Johnson Chase, Katherine, Zhang, Ke, Funes, Salome, Bosco, Daryl, Erlebach, Lena, Welzer, Marc, Kronenberg-Versteeg, Deborah, Lyu, Guochang, Arenas, Ernest, Coccia, Elena, Sarrafha, Lily, Ahfeldt, Tim, Marioni, John, Skarnes, William, Cookson, Mark, Ward, Michael, and Merkle, Florian

Subjects
CRISPR, differentiation, iPSC, karyotype, p53, pluripotent, reference, single-cell, stem cell, whole-genome, Humans, Induced Pluripotent Stem Cells, Cell Differentiation, Gene Editing, Biological Assay
Abstract

Human induced pluripotent stem cell (iPSC) lines are a powerful tool for studying development and disease, but the considerable phenotypic variation between lines makes it challenging to replicate key findings and integrate data across research groups. To address this issue, we sub-cloned candidate human iPSC lines and deeply characterized their genetic properties using whole genome sequencing, their genomic stability upon CRISPR-Cas9-based gene editing, and their phenotypic properties including differentiation to commonly used cell types. These studies identified KOLF2.1J as an all-around well-performing iPSC line. We then shared KOLF2.1J with groups around the world who tested its performance in head-to-head comparisons with their own preferred iPSC lines across a diverse range of differentiation protocols and functional assays. On the strength of these findings, we have made KOLF2.1J and its gene-edited derivative clones readily accessible to promote the standardization required for large-scale collaborative science in the stem cell field.

Published
2022

21. Uncovering the genetic basis of Parkinson's disease globally: from discoveries to the clinic

Author

Lim, Shen-Yang, Tan, Ai Huey, Ahmad-Annuar, Azlina, Okubadejo, Njideka Ulunma, Lohmann, Katja, Morris, Huw R, Toh, Tzi Shin, Tay, Yi Wen, Lange, Lara M, Bandres-Ciga, Sara, Mata, Ignacio, Foo, Jia Nee, Sammler, Esther, Ooi, Joshua Chin Ern, Noyce, Alastair J, Bahr, Natascha, Luo, Wei, Ojha, Rajeev, Singleton, Andrew B, Blauwendraat, Cornelis, and Klein, Christine

Published
2024
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22. Multi-ancestry genome-wide association meta-analysis of Parkinson’s disease

Author

Kim, Jonggeol Jeffrey, Vitale, Dan, Otani, Diego Véliz, Lian, Michelle Mulan, Heilbron, Karl, Iwaki, Hirotaka, Lake, Julie, Solsberg, Caroline Warly, Leonard, Hampton, Makarious, Mary B., Tan, Eng-King, Singleton, Andrew B., Bandres-Ciga, Sara, Noyce, Alastair J., Blauwendraat, Cornelis, Nalls, Mike A., Foo, Jia Nee, and Mata, Ignacio

Published
2024
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23. MAPT H2 haplotype and risk of Pick's disease in the Pick's disease International Consortium: a genetic association study

Author

Warner, Thomas T, Jaunmuktane, Zane, Boeve, Bradley F, Duara, Ranjan, Graff-Radford, Neill R, Josephs, Keith A, Knopman, David S, Koga, Shunsuke, Murray, Melissa E, Lyons, Kelly E, Pahwa, Rajesh, Petersen, Ronald C, Whitwell, Jennifer L, Grinberg, Lea T, Miller, Bruce, Schlereth, Athena, Spina, Salvatore, Grossman, Murray, Irwin, David J, Suh, EunRan, Trojanowski, John Q, Van Deerlin, Vivianna M, Wolk, David A, Connors, Theresa R, Dooley, Patrick M, Oakley, Derek H, Aldecoa, Iban, Balasa, Mircea, Gelpi, Ellen, Borrego-Écija, Sergi, Gascon-Bayarri, Jordi, Sánchez-Valle, Raquel, Sanz-Cartagena, Pilar, Piñol-Ripoll, Gerard, Bigio, Eileen H, Flanagan, Margaret E, Rogalski, Emily J, Weintraub, Sandra, Schneider, Julie A, Peng, Lihua, Zhu, Xiongwei, Chang, Koping, Troncoso, Juan C, Prokop, Stefan, Newell, Kathy L, Jones, Matthew, Richardson, Anna, Roncaroli, Federico, Snowden, Julie, Allinson, Kieren, Singh, Poonam, Serrano, Geidy E, Flowers, Xena E, Goldman, James E, Heaps, Allison C, Leskinen, Sandra P, Black, Sandra E, Masellis, Mario, King, Andrew, Al-Sarraj, Safa, Troakes, Claire, Hodges, John R, Kril, Jillian J, Kwok, John B, Piguet, Olivier, Roeber, Sigrun, Attems, Johannes, Thomas, Alan J, Evers, Bret M., Bieniek, Kevin F, Sieben, Anne A, Cras, Patrick P, De Vil, Bart B, Bird, Thomas, Castellani, Rudolph J, Chaffee, Ann, Franklin, Erin, Haroutunian, Vahram, Jacobsen, Max, Keene, Dirk, Latimer, Caitlin S, Metcalf, Jeff, Perrin, Richard J, Purohit, Dushyant P, Rissman, Robert A, Schantz, Aimee, Walker, Jamie, De Deyn, Peter P, Duyckaerts, Charles, Le Ber, Isabelle, Seilhean, Danielle, Turbant-Leclere, Sabrina, Ervin, John F, Nennesmo, Inger, Riehl, James, Nacmias, Benedetta, Finger, Elizabeth C, Blauwendraat, Cornelis, Nalls, Mike A, Singleton, Andrew B, Vitale, Dan, Cunha, Cristina, Wszolek, Zbigniew K, Valentino, Rebecca R, Scotton, William J, Roemer, Shanu F, Lashley, Tammaryn, Heckman, Michael G, Shoai, Maryam, Martinez-Carrasco, Alejandro, Tamvaka, Nicole, Walton, Ronald L, Baker, Matthew C, Macpherson, Hannah L, Real, Raquel, Soto-Beasley, Alexandra I, Mok, Kin, Revesz, Tamas, Christopher, Elizabeth A, DeTure, Michael, Seeley, William W, Lee, Edward B, Frosch, Matthew P, Molina-Porcel, Laura, Gefen, Tamar, Redding-Ochoa, Javier, Ghetti, Bernardino, Robinson, Andrew C, Kobylecki, Christopher, Rowe, James B, Beach, Thomas G, Teich, Andrew F, Keith, Julia L, Bodi, Istvan, Halliday, Glenda M, Gearing, Marla, Arzberger, Thomas, Morris, Christopher M, White, Charles L, 3rd, Mechawar, Naguib, Boluda, Susana, MacKenzie, Ian R, McLean, Catriona, Cykowski, Matthew D, Wang, Shih-Hsiu J, Graff, Caroline, Nagra, Rashed M, Kovacs, Gabor G, Giaccone, Giorgio, Neumann, Manuela, Ang, Lee-Cyn, Carvalho, Agostinho, Morris, Huw R, Rademakers, Rosa, Hardy, John A, Dickson, Dennis W, Rohrer, Jonathan D, and Ross, Owen A

Published
2024
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24. GenoML: Automated Machine Learning for Genomics

Author

Makarious, Mary B., Leonard, Hampton L., Vitale, Dan, Iwaki, Hirotaka, Saffo, David, Sargent, Lana, Dadu, Anant, Castaño, Eduardo Salmerón, Carter, John F., Maleknia, Melina, Botia, Juan A., Blauwendraat, Cornelis, Campbell, Roy H., Hashemi, Sayed Hadi, Singleton, Andrew B., Nalls, Mike A., and Faghri, Faraz

Subjects
Computer Science - Machine Learning, Quantitative Biology - Quantitative Methods
Abstract

GenoML is a Python package automating machine learning workflows for genomics (genetics and multi-omics) with an open science philosophy. Genomics data require significant domain expertise to clean, pre-process, harmonize and perform quality control of the data. Furthermore, tuning, validation, and interpretation involve taking into account the biology and possibly the limitations of the underlying data collection, protocols, and technology. GenoML's mission is to bring machine learning for genomics and clinical data to non-experts by developing an easy-to-use tool that automates the full development, evaluation, and deployment process. Emphasis is put on open science to make workflows easily accessible, replicable, and transferable within the scientific community. Source code and documentation is available at https://genoml.com.

Published
2021

25. Genetic Stratification of Age‐Dependent Parkinson's Disease Risk by Polygenic Hazard Score

Author

Pihlstrøm, Lasse, Fan, Chun C, Frei, Oleksandr, Tan, Manuela, Karunamuni, Roshan A, Blauwendraat, Cornelis, Bandres‐Ciga, Sara, Gan‐Or, Ziv, Grosset, Donald G, Consortium, International Parkinson's Disease Genomics, Dale, Anders M, Seibert, Tyler M, and Andreassen, Ole A

Subjects
Neurodegenerative, Aging, Brain Disorders, Neurosciences, Prevention, Patient Safety, Parkinson's Disease, Detection, screening and diagnosis, Aetiology, 4.1 Discovery and preclinical testing of markers and technologies, 2.1 Biological and endogenous factors, Neurological, Biomarkers, Humans, Incidence, Multifactorial Inheritance, Parkinson Disease, Risk Factors, Parkinson's disease, age at onset, genetics, polygenic score, prediction, International Parkinson's Disease Genomics Consortium, Clinical Sciences, Human Movement and Sports Sciences, Neurology & Neurosurgery
Abstract

BackgroundParkinson'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.ObjectivesWe aimed to develop and validate a polygenic hazard score model in sporadic PD.MethodsUsing 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.ResultsA 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.ConclusionsWe 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.

Published
2022

26. Insights into the mechanisms and structure of breakage-fusion-bridge cycles in cervical cancer using long-read sequencing

Author

Rodriguez, Isabel, Rossi, Nicole M., Keskus, Ayse G., Xie, Yi, Ahmad, Tanveer, Bryant, Asher, Lou, Hong, Paredes, Jesica Godinez, Milano, Rose, Rao, Nina, Tulsyan, Sonam, Boland, Joseph F., Luo, Wen, Liu, Jia, O’Hanlon, Tim, Bess, Jazmyn, Mukhina, Vera, Gaykalova, Daria, Yuki, Yuko, Malik, Laksh, Billingsley, Kimberley J., Blauwendraat, Cornelis, Carrington, Mary, Yeager, Meredith, Mirabello, Lisa, Kolmogorov, Mikhail, and Dean, Michael

Published
2024
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27. A multi-omics dataset for the analysis of frontotemporal dementia genetic subtypes

Author

Menden, Kevin, Francescatto, Margherita, Nyima, Tenzin, Blauwendraat, Cornelis, Dhingra, Ashutosh, Castillo-Lizardo, Melissa, Fernandes, Noémia, Kaurani, Lalit, Kronenberg-Versteeg, Deborah, Atasu, Burcu, Sadikoglou, Eldem, Borroni, Barbara, Rodriguez-Nieto, Salvador, Simon-Sanchez, Javier, Fischer, Andre, Craig, David Wesley, Neumann, Manuela, Bonn, Stefan, Rizzu, Patrizia, and Heutink, Peter

Published
2023
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28. Author Correction: Elucidating causative gene variants in hereditary Parkinson’s disease in the Global Parkinson’s Genetics Program (GP2)

Author

Lange, Lara M., Avenali, Micol, Ellis, Melina, Illarionova, Anastasia, Keller Sarmiento, Ignacio J., Tan, Ai-Huey, Madoev, Harutyun, Galandra, Caterina, Junker, Johanna, Roopnarain, Karisha, Solle, Justin, Wegel, Claire, Fang, Zih-Hua, Heutink, Peter, Kumar, Kishore R., Lim, Shen-Yang, Valente, Enza Maria, Nalls, Mike, Blauwendraat, Cornelis, Singleton, Andrew, Mencacci, Niccolo, Lohmann, Katja, and Klein, Christine

Published
2023
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29. Defining the causes of sporadic Parkinson’s disease in the global Parkinson’s genetics program (GP2)

Author

Towns, Clodagh, Richer, Madeleine, Jasaityte, Simona, Stafford, Eleanor J., Joubert, Julie, Antar, Tarek, Martinez-Carrasco, Alejandro, Makarious, Mary B., Casey, Bradford, Vitale, Dan, Levine, Kristin, Leonard, Hampton, Pantazis, Caroline B., Screven, Laurel A., Hernandez, Dena G., Wegel, Claire E., Solle, Justin, Nalls, Mike A., Blauwendraat, Cornelis, Singleton, Andrew B., Tan, Manuela M. X., Iwaki, Hirotaka, and Morris, Huw R.

Published
2023
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30. Genome-wide case-only analysis of gene-gene interactions with known Parkinson’s disease risk variants reveals link between LRRK2 and SYT10

Author

Aleknonytė-Resch, Milda, Trinh, Joanne, Leonard, Hampton, Delcambre, Sylvie, Leitão, Elsa, Lai, Dongbing, Smajić, Semra, Orr-Urtreger, Avi, Thaler, Avner, Blauwendraat, Cornelis, Sharma, Arunabh, Makarious, Mary B., Kim, Jonggeol Jeff, Lake, Julie, Rahmati, Pegah, Freitag-Wolf, Sandra, Seibler, Philip, Foroud, Tatiana, Singleton, Andrew B., Grünewald, Anne, Kaiser, Frank, Klein, Christine, Krawczak, Michael, and Dempfle, Astrid

Published
2023
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31. Elucidating causative gene variants in hereditary Parkinson’s disease in the Global Parkinson’s Genetics Program (GP2)

Author

Lange, Lara M., Avenali, Micol, Ellis, Melina, Illarionova, Anastasia, Keller Sarmiento, Ignacio J., Tan, Ai-Huey, Madoev, Harutyun, Galandra, Caterina, Junker, Johanna, Roopnarain, Karisha, Solle, Justin, Wegel, Claire, Fang, Zih-Hua, Heutink, Peter, Kumar, Kishore R., Lim, Shen-Yang, Valente, Enza Maria, Nalls, Mike, Blauwendraat, Cornelis, Singleton, Andrew, Mencacci, Niccolo, Lohmann, Katja, and Klein, Christine

Published
2023
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32. Author Correction: The IPDGC/GP2 Hackathon - an open science event for training in data science, genomics, and collaboration using Parkinson’s disease data

Author

Leonard, Hampton L., Murtadha, Ruqaya, Martinez-Carrasco, Alejandro, Jama, Alina, Müller-Nedebock, Amica Corda, Gil-Martinez, Ana-Luisa, Illarionova, Anastasia, Moore, Anni, Bustos, Bernabe I., Jadhav, Bharati, Huxford, Brook, Storm, Catherine, Towns, Clodagh, Vitale, Dan, Chetty, Devina, Yu, Eric, Grenn, Francis P., Salazar, Gabriela, Rateau, Geoffrey, Iwaki, Hirotaka, Elsayed, Inas, Foote, Isabelle Francesca, Jansen van Rensburg, Zuné, Kim, Jonggeol Jeff, Yuan, Jie, Lake, Julie, Brolin, Kajsa, Senkevich, Konstantin, Wu, Lesley, Tan, Manuela M. X., Periñán, María Teresa, Makarious, Mary B., Ta, Michael, Pillay, Nikita Simone, Betancor, Oswaldo Lorenzo, Reyes-Pérez, Paula R., Alvarez Jerez, Pilar, Saini, Prabhjyot, al-Ouran, Rami, Sivakumar, Ramiya, Real, Raquel, Reynolds, Regina H., Hu, Ruifneg, Abrahams, Shameemah, Rao, Shilpa C., Antar, Tarek, Leal, Thiago Peixoto, Iankova, Vassilena, Scotton, William J., Song, Yeajin, Singleton, Andrew, Nalls, Mike A., Dey, Sumit, Bandres-Ciga, Sara, Blauwendraat, Cornelis, and Noyce, Alastair J.

Published
2023
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33. Genome-wide association study using whole-genome sequencing identifies risk loci for Parkinson’s disease in Chinese population

Author

Pan, Hongxu, Liu, Zhenhua, Ma, Jinghong, Li, Yuanyuan, Zhao, Yuwen, Zhou, Xiaoxia, Xiang, Yaqin, Wang, Yige, Zhou, Xun, He, Runcheng, Xie, Yali, Zhou, Qiao, Yuan, Kai, Xu, Qian, Sun, Qiying, Wang, Junling, Yan, Xinxiang, Zhang, Hainan, Wang, Chunyu, Lei, Lifang, Liu, Weiguo, Wang, Xuejing, Ding, Xuebing, Wang, Tao, Xue, Zheng, Zhang, Zhentao, Chen, Ling, Wang, Qing, Liu, Yonghong, Tang, Jiayu, Zhang, Xuewei, Peng, Shifang, Wang, Chaodong, Ding, Jianqing, Liu, Chunfeng, Wang, Lijuan, Chen, Haibo, Shen, Lu, Jiang, Hong, Wu, Xinyin, Tan, Hongzhuan, Luo, Dan, Xiao, Shuiyuan, Chen, Xiang, Tan, Jieqiong, Hu, Zhengmao, Chen, Chao, Xia, Kun, Zhang, Zhuohua, Foo, Jia Nee, Blauwendraat, Cornelis, Nalls, Mike A., Singleton, Andrew B., Liu, Jun, Chan, Piu, Zheng, Houfeng, Li, Jinchen, Guo, Jifeng, Yang, Jian, and Tang, Beisha

Published
2023
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34. The IPDGC/GP2 Hackathon - an open science event for training in data science, genomics, and collaboration using Parkinson’s disease data

Author

Leonard, Hampton L., Murtadha, Ruqaya, Martinez-Carrasco, Alejandro, Jama, Alina, Müller-Nedebock, Amica Corda, Gil-Martinez, Ana-Luisa, Illarionova, Anastasia, Moore, Anni, Bustos, Bernabe I., Jadhav, Bharati, Huxford, Brook, Storm, Catherine, Towns, Clodagh, Vitale, Dan, Chetty, Devina, Yu, Eric, Grenn, Francis P., Salazar, Gabriela, Rateau, Geoffrey, Iwaki, Hirotaka, Elsayed, Inas, Foote, Isabelle Francesca, Jansen van Rensburg, Zuné, Kim, Jonggeol Jeff, Yuan, Jie, Lake, Julie, Brolin, Kajsa, Senkevich, Konstantin, Wu, Lesley, Tan, Manuela M. X., Periñán, María Teresa, Makarious, Mary B., Ta, Michael, Pillay, Nikita Simone, Betancor, Oswaldo Lorenzo, Reyes-Pérez, Paula R., Alvarez Jerez, Pilar, Saini, Prabhjyot, al-Ouran, Rami, Sivakumar, Ramiya, Real, Raquel, Reynolds, Regina H., Hu, Ruifneg, Abrahams, Shameemah, Rao, Shilpa C., Antar, Tarek, Leal, Thiago Peixoto, Iankova, Vassilena, Scotton, William J., Song, Yeajin, Singleton, Andrew, Nalls, Mike A., Dey, Sumit, Bandres-Ciga, Sara, Blauwendraat, Cornelis, and Noyce, Alastair J.

Published
2023
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35. Exploring the genetic and genomic connection underlying neurodegeneration with brain iron accumulation and the risk for Parkinson’s disease

Author

Alvarez Jerez, Pilar, Alcantud, Jose Luis, de los Reyes-Ramírez, Lucia, Moore, Anni, Ruz, Clara, Vives Montero, Francisco, Rodriguez-Losada, Noela, Saini, Prabhjyot, Gan-Or, Ziv, Alvarado, Chelsea X., Makarious, Mary B., Billingsley, Kimberley J., Blauwendraat, Cornelis, Noyce, Alastair J., Singleton, Andrew B., Duran, Raquel, and Bandres-Ciga, Sara

Published
2023
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37. Genetic Stratification of Age-Dependent Parkinson's Disease Risk by Polygenic Hazard Score.

Author

Pihlstrøm, Lasse, Fan, Chun C, Frei, Oleksandr, Tan, Manuela, Karunamuni, Roshan A, Blauwendraat, Cornelis, Bandres-Ciga, Sara, Gan-Or, Ziv, Grosset, Donald G, International Parkinson's Disease Genomics Consortium (IPDGC), Dale, Anders M, Seibert, Tyler M, and Andreassen, Ole A

Subjects
International Parkinson's Disease Genomics Consortium, Parkinson's disease, age at onset, genetics, polygenic score, prediction, Neurodegenerative, Prevention, Aging, Parkinson's Disease, Neurosciences, Patient Safety, Brain Disorders, 2.1 Biological and endogenous factors, 4.1 Discovery and preclinical testing of markers and technologies, Neurological, Neurology & Neurosurgery, Clinical Sciences, Human Movement and Sports Sciences
Abstract

BackgroundParkinson'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.ObjectivesWe aimed to develop and validate a polygenic hazard score model in sporadic PD.MethodsUsing 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.ResultsA 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.ConclusionsWe 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.

Published
2021

38. Identification of genetic risk loci and causal insights associated with Parkinson's disease in African and African admixed populations: a genome-wide association study

Author

Okubadejo, Njideka, Ojo, Oluwadamilola, Abiodun, Oladunni, Achoru, Charles, Agabi, Osigwe, Agulanna, Uchechi, Akinyemi, Rufus, Ali, Mohammed, Ani-Osheku, Ifeyinwa, Arigbodi, Ohwotemu, Bello, Abiodun, Erameh, Cyril, Farombi, Temitope, Fawale, Michael, Imarhiagbe, Frank, Iwuozo, Emmanuel, Komolafe, Morenikeji, Nwani, Paul, Nwazor, Ernest, Nyandaiti, Yakub, Obiabo, Yahaya, Odeniyi, Olanike, Odiase, Francis, Ojini, Francis, Onwuegbuzie, Gerald, Osaigbovo, Godwin, Osemwegie, Nosakhare, Oshinaike, Olajumoke, Otubogun, Folajimi, Oyakhire, Shyngle, Ozomma, Simon, Samuel, Sarah, Taiwo, Funmilola, Wahab, Kolawole, Zubair, Yusuf, Gams Massi, Daniel, Gueumekane Bila lamou, Eric, Njamnshi Nfor, Leonard, Magnerou, Mélanie Annick, Fogang Fogoum, Yannick, Shalash, Ali, El-FawaI, Hassan, Khedr, Eman, Fawi, Gharib, A. Eltantawi, Mohamed, Salama, Mohamed, El-Jaafary, Shaimaa, Hamed, Sharifa, Tafesse Mengesha, Abenet, Alemayehu Ayele, Biniyam, Melka Oda, Dereje, Zenebe Zewde, Yared, Debebe Gelan, Yohanesse, AkpaIu, Albert, Charway-Felli, Augustina, Stephen Sarfo, Fred, Adjei, Patrick, Obese, Vida, Bocoum, Abdoulaye, Koita, Abdou, Oumar Guinto, Cheick, Coulibaly, Toumany, Maiga, Youssoufa, Kone, Zaynab, Bell, Abiodun, Adebowale, Akintunde A., Akpekpe, John, lyagba, Alagoma, Wulgo, Ali Mohammed, Arabambi, Babawale, Agu, Christian, Dike, Franklin, Ishola, Ismail, Abiodun, Kehinde, Ekenze, Oluchi, Agabi Osigwe, Paul, Balarabe, Salisu, Abubakar, Sani, Williams, Uduak, Fall, Maouly, Mamadou Diop, Alassane, Hilaire Dominique, Ewodo Touna, Mochan, Andre, Modi, Girish, Dindayal, Saiesha, Ali Awadelkareem, Eman, Elsayed, Inas, Dahawi, Maha, Awadelkareem, Mosab Ali, Misbah, Sarah, Mushengez, Brighton, Kimambo, Henrika, Msango, Leonard, Adebayo, Philip, OKeng, Kigocha, Diekker, Marieke, URassa, Sarah, Gouider, Riadh, Ben Djebara, Mouna, Gargouri, Amina, Kacem, Imen, Nasri, Amina, Mrabet, Saloua, Sghaier, Ikram, Mkada, Imen, Atadzhanov, Masharip, Chishimba, Lorraine, Rizig, Mie, Jama, Fatumah, Okunoye, Olaitan, Hardy, John, Houlden, Henry, Singleton, Andrew, Nalls, Mike, Shamim, Ejaz, Jonas, Cabell, Williamson, Jared, Hall, Deborah A., Rosenbaum, Marc, Davis, Staci, Dean, Marissa, Cromer, Candace, Smith, Jenna, Ruffrage, Lauren, Richardson, Joseph, Sipma, Rebeka, Xie, Tao, Padmanaban, Manesh, Warren, Natalie, Mercado, Tomas, Disbrow, Elizabeth, Chauppeta, Brian, Thomas-Dean, Fermine, Toms, Jamie, Lofton, Katelyn, Rawls, Ashley, Rizer, Kyle, Black, Nieci, Solle, Justin, O'Grady, Alyssa, Sherer, Todd, Fiske, Brian, Başak, A. Nazlı, Tan, Ai Huey, Noyce, Alastair, Akpalu, Albert, Espay, Alberto, Martínez-Carrasco, Alejandro, Medina, Alex, Zimprich, Alexander, Brice, Alexis, Karimova, Altynay, Hernandez, Alvaro, Illarionova, Anastasia, Quattrone, Andrea, Singleton, Andrew B, Sobering, Andrew K., Vinuela, Angel, Sanyaolu, Arinola, Schumacher-Schuh, Artur F., Kishore, Asha, Ahmad-Annuar, Azlina, Al Mubarak, Bashayer, Tang, Beisha, Pizarro Galleguillos, Benjamin, Jeon, Beomseok, Siddiqi, Bernadette, Casey, Bradford, Mollenhauer, Brit, Carroll, Camille, Rieder, Carlos, Pantazis, Caroline B., Comart, Charisse, Lin, Chin-Hsien, Klein, Christine, Bale, Claire, Shepherd, Claire E, Wegel, Claire, Blauwendraat, Cornelis, Vitale, Dan, Martinez-Ramirez, Daniel, Hall, Deborah, Hernandez, Dena, KP, Divya, Nguyen, Duan, Fon, Edward A., Dadiotis, Efthymios, Riley, Ekemini, Iakovenko, Elena, Stafford, Ellie, Gatto, Emilia M, Valente, Enza Maria, Vollstedt, Eva-Juliane, Faghri, Faraz, Genc, Gencer, Xiromerisiou, Georgia, Hadjigorgiou, Georgios, Hiu-Fai Chan, Germaine, Arboleda, Gonzalo, Kaishibayeva, Gulnaz, Höglinger, Günter, Leonard, Hampton, Madoev, Harutyun, Iwaki, Hirotaka, Chen, Honglei, Wu, Hsiu-Chuan, Shang, Huifang, Morris, Huw R, F. Mata, Ignacio, Keller Sarmiento, Ignacio Juan, Dagklis, Ioannis, Tarnanas, Ioannis, Aasly, Jan O., Hoenicka, Janet, Corvol, Jean-Christophe, Foo, Jia Nee, Guo, Jifeng, Junker, Johanna, Carr, Jonathan, Kim, Jonggeol Jeff, Orozco, Jorge, Jankovic, Joseph, Shulman, Joshua, Hunter, Julie, Solle, Justin C., Murphy, Kaileigh, Nuytemans, Karen, Kieburtz, Karl, Lohmann, Katja, Marek, Kenneth, Mok, Kin Ying, Kumar, Kishore, Levine, Kristin, Chahine, Lana M., Lange, Lara M., Pihlstrøm, Lasse, Screven, Laurel, Stefanis, Leonidas, Shulman, Lisa, Marsili, Luca, Parnetti, Lucilla, Kuhl, Maggie, Funayama, Manabu, Sharma, Manu, Tan, Manuela, Kauffman, Marcelo, Miranda, Marcelo, Bustamante, Maria Leonor, Stamelou, Maria, Periñan Tocino, Maria Teresa, Cornejo-Olivas, Mario, Jimenez del Rio, Marlene, Makarious, Mary B, Koretsky, Mathew, Rodriguez-Violante, Mayela, Ellis, Melina, Avenali, Micol, Rentería, Miguel E., Inca-Martines, Miguel z, Nalls, Mike A., Ibrahim Norlinah, Mohamed, Umair, Muhammad, Ip, Nancy, Louie, Naomi, Cheung, Nelson Yuk-Fai, Mencacci, Niccolò Emanuele, Wood, Nicholas, Williams, Nigel, Hattori, Nobutaka, Abdul Murad, Nor Azian, Ibrahim, Norlinah Mohamed, Monchi, Oury, Öztop Çakmak, Özgür, Öztop Çakmak, Patricio Öztop Çakmak, Lewis, Patrick Alfryn, Pastor, Pau, Reyes-Pérez, Paula, Saffie Awad, Paula, Chana, Pedro, Chan, Phillip, Kung, Pin-Jui, Chan, Piu, Pal, Pramod, Lingappa Kukkle, Prashanth, Ojha, Rajeev, Kaiyrzhanov, Rauan, Krüger, Rejko, Amouri, Rim, Weil, Rimona, Rajan, Roopa, Alcalay, Roy, Wu, Ruey-Meei, Borgohain, Rupam, Sassi, Samia Ben, Khachatryan, Samson, Bandres-Ciga, Sara, El-Sadig, Sarah, Wu, Serena, Groppa, Sergio, Azmin, Shahrul, Lim, Shen-Yang, Ur-Rehman, Shoaib, Ertan, Sibel, Stott, Simon, Jasaitye, Simona, Chowdhury, Sohini, Dumanis, Sonya, Bardien, Soraya, Lubbe, Steven, Koks, Sulev, Dey, Sumit, Foroud, Tatiana, Fon, Ted, Beach, Thomas, Gasser, Thomas, Anderson, Tim, Nguyen, Toan, Schirinzi, Tommaso, Shiraishi, Tomotaka, Pitcher, Toni, Tumas, Vitor, Mohamed, Wael, Kamel, Walaa A., Luo, Wei, Zhou, Xiaopu, Zewde, Yared Z., Song, Yeajin, Wen, Yi, Wu, Yihru, Joong Kim, Yun, Tavadyan, Zaruhi, Fang, Zih-Hua, Ojo, Oluwadamilola Omolara, Crea, Peter Wild, Abiodun, Oladunni Victoria, Levine, Kristin S, Abubakar, Sani Atta, Achoru, Charles Obiora, Adeniji, Olaleye Akinmola, Agabi, Osigwe Paul, Koretsky, Mathew J, Hall, Deborah A, Akinyemi, Rufus Olusola, Ali, Mohammed Wulgo, Shamim, Ejaz A, Padmanaban, Mahesh, Arigbodi, Ohwotemu Michael, Standaert, David G, Bello, Abiodun Hamzat, Dean, Marissa N, Erameh, Cyril Oshomah, Farombi, Temitope Hannah, Fawale, Michael Bimbola, Billingsley, Kimberley J, Imarhiagbe, Frank Aiwansoba, Jerez, Pilar Alvarez, Iwuozo, Emmanuel Uzodinma, Baker, Breeana, Komolafe, Morenikeji Adeyoyin, Malik, Laksh, Nwani, Paul Osemeke, Daida, Kensuke, Nwazor, Ernest Okwundu, Miano-Burkhardt, Abigail, Nyandaiti, Yakub Wilberforce, Obiabo, Yahaya Olugbo, Kluss, Jillian H, Odeniyi, Olanike Adedoyin, Hernandez, Dena G, Odiase, Francis Ehidiamen, Tayebi, Nahid, Ojini, Francis Ibe, Sidranksy, Ellen, Onwuegbuzie, Gerald Awele, D'Souza, Andrea M, Osaigbovo, Godwin Osawaru, Berhe, Bahafta, Reed, Xylena, Oshinaike, Olajumoke Olufemi, Leonard, Hampton L, Otubogun, Folajimi Morenikeji, Alvarado, Chelsea X, Oyakhire, Shyngle Imiewan, Ozomma, Simon Izuchukwu, Samuel, Sarah Chabiri, Taiwo, Funmilola Tolulope, Wahab, Kolawole Wasiu, Zubair, Yusuf Agboola, Kim, Jonggeol Jeffrey, Nalls, Mike A, Heilbron, Karl, Norcliffe-Kaufmann, Lucy, and Okubadejo, Njideka Ulunma

Published
2023
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39. Genome sequencing analysis identifies new loci associated with Lewy body dementia and provides insights into its genetic architecture

Author

Chia, Ruth, Sabir, Marya S, Bandres-Ciga, Sara, Saez-Atienzar, Sara, Reynolds, Regina H, Gustavsson, Emil, Walton, Ronald L, Ahmed, Sarah, Viollet, Coralie, Ding, Jinhui, Makarious, Mary B, Diez-Fairen, Monica, Portley, Makayla K, Shah, Zalak, Abramzon, Yevgeniya, Hernandez, Dena G, Blauwendraat, Cornelis, Stone, David J, Eicher, John, Parkkinen, Laura, Ansorge, Olaf, Clark, Lorraine, Honig, Lawrence S, Marder, Karen, Lemstra, Afina, St George-Hyslop, Peter, Londos, Elisabet, Morgan, Kevin, Lashley, Tammaryn, Warner, Thomas T, Jaunmuktane, Zane, Galasko, Douglas, Santana, Isabel, Tienari, Pentti J, Myllykangas, Liisa, Oinas, Minna, Cairns, Nigel J, Morris, John C, Halliday, Glenda M, Van Deerlin, Vivianna M, Trojanowski, John Q, Grassano, Maurizio, Calvo, Andrea, Mora, Gabriele, Canosa, Antonio, Floris, Gianluca, Bohannan, Ryan C, Brett, Francesca, Gan-Or, Ziv, Geiger, Joshua T, Moore, Anni, May, Patrick, Krüger, Rejko, Goldstein, David S, Lopez, Grisel, Tayebi, Nahid, Sidransky, Ellen, Norcliffe-Kaufmann, Lucy, Palma, Jose-Alberto, Kaufmann, Horacio, Shakkottai, Vikram G, Perkins, Matthew, Newell, Kathy L, Gasser, Thomas, Schulte, Claudia, Landi, Francesco, Salvi, Erika, Cusi, Daniele, Masliah, Eliezer, Kim, Ronald C, Caraway, Chad A, Monuki, Edwin S, Brunetti, Maura, Dawson, Ted M, Rosenthal, Liana S, Albert, Marilyn S, Pletnikova, Olga, Troncoso, Juan C, Flanagan, Margaret E, Mao, Qinwen, Bigio, Eileen H, Rodríguez-Rodríguez, Eloy, Infante, Jon, Lage, Carmen, González-Aramburu, Isabel, Sanchez-Juan, Pascual, Ghetti, Bernardino, Keith, Julia, Black, Sandra E, Masellis, Mario, Rogaeva, Ekaterina, Duyckaerts, Charles, Brice, Alexis, Lesage, Suzanne, Xiromerisiou, Georgia, Barrett, Matthew J, Tilley, Bension S, Gentleman, Steve, Logroscino, Giancarlo, and Serrano, Geidy E

Subjects
Biological Sciences, Genetics, Human Genome, Alzheimer's Disease Related Dementias (ADRD), Prevention, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Alzheimer's Disease, Aging, Dementia, Brain Disorders, Acquired Cognitive Impairment, Lewy Body Dementia, Biotechnology, Parkinson's Disease, Neurosciences, Neurodegenerative, 2.1 Biological and endogenous factors, Aetiology, Neurological, Adaptor Proteins, Signal Transducing, Alzheimer Disease, Case-Control Studies, Gene Expression Profiling, Genetic Predisposition to Disease, Genome, Human, Genome-Wide Association Study, Glucosylceramidase, Humans, Lewy Body Disease, Nuclear Proteins, Parkinson Disease, Polymorphism, Single Nucleotide, Tumor Suppressor Proteins, alpha-Synuclein, American Genome Center, Medical and Health Sciences, Developmental Biology, Agricultural biotechnology, Bioinformatics and computational biology
Abstract

The genetic basis of Lewy body dementia (LBD) is not well understood. Here, we performed whole-genome sequencing in large cohorts of LBD cases and neurologically healthy controls to study the genetic architecture of this understudied form of dementia, and to generate a resource for the scientific community. Genome-wide association analysis identified five independent risk loci, whereas genome-wide gene-aggregation tests implicated mutations in the gene GBA. Genetic risk scores demonstrate that LBD shares risk profiles and pathways with Alzheimer's disease and Parkinson's disease, providing a deeper molecular understanding of the complex genetic architecture of this age-related neurodegenerative condition.

Published
2021

40. Correction: Identification of genetic risk loci and prioritization of genes and pathways for myasthenia gravis: a genome-wide association study

Author

International Myasthenia Gravis Genomics Consortium, Chia, Ruth, Saez-Atienzar, Sara, Murphy, Natalie, Chiò, Adriano, Blauwendraat, Cornelis, Roda, Ricardo H., Tienari, Pentti J., Kaminski, Henry J., Ricciardi, Roberta, Guida, Melania, De Rosa, Anna, Petrucci, Loredana, Evoli, Amelia, Provenzano, Carlo, Drachman, Daniel B., and Traynor, Bryan J.

Published
2022

41. Longitudinal Measurements of Glucocerebrosidase activity in Parkinson’s patients

Author

Alcalay, Roy N, Wolf, Pavlina, Chiang, Ming Sum Ruby, Helesicova, Karolina, Zhang, Xiaokui Kate, Merchant, Kalpana, Hutten, Samantha J, Scherzer, Clemens, Caspell‐Garcia, Chelsea, Blauwendraat, Cornelis, Foroud, Tatiana, Nudelman, Kelly, Gan‐Or, Ziv, Simuni, Tanya, Chahine, Lana M, Levy, Oren, Zheng, Dandi, Li, Sardi, Sergio Pablo, Marek, Kenneth, Siderowf, Andrew, Seibyl, John, Coffey, Christopher, Tanner, Caroline, Tosun‐Turgut, Duygu, Shaw, Leslie M, Trojanowski, John Q, Singleton, Andrew, Kieburtz, Karl, Toga, Arthur, Mollenhauer, Brit, Galasko, Douglas, Poewe, Werner, Poston, Kathleen, Bressman, Susan, Reimer, Alyssa, Arnedo, Vanessa, Clark, Adrienne, Frasier, Mark, Kopil, Catherine, Chowdhury, Sohini, Sherer, Todd, Casaceli, Cynthia, Dorsey, Ray, Wilson, Renee, Mahes, Sugi, Salerno, Christina, Crawford, Karen, Casalin, Paola, Malferrari, Giulia, Weisz, Mali Gani, Orr‐Urtreger, Avi, Montine, Thomas, Baglieri, Chris, Christini, Amanda, Russell, David, Dahodwala, Nabila, Giladi, Nir, Factor, Stewart, Hogarth, Penelope, Standaert, David, Hauser, Robert, Jankovic, Joseph, Saint‐Hilaire, Marie, Richard, Irene, Shprecher, David, Fernandez, Hubert, Brockmann, Katrina, Rosenthal, Liana, Barone, Paolo, Espay, Alberto, Rowe, Dominic, Marder, Karen, Santiago, Anthony, Hu, Shu‐Ching, Isaacson, Stuart, Martinez, Javiar Ruiz, Tolosa, Eduardo, Tai, Yen, Politis, Marios, Smejdir, Debra, Rees, Linda, Williams, Karen, Kausar, Farah, Richardson, Whitney, Willeke, Diana, Peacock, Shawnees, Sommerfeld, Barbara, Freed, Alison, Wakeman, Katrina, Blair, Courtney, Guthrie, Stephanie, Harrell, Leigh, Hunter, Christine, Thomas, Cathi‐Ann, James, Raymond, Zimmerman, Grace, Brown, Victoria, and Mule, Jennifer

Subjects
Clinical and Health Psychology, Biomedical and Clinical Sciences, Neurosciences, Psychology, Human Genome, Parkinson's Disease, Neurodegenerative, Brain Disorders, Aging, Genetics, Neurological, Adult, Dementia, Disease Progression, Female, Genotype, Glucosylceramidase, Heterozygote, Humans, Male, Mental Status and Dementia Tests, Middle Aged, Mutation, Parkinson Disease, Phenotype, Parkinson’s Progression Markers Initiative, Clinical Sciences, Clinical and health psychology
Abstract

ObjectiveReduction in glucocerebrosidase (GCase; encoded by GBA) enzymatic activity has been linked to Parkinson's disease (PD). Here, we correlated GCase activity and PD phenotype in the Parkinson's Progression Markers Initiative (PPMI) cohort.MethodsWe measured GCase activity in dried blood spots from 1559 samples of participants in the inception PPMI cohort, collected in four annual visits (from baseline visit to Year-3). Participants (PD, n = 392; controls, n = 175) were fully sequenced for GBA variants by means of genome-wide genotyping arrays, whole-exome sequencing, whole-genome sequencing, Sanger sequencing, and RNA-sequencing.ResultsFifty-two PD participants (13.4%) and 13 (7.4%) controls carried a GBA variant. GBA status was strongly associated with GCase activity. Among noncarriers, GCase activity was similar between PD and controls. Among GBA p.E326K carriers (PD, n = 20; controls, n = 5), activity was significantly lower in PD carriers than control carriers (9.53 µmol/L/h vs. 11.68 µmol/L/h, P = 0.035). Glucocerebrosidase activity was moderately (r = 0.45) associated with white blood cell (WBC) count. Next, we divided the noncarriers with PD to tertiles based on WBC count-corrected enzymatic activity. Members of the lower tertile had higher MDS-Unified Parkinson's Disease Rating Scale motor score in the "off" medication examination at year-III exam. Longitudinal analyses demonstrated slight reduction of activity in samples collected earlier on in the study, likely because of longer storage time.InterpretationGCase activity is associated with GBA genotype, WBC count, and among p.E326K variant carriers, with PD status. Reduced activity may also be associated with worse phenotype but longer follow up is required to confirm this observation.

Published
2020

42. Correction to: A nonsynonymous mutation in PLCG2 reduces the risk of Alzheimer's disease, dementia with Lewy bodies and frontotemporal dementia, and increases the likelihood of longevity.

Author

van der Lee, Sven J, Conway, Olivia J, Jansen, Iris, Carrasquillo, Minerva M, Kleineidam, Luca, van den Akker, Erik, Hernández, Isabel, van Eijk, Kristel R, Stringa, Najada, Chen, Jason A, Zettergren, Anna, Andlauer, Till FM, Diez-Fairen, Monica, Simon-Sanchez, Javier, Lleó, Alberto, Zetterberg, Henrik, Nygaard, Marianne, Blauwendraat, Cornelis, Savage, Jeanne E, Mengel-From, Jonas, Moreno-Grau, Sonia, Wagner, Michael, Fortea, Juan, Keogh, Michael J, Blennow, Kaj, Skoog, Ingmar, Friese, Manuel A, Pletnikova, Olga, Zulaica, Miren, Lage, Carmen, de Rojas, Itziar, Riedel-Heller, Steffi, Illán-Gala, Ignacio, Wei, Wei, Jeune, Bernard, Orellana, Adelina, Then Bergh, Florian, Wang, Xue, Hulsman, Marc, Beker, Nina, Tesi, Niccolo, Morris, Christopher M, Indakoetxea, Begoña, Collij, Lyduine E, Scherer, Martin, Morenas-Rodríguez, Estrella, Ironside, James W, van Berckel, Bart NM, Alcolea, Daniel, Wiendl, Heinz, Strickland, Samantha L, Pastor, Pau, Rodríguez Rodríguez, Eloy, DESGESCO (Dementia Genetics Spanish Consortium), EADB (Alzheimer Disease European DNA biobank), IFGC (International FTD-Genomics Consortium), IPDGC (The International Parkinson Disease Genomics Consortium), RiMod-FTD (Risk and Modifying factors in Fronto-Temporal Dementia), Netherlands Brain Bank (NBB), Boeve, Bradley F, Petersen, Ronald C, Ferman, Tanis J, van Gerpen, Jay A, Reinders, Marcel JT, Uitti, Ryan J, Tárraga, Lluís, Maier, Wolfgang, Dols-Icardo, Oriol, Kawalia, Amit, Dalmasso, Maria Carolina, Boada, Mercè, Zettl, Uwe K, van Schoor, Natasja M, Beekman, Marian, Allen, Mariet, Masliah, Eliezer, de Munain, Adolfo López, Pantelyat, Alexander, Wszolek, Zbigniew K, Ross, Owen A, Dickson, Dennis W, Graff-Radford, Neill R, Knopman, David, Rademakers, Rosa, Lemstra, Afina W, Pijnenburg, Yolande AL, Scheltens, Philip, Gasser, Thomas, Chinnery, Patrick F, Hemmer, Bernhard, Huisman, Martijn A, Troncoso, Juan, Moreno, Fermin, Nohr, Ellen A, Sørensen, Thorkild IA, Heutink, Peter, Sánchez-Juan, Pascual, Posthuma, Danielle, GIFT (Genetic Investigation in Frontotemporal Dementia and Alzheimer’s Disease) Study Group, and Clarimón, Jordi

Subjects
DESGESCO, EADB, IFGC, IPDGC, RiMod-FTD, Netherlands Brain Bank, GIFT (Genetic Investigation in Frontotemporal Dementia and Alzheimer’s Disease) Study Group, Acquired Cognitive Impairment, Brain Disorders, Neurodegenerative, Alzheimer's Disease, Dementia, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Neurosciences, Aging, Parkinson's Disease, Genetics, 2.1 Biological and endogenous factors, Neurological, Neurology & Neurosurgery, Clinical Sciences
Abstract

The IPDGC (The International Parkinson Disease Genomics Consortium) and EADB (Alzheimer Disease European DNA biobank) are listed correctly as an author to the article, however, they were incorrectly listed more than once.

Published
2020

44. Identification of novel risk loci, causal insights, and heritable risk for Parkinson's disease: a meta-analysis of genome-wide association studies

Author

Nalls, Mike A, Blauwendraat, Cornelis, Vallerga, Costanza L, Heilbron, Karl, Bandres-Ciga, Sara, Chang, Diana, Tan, Manuela, Kia, Demis A, Noyce, Alastair J, Xue, Angli, Bras, Jose, Young, Emily, von Coelln, Rainer, Simón-Sánchez, Javier, Schulte, Claudia, Sharma, Manu, Krohn, Lynne, Pihlstrøm, Lasse, Siitonen, Ari, Iwaki, Hirotaka, Leonard, Hampton, Faghri, Faraz, Gibbs, J Raphael, Hernandez, Dena G, Scholz, Sonja W, Botia, Juan A, Martinez, Maria, Corvol, Jean-Christophe, Lesage, Suzanne, Jankovic, Joseph, Shulman, Lisa M, Sutherland, Margaret, Tienari, Pentti, Majamaa, Kari, Toft, Mathias, Andreassen, Ole A, Bangale, Tushar, Brice, Alexis, Yang, Jian, Gan-Or, Ziv, Gasser, Thomas, Heutink, Peter, Shulman, Joshua M, Wood, Nicholas W, Hinds, David A, Hardy, John A, Morris, Huw R, Gratten, Jacob, Visscher, Peter M, Graham, Robert R, Singleton, Andrew B, Team, 23andMe Research, Consortium, System Genomics of Parkinson's Disease, Consortium, International Parkinson's Disease Genomics, Adarmes-Gómez, Astrid D, Aguilar, Miquel, Aitkulova, Akbota, Akhmetzhanov, Vadim, Alcalay, Roy N, Alvarez, Ignacio, Alvarez, Victoria, Barrero, Francisco Javier, Yarza, Jesús Alberto Bergareche, Bernal-Bernal, Inmaculada, Billingsley, Kimberley, Blazquez, Marta, Bonilla-Toribio, Marta, Botía, Juan A, Boungiorno, María Teresa, Brockmann, Kathrin, Bubb, Vivien, Buiza-Rueda, Dolores, Cámara, Ana, Carrillo, Fátima, Carrión-Claro, Mario, Cerdan, Debora, Chelban, Viorica, Clarimón, Jordi, Clarke, Carl, Compta, Yaroslau, Cookson, Mark R, Craig, David W, Danjou, Fabrice, Diez-Fairen, Monica, Dols-Icardo, Oriol, Duarte, Jacinto, Duran, Raquel, Escamilla-Sevilla, Francisco, Escott-Price, Valentina, Ezquerra, Mario, Feliz, Cici, Fernández, Manel, Fernández-Santiago, Rubén, and Finkbeiner, Steven

Subjects
Neurosciences, Parkinson's Disease, Brain Disorders, Aging, Biotechnology, Prevention, Genetics, Human Genome, Neurodegenerative, 2.1 Biological and endogenous factors, Aetiology, Neurological, Databases, Genetic, Genetic Loci, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Parkinson Disease, Risk Factors, 23andMe Research Team, System Genomics of Parkinson's Disease Consortium, International Parkinson's Disease Genomics Consortium, Clinical Sciences, Neurology & Neurosurgery
Abstract

BackgroundGenome-wide association studies (GWAS) in Parkinson's disease have increased the scope of biological knowledge about the disease over the past decade. We aimed to use the largest aggregate of GWAS data to identify novel risk loci and gain further insight into the causes of Parkinson's disease.MethodsWe did a meta-analysis of 17 datasets from Parkinson's disease GWAS available from European ancestry samples to nominate novel loci for disease risk. These datasets incorporated all available data. We then used these data to estimate heritable risk and develop predictive models of this heritability. We also used large gene expression and methylation resources to examine possible functional consequences as well as tissue, cell type, and biological pathway enrichments for the identified risk factors. Additionally, we examined shared genetic risk between Parkinson's disease and other phenotypes of interest via genetic correlations followed by Mendelian randomisation.FindingsBetween Oct 1, 2017, and Aug 9, 2018, we analysed 7·8 million single nucleotide polymorphisms in 37 688 cases, 18 618 UK Biobank proxy-cases (ie, individuals who do not have Parkinson's disease but have a first degree relative that does), and 1·4 million controls. We identified 90 independent genome-wide significant risk signals across 78 genomic regions, including 38 novel independent risk signals in 37 loci. These 90 variants explained 16-36% of the heritable risk of Parkinson's disease depending on prevalence. Integrating methylation and expression data within a Mendelian randomisation framework identified putatively associated genes at 70 risk signals underlying GWAS loci for follow-up functional studies. Tissue-specific expression enrichment analyses suggested Parkinson's disease loci were heavily brain-enriched, with specific neuronal cell types being implicated from single cell data. We found significant genetic correlations with brain volumes (false discovery rate-adjusted p=0·0035 for intracranial volume, p=0·024 for putamen volume), smoking status (p=0·024), and educational attainment (p=0·038). Mendelian randomisation between cognitive performance and Parkinson's disease risk showed a robust association (p=8·00 × 10-7).InterpretationThese data provide the most comprehensive survey of genetic risk within Parkinson's disease to date, to the best of our knowledge, by revealing many additional Parkinson's disease risk loci, providing a biological context for these risk factors, and showing that a considerable genetic component of this disease remains unidentified. These associations derived from European ancestry datasets will need to be followed-up with more diverse data.FundingThe National Institute on Aging at the National Institutes of Health (USA), The Michael J Fox Foundation, and The Parkinson's Foundation (see appendix for full list of funding sources).

Published
2019

45. A nonsynonymous mutation in PLCG2 reduces the risk of Alzheimer's disease, dementia with Lewy bodies and frontotemporal dementia, and increases the likelihood of longevity.

Author

van der Lee, Sven J, Conway, Olivia J, Jansen, Iris, Carrasquillo, Minerva M, Kleineidam, Luca, van den Akker, Erik, Hernández, Isabel, van Eijk, Kristel R, Stringa, Najada, Chen, Jason A, Zettergren, Anna, Andlauer, Till FM, Diez-Fairen, Monica, Simon-Sanchez, Javier, Lleó, Alberto, Zetterberg, Henrik, Nygaard, Marianne, Blauwendraat, Cornelis, Savage, Jeanne E, Mengel-From, Jonas, Moreno-Grau, Sonia, Wagner, Michael, Fortea, Juan, Keogh, Michael J, Blennow, Kaj, Skoog, Ingmar, Friese, Manuel A, Pletnikova, Olga, Zulaica, Miren, Lage, Carmen, de Rojas, Itziar, Riedel-Heller, Steffi, Illán-Gala, Ignacio, Wei, Wei, Jeune, Bernard, Orellana, Adelina, Then Bergh, Florian, Wang, Xue, Hulsman, Marc, Beker, Nina, Tesi, Niccolo, Morris, Christopher M, Indakoetxea, Begoña, Collij, Lyduine E, Scherer, Martin, Morenas-Rodríguez, Estrella, Ironside, James W, van Berckel, Bart NM, Alcolea, Daniel, Wiendl, Heinz, Strickland, Samantha L, Pastor, Pau, Rodríguez Rodríguez, Eloy, DESGESCO (Dementia Genetics Spanish Consortium), EADB (Alzheimer Disease European DNA biobank), EADB (Alzheimer Disease European DNA biobank), IFGC (International FTD-Genomics Consortium), IPDGC (The International Parkinson Disease Genomics Consortium), IPDGC (The International Parkinson Disease Genomics Consortium), RiMod-FTD (Risk and Modifying factors in Fronto-Temporal Dementia), Netherlands Brain Bank (NBB), Boeve, Bradley F, Petersen, Ronald C, Ferman, Tanis J, van Gerpen, Jay A, Reinders, Marcel JT, Uitti, Ryan J, Tárraga, Lluís, Maier, Wolfgang, Dols-Icardo, Oriol, Kawalia, Amit, Dalmasso, Maria Carolina, Boada, Mercè, Zettl, Uwe K, van Schoor, Natasja M, Beekman, Marian, Allen, Mariet, Masliah, Eliezer, de Munain, Adolfo López, Pantelyat, Alexander, Wszolek, Zbigniew K, Ross, Owen A, Dickson, Dennis W, Graff-Radford, Neill R, Knopman, David, Rademakers, Rosa, Lemstra, Afina W, Pijnenburg, Yolande AL, Scheltens, Philip, Gasser, Thomas, Chinnery, Patrick F, Hemmer, Bernhard, Huisman, Martijn A, Troncoso, Juan, Moreno, Fermin, Nohr, Ellen A, Sørensen, Thorkild IA, Heutink, Peter, Sánchez-Juan, Pascual, Posthuma, Danielle, GIFT (Genetic Investigation in Frontotemporal Dementia and Alzheimer’s Disease) Study Group, and Clarimón, Jordi

Subjects
DESGESCO (Dementia Genetics Spanish Consortium), EADB, EADB, IFGC (International FTD-Genomics Consortium), IPDGC, IPDGC, RiMod-FTD, Netherlands Brain Bank, GIFT (Genetic Investigation in Frontotemporal Dementia and Alzheimer’s Disease) Study Group, Alzheimer’s disease, Amyotrophic lateral sclerosis, Dementia with Lewy bodies, Frontotemporal dementia, Longevity, Multiple sclerosis, Neurodegenerative disease, PLCG2, Parkinson’s disease, Phospholipase C Gamma 2, Progressive supranuclear palsy, Alzheimer's disease, Parkinson's disease, Alzheimer's Disease, frontotemporal dementia, dementia with Lewy-bodies, progressive suprauclear palsy, Parkinson's Disease, amyotrophic lateral sclerosis, multiple sclerosis, neurodegenerative disease, longevity, Clinical Sciences, Neurosciences, Neurology & Neurosurgery
Abstract

The genetic variant rs72824905-G (minor allele) in the PLCG2 gene was previously associated with a reduced Alzheimer's disease risk (AD). The role of PLCG2 in immune system signaling suggests it may also protect against other neurodegenerative diseases and possibly associates with longevity. We studied the effect of the rs72824905-G on seven neurodegenerative diseases and longevity, using 53,627 patients, 3,516 long-lived individuals and 149,290 study-matched controls. We replicated the association of rs72824905-G with reduced AD risk and we found an association with reduced risk of dementia with Lewy bodies (DLB) and frontotemporal dementia (FTD). We did not find evidence for an effect on Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS) and multiple sclerosis (MS) risks, despite adequate sample sizes. Conversely, the rs72824905-G allele was associated with increased likelihood of longevity. By-proxy analyses in the UK Biobank supported the associations with both dementia and longevity. Concluding, rs72824905-G has a protective effect against multiple neurodegenerative diseases indicating shared aspects of disease etiology. Our findings merit studying the PLCγ2 pathway as drug-target.

Published
2019

46. The endocytic membrane trafficking pathway plays a major role in the risk of Parkinson's disease

Author

Bandres‐Ciga, Sara, Saez‐Atienzar, Sara, Bonet‐Ponce, Luis, Billingsley, Kimberley, Vitale, Dan, Blauwendraat, Cornelis, Gibbs, Jesse Raphael, Pihlstrøm, Lasse, Gan‐Or, Ziv, Noyce, Alastair J, Kaiyrzhanov, Rauan, Middlehurst, Ben, Kia, Demis A, Tan, Manuela, Houlden, Henry, Morris, Huw R, Plun‐Favreau, Helene, Holmans, Peter, Hardy, John, Trabzuni, Daniah, Bras, Jose, Quinn, John, Mok, Kin Y, Kinghorn, Kerri J, Wood, Nicholas W, Lewis, Patrick, Schreglmann, Sebastian, Guerreiro, Rita, Lovering, Ruth, RņBibo, Lea, Manzoni, Claudia, Rizig, Mie, Ryten, Mina, Guelfi, Sebastian, Escott‐Price, Valentina, Chelban, Viorica, Foltynie, Thomas, Williams, Nigel, Morrison, Karen E, Brice, Alexis, Danjou, Fabrice, Lesage, Suzanne, Corvol, Jean‐Christophe, Martinez, Maria, Schulte, Claudia, Brockmann, Kathrin, SimɃn‐Sȥnchez, Javier, Heutink, Peter, Rizzu, Patrizia, Sharma, Manu, Gasser, Thomas, Nicolas, Aude, Cookson, Mark R, Craig, David W, Faghri, Faraz, Gibbs, J Raphael, Hernandez, Dena G, Van Keuren‐Jensen, Kendall, Shulman, Joshua M, Iwaki, Hirotaka, Leonard, Hampton L, Nalls, Mike A, Robak, Laurie, Lubbe, Steven, Finkbeiner, Steven, Mencacci, Niccolo E, Lungu, Codrin, Singleton, Andrew B, Scholz, Sonja W, Reed, Xylena, Alcalay, Roy N, Rouleau, Guy A, Hilten, Jacobus J, Marinus, Johan, Adarmes‐GɃmez, Astrid D, Aguilar, Miquel, Alvarez, Ignacio, Alvarez, Victoria, Barrero, Francisco Javier, Yarza, Jesɐs Alberto Bergareche, Bernal‐Bernal, Inmaculada, Blazquez, Marta, Bonilla‐Toribio, Marta, Botȷa, Juan A, Boungiorno, Marȷa Teresa, Buiza‐Rueda, Dolores, Cȥmara, Ana, Carrillo, Fȥtima, CarriɃn‐Claro, Mario, Cerdan, Debora, ClarimɃn, Jordi, Compta, Yaroslau, Casa, Beatrȷz, Diez‐Fairen, Monica, Dols‐Icardo, Oriol, and Duarte, Jacinto

Subjects
Parkinson's Disease, Human Genome, Genetics, Neurosciences, Brain Disorders, Prevention, Neurodegenerative, Genetic Testing, 2.3 Psychological, social and economic factors, 2.1 Biological and endogenous factors, Aetiology, Decent Work and Economic Growth, Endocytosis, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Mendelian Randomization Analysis, Parkinson Disease, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Risk Factors, International Parkinson's Disease Genomics Consortium, Parkinson's disease, endocytosis, genetic risk, heritability, polygenic risk score, Clinical Sciences, Human Movement and Sports Sciences, Neurology & Neurosurgery
Abstract

BackgroundPD is a complex polygenic disorder. In recent years, several genes from the endocytic membrane-trafficking pathway have been suggested to contribute to disease etiology. However, a systematic analysis of pathway-specific genetic risk factors is yet to be performed.ObjectivesTo comprehensively study the role of the endocytic membrane-trafficking pathway in the risk of PD.MethodsLinkage disequilibrium score regression was used to estimate PD heritability explained by 252 genes involved in the endocytic membrane-trafficking pathway including genome-wide association studies data from 18,869 cases and 22,452 controls. We used pathway-specific single-nucleotide polymorphisms to construct a polygenic risk score reflecting the cumulative risk of common variants. To prioritize genes for follow-up functional studies, summary-data based Mendelian randomization analyses were applied to explore possible functional genomic associations with expression or methylation quantitative trait loci.ResultsThe heritability estimate attributed to endocytic membrane-trafficking pathway was 3.58% (standard error = 1.17). Excluding previously nominated PD endocytic membrane-trafficking pathway genes, the missing heritability was 2.21% (standard error = 0.42). Random heritability simulations were estimated to be 1.44% (standard deviation = 0.54), indicating that the unbiased total heritability explained by the endocytic membrane-trafficking pathway was 2.14%. Polygenic risk score based on endocytic membrane-trafficking pathway showed a 1.25 times increase of PD risk per standard deviation of genetic risk. Finally, Mendelian randomization identified 11 endocytic membrane-trafficking pathway genes showing functional consequence associated to PD risk.ConclusionsWe provide compelling genetic evidence that the endocytic membrane-trafficking pathway plays a relevant role in disease etiology. Further research on this pathway is warranted given that critical effort should be made to identify potential avenues within this biological process suitable for therapeutic interventions. © 2019 International Parkinson and Movement Disorder Society.

Published
2019

47. Mitochondria function associated genes contribute to Parkinson’s Disease risk and later age at onset

Author

Billingsley, Kimberley J, Barbosa, Ines A, Bandrés-Ciga, Sara, Quinn, John P, Bubb, Vivien J, Deshpande, Charu, Botia, Juan A, Reynolds, Regina H, Zhang, David, Simpson, Michael A, Blauwendraat, Cornelis, Gan-Or, Ziv, Gibbs, J Raphael, Nalls, Mike A, Singleton, Andrew, Ryten, Mina, and Koks, Sulev

Subjects
Aging, Brain Disorders, Neurosciences, Parkinson's Disease, Neurodegenerative, Genetics, 2.1 Biological and endogenous factors, Aetiology, Neurological, International Parkinson’s Disease Genomics Consortium, Medical genetics, Risk factors
Abstract

Mitochondrial dysfunction has been implicated in the etiology of monogenic Parkinson's disease (PD). Yet the role that mitochondrial processes play in the most common form of the disease; sporadic PD, is yet to be fully established. Here, we comprehensively assessed the role of mitochondrial function-associated genes in sporadic PD by leveraging improvements in the scale and analysis of PD GWAS data with recent advances in our understanding of the genetics of mitochondrial disease. We calculated a mitochondrial-specific polygenic risk score (PRS) and showed that cumulative small effect variants within both our primary and secondary gene lists are significantly associated with increased PD risk. We further reported that the PRS of the secondary mitochondrial gene list was significantly associated with later age at onset. Finally, to identify possible functional genomic associations we implemented Mendelian randomization, which showed that 14 of these mitochondrial function-associated genes showed functional consequence associated with PD risk. Further analysis suggested that the 14 identified genes are not only involved in mitophagy, but implicate new mitochondrial processes. Our data suggests that therapeutics targeting mitochondrial bioenergetics and proteostasis pathways distinct from mitophagy could be beneficial to treating the early stage of PD.

Published
2019

48. MUC5B Promoter Variant and Rheumatoid Arthritis with Interstitial Lung Disease

Author

Juge, Pierre-Antoine, Lee, Joyce S, Ebstein, Esther, Furukawa, Hiroshi, Dobrinskikh, Evgenia, Gazal, Steven, Kannengiesser, Caroline, Ottaviani, Sébastien, Oka, Shomi, Tohma, Shigeto, Tsuchiya, Naoyuki, Rojas-Serrano, Jorge, González-Pérez, Montserrat I, Mejía, Mayra, Buendía-Roldán, Ivette, Falfán-Valencia, Ramcés, Ambrocio-Ortiz, Enrique, Manali, Effrosyni, Papiris, Spyros A, Karageorgas, Theofanis, Boumpas, Dimitrios, Antoniou, Katarina, van Moorsel, Coline HM, van der Vis, Joanne, de Man, Yaël A, Grutters, Jan C, Wang, Yaping, Borie, Raphaël, Wemeau-Stervinou, Lidwine, Wallaert, Benoît, Flipo, René-Marc, Nunes, Hilario, Valeyre, Dominique, Saidenberg-Kermanac’h, Nathalie, Boissier, Marie-Christophe, Marchand-Adam, Sylvain, Frazier, Aline, Richette, Pascal, Allanore, Yannick, Sibilia, Jean, Dromer, Claire, Richez, Christophe, Schaeverbeke, Thierry, Lioté, Huguette, Thabut, Gabriel, Nathan, Nadia, Amselem, Serge, Soubrier, Martin, Cottin, Vincent, Clément, Annick, Deane, Kevin, Walts, Avram D, Fingerlin, Tasha, Fischer, Aryeh, Ryu, Jay H, Matteson, Eric L, Niewold, Timothy B, Assayag, Deborah, Gross, Andrew, Wolters, Paul, Schwarz, Marvin I, Holers, Michael, Solomon, Joshua J, Doyle, Tracy, Rosas, Ivan O, Blauwendraat, Cornelis, Nalls, Mike A, Debray, Marie-Pierre, Boileau, Catherine, Crestani, Bruno, Schwartz, David A, and Dieudé, Philippe

Subjects
Epidemiology, Biomedical and Clinical Sciences, Health Sciences, Rare Diseases, Arthritis, Lung, Genetics, Autoimmune Disease, Rheumatoid Arthritis, Clinical Research, 2.1 Biological and endogenous factors, Respiratory, Inflammatory and immune system, Aged, Arthritis, Rheumatoid, Female, Gain of Function Mutation, Genetic Predisposition to Disease, Genotype, Humans, Idiopathic Pulmonary Fibrosis, Lung Diseases, Interstitial, Male, Middle Aged, Mucin-5B, Odds Ratio, Promoter Regions, Genetic, Medical and Health Sciences, General & Internal Medicine, Biomedical and clinical sciences, Health sciences
Abstract

BackgroundGiven the phenotypic similarities between rheumatoid arthritis (RA)-associated interstitial lung disease (ILD) (hereafter, RA-ILD) and idiopathic pulmonary fibrosis, we hypothesized that the strongest risk factor for the development of idiopathic pulmonary fibrosis, the gain-of-function MUC5B promoter variant rs35705950, would also contribute to the risk of ILD among patients with RA.MethodsUsing a discovery population and multiple validation populations, we tested the association of the MUC5B promoter variant rs35705950 in 620 patients with RA-ILD, 614 patients with RA without ILD, and 5448 unaffected controls.ResultsAnalysis of the discovery population revealed an association of the minor allele of the MUC5B promoter variant with RA-ILD when patients with RA-ILD were compared with unaffected controls (adjusted odds ratio, 3.8; 95% confidence interval [CI], 2.8 to 5.2; P=9.7×10-17). The MUC5B promoter variant was also significantly overrepresented among patients with RA-ILD, as compared with unaffected controls, in an analysis of the multiethnic case series (adjusted odds ratio, 5.5; 95% CI, 4.2 to 7.3; P=4.7×10-35) and in a combined analysis of the discovery population and the multiethnic case series (adjusted odds ratio, 4.7; 95% CI, 3.9 to 5.8; P=1.3×10-49). In addition, the MUC5B promoter variant was associated with an increased risk of ILD among patients with RA (adjusted odds ratio in combined analysis, 3.1; 95% CI, 1.8 to 5.4; P=7.4×10-5), particularly among those with evidence of usual interstitial pneumonia on high-resolution computed tomography (adjusted odds ratio in combined analysis, 6.1; 95% CI, 2.9 to 13.1; P=2.5×10-6). However, no significant association with the MUC5B promoter variant was observed for the diagnosis of RA alone.ConclusionsWe found that the MUC5B promoter variant was associated with RA-ILD and more specifically associated with evidence of usual interstitial pneumonia on imaging. (Funded by Société Française de Rhumatologie and others.).

Published
2018

49. Deficiency in endocannabinoid synthase DAGLB contributes to early onset Parkinsonism and murine nigral dopaminergic neuron dysfunction

Author

Liu, Zhenhua, Yang, Nannan, Dong, Jie, Tian, Wotu, Chang, Lisa, Ma, Jinghong, Guo, Jifeng, Tan, Jieqiong, Dong, Ao, He, Kaikai, Zhou, Jingheng, Cinar, Resat, Wu, Junbing, Salinas, Armando G., Sun, Lixin, Kumar, Mantosh, Sullivan, Breanna T., Oldham, Braden B., Pitz, Vanessa, Makarious, Mary B., Ding, Jinhui, Kung, Justin, Xie, Chengsong, Hawes, Sarah L., Wang, Lupeng, Wang, Tao, Chan, Piu, Zhang, Zhuohua, Le, Weidong, Chen, Shengdi, Lovinger, David M., Blauwendraat, Cornelis, Singleton, Andrew B., Cui, Guohong, Li, Yulong, Cai, Huaibin, and Tang, Beisha

Published
2022
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50. APOE E4 is associated with impaired self-declared cognition but not disease risk or age of onset in Nigerians with Parkinson’s disease

Author

Okubadejo, Njideka U., Okunoye, Olaitan, Ojo, Oluwadamilola O., Arabambi, Babawale, Akinyemi, Rufus O., Osaigbovo, Godwin O., Abubakar, Sani A., Iwuozo, Emmanuel U., Wahab, Kolawole W., Agabi, Osigwe P., Agulanna, Uchechi, Imarhiagbe, Frank A., Abiodun, Oladunni V., Achoru, Charles O., Adebowale, Akintunde A., Adeniji, Olaleye, Akpekpe, John E., Ali, Mohammed W., Ani-Osheku, Ifeyinwa, Arigbodi, Ohwotemu, Balarabe, Salisu A., Bello, Abiodun H., Ekenze, Oluchi S., Erameh, Cyril O., Farombi, Temitope H., Fawale, Michael B., Komolafe, Morenikeji A., Nwani, Paul O., Nwazor, Ernest O., Nyandaiti, Yakub, Obehighe, Emmanuel E., Obiabo, Yahaya O., Odeniyi, Olanike A., Odiase, Francis E., Ojini, Francis I., Onwuegbuzie, Gerald A., Osemwegie, Nosakhare, Oshinaike, Olajumoke O., Otubogun, Folajimi M., Oyakhire, Shyngle I., Taiwo, Funlola T., Williams, Uduak E., Ozomma, Simon, Zubair, Yusuf, Hernandez, Dena, Bandres-Ciga, Sara, Blauwendraat, Cornelis, Singleton, Andrew, Houlden, Henry, Hardy, John, and Rizig, Mie

Published
2022
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