Search

Your search keyword '"Gibbs, J Raphael"' showing total 313 results
Start Over Author "Gibbs, J Raphael" Search Limiters Full Text
313 results on '"Gibbs, J Raphael"'

1. 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, Neurodegenerative, Genetics, Prevention, Aging, Lewy Body Dementia, Brain Disorders, Dementia, Alzheimer's Disease Related Dementias (ADRD), Parkinson's Disease, Human Genome, Acquired Cognitive Impairment, Clinical Research, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), 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

2. 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
Full Text
View/download PDF

3. 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
Full Text
View/download PDF

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

Author

Kaivola, Karri, Chia, Ruth, Ding, Jinhui, Rasheed, Memoona, Fujita, Masashi, Menon, Vilas, Walton, Ronald L, Collins, Ryan L, Billingsley, Kimberley, Brand, Harrison, Talkowski, Michael, Zhao, Xuefang, Dewan, Ramita, Stark, Ali, Ray, Anindita, Solaiman, Jerez, Pilar Alvarez, Malik, Laksh, Dawson, Ted M, Rosenthal, Liana S, Albert, Marilyn S, Pletnikova, Olga, Troncoso, Juan C, Masellis, Mario, Keith, Julia, Black, Sandra E, Ferrucci, Luigi, Resnick, Susan M, Tanaka, Toshiko, Soltis, Anthony R, Viollet, Coralie, Sukumar, Gauthaman, Alba, Camille, Lott, Nathaniel, Martinez, Elisa McGrath, Tuck, Meila, Singh, Jatinder, Bacikova, Dagmar, Zhang, Xijun, Hupalo, Daniel N, Adeleye, Adelani, Wilkerson, Matthew D, Pollard, Harvey B, Dalgard, Clifton L, Gan-Or, Ziv, Rogaeva, Ekaterina, Brice, Alexis, Lesage, Suzanne, Xiromerisiou, Georgia, Calvo, Andrea, Canosa, Antonio, Chio, Adriano, Logroscino, Giancarlo, Mora, Gabriele, Krüger, Reijko, May, Patrick, Alcolea, Daniel, Clarimon, Jordi, Fortea, Juan, Gonzalez-Aramburu, Isabel, Infante, Jon, Lage, Carmen, Lleó, Alberto, Pastor, Pau, Sanchez-Juan, Pascual, Brett, Francesca, Aarsland, Dag, Al-Sarraj, Safa, Attems, Johannes, Gentleman, Steve, Hardy, John A, Hodges, Angela K, Love, Seth, McKeith, Ian G, Morris, Christopher M, Morris, Huw R, Palmer, Laura, Pickering-Brown, Stuart, Ryten, Mina, Thomas, Alan J, Troakes, Claire, Barrett, Matthew J, Beach, Thomas G, Bekris, Lynn M, Bennett, David A, Boeve, Bradley F, Dickson, Dennis W, Faber, Kelley, Ferman, Tanis, Flanagan, Margaret E, Foroud, Tatiana M, Ghetti, Bernardino, and Gibbs, J Raphael

Subjects
Biological Sciences, Genetics, Brain Disorders, Dementia, ALS, Rare Diseases, Neurodegenerative, Neurosciences, Human Genome, Frontotemporal Dementia (FTD), Alzheimer's Disease, Alzheimer's Disease Related Dementias (ADRD), Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Acquired Cognitive Impairment, Aging, Aetiology, 2.1 Biological and endogenous factors, Neurological, American Genome Center, International LBD Genomics Consortium, International ALS/FTD Consortium, PROSPECT Consortium, Lewy body dementia, amyotrophic lateral sclerosis, case-control study, frontotemporal dementia, genome-wide association study, non–Alzheimer's dementia, resource, structural variant
Abstract

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

Published
2023

6. 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

7. Genetic evaluation of dementia with Lewy bodies implicates distinct disease subgroups.

Author

Kaivola, Karri, Shah, Zalak, Chia, Ruth, Black, Sandra E, Gan-Or, Ziv, Keith, Julia, Masellis, Mario, Rogaeva, Ekaterina, Brice, Alexis, Lesage, Suzanne, Xiromerisiou, Georgia, Calvo, Andrea, Canosa, Antonio, Chio, Adriano, Logroscino, Giancarlo, Mora, Gabriele, Krüger, Reijko, May, Patrick, Alcolea, Daniel, Clarimon, Jordi, Fortea, Juan, Gonzalez-Aramburu, Isabel, Infante, Jon, Lage, Carmen, Lleó, Alberto, Pastor, Pau, Sanchez-Juan, Pascual, Brett, Francesca, Aarsland, Dag, Al-Sarraj, Safa, Attems, Johannes, Gentleman, Steve, Hardy, John A, Hodges, Angela K, Love, Seth, McKeith, Ian G, Morris, Christopher M, Morris, Huw R, Palmer, Laura, Pickering-Brown, Stuart, Ryten, Mina, Thomas, Alan J, Troakes, Claire, Albert, Marilyn S, Barrett, Matthew J, Beach, Thomas G, Bekris, Lynn M, Bennett, David A, Boeve, Bradley F, Dalgard, Clifton L, Dawson, Ted M, Dickson, Dennis W, Faber, Kelley, Ferman, Tanis, Ferrucci, Luigi, Flanagan, Margaret E, Foroud, Tatiana M, Ghetti, Bernardino, Gibbs, J Raphael, Goate, Alison, Goldstein, David S, Graff-Radford, Neill R, Kaufmann, Horacio, Kukull, Walter A, Leverenz, James B, Mao, Qinwen, Masliah, Eliezer, Monuki, Edwin, Newell, Kathy L, Palma, Jose Alberto, Pletnikova, Olga, Renton, Alan E, Resnick, Susan M, Rosenthal, Liana S, Ross, Owen A, Scherzer, Clemens R, Serrano, Geidy E, Shakkottai, Vikram G, Sidransky, Ellen, Tanaka, Toshiko, Topol, Eric, Torkamani, Ali, Troncoso, Juan C, Woltjer, Randy, Wszolek, Zbigniew K, and Scholz, Sonja W

Subjects
Genetics, Lewy Body Dementia, Neurodegenerative, Aging, Brain Disorders, Dementia, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Neurosciences, Alzheimer's Disease, Acquired Cognitive Impairment, Human Genome, Aetiology, 2.1 Biological and endogenous factors, Neurological, Aged, Alzheimer Disease, Apolipoprotein E4, Genome-Wide Association Study, Humans, Lewy Body Disease, alpha-Synuclein, International LBD Genomics Consortium, APOE, Alzheimer’s disease, co-pathology, dementia with Lewy bodies, Medical and Health Sciences, Psychology and Cognitive Sciences, Neurology & Neurosurgery
Abstract

The APOE locus is strongly associated with risk for developing Alzheimer's disease and dementia with Lewy bodies. In particular, the role of the APOE ε4 allele as a putative driver of α-synuclein pathology is a topic of intense debate. Here, we performed a comprehensive evaluation in 2466 dementia with Lewy bodies cases versus 2928 neurologically healthy, aged controls. Using an APOE-stratified genome-wide association study approach, we found that GBA is associated with risk for dementia with Lewy bodies in patients without APOE ε4 (P = 6.58 × 10-9, OR = 3.41, 95% CI = 2.25-5.17), but not with dementia with Lewy bodies with APOE ε4 (P = 0.034, OR = 1.87, 95%, 95% CI = 1.05-3.37). We then divided 495 neuropathologically examined dementia with Lewy bodies cases into three groups based on the extent of concomitant Alzheimer's disease co-pathology: pure dementia with Lewy bodies (n = 88), dementia with Lewy bodies with intermediate Alzheimer's disease co-pathology (n = 66) and dementia with Lewy bodies with high Alzheimer's disease co-pathology (n = 341). In each group, we tested the association of the APOE ε4 against the 2928 neurologically healthy controls. Our examination found that APOE ε4 was associated with dementia with Lewy bodies + Alzheimer's disease (P = 1.29 × 10-32, OR = 4.25, 95% CI = 3.35-5.39) and dementia with Lewy bodies + intermediate Alzheimer's disease (P = 0.0011, OR = 2.31, 95% CI = 1.40-3.83), but not with pure dementia with Lewy bodies (P = 0.31, OR = 0.75, 95% CI = 0.43-1.30). In conclusion, although deep clinical data were not available for these samples, our findings do not support the notion that APOE ε4 is an independent driver of α-synuclein pathology in pure dementia with Lewy bodies, but rather implicate GBA as the main risk gene for the pure dementia with Lewy bodies subgroup.

Published
2022

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

Author

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

Published
2023
Full Text
View/download PDF

9. 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

10. 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

11. 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

12. Genome-wide Pleiotropy Between Parkinson Disease and Autoimmune Diseases.

Author

Witoelar, Aree, Jansen, Iris E, Wang, Yunpeng, Desikan, Rahul S, Gibbs, J Raphael, Blauwendraat, Cornelis, Thompson, Wesley K, Hernandez, Dena G, Djurovic, Srdjan, Schork, Andrew J, Bettella, Francesco, Ellinghaus, David, Franke, Andre, Lie, Benedicte A, McEvoy, Linda K, Karlsen, Tom H, Lesage, Suzanne, Morris, Huw R, Brice, Alexis, Wood, Nicholas W, Heutink, Peter, Hardy, John, Singleton, Andrew B, Dale, Anders M, Gasser, Thomas, Andreassen, Ole A, Sharma, Manu, and International Parkinson’s Disease Genomics Consortium (IPDGC), North American Brain Expression Consortium (NABEC), and United Kingdom Brain Expression Consortium (UKBEC) Investigators

Subjects
International Parkinson’s Disease Genomics Consortium (IPDGC), North American Brain Expression Consortium (NABEC), and United Kingdom Brain Expression Consortium (UKBEC) Investigators, Humans, Arthritis, Rheumatoid, Colitis, Ulcerative, Crohn Disease, Celiac Disease, Multiple Sclerosis, Parkinson Disease, Psoriasis, Diabetes Mellitus, Type 1, Autoimmune Diseases, Genetic Predisposition to Disease, Risk Factors, Genome-Wide Association Study, Genetic Loci, Genetic Pleiotropy, Prevention, Neurosciences, Brain Disorders, Digestive Diseases, Autoimmune Disease, Aging, Arthritis, Biotechnology, Neurodegenerative, Parkinson's Disease, Genetics, Human Genome, Inflammatory Bowel Disease, 2.1 Biological and endogenous factors, Aetiology, Inflammatory and immune system, Neurological, Clinical Sciences, Cognitive Sciences, Neurology & Neurosurgery
Abstract

ImportanceRecent genome-wide association studies (GWAS) and pathway analyses supported long-standing observations of an association between immune-mediated diseases and Parkinson disease (PD). The post-GWAS era provides an opportunity for cross-phenotype analyses between different complex phenotypes.ObjectivesTo test the hypothesis that there are common genetic risk variants conveying risk of both PD and autoimmune diseases (ie, pleiotropy) and to identify new shared genetic variants and their pathways by applying a novel statistical framework in a genome-wide approach.Design, setting, and participantsUsing the conjunction false discovery rate method, this study analyzed GWAS data from a selection of archetypal autoimmune diseases among 138 511 individuals of European ancestry and systemically investigated pleiotropy between PD and type 1 diabetes, Crohn disease, ulcerative colitis, rheumatoid arthritis, celiac disease, psoriasis, and multiple sclerosis. NeuroX data (6927 PD cases and 6108 controls) were used for replication. The study investigated the biological correlation between the top loci through protein-protein interaction and changes in the gene expression and methylation levels. The dates of the analysis were June 10, 2015, to March 4, 2017.Main outcomes and measuresThe primary outcome was a list of novel loci and their pathways involved in PD and autoimmune diseases.ResultsGenome-wide conjunctional analysis identified 17 novel loci at false discovery rate less than 0.05 with overlap between PD and autoimmune diseases, including known PD loci adjacent to GAK, HLA-DRB5, LRRK2, and MAPT for rheumatoid arthritis, ulcerative colitis and Crohn disease. Replication confirmed the involvement of HLA, LRRK2, MAPT, TRIM10, and SETD1A in PD. Among the novel genes discovered, WNT3, KANSL1, CRHR1, BOLA2, and GUCY1A3 are within a protein-protein interaction network with known PD genes. A subset of novel loci was significantly associated with changes in methylation or expression levels of adjacent genes.Conclusions and relevanceThe study findings provide novel mechanistic insights into PD and autoimmune diseases and identify a common genetic pathway between these phenotypes. The results may have implications for future therapeutic trials involving anti-inflammatory agents.

Published
2017

14. Diagnosis of Parkinson's disease on the basis of clinical and genetic classification: a population-based modelling study

Author

Nalls, Mike A, McLean, Cory Y, Rick, Jacqueline, Eberly, Shirley, Hutten, Samantha J, Gwinn, Katrina, Sutherland, Margaret, Martinez, Maria, Heutink, Peter, Williams, Nigel M, Hardy, John, Gasser, Thomas, Brice, Alexis, Price, T Ryan, Nicolas, Aude, Keller, Margaux F, Molony, Cliona, Gibbs, J Raphael, Chen-Plotkin, Alice, Suh, Eunran, Letson, Christopher, Fiandaca, Massimo S, Mapstone, Mark, Federoff, Howard J, Noyce, Alastair J, Morris, Huw, Van Deerlin, Vivianna M, Weintraub, Daniel, Zabetian, Cyrus, Hernandez, Dena G, Lesage, Suzanne, Mullins, Meghan, Conley, Emily Drabant, Northover, Carrie AM, Frasier, Mark, Marek, Ken, Day-Williams, Aaron G, Stone, David J, Ioannidis, John PA, Singleton, Andrew B, and investigators*, Parkinson's Disease Biomarkers Program and Parkinson's Progression Marker Initiative

Subjects
Aging, Prevention, Neurodegenerative, Brain Disorders, Neurosciences, Parkinson's Disease, Clinical Research, 2.1 Biological and endogenous factors, 4.2 Evaluation of markers and technologies, Detection, screening and diagnosis, Aetiology, 4.1 Discovery and preclinical testing of markers and technologies, Neurological, Good Health and Well Being, Aged, Cohort Studies, Disease Progression, Female, Humans, Male, Middle Aged, Models, Statistical, Parkinson Disease, Prodromal Symptoms, Parkinson's Disease Biomarkers Program and Parkinson's Progression Marker Initiative investigators, Clinical Sciences, Neurology & Neurosurgery
Abstract

BackgroundAccurate diagnosis and early detection of complex diseases, such as Parkinson's disease, has the potential to be of great benefit for researchers and clinical practice. We aimed to create a non-invasive, accurate classification model for the diagnosis of Parkinson's disease, which could serve as a basis for future disease prediction studies in longitudinal cohorts.MethodsWe developed a model for disease classification using data from the Parkinson's Progression Marker Initiative (PPMI) study for 367 patients with Parkinson's disease and phenotypically typical imaging data and 165 controls without neurological disease. Olfactory function, genetic risk, family history of Parkinson's disease, age, and gender were algorithmically selected by stepwise logistic regression as significant contributors to our classifying model. We then tested the model with data from 825 patients with Parkinson's disease and 261 controls from five independent cohorts with varying recruitment strategies and designs: the Parkinson's Disease Biomarkers Program (PDBP), the Parkinson's Associated Risk Study (PARS), 23andMe, the Longitudinal and Biomarker Study in PD (LABS-PD), and the Morris K Udall Parkinson's Disease Research Center of Excellence cohort (Penn-Udall). Additionally, we used our model to investigate patients who had imaging scans without evidence of dopaminergic deficit (SWEDD).FindingsIn the population from PPMI, our initial model correctly distinguished patients with Parkinson's disease from controls at an area under the curve (AUC) of 0·923 (95% CI 0·900-0·946) with high sensitivity (0·834, 95% CI 0·711-0·883) and specificity (0·903, 95% CI 0·824-0·946) at its optimum AUC threshold (0·655). All Hosmer-Lemeshow simulations suggested that when parsed into random subgroups, the subgroup data matched that of the overall cohort. External validation showed good classification of Parkinson's disease, with AUCs of 0·894 (95% CI 0·867-0·921) in the PDBP cohort, 0·998 (0·992-1·000) in PARS, 0·955 (no 95% CI available) in 23andMe, 0·929 (0·896-0·962) in LABS-PD, and 0·939 (0·891-0·986) in the Penn-Udall cohort. Four of 17 SWEDD participants who our model classified as having Parkinson's disease converted to Parkinson's disease within 1 year, whereas only one of 38 SWEDD participants who were not classified as having Parkinson's disease underwent conversion (test of proportions, p=0·003).InterpretationOur model provides a potential new approach to distinguish participants with Parkinson's disease from controls. If the model can also identify individuals with prodromal or preclinical Parkinson's disease in prospective cohorts, it could facilitate identification of biomarkers and interventions.FundingNational Institute on Aging, National Institute of Neurological Disorders and Stroke, and the Michael J Fox Foundation.

Published
2015

15. A Genome-Wide Association Study of Myasthenia Gravis

Author

Renton, Alan E, Pliner, Hannah A, Provenzano, Carlo, Evoli, Amelia, Ricciardi, Roberta, Nalls, Michael A, Marangi, Giuseppe, Abramzon, Yevgeniya, Arepalli, Sampath, Chong, Sean, Hernandez, Dena G, Johnson, Janel O, Bartoccioni, Emanuela, Scuderi, Flavia, Maestri, Michelangelo, Gibbs, J Raphael, Errichiello, Edoardo, Chiò, Adriano, Restagno, Gabriella, Sabatelli, Mario, Macek, Mark, Scholz, Sonja W, Corse, Andrea, Chaudhry, Vinay, Benatar, Michael, Barohn, Richard J, McVey, April, Pasnoor, Mamatha, Dimachkie, Mazen M, Rowin, Julie, Kissel, John, Freimer, Miriam, Kaminski, Henry J, Sanders, Donald B, Lipscomb, Bernadette, Massey, Janice M, Chopra, Manisha, Howard, James F, Koopman, Wilma J, Nicolle, Michael W, Pascuzzi, Robert M, Pestronk, Alan, Wulf, Charlie, Florence, Julaine, Blackmore, Derrick, Soloway, Aimee, Siddiqi, Zaeem, Muppidi, Srikanth, Wolfe, Gil, Richman, David, Mezei, Michelle M, Jiwa, Theresa, Oger, Joel, Drachman, Daniel B, and Traynor, Bryan J

Subjects
Rare Diseases, Genetics, Neurosciences, Autoimmune Disease, Myasthenia Gravis, Clinical Research, Human Genome, 2.1 Biological and endogenous factors, Aetiology, Adult, Age of Onset, CTLA-4 Antigen, Case-Control Studies, Female, Gene Frequency, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, HLA-DQ alpha-Chains, Humans, Male, Middle Aged, Polymorphism, Single Nucleotide, United States, Clinical Sciences, Cognitive Sciences, Neurology & Neurosurgery
Abstract

ImportanceMyasthenia gravis is a chronic, autoimmune, neuromuscular disease characterized by fluctuating weakness of voluntary muscle groups. Although genetic factors are known to play a role in this neuroimmunological condition, the genetic etiology underlying myasthenia gravis is not well understood.ObjectiveTo identify genetic variants that alter susceptibility to myasthenia gravis, we performed a genome-wide association study.Design, setting, and participantsDNA was obtained from 1032 white individuals from North America diagnosed as having acetylcholine receptor antibody-positive myasthenia gravis and 1998 race/ethnicity-matched control individuals from January 2010 to January 2011. These samples were genotyped on Illumina OmniExpress single-nucleotide polymorphism arrays. An independent cohort of 423 Italian cases and 467 Italian control individuals were used for replication.Main outcomes and measuresWe calculated P values for association between 8,114,394 genotyped and imputed variants across the genome and risk for developing myasthenia gravis using logistic regression modeling. A threshold P value of 5.0×10(-8) was set for genome-wide significance after Bonferroni correction for multiple testing.ResultsIn the overall case-control cohort, we identified association signals at CTLA4 (rs231770; P=3.98×10(-8); odds ratio, 1.37; 95% CI, 1.25-1.49), HLA-DQA1 (rs9271871; P=1.08×10(-8); odds ratio, 2.31; 95% CI, 2.02-2.60), and TNFRSF11A (rs4263037; P=1.60×10(-9); odds ratio, 1.41; 95% CI, 1.29-1.53). These findings replicated for CTLA4 and HLA-DQA1 in an independent cohort of Italian cases and control individuals. Further analysis revealed distinct, but overlapping, disease-associated loci for early- and late-onset forms of myasthenia gravis. In the late-onset cases, we identified 2 association peaks: one was located in TNFRSF11A (rs4263037; P=1.32×10(-12); odds ratio, 1.56; 95% CI, 1.44-1.68) and the other was detected in the major histocompatibility complex on chromosome 6p21 (HLA-DQA1; rs9271871; P=7.02×10(-18); odds ratio, 4.27; 95% CI, 3.92-4.62). Association within the major histocompatibility complex region was also observed in early-onset cases (HLA-DQA1; rs601006; P=2.52×10(-11); odds ratio, 4.0; 95% CI, 3.57-4.43), although the set of single-nucleotide polymorphisms was different from that implicated among late-onset cases.Conclusions and relevanceOur genetic data provide insights into aberrant cellular mechanisms responsible for this prototypical autoimmune disorder. They also suggest that clinical trials of immunomodulatory drugs related to CTLA4 and that are already Food and Drug Administration approved as therapies for other autoimmune diseases could be considered for patients with refractory disease.

Published
2015

16. Whole-genome sequencing to understand the genetic architecture of common gene expression and biomarker phenotypes

Author

Wood, Andrew R, Tuke, Marcus A, Nalls, Mike, Hernandez, Dena, Gibbs, J Raphael, Lin, Haoxiang, Xu, Christopher S, Li, Qibin, Shen, Juan, Jun, Goo, Almeida, Marcio, Tanaka, Toshiko, Perry, John RB, Gaulton, Kyle, Rivas, Manny, Pearson, Richard, Curran, Joanne E, Johnson, Matthew P, Göring, Harald HH, Duggirala, Ravindranath, Blangero, John, Mccarthy, Mark I, Bandinelli, Stefania, Murray, Anna, Weedon, Michael N, Singleton, Andrew, Melzer, David, Ferrucci, Luigi, and Frayling, Timothy M

Subjects
Clinical Research, Human Genome, Genetics, Detection, screening and diagnosis, Aetiology, 2.1 Biological and endogenous factors, 4.1 Discovery and preclinical testing of markers and technologies, Adult, Aged, Aged, 80 and over, Female, Gene Frequency, Genetic Association Studies, Genetic Markers, Genetic Variation, Genome, Human, Genotyping Techniques, High-Throughput Nucleotide Sequencing, Humans, Male, Middle Aged, Phenotype, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Young Adult, Biological Sciences, Medical and Health Sciences, Genetics & Heredity
Abstract

Initial results from sequencing studies suggest that there are relatively few low-frequency (

Published
2015

17. NeuroX, a fast and efficient genotyping platform for investigation of neurodegenerative diseases

Author

Nalls, Mike A, Bras, Jose, Hernandez, Dena G, Keller, Margaux F, Majounie, Elisa, Renton, Alan E, Saad, Mohamad, Jansen, Iris, Guerreiro, Rita, Lubbe, Steven, Plagnol, Vincent, Gibbs, J Raphael, Schulte, Claudia, Pankratz, Nathan, Sutherland, Margaret, Bertram, Lars, Lill, Christina M, DeStefano, Anita L, Faroud, Tatiana, Eriksson, Nicholas, Tung, Joyce Y, Edsall, Connor, Nichols, Noah, Brooks, Janet, Arepalli, Sampath, Pliner, Hannah, Letson, Chris, Heutink, Peter, Martinez, Maria, Gasser, Thomas, Traynor, Bryan J, Wood, Nick, Hardy, John, Singleton, Andrew B, Consortium, International Parkinson's Disease Genomics, and consortium, Parkinson's Disease meta-analysis

Subjects
Biological Psychology, Biomedical and Clinical Sciences, Neurosciences, Psychology, Genetics, Genetic Testing, Human Genome, Neurodegenerative, Clinical Research, Rare Diseases, Alleles, Costs and Cost Analysis, Genetic Association Studies, Genetic Predisposition to Disease, Genetic Variation, Genotyping Techniques, Neurodegenerative Diseases, Oligonucleotide Array Sequence Analysis, Genotyping, Methods, Neurodegeneration, Parkinson's, Meta-analysis, Imputation, International Parkinson's Disease Genomics Consortium, Parkinson's Disease meta-analysis consortium, Clinical Sciences, Neurology & Neurosurgery, Biological psychology
Abstract

Our objective was to design a genotyping platform that would allow rapid genetic characterization of samples in the context of genetic mutations and risk factors associated with common neurodegenerative diseases. The platform needed to be relatively affordable, rapid to deploy, and use a common and accessible technology. Central to this project, we wanted to make the content of the platform open to any investigator without restriction. In designing this array we prioritized a number of types of genetic variability for inclusion, such as known risk alleles, disease-causing mutations, putative risk alleles, and other functionally important variants. The array was primarily designed to allow rapid screening of samples for disease-causing mutations and large population studies of risk factors. Notably, an explicit aim was to make this array widely available to facilitate data sharing across and within diseases. The resulting array, NeuroX, is a remarkably cost and time effective solution for high-quality genotyping. NeuroX comprises a backbone of standard Illumina exome content of approximately 240,000 variants, and over 24,000 custom content variants focusing on neurologic diseases. Data are generated at approximately $50-$60 per sample using a 12-sample format chip and regular Infinium infrastructure; thus, genotyping is rapid and accessible to many investigators. Here, we describe the design of NeuroX, discuss the utility of NeuroX in the analyses of rare and common risk variants, and present quality control metrics and a brief primer for the analysis of NeuroX derived data.

Published
2015

18. Genome-wide Analyses Identify KIF5A as a Novel ALS Gene

Author

Logullo, Francesco O., Simone, Isabella, Logroscino, Giancarlo, Salvi, Fabrizio, Bartolomei, Ilaria, Borghero, Giuseppe, Murru, Maria Rita, Costantino, Emanuela, Pani, Carla, Puddu, Roberta, Caredda, Carla, Piras, Valeria, Tranquilli, Stefania, Cuccu, Stefania, Corongiu, Daniela, Melis, Maurizio, Milia, Antonio, Marrosu, Francesco, Marrosu, Maria Giovanna, Floris, Gianluca, Cannas, Antonino, Capasso, Margherita, Caponnetto, Claudia, Mancardi, Gianluigi, Origone, Paola, Mandich, Paola, Conforti, Francesca L., Cavallaro, Sebastiano, Mora, Gabriele, Marinou, Kalliopi, Sideri, Riccardo, Penco, Silvana, Mosca, Lorena, Lunetta, Christian, Pinter, Giuseppe Lauria, Corbo, Massimo, Riva, Nilo, Carrera, Paola, Volanti, Paolo, Mandrioli, Jessica, Fini, Nicola, Fasano, Antonio, Tremolizzo, Lucio, Arosio, Alessandro, Ferrarese, Carlo, Trojsi, Francesca, Tedeschi, Gioacchino, Monsurrò, Maria Rosaria, Piccirillo, Giovanni, Femiano, Cinzia, Ticca, Anna, Ortu, Enzo, La Bella, Vincenzo, Spataro, Rossella, Colletti, Tiziana, Sabatelli, Mario, Zollino, Marcella, Conte, Amelia, Luigetti, Marco, Lattante, Serena, Marangi, Giuseppe, Santarelli, Marialuisa, Petrucci, Antonio, Pugliatti, Maura, Pirisi, Angelo, Parish, Leslie D., Occhineri, Patrizia, Giannini, Fabio, Battistini, Stefania, Ricci, Claudia, Benigni, Michele, Cau, Tea B., Loi, Daniela, Calvo, Andrea, Moglia, Cristina, Brunetti, Maura, Barberis, Marco, Restagno, Gabriella, Casale, Federico, Marrali, Giuseppe, Fuda, Giuseppe, Ossola, Irene, Cammarosano, Stefania, Canosa, Antonio, Ilardi, Antonio, Manera, Umberto, Grassano, Maurizio, Tanel, Raffaella, Pisano, Fabrizio, Harms, Matthew B., Goldstein, David B., Shneider, Neil A., Goutman, Stephen, Simmons, Zachary, Miller, Timothy M., Chandran, Siddharthan, Pal, Suvankar, Manousakis, Georgios, Appel, Stanley H., Simpson, Ericka, Wang, Leo, Baloh, Robert H., Gibson, Summer, Bedlack, Richard, Lacomis, David, Sareen, Dhruv, Sherman, Alexander, Bruijn, Lucie, Penny, Michelle, Allen, Andrew S., Appel, Stanley, Bedlack, Richard S., Boone, Braden E., Brown, Robert, Carulli, John P., Chesi, Alessandra, Chung, Wendy K., Cirulli, Elizabeth T., Cooper, Gregory M., Couthouis, Julien, Day-Williams, Aaron G., Dion, Patrick A., Gitler, Aaron D., Glass, Jonathan D., Han, Yujun, Harris, Tim, Hayes, Sebastian D., Jones, Angela L., Keebler, Jonathan, Krueger, Brian J., Lasseigne, Brittany N., Levy, Shawn E., Lu, Yi-Fan, Maniatis, Tom, McKenna-Yasek, Diane, Myers, Richard M., Petrovski, Slavé, Pulst, Stefan M., Raphael, Alya R., Ravits, John M., Ren, Zhong, Rouleau, Guy A., Sapp, Peter C., Sims, Katherine B., Staropoli, John F., Waite, Lindsay L., Wang, Quanli, Wimbish, Jack R., Xin, Winnie W., Phatnani, Hemali, Kwan, Justin, Broach, James R., Arcila-Londono, Ximena, Lee, Edward B., Van Deerlin, Vivianna M., Fraenkel, Ernest, Ostrow, Lyle W., Baas, Frank, Zaitlen, Noah, Berry, James D., Malaspina, Andrea, Fratta, Pietro, Cox, Gregory A., Thompson, Leslie M., Finkbeiner, Steve, Dardiotis, Efthimios, Hornstein, Eran, MacGowan, Daniel J., Heiman-Patterson, Terry, Hammell, Molly G., Patsopoulos, Nikolaos A., Dubnau, Joshua, Nath, Avindra, Kaye, Julia, Finkbeiner, Steven, Wyman, Stacia, LeNail, Alexander, Lima, Leandro, Rothstein, Jeffrey D., Svendsen, Clive N., Van Eyk, Jenny, Maragakis, Nicholas J., Kolb, Stephen J., Cudkowicz, Merit, Baxi, Emily, Benatar, Michael, Taylor, J. Paul, Wu, Gang, Rampersaud, Evadnie, Wuu, Joanne, Rademakers, Rosa, Züchner, Stephan, Schule, Rebecca, McCauley, Jacob, Hussain, Sumaira, Cooley, Anne, Wallace, Marielle, Clayman, Christine, Barohn, Richard, Statland, Jeffrey, Ravits, John, Swenson, Andrea, Jackson, Carlayne, Trivedi, Jaya, Khan, Shaida, Katz, Jonathan, Jenkins, Liberty, Burns, Ted, Gwathmey, Kelly, Caress, James, McMillan, Corey, Elman, Lauren, Pioro, Erik, Heckmann, Jeannine, So, Yuen, Walk, David, Maiser, Samuel, Zhang, Jinghui, Silani, Vincenzo, Ticozzi, Nicola, Gellera, Cinzia, Ratti, Antonia, Taroni, Franco, Lauria, Giuseppe, Verde, Federico, Fogh, Isabella, Tiloca, Cinzia, Comi, Giacomo P., Sorarù, Gianni, Cereda, Cristina, D’Alfonso, Sandra, Corrado, Lucia, De Marchi, Fabiola, Corti, Stefania, Ceroni, Mauro, Mazzini, Letizia, Siciliano, Gabriele, Filosto, Massimiliano, Inghilleri, Maurizio, Peverelli, Silvia, Colombrita, Claudia, Poletti, Barbara, Maderna, Luca, Del Bo, Roberto, Gagliardi, Stella, Querin, Giorgia, Bertolin, Cinzia, Pensato, Viviana, Castellotti, Barbara, Camu, William, Mouzat, Kevin, Lumbroso, Serge, Corcia, Philippe, Meininger, Vincent, Besson, Gérard, Lagrange, Emmeline, Clavelou, Pierre, Guy, Nathalie, Couratier, Philippe, Vourch, Patrick, Danel, Véronique, Bernard, Emilien, Lemasson, Gwendal, Al Kheifat, Ahmad, Al-Chalabi, Ammar, Andersen, Peter, Basak, A. Nazli, Blair, Ian P., Chio, Adriano, Cooper-Knock, Jonathan, de Carvalho, Mamede, Dekker, Annelot, Drory, Vivian, Redondo, Alberto Garcia, Gotkine, Marc, Hardiman, Orla, Hide, Winston, Iacoangeli, Alfredo, Glass, Jonathan, Kenna, Kevin, Kiernan, Matthew, Kooyman, Maarten, Landers, John, McLaughlin, Russell, Middelkoop, Bas, Mill, Jonathan, Neto, Miguel Mitne, Moisse, Mattieu, Pardina, Jesus Mora, Morrison, Karen, Newhouse, Stephen, Pinto, Susana, Pulit, Sara, Robberecht, Wim, Shatunov, Aleksey, Shaw, Pamela, Shaw, Chris, Sproviero, William, Tazelaar, Gijs, van Damme, Philip, van den Berg, Leonard, van der Spek, Rick, van Eijk, Kristel, van Es, Michael, van Rheenen, Wouter, van Vugt, Joke, Veldink, Jan, Weber, Markus, Williams, Kelly L., Zatz, Mayana, Bauer, Denis C., Twine, Natalie A., Nicolas, Aude, Kenna, Kevin P., Renton, Alan E., Faghri, Faraz, Chia, Ruth, Dominov, Janice A., Kenna, Brendan J., Nalls, Mike A., Keagle, Pamela, Rivera, Alberto M., Murphy, Natalie A., van Vugt, Joke J.F.A., Geiger, Joshua T., Van der Spek, Rick A., Pliner, Hannah A., Shankaracharya, Smith, Bradley N., Topp, Simon D., Abramzon, Yevgeniya, Gkazi, Athina Soragia, Eicher, John D., Kenna, Aoife, Messina, Sonia, Simone, Isabella L., Ferrucci, Luigi, Moreno, Cristiane de Araujo Martins, Kamalakaran, Sitharthan, Musunuri, Rajeeva Lochan, Evani, Uday Shankar, Abhyankar, Avinash, Zody, Michael C., Wyman, Stacia K., LeNail, Alex, Van Eyk, Jennifer E., Laaksovirta, Hannu, Myllykangas, Liisa, Jansson, Lilja, Valori, Miko, Ealing, John, Hamdalla, Hisham, Rollinson, Sara, Pickering-Brown, Stuart, Orrell, Richard W., Sidle, Katie C., Hardy, John, Singleton, Andrew B., Johnson, Janel O., Arepalli, Sampath, Polak, Meraida, Asress, Seneshaw, Al-Sarraj, Safa, King, Andrew, Troakes, Claire, Vance, Caroline, de Belleroche, Jacqueline, ten Asbroek, Anneloor L.M.A., Muñoz-Blanco, José Luis, Hernandez, Dena G., Ding, Jinhui, Gibbs, J. Raphael, Scholz, Sonja W., Floeter, Mary Kay, Campbell, Roy H., Landi, Francesco, Bowser, Robert, MacGowan, Daniel J.L., Kirby, Janine, Pioro, Erik P., Pamphlett, Roger, Broach, James, Gerhard, Glenn, Dunckley, Travis L., Brady, Christopher B., Kowall, Neil W., Troncoso, Juan C., Le Ber, Isabelle, Heiman-Patterson, Terry D., Kamel, Freya, Van Den Bosch, Ludo, Strom, Tim M., Meitinger, Thomas, Van Eijk, Kristel R., Moisse, Matthieu, McLaughlin, Russell L., Van Es, Michael A., Boylan, Kevin B., Van Blitterswijk, Marka, Morrison, Karen E., Mora, Jesús S., Drory, Vivian E., Shaw, Pamela J., Turner, Martin R., Talbot, Kevin, Fifita, Jennifer A., Nicholson, Garth A., Esteban-Pérez, Jesús, García-Redondo, Alberto, Rogaeva, Ekaterina, Zinman, Lorne, Cooper-Knock, Johnathan, Brice, Alexis, Goutman, Stephen A., Feldman, Eva L., Gibson, Summer B., Van Damme, Philip, Ludolph, Albert C., Andersen, Peter M., Weishaupt, Jochen H., Trojanowski, John Q., Brown, Robert H., Jr., van den Berg, Leonard H., Veldink, Jan H., Stone, David J., Tienari, Pentti, Chiò, Adriano, Shaw, Christopher E., Traynor, Bryan J., and Landers, John E.

Published
2018
Full Text
View/download PDF

19. Genome-wide contribution of common short-tandem repeats to Parkinson’s disease genetic risk

Author

Bustos, Bernabe I, Billingsley, Kimberley, Blauwendraat, Cornelis, Gibbs, J Raphael, Gan-Or, Ziv, Krainc, Dimitri, Singleton, Andrew B, and Lubbe, Steven J

Subjects
Original Article, Neurology (clinical)
Abstract

Parkinson’s disease is a complex neurodegenerative disorder with a strong genetic component, for which most known disease-associated variants are single nucleotide polymorphisms (SNPs) and small insertions and deletions (indels). DNA repetitive elements account for >50% of the human genome; however, little is known of their contribution to Parkinson’s disease aetiology. While select short tandem repeats (STRs) within candidate genes have been studied in Parkinson’s disease, their genome-wide contribution remains unknown. Here we present the first genome-wide association study of STRs in Parkinson’s disease. Through a meta-analysis of 16 imputed genome-wide association study cohorts from the International Parkinson’s Disease Genomic Consortium (IPDGC), totalling 39 087 individuals (16 642 cases and 22 445 controls of European ancestry), we identified 34 genome-wide significant STR loci (P < 5.34 × 10−6), with the strongest signal located in KANSL1 [chr17:44 205 351:[T]11, P = 3 × 10−39, odds ratio = 1.31 (95% confidence interval = 1.26–1.36)]. Conditional-joint analyses suggested that four significant STRs mapping nearby NDUFAF2, TRIML2, MIRNA-129–1 and NCOR1 were independent from known risk SNPs. Including STRs in heritability estimates increased the variance explained by SNPs alone. Gene expression analysis of STRs (eSTRs) in RNA sequencing data from 13 brain regions identified significant associations of STRs influencing the expression of multiple genes, including known Parkinson’s disease genes. Further functional annotation of candidate STRs revealed that significant eSTRs within NUDFAF2 and ZSWIM7 overlap with regulatory features and are associated with change in the expression levels of nearby genes. Here, we show that STRs at known and novel candidate loci contribute to Parkinson’s disease risk and have functional effects in disease-relevant tissues and pathways, supporting previously reported disease-associated genes and giving further evidence for their functional prioritization. These data represent a valuable resource for researchers currently dissecting Parkinson’s disease risk loci.

Published
2022

20. Identification of common variants influencing risk of the tauopathy progressive supranuclear palsy

Author

Höglinger, Günter U, Melhem, Nadine M, Dickson, Dennis W, Sleiman, Patrick MA, Wang, Li-San, Klei, Lambertus, Rademakers, Rosa, de Silva, Rohan, Litvan, Irene, Riley, David E, van Swieten, John C, Heutink, Peter, Wszolek, Zbigniew K, Uitti, Ryan J, Vandrovcova, Jana, Hurtig, Howard I, Gross, Rachel G, Maetzler, Walter, Goldwurm, Stefano, Tolosa, Eduardo, Borroni, Barbara, Pastor, Pau, Cantwell, Laura B, Han, Mi Ryung, Dillman, Allissa, van der Brug, Marcel P, Gibbs, J Raphael, Cookson, Mark R, Hernandez, Dena G, Singleton, Andrew B, Farrer, Matthew J, Yu, Chang-En, Golbe, Lawrence I, Revesz, Tamas, Hardy, John, Lees, Andrew J, Devlin, Bernie, Hakonarson, Hakon, Müller, Ulrich, and Schellenberg, Gerard D

Subjects
Biological Sciences, Genetics, Pediatric, Prevention, Cerebral Palsy, Rare Diseases, Neurodegenerative, Brain Disorders, Acquired Cognitive Impairment, Human Genome, Perinatal Period - Conditions Originating in Perinatal Period, Frontotemporal Dementia (FTD), Dementia, Neurosciences, Aetiology, 2.1 Biological and endogenous factors, Neurological, Case-Control Studies, Chromosomes, Human, Cohort Studies, Genetic Loci, Genetic Predisposition to Disease, Genetic Variation, Genome-Wide Association Study, Humans, Polymorphism, Single Nucleotide, Prognosis, Risk Factors, Supranuclear Palsy, Progressive, Tauopathies, tau Proteins, PSP Genetics Study Group, Medical and Health Sciences, Developmental Biology, Agricultural biotechnology, Bioinformatics and computational biology
Abstract

Progressive supranuclear palsy (PSP) is a movement disorder with prominent tau neuropathology. Brain diseases with abnormal tau deposits are called tauopathies, the most common of which is Alzheimer's disease. Environmental causes of tauopathies include repetitive head trauma associated with some sports. To identify common genetic variation contributing to risk for tauopathies, we carried out a genome-wide association study of 1,114 individuals with PSP (cases) and 3,247 controls (stage 1) followed by a second stage in which we genotyped 1,051 cases and 3,560 controls for the stage 1 SNPs that yielded P ≤ 10(-3). We found significant previously unidentified signals (P < 5 × 10(-8)) associated with PSP risk at STX6, EIF2AK3 and MOBP. We confirmed two independent variants in MAPT affecting risk for PSP, one of which influences MAPT brain expression. The genes implicated encode proteins for vesicle-membrane fusion at the Golgi-endosomal interface, for the endoplasmic reticulum unfolded protein response and for a myelin structural component.

Published
2011

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

Author

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

Abstract

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

Published
2023

22. Unexpected frequency of the pathogenic AR CAG repeat expansion in the general population

Author

Zanovello, Matteo, Ibáñez, Kristina, Brown, Anna-Leigh, Sivakumar, Prasanth, Bombaci, Alessandro, Santos, Liana, van Vugt, Joke J F A, Narzisi, Giuseppe, Karra, Ramita, Scholz, Sonja, Ding, Jinhui, Gibbs, J Raphael, Chiò, Adriano, Dalgard, Clifton, Weisburd, Ben, Hanna, Michael G, Greensmith, Linda, Phatnani, Hemali, Veldink, Jan H, Traynor, Bryan J, Polke, James, Houlden, Henry, Fratta, Pietro, and Tucci, Arianna

Subjects
spinal and bulbar muscular atrophy, whole-genome sequencing, androgen receptor, population genetics, bioinformatics, Neurology (clinical)
Abstract

CAG repeat expansions in exon 1 of the AR gene on the X chromosome cause spinal and bulbar muscular atrophy, a male-specific progressive neuromuscular disorder associated with a variety of extra-neurological symptoms. The disease has a reported male prevalence of approximately 1:30 000 or less, but the AR repeat expansion frequency is unknown. We established a pipeline, which combines the use of the ExpansionHunter tool and visual validation, to detect AR CAG expansion on whole-genome sequencing data, benchmarked it to fragment PCR sizing, and applied it to 74 277 unrelated individuals from four large cohorts. Our pipeline showed sensitivity of 100% [95% confidence interval (CI) 90.8–100%], specificity of 99% (95% CI 94.2–99.7%), and a positive predictive value of 97.4% (95% CI 84.4–99.6%). We found the mutation frequency to be 1:3182 (95% CI 1:2309–1:4386, n = 117 734) X chromosomes—10 times more frequent than the reported disease prevalence. Modelling using the novel mutation frequency led to estimate disease prevalence of 1:6887 males, more than four times more frequent than the reported disease prevalence. This discrepancy is possibly due to underdiagnosis of this neuromuscular condition, reduced penetrance, and/or pleomorphic clinical manifestations.

Published
2023

23. Genome-Wide Analysis of Structural Variants in Parkinson Disease

Author

Billingsley, Kimberley J, Ding, Jinhui, Hernandez, Dena, Torkamani, Ali, Ryten, Mina, Hardy, John, Consortium, UK Brain Expression, Chia, Ruth, Scholz, Sonja W, Traynor, Bryan J, Dalgard, Clifton L, Ehrlich, Debra J, Jerez, Pilar Alvarez, Tanaka, Toshiko, Ferrucci, Luigi, Beach, Thomas G, Serrano, Geidy E, Quinn, John P, Bubb, Vivien J, Collins, Ryan L, Zhao, Xuefang, Walker, Mark, Pierce-Hoffman, Emma, Illarionova, Anastasia, Brand, Harrison, Talkowski, Michael E, Casey, Bradford, Cookson, Mark R, Markham, Androo, Nalls, Mike A, Mahmoud, Medhat, Sedlazeck, Fritz J, Blauwendraat, Cornelis, Gibbs, J Raphael, Levine, Kristin, Singleton, Andrew B, Grenn, Francis P, Makarious, Mary B, Moore, Anni, Vitale, Daniel, and Reed, Xylena

Subjects
Neurology, Neurology (clinical), ddc:610
Abstract

Identification of genetic risk factors for Parkinson disease (PD) has to date been primarily limited to the study of single nucleotide variants, which only represent a small fraction of the genetic variation in the human genome. Consequently, causal variants for most PD risk are not known. Here we focused on structural variants (SVs), which represent a major source of genetic variation in the human genome. We aimed to discover SVs associated with PD risk by performing the first large-scale characterization of SVs in PD.We leveraged a recently developed computational pipeline to detect and genotype SVs from 7,772 Illumina short-read whole genome sequencing samples. Using this set of SV variants, we performed a genome-wide association study using 2,585 cases and 2,779 controls and identified SVs associated with PD risk. Furthermore, to validate the presence of these variants, we generated a subset of matched whole-genome long-read sequencing data.We genotyped and tested 3,154 common SVs, representing over 412 million nucleotides of previously uncatalogued genetic variation. Using long-read sequencing data, we validated the presence of three novel deletion SVs that are associated with risk of PD from our initial association analysis, including a 2 kb intronic deletion within the gene LRRN4.We identified three SVs associated with genetic risk of PD. This study represents the most comprehensive assessment of the contribution of SVs to the genetic risk of PD to date. ANN NEUROL 2023.

Published
2023

24. Heterozygous PRKN mutations are common but do not increase the risk of Parkinson’s disease

Author

Zhu, William, primary, Huang, Xiaoping, additional, Yoon, Esther, additional, Bandres-Ciga, Sara, additional, Blauwendraat, Cornelis, additional, Billingsley, Kimberly J, additional, Cade, Joshua H, additional, Wu, Beverly P, additional, Williams, Victoria H, additional, Schindler, Alice B, additional, Brooks, Janet, additional, Gibbs, J Raphael, additional, Hernandez, Dena G, additional, Ehrlich, Debra, additional, Singleton, Andrew B, additional, and Narendra, Derek P, additional

Published
2022
Full Text
View/download PDF

25. Shared Genetics of Multiple System Atrophy and Inflammatory Bowel Disease

Author

Shadrin, Alexey A, Health, Division of Mental, Foubert-Samier, Alexandra, Meissner, Wassilios G, Rascol, Olivier, Pavy-Le Traon, Anne, Cardiovascular, INSERM U 1048 Institute of, Frei, Oleksandr, O'Connell, Kevin S, Bahrami, Shahram, Schreiber, Stefan, Mucha, Sören, Lieb, Wolfgang, Müller-Nurasyid, Martina, Schminke, Ulf, Homuth, Georg, Schmidt, Carsten O, Nöthen, Markus M, Hoffmann, Per, Gieger, Christian, Wenning, Gregor, Gibbs, J Raphael, Ellinghaus, David, Franke, Andre, Hardy, John, Stefanova, Nadia, Gasser, Thomas, Singleton, Andrew, Houlden, Henry, Scholz, Sonja W, Andreassen, Ole A, Sharma, Manu, Makarious, Mary B, Blauwendraat, Cornelis, Sreelatha, Ashwin A K, Heras-Garvin, Antonio, Ding, Jinhui, and Hammer, Monia

Subjects
0301 basic medicine, Candidate gene, Transgene, multiple system atrophy, Mice, Transgenic, Disease, Biology, Inflammatory bowel disease, Pathogenesis, Mice, 03 medical and health sciences, 0302 clinical medicine, Atrophy, stomatognathic system, inflammatory bowel disease, mental disorders, medicine, Animals, Humans, ddc:610, Genetic variability, Autoimmune disease, genetics [Inflammatory Bowel Diseases], Multiple System Atrophy, Inflammatory Bowel Diseases, medicine.disease, conjunctional false discovery rate, nervous system diseases, 030104 developmental biology, nervous system, Neurology, Immunology, alpha-Synuclein, genetics [alpha-Synuclein], genetics [Multiple System Atrophy], Neurology (clinical), genetic overlap, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract

Background Multiple system atrophy (MSA) is a rare neurodegenerative disease characterized by intracellular accumulations of α-synuclein and nerve cell loss in striatonigral and olivopontocerebellar structures. Epidemiological and clinical studies have reported potential involvement of autoimmune mechanisms in MSA pathogenesis. However, genetic etiology of this interaction remains unknown. We aimed to investigate genetic overlap between MSA and 7 autoimmune diseases and to identify shared genetic loci. Methods Genome-wide association study summary statistics of MSA and 7 autoimmune diseases were combined in cross-trait conjunctional false discovery rate analysis to explore overlapping genetic background. Expression of selected candidate genes was compared in transgenic MSA mice and wild-type mice. Genetic variability of candidate genes was further investigated using independent whole-exome genotyping data from large cohorts of MSA and autoimmune disease patients and healthy controls. Results We observed substantial polygenic overlap between MSA and inflammatory bowel disease and identified 3 shared genetic loci with leading variants upstream of the DENND1B and RSP04 genes, and in intron of the C7 gene. Further, the C7 gene showed significantly dysregulated expression in the degenerating midbrain of transgenic MSA mice compared with wild-type mice and had elevated burden of protein-coding variants in independent MSA and inflammatory bowel disease cohorts. Conclusion Our study provides evidence of shared genetic etiology between MSA and inflammatory bowel disease with an important role of the C7 gene in both phenotypes, with the implication of immune and gut dysfunction in MSA pathophysiology. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Published
2020

26. RNA Binding Activity of the Recessive Parkinsonism Protein DJ-1 Supports Involvement in Multiple Cellular Pathways

Author

van der Brug, Marcel P., Blackinton, Jeff, Chandran, Jayanth, Hao, Ling-Yang, Lal, Ashish, Mazan-Mamczarz, Krystyna, Martindale, Jennifer, Xie, Chengsong, Ahmad, Rili, Thomas, Kelly J., Beilina, Alexandra, Gibbs, J. Raphael, Ding, Jinhui, Myers, Amanda J., Zhan, Ming, Cai, Huaibin, Bonini, Nancy M., Gorospe, Myriam, and Cookson, Mark R.

Published
2008
Full Text
View/download PDF

27. Genome-wide contribution of common short-tandem repeats to Parkinson's disease genetic risk.

Author

Bustos, Bernabe I, Billingsley, Kimberley, Blauwendraat, Cornelis, Gibbs, J Raphael, Gan-Or, Ziv, Krainc, Dimitri, Singleton, Andrew B, Lubbe, Steven J, (IPDGC), International Parkinson's Disease Genomics Consortium, and International Parkinson’s Disease Genomics Consortium (IPDGC)

Subjects
PARKINSON'S disease, GENE frequency, MICROSATELLITE repeats, GENETIC disorders, GENOME-wide association studies, GENE expression
Abstract

Parkinson's disease is a complex neurodegenerative disorder with a strong genetic component, for which most known disease-associated variants are single nucleotide polymorphisms (SNPs) and small insertions and deletions (indels). DNA repetitive elements account for >50% of the human genome; however, little is known of their contribution to Parkinson's disease aetiology. While select short tandem repeats (STRs) within candidate genes have been studied in Parkinson's disease, their genome-wide contribution remains unknown. Here we present the first genome-wide association study of STRs in Parkinson's disease. Through a meta-analysis of 16 imputed genome-wide association study cohorts from the International Parkinson's Disease Genomic Consortium (IPDGC), totalling 39 087 individuals (16 642 cases and 22 445 controls of European ancestry), we identified 34 genome-wide significant STR loci (P < 5.34 × 10-6), with the strongest signal located in KANSL1 [chr17:44 205 351:[T]11, P = 3 × 10-39, odds ratio = 1.31 (95% confidence interval = 1.26-1.36)]. Conditional-joint analyses suggested that four significant STRs mapping nearby NDUFAF2, TRIML2, MIRNA-129-1 and NCOR1 were independent from known risk SNPs. Including STRs in heritability estimates increased the variance explained by SNPs alone. Gene expression analysis of STRs (eSTRs) in RNA sequencing data from 13 brain regions identified significant associations of STRs influencing the expression of multiple genes, including known Parkinson's disease genes. Further functional annotation of candidate STRs revealed that significant eSTRs within NUDFAF2 and ZSWIM7 overlap with regulatory features and are associated with change in the expression levels of nearby genes. Here, we show that STRs at known and novel candidate loci contribute to Parkinson's disease risk and have functional effects in disease-relevant tissues and pathways, supporting previously reported disease-associated genes and giving further evidence for their functional prioritization. These data represent a valuable resource for researchers currently dissecting Parkinson's disease risk loci. [ABSTRACT FROM AUTHOR]

Published
2023
Full Text
View/download PDF

28. A pathway-based analysis provides additional support for an immune-related genetic susceptibility to Parkinsonʼs disease

Author

Holmans, Peter, Moskvina, Valentina, Jones, Lesley, Sharma, Manu, Vedernikov, Alexey, Buchel, Finja, Sadd, Mohamad, Bras, Jose M., Bettella, Francesco, Nicolaou, Nayia, Simón-Sánchez, Javier, Mittag, Florian, Gibbs, J. Raphael, Schulte, Claudia, Durr, Alexandra, Guerreiro, Rita, Hernandez, Dena, Brice, Alexis, Stefánsson, Hreinn, Majamaa, Kari, Gasser, Thomas, Heutink, Peter, Wood, Nicholas W., Martinez, Maria, Singleton, Andrew B., Nalls, Michael A., Hardy, John, Morris, Huw R., Williams, Nigel M., Arepalli, Sampath, Barker, Roger, Barrett, Jeffrey, Ben-Shlomo, Yoav, Berendse, Henk W., Berg, Daniela, Bhatia, Kailash, de Bie, Rob M.A., Biffi, Alessandro, Bloem, Bas, Brice, Alexis, Bochdanovits, Zoltan, Bonin, Michael, Bras, Jose M., Brockmann, Kathrin, Brooks, Janet, Burn, David J., Charlesworth, Gavin, Chen, Honglei, Chinnery, Patrick F., Chong, Sean, Clarke, Carl E., Cookson, Mark R., Cooper, Jonathan M., Corvol, Jen-Christophe, Counsell, Carl, Damier, Philippe, Dartigues, Jean Francois, Deloukas, Panagiotis, Deuschl, Günther, Dexter, David T., van Dijk, Karin D., Dillman, Allissa, Durif, Frank, Durr, Alexandra, Edkins, Sarah, Evans, Jonathan R., Foltynie, Thomas, Gao, Jianjun, Gardner, Michelle, Gasser, Thomas, Gibbs, J. Raphael, Goate, Alison, Gray, Emma, Guerreiro, Rita, Gústafsson, Ómar, Hardy, John, Harris, Clare, Hernandez, Dena G., Heutink, Peter, van Hilten, Jacobus J., Hofman, Albert, Hollenbeck, Albert, Holmans, Peter, Holton, Janice, Hu, Michele, Huber, Heiko, Hudson, Gavin, Hunt, Sarah E., Huttenlocher, Johanna, Illig, Thomas, Langford, Cordelia, Lees, Andrew, Lesage, Suzanne, Lichtner, Peter, Limousin, Patricia, Lopez, Grisel, Lorenz, Delia, Martinez, Maria, McNeill, Alisdair, Moorby, Catriona, Moore, Matthew, Morris, Huw, Morrison, Karen E., Moskvina, Valentina, Mudanohwo, Ese, Nalls, Michael A., Pearson, Justin, Perlmutter, Joel S., Pétursson, Hjörvar, Plagnol, Vincent, Pollak, Pierre, Post, Bart, Potter, Simon, Ravina, Bernard, Revesz, Tamas, Riess, Olaf, Rivadeneira, Fernando, Rizzu, Patrizia, Ryten, Mina, Saad, Mohamad, Sawcer, Stephen, Schapira, Anthony, Scheffer, Hans, Sharma, Manu, Shaw, Karen, Sheerin, Una-Marie, Shoulson, Ira, Schulte, Claudia, Sidransky, Ellen, Simón-Sánchez, Javier, Singleton, Andrew B., Smith, Colin, Stefánsson, Hreinn, Stefánsson, Kári, Steinberg, Stacy, Stockton, Joanna D., Sveinbjornsdottir, Sigurlaug, Talbot, Kevin, Tanner, Carlie M., Tashakkori-Ghanbaria, Avazeh, Tison, François, Trabzuni, Daniah, Traynor, Bryan J., Uitterlinden, André G., Velseboer, Daan, Vidailhet, Marie, Walker, Robert, van de Warrenburg, Bart, Wickremaratchi, Mirdhu, Williams, Nigel, Williams-Gray, Caroline H., Winder-Rhodes, Sophie, and Wood, Nicholas

Published
2013
Full Text
View/download PDF

29. Identification of candidate parkinson disease genes by integrating genome-wide association study, expression, and epigenetic data sets

Author

Kia, Demis A., Zhang, David, Guelfi, Sebastian, Manzoni, Claudia, Hubbard, Leon, Reynolds, Regina H., Botía, Juan, Ryten, Mina, Ferrari, Raffaele, Lewis, Patrick A., Williams, Nigel, Trabzuni, Daniah, Hardy, John, Wood, Nicholas W., Noyce, Alastair J., Kaiyrzhanov, Rauan, Middlehurst, Ben, Tan, Manuela, Houlden, Henry, Morris, Huw R., Plun-Favreau, Helene, Holmans, Peter, Bras, Jose, PhD, John Quinn, Mok, Kin Y., Kinghorn, Kerri J., Billingsley, Kimberley, Lewis, Patrick, Schreglmann, Sebastian, Guerreiro, Rita, Lovering, Ruth, R'Bibo, Lea, Rizig, Mie, Escott-Price, Valentina, Chelban, Viorica, Foltynie, Thomas, Brice, Alexis, Danjou, Fabrice, Lesage, Suzanne, Corvol, Jean-Christophe, Martinez, Maria, Schulte, Claudia, Brockmann, Kathrin, Simón-Sánchez, Javier, Heutink, Peter, Rizzu, Patrizia, Sharma, Manu, Gasser, Thomas, Nicolas, Aude, Cookson, Mark R., Bandres-Ciga, Sara, Blauwendraat, Cornelis, Craig, David W., Faghri, Faraz, Gibbs, J. Raphael, Hernandez, Dena G., Van Keuren-Jensen, Kendall, Shulman, Joshua M., 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., Gan-Or, Ziv, Rouleau, Guy A., Krohn, Lynne, van Hilten, Jacobus J., Marinus, Johan, Adarmes-Gómez, Astrid D., Aguilar, Miquel, Alvarez, Ignacio, Alvarez, Victoria, Javier Barrero, Francisco, Bergareche Yarza, Jesús A., Bernal-Bernal, Inmaculada, Blazquez, Marta, Bonilla-Toribio, Marta, Botía, Juan A., Boungiorno, María T., Buiza-Rueda, Dolores, Càmara, Ana, Carrillo, Fátima, Carrión-Claro, Mario, Cerdan, Debora, Clarimón, Jordi, Compta, Yaroslau, Diez-Fairen, Monica, Dols-Icardo, Oriol, Duarte, Jacinto, Duran, Raquel, Escamilla-Sevilla, Francisco, Ezquerra, Mario, Feliz, Cici, Fernàndez, Manel, Fernàndez-Santiago, Rubén, Garcia, Ciara, García-Ruiz, Pedro, Gómez-Garre, Pilar, Gomez Heredia, Maria J., Gonzalez-Aramburu, Isabel, Pagola, Ana G., Hoenicka, Janet, Infante, Jon, Jimenez-Escrig, Adriano, Kulisevsky, Jaime, Labrador-Espinosa, Miguel A., Lopez-Sendon, Jose Luis, Arregui, Adolfo López de Munain, Macias, Daniel, Torres, Irene Martínez, Marín, Juan, Marti, Maria Jose, Martínez-Castrillo, Juan Carlos, Mèndez-del-Barrio, Carlota, González, Manuel Menéndez, Adolfo Mínguez, Marina Mata, Mir, Pablo, Rezola, Elisabet Mondragon, Muñoz, Esteban, Pagonabarraga, Javier, Pastor, Pau, Errazquin, Francisco Perez, Perinán-Tocino, Teresa, Ruiz-Martínez, Javier, Ruz, Clara, Rodriguez, Antonio Sanchez, Sierra, María, Suarez-Sanmartin, Esther, Tabernero, Cesar, Tartari, Juan Pablo, Tejera-Parrado, Cristina, Tolosa, Eduard, Valldeoriola, Francesc, Vargas-González, Laura, Vela, Lydia, Vives, Francisco, Zimprich, Alexander, Pihlstrom, Lasse, Toft, Mathias, Koks, Sulev, Taba, Pille, Hassin-Baer, Sharon, Weale, Michael, Ramasamy, Adaikalavan, Smith, Colin, Guelfi, Manuel Sebastian, D'sa, Karishma, Forabosco, Paola, Botiá, Juan A., and Universidad de Cantabria

Subjects
Candidate gene, Protein catabolic process, Gene Expression, Genome-wide association study, Computational biology, Biology, Epigenesis, Genetic, 03 medical and health sciences, 0302 clinical medicine, Databases, Genetic, Humans, Online First, 030212 general & internal medicine, Epigenetics, Gene, Genetic Association Studies, Genetic association, Original Investigation, Research, Parkinson Disease, Protein ubiquitination, Neurology (clinical), Candidate Disease Gene, 030217 neurology & neurosurgery, Comments, Genome-Wide Association Study
Abstract

Key Points Question What genes and genomic processes underlie risk of sporadic Parkinson disease? Findings This genetic association study integrated Parkinson disease genome-wide association study data and brain-derived gene regulation data using various complementary bioinformatic tools and identified 11 candidate genes with evidence of disease-associated regulatory changes. Coexpression and protein level analyses of these genes demonstrated a significant functional association with known mendelian Parkinson disease genes. Meaning This study suggests that gene regulation data may be used to identify candidate genes and pathways involved in sporadic Parkinson disease., Importance Substantial genome-wide association study (GWAS) work in Parkinson disease (PD) has led to the discovery of an increasing number of loci shown reliably to be associated with increased risk of disease. Improved understanding of the underlying genes and mechanisms at these loci will be key to understanding the pathogenesis of PD. Objective To investigate what genes and genomic processes underlie the risk of sporadic PD. Design and Setting This genetic association study used the bioinformatic tools Coloc and transcriptome-wide association study (TWAS) to integrate PD case-control GWAS data published in 2017 with expression data (from Braineac, the Genotype-Tissue Expression [GTEx], and CommonMind) and methylation data (derived from UK Parkinson brain samples) to uncover putative gene expression and splicing mechanisms associated with PD GWAS signals. Candidate genes were further characterized using cell-type specificity, weighted gene coexpression networks, and weighted protein-protein interaction networks. Main Outcomes and Measures It was hypothesized a priori that some genes underlying PD loci would alter PD risk through changes to expression, splicing, or methylation. Candidate genes are presented whose change in expression, splicing, or methylation are associated with risk of PD as well as the functional pathways and cell types in which these genes have an important role. Results Gene-level analysis of expression revealed 5 genes (WDR6 [OMIM 606031], CD38 [OMIM 107270], GPNMB [OMIM 604368], RAB29 [OMIM 603949], and TMEM163 [OMIM 618978]) that replicated using both Coloc and TWAS analyses in both the GTEx and Braineac expression data sets. A further 6 genes (ZRANB3 [OMIM 615655], PCGF3 [OMIM 617543], NEK1 [OMIM 604588], NUPL2 [NCBI 11097], GALC [OMIM 606890], and CTSB [OMIM 116810]) showed evidence of disease-associated splicing effects. Cell-type specificity analysis revealed that gene expression was overall more prevalent in glial cell types compared with neurons. The weighted gene coexpression performed on the GTEx data set showed that NUPL2 is a key gene in 3 modules implicated in catabolic processes associated with protein ubiquitination and in the ubiquitin-dependent protein catabolic process in the nucleus accumbens, caudate, and putamen. TMEM163 and ZRANB3 were both important in modules in the frontal cortex and caudate, respectively, indicating regulation of signaling and cell communication. Protein interactor analysis and simulations using random networks demonstrated that the candidate genes interact significantly more with known mendelian PD and parkinsonism proteins than would be expected by chance. Conclusions and Relevance Together, these results suggest that several candidate genes and pathways are associated with the findings observed in PD GWAS studies., This genetic association study investigates what genes and genomic processes underlie the risk of sporadic Parkinson disease.

Published
2021

30. ATXN2 intermediate expansions in amyotrophic lateral sclerosis.

Author

Glass, Jonathan D, Dewan, Ramita, Ding, Jinhui, Gibbs, J Raphael, Dalgard, Clifton, Keagle, Pamela J, Shankaracharya, García-Redondo, Alberto, Traynor, Bryan J, Chia, Ruth, and Landers, John E

Subjects
LEWY body dementia, AMYOTROPHIC lateral sclerosis, RESEARCH funding, FRONTOTEMPORAL dementia, PHENOTYPES
Abstract

Intermediate CAG (polyQ) expansions in the gene ataxin-2 (ATXN2) are now recognized as a risk factor for amyotrophic lateral sclerosis. The threshold for increased risk is not yet firmly established, with reports ranging from 27 to 31 repeats. We investigated the presence of ATXN2 polyQ expansions in 9268 DNA samples collected from people with amyotrophic lateral sclerosis, amyotrophic lateral sclerosis with frontotemporal dementia, frontotemporal dementia alone, Lewy body dementia and age matched controls. This analysis confirmed ATXN2 intermediate polyQ expansions of ≥31 as a risk factor for amyotrophic lateral sclerosis with an odds ratio of 6.31. Expansions were an even greater risk for amyotrophic lateral sclerosis with frontotemporal dementia (odds ratio 27.59) and a somewhat lesser risk for frontotemporal dementia alone (odds ratio 3.14). There was no increased risk for Lewy body dementia. In a subset of 1362 patients with amyotrophic lateral sclerosis with complete clinical data, we could not confirm previous reports of earlier onset of amyotrophic lateral sclerosis or shorter survival in 25 patients with expansions. These new data confirm ≥31 polyQ repeats in ATXN2 increase the risk for amyotrophic lateral sclerosis, and also for the first time show an even greater risk for amyotrophic lateral sclerosis with frontotemporal dementia. The lack of a more aggressive phenotype in amyotrophic lateral sclerosis patients with expansions has implications for ongoing gene-silencing trials for amyotrophic lateral sclerosis. [ABSTRACT FROM AUTHOR]

Published
2022
Full Text
View/download PDF

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

Author

Chia, Ruth, Sabir, Marya S, Makarious, Mary B, Serrano, Geidy E, Beach, Thomas G, McKeith, Ian G, Thomas, Alan J, Attems, Johannes, Morris, Christopher M, Palmer, Laura, Love, Seth, Troakes, Claire, Al-Sarraj, Safa, Diez-Fairen, Monica, Hodges, Angela K, Aarsland, Dag, Klein, Gregory, Kaiser, Scott M, Woltjer, Randy, Pastor, Pau, Bekris, Lynn M, Leverenz, James B, Besser, Lilah M, Kuzma, Amanda, Portley, Makayla K, Renton, Alan E, Goate, Alison, Bennett, David A, Scherzer, Clemens R, Morris, Huw R, Ferrari, Raffaele, Albani, Diego, Pickering-Brown, Stuart, Faber, Kelley, Kukull, Walter A, Shah, Zalak, Morenas-Rodriguez, Estrella, Lleó, Alberto, Fortea, Juan, Alcolea, Daniel, Clarimon, Jordi, Nalls, Mike A, Ferrucci, Luigi, Resnick, Susan M, Tanaka, Toshiko, Foroud, Tatiana M, Abramzon, Yevgeniya, Graff-Radford, Neill R, Wszolek, Zbigniew K, Ferman, Tanis, Boeve, Bradley F, Hardy, John A, Topol, Eric J, Torkamani, Ali, Singleton, Andrew B, Ryten, Mina, Dickson, Dennis W, Hernandez, Dena Michelle Godwin, Chiò, Adriano, Ross, Owen A, Gibbs, J Raphael, Dalgard, Clifton L, Traynor, Bryan J, Scholz, Sonja W, Sotis, Anthony R, Sukumar, Gauthaman, Alba, Camille, Lott, Nathaniel, Blauwendraat, Cornelis, Martinez, Elisa McGrath, Tuck, Meila, Singh, Jatinder, Bacikova, Dagmar, Zhang, Xijun, Hupalo, Daniel N, Adeleye, Adelani, Wilkerson, Matthew D, Pollard, Harvey B, Stone, David J, Eicher, John, Parkkinen, Laura, Bandres-Ciga, Sara, Ansorge, Olaf, Clark, Lorraine, Honig, Lawrence S, Marder, Karen, Lemstra, Afina, St George-Hyslop, Peter, Londos, Elisabet, Morgan, Kevin, Lashley, Tammaryn, Warner, Thomas T, Saez-Atienzar, Sara, 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, Reynolds, Regina H, Trojanowski, John Q, Grassano, Maurizio, Calvo, Andrea, Mora, Gabriele, Canosa, Antonio, Floris, Gianluca, Bohannan, Ryan C, Brett, Francesca, Gan-Or, Ziv, Geiger, Joshua T, Gustavsson, Emil, Moore, Anni, May, Patrick, Krüger, Rejko, Goldstein, David S, Lopez, Grisel, Tayebi, Nahid, Sidransky, Ellen, Center, American Genome, Norcliffe-Kaufmann, Lucy, Palma, Jose-Alberto, Walton, Ronald L, Kaufmann, Horacio, Shakkottai, Vikram G, Perkins, Matthew, Newell, Kathy L, Gasser, Thomas, Schulte, Claudia, Landi, Francesco, Salvi, Erika, Cusi, Daniele, Masliah, Eliezer, Ahmed, Sarah, 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, Viollet, Coralie, 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, Ding, Jinhui, Masellis, Mario, Rogaeva, Ekaterina, Duyckaerts, Charles, Brice, Alexis, Lesage, Suzanne, Xiromerisiou, Georgia, Barrett, Matthew J, Tilley, Bension S, Gentleman, Steve, Logroscino, Giancarlo, Neurology, and Amsterdam Neuroscience - Neurodegeneration

Subjects
Genome-wide association study, genetics [Alzheimer Disease], Computational biology, Biology, Polymorphism, Single Nucleotide, DNA sequencing, Article, genetics [Glucosylceramidase], BIN1 protein, human, 03 medical and health sciences, 0302 clinical medicine, genetics [Lewy Body Disease], genetics [Tumor Suppressor Proteins], genetics [Parkinson Disease], ddc:570, genetics [Adaptor Proteins, Signal Transducing], Genetics, medicine, Dementia, Humans, Genetic Predisposition to Disease, SNCA protein, human, GBA protein, human, 030304 developmental biology, Genetic association, Adaptor Proteins, Signal Transducing, Whole genome sequencing, 0303 health sciences, Lewy body, Genome, Human, Gene Expression Profiling, Tumor Suppressor Proteins, Nuclear Proteins, genetics [Nuclear Proteins], medicine.disease, Genetic architecture, Gene expression profiling, Case-Control Studies, genetics [alpha-Synuclein], alpha-Synuclein, Glucosylceramidase, 030217 neurology & neurosurgery, hormones, hormone substitutes, and hormone antagonists, Genome-Wide Association Study
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

33. Investigation of Autosomal Genetic Sex Differences in Parkinson's Disease

Author

Blauwendraat, Cornelis, Iwaki, Hirotaka, Gibbs, Jesse R, Bras, Jose, Guerreiro, Rita, Lubbe, Steven, Troycoco, Timothy, Finkbeiner, Steven, Mencacci, Niccolo E, Lungu, Codrin, Singleton, Andrew B, Scholz, Sonja W, Reed, Xylena, Hernandez, Dena Michelle Godwin, Uitti, Ryan J, Ross, Owen A, Grenn, Francis P, Moore, Anni, Alcalay, Roy N, Wszolek, Zbigniew K, Gan-Or, Ziv, Rouleau, Guy A, Krohn, Lynne, Mufti, Kheireddin, Ruskey, Jennifer A, van Hilten, Jacobus J, Marinus, Johan, Adarmes-Gómez, Astrid D, Aguilar, Miquel, Alvarez, Ignacio, Alvarez, Victoria, Barrero, Francisco Javier, Yarza, Jesús Alberto Bergareche, Bernal-Bernal, Inmaculada, Blazquez, Marta, Pihlstrøm, Lasse, Bonilla-Toribio, Marta, Botía, Juan A, Boungiorno, María Teresa, Buiza-Rueda, Dolores, Cámara, Ana, Carrillo, Fátima, Carrión-Claro, Mario, Cerdan, Debora, Clarimón, Jordi, Compta, Yaroslau, Toft, Mathias, Diez-Fairen, Monica, Dols-Icardo, Oriol, Duarte, Jacinto, Duran, Raquel, Escamilla-Sevilla, Francisco, Ezquerra, Mario, Feliz, Cici, Fernández, Manel, Fernández-Santiago, Rubén, Garcia, Ciara, García-Ruiz, Pedro, Gómez-Garre, Pilar, Heredia, Maria Jose Gomez, Gonzalez-Aramburu, Isabel, Pagola, Ana Gorostidi, Hoenicka, Janet, Infante, Jon, Jesús, Silvia, Jimenez-Escrig, Adriano, Kulisevsky, Jaime, Labrador-Espinosa, Miguel A, Lopez-Sendon, Jose Luis, de Munain Arregui, Adolfo López, Macias, Daniel, Torres, Irene Martínez, Marín, Juan, Marti, Maria Jose, Martínez-Castrillo, Juan Carlos, Méndez-Del-Barrio, Carlota, González, Manuel Menéndez, Schulte, Claudia, Mata, Marina, Mínguez, Adolfo, Mir, Pablo, Rezola, Elisabet Mondragon, Muñoz, Esteban, Pagonabarraga, Javier, Pastor, Pau, Errazquin, Francisco Perez, Periñán-Tocino, Teresa, Ruiz-Martínez, Javier, Brockmann, Kathrin, Ruz, Clara, Rodriguez, Antonio Sanchez, Sierra, María, Suarez-Sanmartin, Esther, Tabernero, Cesar, Tartari, Juan Pablo, Tejera-Parrado, Cristina, Tolosa, Eduard, Valldeoriola, Francesc, Vargas-González, Laura, Sharma, Manu, Vela, Lydia, Vives, Francisco, Zimprich, Alexander, Pihlstrom, Lasse, Taba, Pille, Koks, Sulev, Hassin-Baer, Sharon, Majamaa, Kari, Siitonen, Ari, Makarious, Mary B, Tienari, Pentti, Okubadejo, Njideka U, Ojo, Oluwadamilola O, Kaiyrzhanov, Rauan, Shashkin, Chingiz, Zharkinbekova, Nazira, Akhmetzhanov, Vadim, Kaishybayeva, Gulnaz, Karimova, Altynay, Khaibullin, Talgat, Lynch, Timothy L, Eerola-Rautio, Johanna, Tienari, Pentti J, Grosset, Donald G, Lesage, Suzanne, Corvol, Jean-Christophe, Brice, Alexis, Wood, Nick, Hardy, John, Bandres-Ciga, Sara, Heutink, Peter, Gasser, Thomas, Morris, Huw R, Noyce, Alastair J, Nalls, Mike A, Consortium, and the International Parkinson's Disease Genomics, Leonard, Hampton L, Middlehurst, Ben, Kia, Demis A, Tan, Manuela, Houlden, Henry, Storm, Catherine S, Plun-Favreau, Helene, Holmans, Peter, Trabzuni, Daniah, Quinn, John, Bubb, Vivien, Mok, Kin Y, Kinghorn, Kerri J, Wood, Nicholas W, Lewis, Patrick, Schreglmann, Sebastian R, Lovering, Ruth, R'Bibo, Lea, Manzoni, Claudia, Lake, Julie, Rizig, Mie, Ryten, Mina, Guelfi, Sebastian, Escott-Price, Valentina, Chelban, Viorica, Foltynie, Thomas, Williams, Nigel, Morrison, Karen E, Clarke, Carl, Harvey, Kirsten, Jacobs, Benjamin M, Danjou, Fabrice, Martinez, Maria, Simón-Sánchez, Javier, Rizzu, Patrizia, Schneider, Susanne A, Cookson, Mark R, Craig, David W, Billingsley, Kimberley, Kim, Jonggeol J, Narendra, Derek P, Faghri, Faraz, Gibbs, J Raphael, Van Keuren-Jensen, Kendall, Shulman, Joshua M, Robak, Laurie, Universidad de Cantabria, HUS Neurocenter, Neurologian yksikkö, Department of Neurosciences, University of Helsinki, Clinicum, Research Programs Unit, and Eija Pirinen / Principal Investigator

Subjects
0301 basic medicine, Male, Genotype, EFFICIENT, Physiology, Genome-wide association study, Disease, Biology, Genetic correlation, 3124 Neurology and psychiatry, 03 medical and health sciences, Sex Factors, 0302 clinical medicine, genetics [Parkinson Disease], Genetic variation, Humans, Genetic Predisposition to Disease, ddc:610, Parkinson Disease/genetics, METAANALYSIS, Research Articles, Genetic association, Aged, RISK, Sex Characteristics, Autosome, 3112 Neurosciences, Parkinson Disease, Heritability, Middle Aged, Genetic architecture, 3. Good health, 030104 developmental biology, Neurology, Female, GENDER, Neurology (clinical), 030217 neurology & neurosurgery, Research Article, Genome-Wide Association Study
Abstract

Methods: In an effort to study sex-specific genetic factors associated with PD, we explored 2 large genetic datasets from the International Parkinson?s Disease Genomics Consortium and the UK Biobank consisting of 13,020male PD cases, 7,936 paternal proxy cases, 89,660 male controls, 7,947 female PD cases, 5,473 maternal proxy cases, and 90,662 female controls. We performed GWASmeta-analyses to identify distinct patterns of genetic risk contributing to disease inmale versus female PD cases. Results: In total, 19 genomewide significant regions were identified and no sex-specific effects were observed. A high genetic correlation between the male and female PD GWAS were identified (rg = 0.877) and heritability estimates were identical between male and female PD cases (~ 20%). Interpretation: We did not detect any significant genetic differences between male or female PD cases. Our study does not support the notion that common genetic variation on the autosomes could explain the difference in prevalence of PD between males and females cases at least when considering the current sample size under study. Further studies are warranted to investigate the genetic architecture of PD explained by X and Y chromosomes and further evaluate environmental effects that could potentially contribute to PD etiology in male versus female patients. FUNDING: This work was supported in part by the Intramural Research Programs of the National Institute of Neurological Disorders and Stroke (NINDS), the National Institute on Aging (NIA), and the National Institute of Environmental Health Sciences both part of the National Institutes of Health, Department of Health and Human Services; Project numbers 1ZIA-NS003154, Z01-AG000949-02, and Z01-ES101986. In addition, this work was supported by the Department of Defense (award W81XWH-09-2-0128), and The Michael J. Fox Foundation for Parkinson’s Research. This work was supported by National Institutes of Health grants R01NS037167, R01CA141668, and P50NS071674, American Parkinson Disease Association (APDA); Barnes Jewish Hospital Foundation; Greater St Louis Chapter of the APDA. The KORA (Cooperative Research in the Region of Augsburg) research platform was started and financed by the Forschungszentrum für Umwelt und Gesundheit, which is funded by the German Federal Ministry of Education, Science, Research, and Technology and by the State of Bavaria. This study was also funded by the German Federal Ministry of Education and Research (BMBF) under the funding code 031A430A, the EU Joint Programme - Neurodegenerative Diseases Research (JPND) project under the aegis of JPND -www.jpnd.eu – through Germany, BMBF, funding code 01ED1406 and iMed – the Helmholtz Initiative on Personalized Medicine. This study utilized the high-performance computational capabilities of the Biowulf Linux cluster at the National Institutes of Health, Bethesda, MD, USA (http://biowulf.nih.gov), and DNA panels, samples, and clinical data from the National Institute of Neurological Disorders and Stroke Human Genetics Resource Center DNA and Cell Line Repository. People who contributed samples are acknowledged in descriptions of every panel on the repository website. We thank P. Tienari (Molecular Neurology Programme, Biomedicum, University of Helsinki), T. Peuralinna (Department of Neurology, Helsinki University Central Hospital), L. Myllykangas (Folkhalsan Institute of Genetics and Department of Pathology, University of Helsinki), and R. Sulkava (Department of Public Health and General Practice Division of Geriatrics, University of Eastern Finland) for the Finnish controls (Vantaa85+ GWAS data). This study was also funded by the Sigrid Juselius Foundation (KM). We used genomewide association data generated by the Wellcome Trust Case–Control Consortium 2 (WTCCC2) from UK patients with Parkinson’s disease and UK control individuals from the 1958 Birth Cohort and National Blood Service. UK population control data was made available through WTCCC1. As with previous IPDGC efforts, this study makes use of data generated by the Wellcome Trust Case-Control Consortium. A full list of the investigators who contributed to the generation of the data is available from www.wtccc.org.uk. Funding for the project was provided by the Wellcome Trust under awards 076113, 085475, and 090355. This study was also supported by Parkinson’s UK (grants 8047 and J-0804) and the Medical Research Council (G0700943 and G1100643). Sequencing and genotyping done in McGill University was supported by grants from the Michael J. Fox Foundation, the Canadian Consortium on Neurodegeneration in Aging (CCNA), the Canada First Research Excellence Fund (CFREF), awarded to McGill University for the Healthy Brains for Healthy Lives (HBHL) program and Parkinson’s Society Canada. The access to part of the participants at McGill has been made possible thanks to the Quebec Parkinson’s Network (http://rpq-qpn.ca/en). We thank the Quebec Parkinson’s Network (http://rpq-qpn.org) and its members. Harvard NeuroDiscovery Biomarker Study (HBS) is a collaboration of HBS investigators and funded through philanthropy and NIH and Non-NIH funding sources. The HBS Investigators have not participated in reviewing the data analysis or content of the manuscript. PPMI – a public-private partnership – is funded by the Michael J. Fox Foundation for Parkinson’s Research and funding partners, the full names of all of the PPMI funding partners can be found at www.ppmi-info.org/ fundingpartners. The PPMI Investigators have not participated in reviewing the data analysis or content of the manuscript. For up-to-date information on the study, visit www.ppmi-info.org. Parkinson’s Disease Biomarker Program (PDBP) consortium is supported by the National Institute of Neurological Disorders and Stroke (NINDS) at the National Institutes of Health. A full list of PDBP investigators can be found at https://pdbp.ninds.nih.gov/ policy. The PDBP Investigators have not participated in reviewing the data analysis or content of the manuscript

Published
2021

34. Association of variants in the SPTLC1 gene with juvenile amyotrophic lateral sclerosis

Author

Başak, Ayşe Nazlı (ORCID 0000-0001-9257-3540 & YÖK ID 1512); Palvadeau, Robin, Johnson, Janel O.; Chia, Ruth; Miller, Danny E.; Li, Rachel; Kumaran, Ravindran; Abramzon, Yevgeniya; Alahmady, Nada; Renton, Alan E.; Topp, Simon D.; Gibbs, J. Raphael; Cookson, Mark R.; Sabir, Marya S.; Dalgard, Clifton L.; Troakes, Claire; Jones, Ashley R.; Shatunov, Aleksey; Lacoangeli, Alfredo; Al Khleifat, Ahmad; Ticozzi, Nicola; Silani, Vincenzo; Gellera, Cinzia; Blair, Ian P.; Dobson-Stone, Carol; Kwok, John B.; Bonkowski, Emily S.; Palvadeau, Robin; Tienari, Pentti J.; Morrison, Karen E.; Shaw, Pamela J.; Al-Chalabi, Ammar; Jr, Robert H. Brown; Calvo, Andrea; Mora, Gabriele; Al-Saif, Hind; Gotkine, Marc; Leigh, Fawn; Chang, Irene J.; Perlman, Seth J.; Glass, Ian; Scott, Anna, I.; Landers, John E.; Chio, Adriano; Crawford, Thomas O.; Smith, Bradley N.; Traynor, Bryan J., Başak, Ayşe Nazlı (ORCID 0000-0001-9257-3540 & YÖK ID 1512); Palvadeau, Robin, and Johnson, Janel O.; Chia, Ruth; Miller, Danny E.; Li, Rachel; Kumaran, Ravindran; Abramzon, Yevgeniya; Alahmady, Nada; Renton, Alan E.; Topp, Simon D.; Gibbs, J. Raphael; Cookson, Mark R.; Sabir, Marya S.; Dalgard, Clifton L.; Troakes, Claire; Jones, Ashley R.; Shatunov, Aleksey; Lacoangeli, Alfredo; Al Khleifat, Ahmad; Ticozzi, Nicola; Silani, Vincenzo; Gellera, Cinzia; Blair, Ian P.; Dobson-Stone, Carol; Kwok, John B.; Bonkowski, Emily S.; Palvadeau, Robin; Tienari, Pentti J.; Morrison, Karen E.; Shaw, Pamela J.; Al-Chalabi, Ammar; Jr, Robert H. Brown; Calvo, Andrea; Mora, Gabriele; Al-Saif, Hind; Gotkine, Marc; Leigh, Fawn; Chang, Irene J.; Perlman, Seth J.; Glass, Ian; Scott, Anna, I.; Landers, John E.; Chio, Adriano; Crawford, Thomas O.; Smith, Bradley N.; Traynor, Bryan J.

Abstract

Importance: Juvenile amyotrophic lateral sclerosis (ALS) is a rare form of ALS characterized by age of symptom onset less than 25 years and a variable presentation. Objective: to identify the genetic variants associated with juvenile ALS. Design, setting, and participants: in this multicenter family-based genetic study, trio whole-exome sequencing was performed to identify the disease-associated gene in a case series of unrelated patients diagnosed with juvenile ALS and severe growth retardation. The patients and their family members were enrolled at academic hospitals and a government research facility between March 1, 2016, and March 13, 2020, and were observed until October 1, 2020. Whole-exome sequencing was also performed in a series of patients with juvenile ALS. A total of 66 patients with juvenile ALS and 6258 adult patients with ALS participated in the study. Patients were selected for the study based on their diagnosis, and all eligible participants were enrolled in the study. None of the participants had a family history of neurological disorders, suggesting de novo variants as the underlying genetic mechanism. Main outcomes and measures: De novo variants present only in the index case and not in unaffected family members. Results: Trio whole-exome sequencing was performed in 3 patients diagnosed with juvenile ALS and their parents. An additional 63 patients with juvenile ALS and 6258 adult patients with ALS were subsequently screened for variants in the SPTLC1 gene. De novo variants in SPTLC1 (p. Ala20Ser in 2 patients and p.Ser331Tyr in 1 patient) were identified in 3 unrelated patients diagnosed with juvenile ALS and failure to thrive. A fourth variant (p.Leu39del) was identified in a patient with juvenile ALS where parental DNA was unavailable. Variants in this gene have been previously shown to be associated with autosomal-dominant hereditary sensory autonomic neuropathy, type 1A, by disrupting an essential enzyme complex in the sphingolipid synthesi

Published
2021

35. Pathogenic Huntingtin Repeat Expansions in Patients with Frontotemporal Dementia and Amyotrophic Lateral Sclerosis.

Author

Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) [research center], Luxembourg Centre for Systems Biomedicine (LCSB): Clinical & Experimental Neuroscience (Krüger Group) [research center], Dewan, Ramita, Chia, Ruth, Ding, Jinhui, Hickman, Richard A., Stein, Thor D., Abramzon, Yevgeniya, Ahmed, Sarah, Sabir, Marya S., Portley, Makayla K., Tucci, Arianna, Ibáñez, Kristina, Shankaracharya, F. N. U., Keagle, Pamela, Rossi, Giacomina, Caroppo, Paola, Tagliavini, Fabrizio, Waldo, Maria L., Johansson, Per M., Nilsson, Christer F., May, Patrick, Krüger, Rejko, Rowe, James B., Benussi, Luisa, Binetti, Giuliano, Ghidoni, Roberta, Jabbari, Edwin, Viollet, Coralie, Glass, Jonathan D., Singleton, Andrew B., Silani, Vincenzo, Ross, Owen A., Ryten, Mina, Torkamani, Ali, Tanaka, Toshiko, Ferrucci, Luigi, Resnick, Susan M., Pickering-Brown, Stuart, Brady, Christopher B., Kowal, Neil, Hardy, John A., Van Deerlin, Vivianna, Vonsattel, Jean Paul, Harms, Matthew B., Morris, Huw R., Ferrari, Raffaele, Landers, John E., Chiò, Adriano, Gibbs, J. Raphael, Dalgard, Clifton L., Scholz, Sonja W., Traynor, Bryan J., Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) [research center], Luxembourg Centre for Systems Biomedicine (LCSB): Clinical & Experimental Neuroscience (Krüger Group) [research center], Dewan, Ramita, Chia, Ruth, Ding, Jinhui, Hickman, Richard A., Stein, Thor D., Abramzon, Yevgeniya, Ahmed, Sarah, Sabir, Marya S., Portley, Makayla K., Tucci, Arianna, Ibáñez, Kristina, Shankaracharya, F. N. U., Keagle, Pamela, Rossi, Giacomina, Caroppo, Paola, Tagliavini, Fabrizio, Waldo, Maria L., Johansson, Per M., Nilsson, Christer F., May, Patrick, Krüger, Rejko, Rowe, James B., Benussi, Luisa, Binetti, Giuliano, Ghidoni, Roberta, Jabbari, Edwin, Viollet, Coralie, Glass, Jonathan D., Singleton, Andrew B., Silani, Vincenzo, Ross, Owen A., Ryten, Mina, Torkamani, Ali, Tanaka, Toshiko, Ferrucci, Luigi, Resnick, Susan M., Pickering-Brown, Stuart, Brady, Christopher B., Kowal, Neil, Hardy, John A., Van Deerlin, Vivianna, Vonsattel, Jean Paul, Harms, Matthew B., Morris, Huw R., Ferrari, Raffaele, Landers, John E., Chiò, Adriano, Gibbs, J. Raphael, Dalgard, Clifton L., Scholz, Sonja W., and Traynor, Bryan J.

Abstract

We examined the role of repeat expansions in the pathogenesis of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) by analyzing whole-genome sequence data from 2,442 FTD/ALS patients, 2,599 Lewy body dementia (LBD) patients, and 3,158 neurologically healthy subjects. Pathogenic expansions (range, 40-64 CAG repeats) in the huntingtin (HTT) gene were found in three (0.12%) patients diagnosed with pure FTD/ALS syndromes but were not present in the LBD or healthy cohorts. We replicated our findings in an independent collection of 3,674 FTD/ALS patients. Postmortem evaluations of two patients revealed the classical TDP-43 pathology of FTD/ALS, as well as huntingtin-positive, ubiquitin-positive aggregates in the frontal cortex. The neostriatal atrophy that pathologically defines Huntington's disease was absent in both cases. Our findings reveal an etiological relationship between HTT repeat expansions and FTD/ALS syndromes and indicate that genetic screening of FTD/ALS patients for HTT repeat expansions should be considered.

Published
2021

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

Author

Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) [research center], Luxembourg Centre for Systems Biomedicine (LCSB): Clinical & Experimental Neuroscience (Krüger Group) [research center], Fonds National de la Recherche - FnR [sponsor], 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, Sotis, Anthony R., Sukumar, Gauthaman, Alba, Camille, Lott, Nathaniel, Martinez, Elisa Mcgrath, Tuck, Meila, Singh, Jatinder, Bacikova, Dagmar, Zhang, Xijun, Hupalo, Daniel N., Adeleye, Adelani, Wilkerson, Matthew D., Pollard, Harvey B., 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, Serrano, Geidy E., Beach, Thomas G., McKeith, Ian G., Thomas, Alan J., Attems, Johannes, Morris, Christopher M., Palmer, Laura, Love, Seth, Troakes, Claire, Al-Sarraj, Safa, Hodges, Angela K., Aarsland, Dag, Klein, Gregory, Kaiser, Scott M., Woltjer, Randy, Pastor, Pau, Bekris, Lynn M., Leverenz, James B., Besser, Lilah M., Kuzma, Amanda, Renton, Alan E., Goate, Alison, Bennett, David A., Scherzer, Clemens R., Morris, Huw R., Ferrari, Raffaele, Albani, Diego, Pickering-Brown, Stuart, Faber, Kelley, Kukull, Walter A., Morenas-Rodriguez, Estrella, Lleó, Alberto, Fortea, Juan, Alcolea, Daniel, Clarimon, Jordi, Nalls, Mike A., Ferrucci, Luigi, Resnick, Susan M., Tanaka, Toshiko, Foroud, Tatiana M., Graff-Radford, Neill R., Wszolek, Zbigniew K., Ferman, Tanis, Boeve, Bradley F., Hardy, John A., Topol, Eric J., Torkamani, Ali, Singleton, Andrew B., Ryten, Mina, Dickson, Dennis W., Chiò, Adriano, Ross, Owen A., Gibbs, J. Raphael, Dalgard, Clifton L., Traynor, Bryan J., Scholz, Sonja W., Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) [research center], Luxembourg Centre for Systems Biomedicine (LCSB): Clinical & Experimental Neuroscience (Krüger Group) [research center], Fonds National de la Recherche - FnR [sponsor], 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, Sotis, Anthony R., Sukumar, Gauthaman, Alba, Camille, Lott, Nathaniel, Martinez, Elisa Mcgrath, Tuck, Meila, Singh, Jatinder, Bacikova, Dagmar, Zhang, Xijun, Hupalo, Daniel N., Adeleye, Adelani, Wilkerson, Matthew D., Pollard, Harvey B., 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, Serrano, Geidy E., Beach, Thomas G., McKeith, Ian G., Thomas, Alan J., Attems, Johannes, Morris, Christopher M., Palmer, Laura, Love, Seth, Troakes, Claire, Al-Sarraj, Safa, Hodges, Angela K., Aarsland, Dag, Klein, Gregory, Kaiser, Scott M., Woltjer, Randy, Pastor, Pau, Bekris, Lynn M., Leverenz, James B., Besser, Lilah M., Kuzma, Amanda, Renton, Alan E., Goate, Alison, Bennett, David A., Scherzer, Clemens R., Morris, Huw R., Ferrari, Raffaele, Albani, Diego, Pickering-Brown, Stuart, Faber, Kelley, Kukull, Walter A., Morenas-Rodriguez, Estrella, Lleó, Alberto, Fortea, Juan, Alcolea, Daniel, Clarimon, Jordi, Nalls, Mike A., Ferrucci, Luigi, Resnick, Susan M., Tanaka, Toshiko, Foroud, Tatiana M., Graff-Radford, Neill R., Wszolek, Zbigniew K., Ferman, Tanis, Boeve, Bradley F., Hardy, John A., Topol, Eric J., Torkamani, Ali, Singleton, Andrew B., Ryten, Mina, Dickson, Dennis W., Chiò, Adriano, Ross, Owen A., Gibbs, J. Raphael, Dalgard, Clifton L., Traynor, Bryan J., and Scholz, Sonja W.

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

37. Pathogenic Huntingtin Repeat Expansions in Patients with Frontotemporal Dementia and Amyotrophic Lateral Sclerosis.

Author

Dewan, Ramita, Dewan, Ramita, Chia, Ruth, Ding, Jinhui, Hickman, Richard A, Stein, Thor D, Abramzon, Yevgeniya, Ahmed, Sarah, Sabir, Marya S, Portley, Makayla K, Tucci, Arianna, Ibáñez, Kristina, Shankaracharya, FNU, Keagle, Pamela, Rossi, Giacomina, Caroppo, Paola, Tagliavini, Fabrizio, Waldo, Maria L, Johansson, Per M, Nilsson, Christer F, American Genome Center (TAGC), FALS Sequencing Consortium, Genomics England Research Consortium, International ALS/FTD Genomics Consortium (iAFGC), International FTD Genetics Consortium (IFGC), International LBD Genomics Consortium (iLBDGC), NYGC ALS Consortium, PROSPECT Consortium, Rowe, James B, Benussi, Luisa, Binetti, Giuliano, Ghidoni, Roberta, Jabbari, Edwin, Viollet, Coralie, Glass, Jonathan D, Singleton, Andrew B, Silani, Vincenzo, Ross, Owen A, Ryten, Mina, Torkamani, Ali, Tanaka, Toshiko, Ferrucci, Luigi, Resnick, Susan M, Pickering-Brown, Stuart, Brady, Christopher B, Kowal, Neil, Hardy, John A, Van Deerlin, Vivianna, Vonsattel, Jean Paul, Harms, Matthew B, Morris, Huw R, Ferrari, Raffaele, Landers, John E, Chiò, Adriano, Gibbs, J Raphael, Dalgard, Clifton L, Scholz, Sonja W, Traynor, Bryan J, Dewan, Ramita, Dewan, Ramita, Chia, Ruth, Ding, Jinhui, Hickman, Richard A, Stein, Thor D, Abramzon, Yevgeniya, Ahmed, Sarah, Sabir, Marya S, Portley, Makayla K, Tucci, Arianna, Ibáñez, Kristina, Shankaracharya, FNU, Keagle, Pamela, Rossi, Giacomina, Caroppo, Paola, Tagliavini, Fabrizio, Waldo, Maria L, Johansson, Per M, Nilsson, Christer F, American Genome Center (TAGC), FALS Sequencing Consortium, Genomics England Research Consortium, International ALS/FTD Genomics Consortium (iAFGC), International FTD Genetics Consortium (IFGC), International LBD Genomics Consortium (iLBDGC), NYGC ALS Consortium, PROSPECT Consortium, Rowe, James B, Benussi, Luisa, Binetti, Giuliano, Ghidoni, Roberta, Jabbari, Edwin, Viollet, Coralie, Glass, Jonathan D, Singleton, Andrew B, Silani, Vincenzo, Ross, Owen A, Ryten, Mina, Torkamani, Ali, Tanaka, Toshiko, Ferrucci, Luigi, Resnick, Susan M, Pickering-Brown, Stuart, Brady, Christopher B, Kowal, Neil, Hardy, John A, Van Deerlin, Vivianna, Vonsattel, Jean Paul, Harms, Matthew B, Morris, Huw R, Ferrari, Raffaele, Landers, John E, Chiò, Adriano, Gibbs, J Raphael, Dalgard, Clifton L, Scholz, Sonja W, and Traynor, Bryan J

Abstract

We examined the role of repeat expansions in the pathogenesis of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) by analyzing whole-genome sequence data from 2,442 FTD/ALS patients, 2,599 Lewy body dementia (LBD) patients, and 3,158 neurologically healthy subjects. Pathogenic expansions (range, 40-64 CAG repeats) in the huntingtin (HTT) gene were found in three (0.12%) patients diagnosed with pure FTD/ALS syndromes but were not present in the LBD or healthy cohorts. We replicated our findings in an independent collection of 3,674 FTD/ALS patients. Postmortem evaluations of two patients revealed the classical TDP-43 pathology of FTD/ALS, as well as huntingtin-positive, ubiquitin-positive aggregates in the frontal cortex. The neostriatal atrophy that pathologically defines Huntington's disease was absent in both cases. Our findings reveal an etiological relationship between HTT repeat expansions and FTD/ALS syndromes and indicate that genetic screening of FTD/ALS patients for HTT repeat expansions should be considered.

Published
2021

38. Association of Variants in the SPTLC1 Gene With Juvenile Amyotrophic Lateral Sclerosis

Author

Johnson, J, Chia, R, Miller, D, Li, R, Kumaran, R, Abramzon, Y, Alahmady, N, Renton, A, Topp, S, Gibbs, J, Cookson, M, Sabir, M, Dalgard, C, Troakes, C, Jones, A, Shatunov, A, Iacoangeli, A, Al Khleifat, A, Ticozzi, N, Silani, V, Gellera, C, Blair, I, Dobson-Stone, C, Kwok, J, Bonkowski, E, Palvadeau, R, Tienari, P, Morrison, K, Shaw, P, Al-Chalabi, A, Brown, R, Calvo, A, Mora, G, Al-Saif, H, Gotkine, M, Leigh, F, Chang, I, Perlman, S, Glass, I, Scott, A, Shaw, C, Basak, A, Landers, J, Chiò, A, Crawford, T, Smith, B, Traynor, B, Fallini, C, Gkazi, A, Scotter, E, Kenna, K, Keagle, P, Tiloca, C, Vance, C, Colombrita, C, King, A, Pensato, V, Castellotti, B, Baas, F, Ten Asbroek, A, McKenna-Yasek, D, Mclaughlin, R, Polak, M, Asress, S, Esteban-Pérez, J, Stevic, Z, D'Alfonso, S, Mazzini, L, Comi, G, Del Bo, R, Ceroni, M, Gagliardi, S, Querin, G, Bertolin, C, van Rheenen, W, Rademakers, R, van Blitterswijk, M, Lauria, G, Duga, S, Corti, S, Cereda, C, Corrado, L, Sorarù, G, Williams, K, Nicholson, G, Leblond-Manry, C, Rouleau, G, Hardiman, O, Veldink, J, van den Berg, L, Pall, H, Turner, M, Talbot, K, Taroni, F, García-Redondo, A, Wu, Z, Glass, J, Ratti, A, Adeleye, A, Soltis, A, Alba, C, Viollet, C, Bacikova, D, Hupalo, D, Sukumar, G, Pollard, H, Wilkerson, M, Martinez, E, Ahmed, S, Arepalli, S, Baloh, R, Bowser, R, Brady, C, Brice, A, Broach, J, Campbell, R, Camu, W, Cooper-Knock, J, Ding, J, Drepper, C, Drory, V, Dunckley, T, Eicher, J, England, B, Faghri, F, Feldman, E, Floeter, M, Fratta, P, Geiger, J, Gerhard, G, Gibson, S, Hardy, J, Harms, M, Heiman-Patterson, T, Hernandez, D, Jansson, L, Kirby, J, Kowall, N, Laaksovirta, H, Landeck, N, Landi, F, Le Ber, I, Lumbroso, S, Macgowan, D, Maragakis, N, Mouzat, K, Murphy, N, Myllykangas, L, Nalls, M, Orrell, R, Ostrow, L, Pamphlett, R, Pickering-Brown, S, Pioro, E, Pletnikova, O, Pliner, H, Pulst, S, Ravits, J, Rivera, A, Robberecht, W, Rogaeva, E, Rollinson, S, Rothstein, J, Scholz, S, Sendtner, M, Sidle, K, Simmons, Z, Singleton, A, Smith, N, Stone, D, Troncoso, J, Valori, M, Van Damme, P, Van Deerlin, V, Van Den Bosch, L, Zinman, L, Angelocola, S, Ausiello, F, Barberis, M, Bartolomei, I, Battistini, S, Bersano, E, Bisogni, G, Borghero, G, Brunetti, M, Cabona, C, Canale, F, Canosa, A, Cantisani, T, Capasso, M, Caponnetto, C, Cardinali, P, Carrera, P, Casale, F, Colletti, T, Conforti, F, Conte, A, Conti, E, Corbo, M, Cuccu, S, Dalla Bella, E, D'Errico, E, Demarco, G, Dubbioso, R, Ferrarese, C, Ferraro, P, Filippi, M, Fini, N, Floris, G, Fuda, G, Gallone, S, Gianferrari, G, Giannini, F, Grassano, M, Greco, L, Iazzolino, B, Introna, A, La Bella, V, Lattante, S, Liguori, R, Logroscino, G, Logullo, F, Lunetta, C, Mandich, P, Mandrioli, J, Manera, U, Manganelli, F, Marangi, G, Marinou, K, Marrosu, M, Martinelli, I, Messina, S, Moglia, C, Mosca, L, Murru, M, Origone, P, Passaniti, C, Petrelli, C, Petrucci, A, Pozzi, S, Pugliatti, M, Quattrini, A, Ricci, C, Riolo, G, Riva, N, Russo, M, Sabatelli, M, Salamone, P, Salivetto, M, Salvi, F, Santarelli, M, Sbaiz, L, Sideri, R, Simone, I, Simonini, C, Spataro, R, Tanel, R, Tedeschi, G, Ticca, A, Torriello, A, Tranquilli, S, Tremolizzo, L, Trojsi, F, Vasta, R, Vacchiano, V, Vita, G, Volanti, P, Zollino, M, Zucchi, E, Johnson, Janel O, Chia, Ruth, Miller, Danny E, Li, Rachel, Kumaran, Ravindran, Abramzon, Yevgeniya, Alahmady, Nada, Renton, Alan E, Topp, Simon D, Gibbs, J Raphael, Cookson, Mark R, Sabir, Marya S, Dalgard, Clifton L, Troakes, Claire, Jones, Ashley R, Shatunov, Aleksey, Iacoangeli, Alfredo, Al Khleifat, Ahmad, Ticozzi, Nicola, Silani, Vincenzo, Gellera, Cinzia, Blair, Ian P, Dobson-Stone, Carol, Kwok, John B, Bonkowski, Emily S, Palvadeau, Robin, Tienari, Pentti J, Morrison, Karen E, Shaw, Pamela J, Al-Chalabi, Ammar, Brown, Robert H, Calvo, Andrea, Mora, Gabriele, Al-Saif, Hind, Gotkine, Marc, Leigh, Fawn, Chang, Irene J, Perlman, Seth J, Glass, Ian, Scott, Anna I, Shaw, Christopher E, Basak, A Nazli, Landers, John E, Chiò, Adriano, Crawford, Thomas O, Smith, Bradley N, Traynor, Bryan J, Fallini, Claudia, Gkazi, Athina Soragia, Scotter, Emma L, Kenna, Kevin P, Keagle, Pamela, Tiloca, Cinzia, Vance, Caroline, Colombrita, Claudia, King, Andrew, Pensato, Viviana, Castellotti, Barbara, Baas, Frank, Ten Asbroek, Anneloor L M A, McKenna-Yasek, Diane, McLaughlin, Russell L, Polak, Meraida, Asress, Seneshaw, Esteban-Pérez, Jesús, Stevic, Zorica, D'Alfonso, Sandra, Mazzini, Letizia, Comi, Giacomo P, Del Bo, Roberto, Ceroni, Mauro, Gagliardi, Stella, Querin, Giorgia, Bertolin, Cinzia, van Rheenen, Wouter, Rademakers, Rosa, van Blitterswijk, Marka, Lauria, Giuseppe, Duga, Stefano, Corti, Stefania, Cereda, Cristina, Corrado, Lucia, Sorarù, Gianni, Williams, Kelly L, Nicholson, Garth A, Leblond-Manry, Claire, Rouleau, Guy A, Hardiman, Orla, Veldink, Jan H, van den Berg, Leonard H, Pall, Hardev, Turner, Martin R, Talbot, Kevin, Taroni, Franco, García-Redondo, Alberto, Wu, Zheyang, Glass, Jonathan D, Ratti, Antonia, Adeleye, Adelani, Soltis, Anthony R, Alba, Camille, Viollet, Coralie, Bacikova, Dagmar, Hupalo, Daniel N, Sukumar, Gauthaman, Pollard, Harvey B, Wilkerson, Matthew D, Martinez, Elisa McGrath, Ahmed, Sarah, Arepalli, Sampath, Baloh, Robert H, Bowser, Robert, Brady, Christopher B, Brice, Alexis, Broach, James, Campbell, Roy H, Camu, William, Cooper-Knock, John, Ding, Jinhui, Drepper, Carsten, Drory, Vivian E, Dunckley, Travis L, Eicher, John D, England, Bryce K, Faghri, Faraz, Feldman, Eva, Floeter, Mary Kay, Fratta, Pietro, Geiger, Joshua T, Gerhard, Glenn, Gibson, Summer B, Hardy, John, Harms, Matthew B, Heiman-Patterson, Terry D, Hernandez, Dena G, Jansson, Lilja, Kirby, Janine, Kowall, Neil W, Laaksovirta, Hannu, Landeck, Natalie, Landi, Francesco, Le Ber, Isabelle, Lumbroso, Serge, MacGowan, Daniel J L, Maragakis, Nicholas J, Mouzat, Kevin, Murphy, Natalie A, Myllykangas, Liisa, Nalls, Mike A, Orrell, Richard W, Ostrow, Lyle W, Pamphlett, Roger, Pickering-Brown, Stuart, Pioro, Erik P, Pletnikova, Olga, Pliner, Hannah A, Pulst, Stefan M, Ravits, John M, Rivera, Alberto, Robberecht, Wim, Rogaeva, Ekaterina, Rollinson, Sara, Rothstein, Jeffrey D, Scholz, Sonja W, Sendtner, Michael, Sidle, Katie C, Simmons, Zachary, Singleton, Andrew B, Smith, Nathan, Stone, David J, Troncoso, Juan C, Valori, Miko, Van Damme, Philip, Van Deerlin, Vivianna M, Van Den Bosch, Ludo, Zinman, Lorne, Angelocola, Stefania M, Ausiello, Francesco P, Barberis, Marco, Bartolomei, Ilaria, Battistini, Stefania, Bersano, Enrica, Bisogni, Giulia, Borghero, Giuseppe, Brunetti, Maura, Cabona, Corrado, Canale, Fabrizio, Canosa, Antonio, Cantisani, Teresa A, Capasso, Margherita, Caponnetto, Claudia, Cardinali, Patrizio, Carrera, Paola, Casale, Federico, Colletti, Tiziana, Conforti, Francesca L, Conte, Amelia, Conti, Elisa, Corbo, Massimo, Cuccu, Stefania, Dalla Bella, Eleonora, D'Errico, Eustachio, DeMarco, Giovanni, Dubbioso, Raffaele, Ferrarese, Carlo, Ferraro, Pilar M, Filippi, Massimo, Fini, Nicola, Floris, Gianluca, Fuda, Giuseppe, Gallone, Salvatore, Gianferrari, Giulia, Giannini, Fabio, Grassano, Maurizio, Greco, Lucia, Iazzolino, Barbara, Introna, Alessandro, La Bella, Vincenzo, Lattante, Serena, Liguori, Rocco, Logroscino, Giancarlo, Logullo, Francesco O, Lunetta, Christian, Mandich, Paola, Mandrioli, Jessica, Manera, Umberto, Manganelli, Fiore, Marangi, Giuseppe, Marinou, Kalliopi, Marrosu, Maria Giovanna, Martinelli, Ilaria, Messina, Sonia, Moglia, Cristina, Mosca, Lorena, Murru, Maria R, Origone, Paola, Passaniti, Carla, Petrelli, Cristina, Petrucci, Antonio, Pozzi, Susanna, Pugliatti, Maura, Quattrini, Angelo, Ricci, Claudia, Riolo, Giulia, Riva, Nilo, Russo, Massimo, Sabatelli, Mario, Salamone, Paolina, Salivetto, Marco, Salvi, Fabrizio, Santarelli, Marialuisa, Sbaiz, Luca, Sideri, Riccardo, Simone, Isabella, Simonini, Cecilia, Spataro, Rossella, Tanel, Raffaella, Tedeschi, Gioacchino, Ticca, Anna, Torriello, Antonella, Tranquilli, Stefania, Tremolizzo, Lucio, Trojsi, Francesca, Vasta, Rosario, Vacchiano, Veria, Vita, Giuseppe, Volanti, Paolo, Zollino, Marcella, Zucchi, Elisabetta, Johnson, J, Chia, R, Miller, D, Li, R, Kumaran, R, Abramzon, Y, Alahmady, N, Renton, A, Topp, S, Gibbs, J, Cookson, M, Sabir, M, Dalgard, C, Troakes, C, Jones, A, Shatunov, A, Iacoangeli, A, Al Khleifat, A, Ticozzi, N, Silani, V, Gellera, C, Blair, I, Dobson-Stone, C, Kwok, J, Bonkowski, E, Palvadeau, R, Tienari, P, Morrison, K, Shaw, P, Al-Chalabi, A, Brown, R, Calvo, A, Mora, G, Al-Saif, H, Gotkine, M, Leigh, F, Chang, I, Perlman, S, Glass, I, Scott, A, Shaw, C, Basak, A, Landers, J, Chiò, A, Crawford, T, Smith, B, Traynor, B, Fallini, C, Gkazi, A, Scotter, E, Kenna, K, Keagle, P, Tiloca, C, Vance, C, Colombrita, C, King, A, Pensato, V, Castellotti, B, Baas, F, Ten Asbroek, A, McKenna-Yasek, D, Mclaughlin, R, Polak, M, Asress, S, Esteban-Pérez, J, Stevic, Z, D'Alfonso, S, Mazzini, L, Comi, G, Del Bo, R, Ceroni, M, Gagliardi, S, Querin, G, Bertolin, C, van Rheenen, W, Rademakers, R, van Blitterswijk, M, Lauria, G, Duga, S, Corti, S, Cereda, C, Corrado, L, Sorarù, G, Williams, K, Nicholson, G, Leblond-Manry, C, Rouleau, G, Hardiman, O, Veldink, J, van den Berg, L, Pall, H, Turner, M, Talbot, K, Taroni, F, García-Redondo, A, Wu, Z, Glass, J, Ratti, A, Adeleye, A, Soltis, A, Alba, C, Viollet, C, Bacikova, D, Hupalo, D, Sukumar, G, Pollard, H, Wilkerson, M, Martinez, E, Ahmed, S, Arepalli, S, Baloh, R, Bowser, R, Brady, C, Brice, A, Broach, J, Campbell, R, Camu, W, Cooper-Knock, J, Ding, J, Drepper, C, Drory, V, Dunckley, T, Eicher, J, England, B, Faghri, F, Feldman, E, Floeter, M, Fratta, P, Geiger, J, Gerhard, G, Gibson, S, Hardy, J, Harms, M, Heiman-Patterson, T, Hernandez, D, Jansson, L, Kirby, J, Kowall, N, Laaksovirta, H, Landeck, N, Landi, F, Le Ber, I, Lumbroso, S, Macgowan, D, Maragakis, N, Mouzat, K, Murphy, N, Myllykangas, L, Nalls, M, Orrell, R, Ostrow, L, Pamphlett, R, Pickering-Brown, S, Pioro, E, Pletnikova, O, Pliner, H, Pulst, S, Ravits, J, Rivera, A, Robberecht, W, Rogaeva, E, Rollinson, S, Rothstein, J, Scholz, S, Sendtner, M, Sidle, K, Simmons, Z, Singleton, A, Smith, N, Stone, D, Troncoso, J, Valori, M, Van Damme, P, Van Deerlin, V, Van Den Bosch, L, Zinman, L, Angelocola, S, Ausiello, F, Barberis, M, Bartolomei, I, Battistini, S, Bersano, E, Bisogni, G, Borghero, G, Brunetti, M, Cabona, C, Canale, F, Canosa, A, Cantisani, T, Capasso, M, Caponnetto, C, Cardinali, P, Carrera, P, Casale, F, Colletti, T, Conforti, F, Conte, A, Conti, E, Corbo, M, Cuccu, S, Dalla Bella, E, D'Errico, E, Demarco, G, Dubbioso, R, Ferrarese, C, Ferraro, P, Filippi, M, Fini, N, Floris, G, Fuda, G, Gallone, S, Gianferrari, G, Giannini, F, Grassano, M, Greco, L, Iazzolino, B, Introna, A, La Bella, V, Lattante, S, Liguori, R, Logroscino, G, Logullo, F, Lunetta, C, Mandich, P, Mandrioli, J, Manera, U, Manganelli, F, Marangi, G, Marinou, K, Marrosu, M, Martinelli, I, Messina, S, Moglia, C, Mosca, L, Murru, M, Origone, P, Passaniti, C, Petrelli, C, Petrucci, A, Pozzi, S, Pugliatti, M, Quattrini, A, Ricci, C, Riolo, G, Riva, N, Russo, M, Sabatelli, M, Salamone, P, Salivetto, M, Salvi, F, Santarelli, M, Sbaiz, L, Sideri, R, Simone, I, Simonini, C, Spataro, R, Tanel, R, Tedeschi, G, Ticca, A, Torriello, A, Tranquilli, S, Tremolizzo, L, Trojsi, F, Vasta, R, Vacchiano, V, Vita, G, Volanti, P, Zollino, M, Zucchi, E, Johnson, Janel O, Chia, Ruth, Miller, Danny E, Li, Rachel, Kumaran, Ravindran, Abramzon, Yevgeniya, Alahmady, Nada, Renton, Alan E, Topp, Simon D, Gibbs, J Raphael, Cookson, Mark R, Sabir, Marya S, Dalgard, Clifton L, Troakes, Claire, Jones, Ashley R, Shatunov, Aleksey, Iacoangeli, Alfredo, Al Khleifat, Ahmad, Ticozzi, Nicola, Silani, Vincenzo, Gellera, Cinzia, Blair, Ian P, Dobson-Stone, Carol, Kwok, John B, Bonkowski, Emily S, Palvadeau, Robin, Tienari, Pentti J, Morrison, Karen E, Shaw, Pamela J, Al-Chalabi, Ammar, Brown, Robert H, Calvo, Andrea, Mora, Gabriele, Al-Saif, Hind, Gotkine, Marc, Leigh, Fawn, Chang, Irene J, Perlman, Seth J, Glass, Ian, Scott, Anna I, Shaw, Christopher E, Basak, A Nazli, Landers, John E, Chiò, Adriano, Crawford, Thomas O, Smith, Bradley N, Traynor, Bryan J, Fallini, Claudia, Gkazi, Athina Soragia, Scotter, Emma L, Kenna, Kevin P, Keagle, Pamela, Tiloca, Cinzia, Vance, Caroline, Colombrita, Claudia, King, Andrew, Pensato, Viviana, Castellotti, Barbara, Baas, Frank, Ten Asbroek, Anneloor L M A, McKenna-Yasek, Diane, McLaughlin, Russell L, Polak, Meraida, Asress, Seneshaw, Esteban-Pérez, Jesús, Stevic, Zorica, D'Alfonso, Sandra, Mazzini, Letizia, Comi, Giacomo P, Del Bo, Roberto, Ceroni, Mauro, Gagliardi, Stella, Querin, Giorgia, Bertolin, Cinzia, van Rheenen, Wouter, Rademakers, Rosa, van Blitterswijk, Marka, Lauria, Giuseppe, Duga, Stefano, Corti, Stefania, Cereda, Cristina, Corrado, Lucia, Sorarù, Gianni, Williams, Kelly L, Nicholson, Garth A, Leblond-Manry, Claire, Rouleau, Guy A, Hardiman, Orla, Veldink, Jan H, van den Berg, Leonard H, Pall, Hardev, Turner, Martin R, Talbot, Kevin, Taroni, Franco, García-Redondo, Alberto, Wu, Zheyang, Glass, Jonathan D, Ratti, Antonia, Adeleye, Adelani, Soltis, Anthony R, Alba, Camille, Viollet, Coralie, Bacikova, Dagmar, Hupalo, Daniel N, Sukumar, Gauthaman, Pollard, Harvey B, Wilkerson, Matthew D, Martinez, Elisa McGrath, Ahmed, Sarah, Arepalli, Sampath, Baloh, Robert H, Bowser, Robert, Brady, Christopher B, Brice, Alexis, Broach, James, Campbell, Roy H, Camu, William, Cooper-Knock, John, Ding, Jinhui, Drepper, Carsten, Drory, Vivian E, Dunckley, Travis L, Eicher, John D, England, Bryce K, Faghri, Faraz, Feldman, Eva, Floeter, Mary Kay, Fratta, Pietro, Geiger, Joshua T, Gerhard, Glenn, Gibson, Summer B, Hardy, John, Harms, Matthew B, Heiman-Patterson, Terry D, Hernandez, Dena G, Jansson, Lilja, Kirby, Janine, Kowall, Neil W, Laaksovirta, Hannu, Landeck, Natalie, Landi, Francesco, Le Ber, Isabelle, Lumbroso, Serge, MacGowan, Daniel J L, Maragakis, Nicholas J, Mouzat, Kevin, Murphy, Natalie A, Myllykangas, Liisa, Nalls, Mike A, Orrell, Richard W, Ostrow, Lyle W, Pamphlett, Roger, Pickering-Brown, Stuart, Pioro, Erik P, Pletnikova, Olga, Pliner, Hannah A, Pulst, Stefan M, Ravits, John M, Rivera, Alberto, Robberecht, Wim, Rogaeva, Ekaterina, Rollinson, Sara, Rothstein, Jeffrey D, Scholz, Sonja W, Sendtner, Michael, Sidle, Katie C, Simmons, Zachary, Singleton, Andrew B, Smith, Nathan, Stone, David J, Troncoso, Juan C, Valori, Miko, Van Damme, Philip, Van Deerlin, Vivianna M, Van Den Bosch, Ludo, Zinman, Lorne, Angelocola, Stefania M, Ausiello, Francesco P, Barberis, Marco, Bartolomei, Ilaria, Battistini, Stefania, Bersano, Enrica, Bisogni, Giulia, Borghero, Giuseppe, Brunetti, Maura, Cabona, Corrado, Canale, Fabrizio, Canosa, Antonio, Cantisani, Teresa A, Capasso, Margherita, Caponnetto, Claudia, Cardinali, Patrizio, Carrera, Paola, Casale, Federico, Colletti, Tiziana, Conforti, Francesca L, Conte, Amelia, Conti, Elisa, Corbo, Massimo, Cuccu, Stefania, Dalla Bella, Eleonora, D'Errico, Eustachio, DeMarco, Giovanni, Dubbioso, Raffaele, Ferrarese, Carlo, Ferraro, Pilar M, Filippi, Massimo, Fini, Nicola, Floris, Gianluca, Fuda, Giuseppe, Gallone, Salvatore, Gianferrari, Giulia, Giannini, Fabio, Grassano, Maurizio, Greco, Lucia, Iazzolino, Barbara, Introna, Alessandro, La Bella, Vincenzo, Lattante, Serena, Liguori, Rocco, Logroscino, Giancarlo, Logullo, Francesco O, Lunetta, Christian, Mandich, Paola, Mandrioli, Jessica, Manera, Umberto, Manganelli, Fiore, Marangi, Giuseppe, Marinou, Kalliopi, Marrosu, Maria Giovanna, Martinelli, Ilaria, Messina, Sonia, Moglia, Cristina, Mosca, Lorena, Murru, Maria R, Origone, Paola, Passaniti, Carla, Petrelli, Cristina, Petrucci, Antonio, Pozzi, Susanna, Pugliatti, Maura, Quattrini, Angelo, Ricci, Claudia, Riolo, Giulia, Riva, Nilo, Russo, Massimo, Sabatelli, Mario, Salamone, Paolina, Salivetto, Marco, Salvi, Fabrizio, Santarelli, Marialuisa, Sbaiz, Luca, Sideri, Riccardo, Simone, Isabella, Simonini, Cecilia, Spataro, Rossella, Tanel, Raffaella, Tedeschi, Gioacchino, Ticca, Anna, Torriello, Antonella, Tranquilli, Stefania, Tremolizzo, Lucio, Trojsi, Francesca, Vasta, Rosario, Vacchiano, Veria, Vita, Giuseppe, Volanti, Paolo, Zollino, Marcella, and Zucchi, Elisabetta

Abstract

Importance: Juvenile amyotrophic lateral sclerosis (ALS) is a rare form of ALS characterized by age of symptom onset less than 25 years and a variable presentation. Objective: To identify the genetic variants associated with juvenile ALS. Design, setting, and participants: In this multicenter family-based genetic study, trio whole-exome sequencing was performed to identify the disease-associated gene in a case series of unrelated patients diagnosed with juvenile ALS and severe growth retardation. The patients and their family members were enrolled at academic hospitals and a government research facility between March 1, 2016, and March 13, 2020, and were observed until October 1, 2020. Whole-exome sequencing was also performed in a series of patients with juvenile ALS. A total of 66 patients with juvenile ALS and 6258 adult patients with ALS participated in the study. Patients were selected for the study based on their diagnosis, and all eligible participants were enrolled in the study. None of the participants had a family history of neurological disorders, suggesting de novo variants as the underlying genetic mechanism. Main outcomes and measures: De novo variants present only in the index case and not in unaffected family members. Results: Trio whole-exome sequencing was performed in 3 patients diagnosed with juvenile ALS and their parents. An additional 63 patients with juvenile ALS and 6258 adult patients with ALS were subsequently screened for variants in the SPTLC1 gene. De novo variants in SPTLC1 (p.Ala20Ser in 2 patients and p.Ser331Tyr in 1 patient) were identified in 3 unrelated patients diagnosed with juvenile ALS and failure to thrive. A fourth variant (p.Leu39del) was identified in a patient with juvenile ALS where parental DNA was unavailable. Variants in this gene have been previously shown to be associated with autosomal-dominant hereditary sensory autonomic neuropathy, type 1A, by disrupting an essential enzyme complex in the sphingolipid synthesis

Published
2021

39. Pathogenic Huntingtin Repeat Expansions in Patients with Frontotemporal Dementia and Amyotrophic Lateral Sclerosis

Author

Dewan, Ramita, primary, Chia, Ruth, additional, Ding, Jinhui, additional, Hickman, Richard A., additional, Stein, Thor D., additional, Abramzon, Yevgeniya, additional, Ahmed, Sarah, additional, Sabir, Marya S., additional, Portley, Makayla K., additional, Tucci, Arianna, additional, Ibáñez, Kristina, additional, Shankaracharya, F.N.U., additional, Keagle, Pamela, additional, Rossi, Giacomina, additional, Caroppo, Paola, additional, Tagliavini, Fabrizio, additional, Waldo, Maria L., additional, Johansson, Per M., additional, Nilsson, Christer F., additional, Rowe, James B., additional, Benussi, Luisa, additional, Binetti, Giuliano, additional, Ghidoni, Roberta, additional, Jabbari, Edwin, additional, Viollet, Coralie, additional, Glass, Jonathan D., additional, Singleton, Andrew B., additional, Silani, Vincenzo, additional, Ross, Owen A., additional, Ryten, Mina, additional, Torkamani, Ali, additional, Tanaka, Toshiko, additional, Ferrucci, Luigi, additional, Resnick, Susan M., additional, Pickering-Brown, Stuart, additional, Brady, Christopher B., additional, Kowal, Neil, additional, Hardy, John A., additional, Van Deerlin, Vivianna, additional, Vonsattel, Jean Paul, additional, Harms, Matthew B., additional, Morris, Huw R., additional, Ferrari, Raffaele, additional, Landers, John E., additional, Chiò, Adriano, additional, Gibbs, J. Raphael, additional, Dalgard, Clifton L., additional, Scholz, Sonja W., additional, Traynor, Bryan J., additional, Adeleye, Adelani, additional, Alba, Camille, additional, Bacikova, Dagmar, additional, Hupalo, Daniel N., additional, Martinez, Elisa McGrath, additional, Pollard, Harvey B., additional, Sukumar, Gauthaman, additional, Soltis, Anthony R., additional, Tuck, Meila, additional, Zhang, Xijun, additional, Wilkerson, Matthew D., additional, Smith, Bradley N., additional, Ticozzi, Nicola, additional, Fallini, Claudia, additional, Gkazi, Athina Soragia, additional, Topp, Simon D., additional, Kost, Jason, additional, Scotter, Emma L., additional, Kenna, Kevin P., additional, Miller, Jack W., additional, Tiloca, Cinzia, additional, Vance, Caroline, additional, Danielson, Eric W., additional, Troakes, Claire, additional, Colombrita, Claudia, additional, Al-Sarraj, Safa, additional, Lewis, Elizabeth A., additional, King, Andrew, additional, Calini, Daniela, additional, Pensato, Viviana, additional, Castellotti, Barbara, additional, de Belleroche, Jacqueline, additional, Baas, Frank, additional, ten Asbroek, Anneloor L.M.A., additional, Sapp, Peter C., additional, McKenna-Yasek, Diane, additional, McLaughlin, Russell L., additional, Polak, Meraida, additional, Asress, Seneshaw, additional, Esteban-Pérez, Jesús, additional, Muñoz-Blanco, José Luis, additional, Stevic, Zorica, additional, D’Alfonso, Sandra, additional, Mazzini, Letizia, additional, Comi, Giacomo P., additional, Del Bo, Roberto, additional, Ceroni, Mauro, additional, Gagliardi, Stella, additional, Querin, Giorgia, additional, Bertolin, Cinzia, additional, van Rheenen, Wouter, additional, Diekstra, Frank P., additional, Rademakers, Rosa, additional, van Blitterswijk, Marka, additional, Boylan, Kevin B., additional, Lauria, Giuseppe, additional, Duga, Stefano, additional, Corti, Stefania, additional, Cereda, Cristina, additional, Corrado, Lucia, additional, Sorarù, Gianni, additional, Williams, Kelly L., additional, Nicholson, Garth A., additional, Blair, Ian P., additional, Leblond-Manry, Claire, additional, Rouleau, Guy A., additional, Hardiman, Orla, additional, Morrison, Karen E., additional, Veldink, Jan H., additional, van den Berg, Leonard H., additional, Al-Chalabi, Ammar, additional, Pall, Hardev, additional, Shaw, Pamela J., additional, Turner, Martin R., additional, Talbot, Kevin, additional, Taroni, Franco, additional, García-Redondo, Alberto, additional, Wu, Zheyang, additional, Gellera, Cinzia, additional, Ratti, Antonia, additional, Brown, Robert H., additional, Shaw, Christopher E., additional, Ambrose, John C., additional, Arumugam, Prabhu, additional, Baple, Emma L., additional, Bleda, Marta, additional, Boardman-Pretty, Freya, additional, Boissiere, Jeanne M., additional, Boustred, Christopher R., additional, Brittain, H., additional, Caulfield, Mark J., additional, Chan, Georgia C., additional, Craig, Clare E.H., additional, Daugherty, Louise C., additional, de Burca, Anna, additional, Devereau, Andrew, additional, Elgar, Greg, additional, Foulger, Rebecca E., additional, Fowler, Tom, additional, Furió-Tarí, Pedro, additional, Hackett, Joanne M., additional, Halai, Dina, additional, Hamblin, Angela, additional, Henderson, Shirley, additional, Holman, James E., additional, Hubbard, Tim J.P., additional, Jackson, Rob, additional, Jones, Louise J., additional, Kasperaviciute, Dalia, additional, Kayikci, Melis, additional, Lahnstein, Lea, additional, Lawson, Kay, additional, Leigh, Sarah E.A., additional, Leong, Ivonne U.S., additional, Lopez, Javier F., additional, Maleady-Crowe, Fiona, additional, Mason, Joanne, additional, McDonagh, Ellen M., additional, Moutsianas, Loukas, additional, Mueller, Michael, additional, Murugaesu, Nirupa, additional, Need, Anna C., additional, Odhams, Chris A., additional, Patch, Christine, additional, Perez-Gil, Daniel, additional, Polychronopoulos, Dimitris, additional, Pullinger, John, additional, Rahim, Tahrima, additional, Rendon, Augusto, additional, Riesgo-Ferreiro, Pablo, additional, Rogers, Tim, additional, Savage, Kevin, additional, Sawant, Kushmita, additional, Scott, Richard H., additional, Siddiq, Afshan, additional, Sieghart, Alexander, additional, Smedley, Damian, additional, Smith, Katherine R., additional, Sosinsky, Alona, additional, Spooner, William, additional, Stevens, Helen E., additional, Stuckey, Alexander, additional, Sultana, Razvan, additional, Thomas, Ellen R.A., additional, Thompson, Simon R., additional, Tregidgo, Carolyn, additional, Walsh, Emma, additional, Watters, Sarah A., additional, Welland, Matthew J., additional, Williams, Eleanor, additional, Witkowska, Katarzyna, additional, Wood, Suzanne M., additional, Zarowiecki, Magdalena, additional, Arepalli, Sampath, additional, Auluck, Pavan, additional, Baloh, Robert H., additional, Bowser, Robert, additional, Brice, Alexis, additional, Broach, James, additional, Camu, William, additional, Cooper-Knock, John, additional, Corcia, Philippe, additional, Drepper, Carsten, additional, Drory, Vivian E., additional, Dunckley, Travis L., additional, Faghri, Faraz, additional, Farren, Jennifer, additional, Feldman, Eva, additional, Floeter, Mary Kay, additional, Fratta, Pietro, additional, Gerhard, Glenn, additional, Gibson, Summer B., additional, Goutman, Stephen A., additional, Heiman-Patterson, Terry D., additional, Hernandez, Dena G., additional, Hoover, Ben, additional, Jansson, Lilja, additional, Kamel, Freya, additional, Kirby, Janine, additional, Kowall, Neil W., additional, Laaksovirta, Hannu, additional, Landi, Francesco, additional, Le Ber, Isabelle, additional, Lumbroso, Serge, additional, MacGowan, Daniel JL., additional, Maragakis, Nicholas J., additional, Mora, Gabriele, additional, Mouzat, Kevin, additional, Myllykangas, Liisa, additional, Nalls, Mike A., additional, Orrell, Richard W., additional, Ostrow, Lyle W., additional, Pamphlett, Roger, additional, Pioro, Erik, additional, Pulst, Stefan M., additional, Ravits, John M., additional, Renton, Alan E., additional, Robberecht, Wim, additional, Robey, Ian, additional, Rogaeva, Ekaterina, additional, Rothstein, Jeffrey D., additional, Sendtner, Michael, additional, Sidle, Katie C., additional, Simmons, Zachary, additional, Stone, David J., additional, Tienari, Pentti J., additional, Trojanowski, John Q., additional, Troncoso, Juan C., additional, Valori, Miko, additional, Van Damme, Philip, additional, Van Den Bosch, Ludo, additional, Zinman, Lorne, additional, Albani, Diego, additional, Borroni, Barbara, additional, Padovani, Alessandro, additional, Bruni, Amalia, additional, Clarimon, Jordi, additional, Dols-Icardo, Oriol, additional, Illán-Gala, Ignacio, additional, Lleó, Alberto, additional, Danek, Adrian, additional, Galimberti, Daniela, additional, Scarpini, Elio, additional, Serpente, Maria, additional, Graff, Caroline, additional, Chiang, Huei-Hsin, additional, Khoshnood, Behzad, additional, Öijerstedt, Linn, additional, Morris, Christopher M., additional, Nacmias, Benedetta, additional, Sorbi, Sandro, additional, Nielsen, Jorgen E., additional, Hjermind, Lynne E., additional, Novelli, Valeria, additional, Puca, Annibale A., additional, Pastor, Pau, additional, Alvarez, Ignacio, additional, Diez-Fairen, Monica, additional, Aguilar, Miquel, additional, Perneczky, Robert, additional, Diehl-Schimd, Janine, additional, Rossi, Mina, additional, Ruiz, Agustin, additional, Boada, Mercè, additional, Hernández, Isabel, additional, Moreno-Grau, Sonia, additional, Schlachetzki, Johannes C., additional, Aarsland, Dag, additional, Albert, Marilyn S., additional, Attems, Johannes, additional, Barrett, Matthew J., additional, Beach, Thomas G., additional, Bekris, Lynn M., additional, Bennett, David A., additional, Besser, Lilah M., additional, Bigio, Eileen H., additional, Black, Sandra E., additional, Boeve, Bradley F., additional, Bohannan, Ryan C., additional, Brett, Francesca, additional, Brunetti, Maura, additional, Caraway, Chad A., additional, Palma, Jose-Alberto, additional, Calvo, Andrea, additional, Canosa, Antonio, additional, Dickson, Dennis, additional, Duyckaerts, Charles, additional, Faber, Kelley, additional, Ferman, Tanis, additional, Flanagan, Margaret E., additional, Floris, Gianluca, additional, Foroud, Tatiana M., additional, Fortea, Juan, additional, Gan-Or, Ziv, additional, Gentleman, Steve, additional, Ghetti, Bernardino, additional, Gibbs, Jesse Raphael, additional, Goate, Alison, additional, Goldstein, David, additional, González-Aramburu, Isabel, additional, Graff-Radford, Neill R., additional, Hodges, Angela K., additional, Hu, Heng-Chen, additional, Hupalo, Daniel, additional, Infante, Jon, additional, Iranzo, Alex, additional, Kaiser, Scott M., additional, Kaufmann, Horacio, additional, Keith, Julia, additional, Kim, Ronald C., additional, Klein, Gregory, additional, Krüger, Rejko, additional, Kukull, Walter, additional, Kuzma, Amanda, additional, Lage, Carmen, additional, Lesage, Suzanne, additional, Leverenz, James B., additional, Logroscino, Giancarlo, additional, Lopez, Grisel, additional, Love, Seth, additional, Mao, Qinwen, additional, Marti, Maria Jose, additional, Martinez-McGrath, Elisa, additional, Masellis, Mario, additional, Masliah, Eliezer, additional, May, Patrick, additional, McKeith, Ian, additional, Mesulam, Marek-Marsel, additional, Monuki, Edwin S., additional, Newell, Kathy L., additional, Norcliffe-Kaufmann, Lucy, additional, Palmer, Laura, additional, Perkins, Matthew, additional, Pletnikova, Olga, additional, Molina-Porcel, Laura, additional, Reynolds, Regina H., additional, Rodríguez-Rodríguez, Eloy, additional, Rohrer, Jonathan D., additional, Sanchez-Juan, Pascual, additional, Scherzer, Clemens R., additional, Serrano, Geidy E., additional, Shakkottai, Vikram, additional, Sidransky, Ellen, additional, Tayebi, Nahid, additional, Thomas, Alan J., additional, Tilley, Bension S., additional, Walton, Ronald L., additional, Woltjer, Randy, additional, Wszolek, Zbigniew K., additional, Xiromerisiou, Georgia, additional, Zecca, Chiara, additional, Phatnani, Hemali, additional, Kwan, Justin, additional, Sareen, Dhruv, additional, Broach, James R., additional, Arcila-Londono, Ximena, additional, Lee, Edward B., additional, Shneider, Neil A., additional, Fraenkel, Ernest, additional, Zaitlen, Noah, additional, Berry, James D., additional, Malaspina, Andrea, additional, Cox, Gregory A., additional, Thompson, Leslie M., additional, Finkbeiner, Steve, additional, Dardiotis, Efthimios, additional, Miller, Timothy M., additional, Chandran, Siddharthan, additional, Pal, Suvankar, additional, Hornstein, Eran, additional, MacGowan, Daniel J., additional, Heiman-Patterson, Terry, additional, Hammell, Molly G., additional, Patsopoulos, Nikolaos.A., additional, Butovsky, Oleg, additional, Dubnau, Joshua, additional, Nath, Avindra, additional, Harms, Matt, additional, Aronica, Eleonora, additional, Poss, Mary, additional, Phillips-Cremins, Jennifer, additional, Crary, John, additional, Atassi, Nazem, additional, Lange, Dale J., additional, Adams, Darius J., additional, Stefanis, Leonidas, additional, Gotkine, Marc, additional, Babu, Suma, additional, Raj, Towfique, additional, Paganoni, Sabrina, additional, Shalem, Ophir, additional, Smith, Colin, additional, Zhang, Bin, additional, Harris, Brent, additional, Broce, Iris, additional, Drory, Vivian, additional, Ravits, John, additional, McMillan, Corey, additional, Menon, Vilas, additional, Wu, Lani, additional, Altschuler, Steven, additional, Amar, Khaled, additional, Archibald, Neil, additional, Bandmann, Oliver, additional, Capps, Erica, additional, Church, Alistair, additional, Coebergh, Jan, additional, Costantini, Alyssa, additional, Critchley, Peter, additional, Ghosh, Boyd CP., additional, Hu, Michele T.M., additional, Kobylecki, Christopher, additional, Leigh, P. Nigel, additional, Mann, Carl, additional, Massey, Luke A., additional, Nath, Uma, additional, Pavese, Nicola, additional, Paviour, Dominic, additional, Sharma, Jagdish, additional, and Vaughan, Jenny, additional

Published
2021
Full Text
View/download PDF

40. RNA binding activity of the recessive parkinsonism protein D J-1 supports involvement in multiple cellular pathways

Author

van der Brug, Marcel P., Blackinton, Jeff, Chandran, Jayanth, Hao, Ling-Yang, Lal, Ashish, Mazan-Mamczarz, Krystyna, Martindale, Jennifer, Xie, Chengsong, Ahmad, Rili, Thomas, Kelly J.Beilina, Alexandra, Gibbs, J. Raphael, Ding, Jinhui, Myers, Amanda J., Zhan, Ming, Cai, Huaibin, Bonini, Nancy M., Gorospe, Myriam, and Cookson, Mark R.

Subjects
Ligand binding (Biochemistry) -- Observations, Parkinson's disease -- Development and progression, Parkinson's disease -- Genetic aspects, Genetic translation -- Research, Oxidative stress -- Influence, Neurogenetics -- Research, Science and technology
Abstract

Parkinson's disease (PD) is a major neurodegenerative condition with several rare Mendelian forms. Oxidative stress and mitochondrial function have been implicated in the pathogenesis of PD but the molecular mechanisms involved in the degeneration of neurons remain unclear. D J-1 mutations are one cause of recessive parkinsonism, but this gene is also reported to be involved in cancer by promoting Ras signaling and suppressing PTEN-induced apoptosis. The specific function of D J-1 is unknown, although it is responsive to oxidative stress and may play a role in the maintenance of mitochondria. Here, we show, using four independent methods, that D J-1 associates with RNA targets in cells and the brain, including mitochondrial genes, genes involved in glutathione metabolism, and members of the PTEN/PI3K cascade. Pathogenic recessive mutants are deficient in this activity. We show that D J-1 is sufficient for RNA binding at nanomolar concentrations. Further, we show that D J-1 binds RNA but dissociates after oxidative stress. These data implicate a single mechanism for the pleiotropic effects of D J-1 in different model systems, namely that the protein binds multiple RNA targets in an oxidation-dependent manner. gene expression | oxidative stress | Parkinson's disease | translation

Published
2008

41. Genotype, haplotype and copy-number variation in worldwide human populations

Author

Jakobsson, Mattias, Scholz, Sonja W., Scheet, Paul, Gibbs, J. Raphael, VanLiere, Jenna M., Fung, Hon-Chung, Szpiech, Zachary A., Degnan, James H., Wang, Kai, Guerreiro, Rita, Bras, Jose M., Schymick, Jennifer C., Hernandez, Dena G., Traynor, Bryan J., Simon-Sanchez, Javier, Matarin, Mar, Britton, Angela, van de Leemput, Joyce, Rafferty, Ian, Bucan, Maja, Cann, Howard M., Hardy, John A., Rosenberg, Noah A., and Singleton, Andrew B.

Subjects
Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract

Genome-wide patterns of variation across individuals provide a powerful source of data for uncovering the history of migration, range expansion, and adaptation of the human species. However, high-resolution surveys of [...]

Published
2008

42. Genome sequencing analysis identifies new loci associated with Lewy body dementia and provides insights into the complex 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, George-Hyslop, Peter St, 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, Lopez, Grisel, Tayebi, Nahid, Sidransky, Ellen, Palma, Jose-Alberto, Kaufmann, Horacio, Shakkottai, Vikram, Perkins, Matthew, Newell, Kathy L., Gasser, Thomas, Schulte, Claudia, Landi, Francesco, Salvi, Erika, Cusi, Daniele, Masliah, Eliezer, Kim, Ronald C., Caraway, Chad A., Monuki, Ed, 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, Serrano, Geidy E., Beach, Thomas G., McKeith, Ian G., Thomas, Alan J., Attems, Johannes, Morris, Christopher M., Palmer, Laura, Love, Seth, Troakes, Claire, Al-Sarraj, Safa, Hodges, Angela K., Aarsland, Dag, Klein, Gregory, Kaiser, Scott M., Woltjer, Randy, Pastor, Pau, Bekris, Lynn M., Leverenz, James, Besser, Lilah M., Kuzma, Amanda, Renton, Alan E., Goate, Alison, Bennett, David A., Scherzer, Clemens R., Morris, Huw R., Ferrari, Raffaele, Albani, Diego, Brown, Stuart Pickering, Faber, Kelley, Kukull, Walter, Morenas-Rodriguez, Estrella, Lleó, Alberto, Fortea, Juan, Alcolea, Daniel, Clarimon, Jordi, Nalls, Michael A., Ferrucci, Luigi, Resnick, Susan M., Tanaka, Toshiko, Foroud, Tatiana M., Graff-Radford, Neill R., Wszolek, Zbigniew K., Ferman, Tanis, Boeve, Bradley F., Hardy, John A., Topol, Eric, Torkamani, Ali, Singleton, Andrew B., Ryten, Mina, Dickson, Dennis, Chiò, Adriano, Ross, Owen A., Gibbs, J. Raphael, Dalgard, Clifton L., Traynor, Bryan J., and Scholz, Sonja W.

Subjects
whole-genome sequencing, GBA, Lewy body dementia, Biochemistry, biophysics & molecular biology [F05] [Life sciences], Biochimie, biophysique & biologie moléculaire [F05] [Sciences du vivant]
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 and Parkinson’s disease, providing a deeper molecular understanding of the complex genetic architecture of this age-related neurodegenerative condition.Competing Interest StatementThomas G. Beach is a consultant for Prothena, Vivid Genomics and Avid Radiopharmaceuticals. He is a scientific advisory board member for Vivid Genomics. John A. Hardy, Huw R. Morris, Stuart Pickering-Brown, Andrew B. Singleton, and Bryan J. Traynor hold US, EU and Canadian patents on the clinical testing and therapeutic intervention for the hexanucleotide repeat expansion of C9orf72. Michael A. Nalls is supported by a consulting contract between Data Tecnica International and the National Institute on Aging, NIH, Bethesda, MD, USA; as a possible conflict of interest Dr. Nalls also consults for Neuron23 Inc., Lysosomal Therapeutics Inc., Illumina Inc., the Michael J. Fox Foundation and Vivid Genomics among others. Jose A. Palma is an editorial board member of Movement Disorders, Parkinsonism & Related Disorders, BMC Neurology, and Clinical Autonomic Research. Bradley F. Boeve, James Leverenz, and Sonja W. Scholz serve on the Scientific Advisory Council of the Lewy Body Dementia Association. Sonja W. Scholz is an editorial board member for the Journal of Parkinson's Disease. Bryan J. Traynor is an editorial board member for JAMA Neurology; Journal of Neurology, Neurosurgery, and Psychiatry; Brain; and Neurobiology of Aging. Zbigniew K. Wszolek serves as a principal investigator or co-principal investigator on Abbvie, Inc. (M15-562 and M15-563), Biogen, Inc. (228PD201) grant, and Biohaven Pharmaceuticals, Inc. (BHV4157-206 and BHV3241-301). Zbigniew K. Wszolek serves as the principal investigator of the Mayo Clinic American Parkinson Disease Association (APDA) Information and Referral Center, and as co-principal investigator of the Mayo Clinic APDA Center for Advanced Research. All other authors report no competing interests.

Published
2020

43. The Parkinson's Disease Genome‐Wide Association Study Locus Browser

Author

National Institute of Neurological Disorders and Stroke (US), National Institute on Aging (US), National Institute of Environmental Health Sciences (US), Medical Research Council (UK), Alzheimer's Research UK, Alzheimer Society, Cardiff University, European Commission, Welsh Government, National Heart, Lung, and Blood Institute (US), National Institutes of Health (US), Case Western Reserve University, Fondation Leducq, Cleveland Clinic, National Cancer Institute (US), Donald W. Reynolds Foundation, Amgen, Harris Family Foundation, Watkins Foundation, American Heart Association, COPD Foundation, National Human Genome Research Institute (US), Grenn, Francis P., Kim, Jonggeol J., Makarious, Mary B., Iwaki, Hirotaka, Illarionova, Anastasia, Brolin, Kajsa, Kluss, Jillian H., Schumacher‐Schuh, Artur F., Leonard, Hampton, Faghri, Faraz, Billingsley, Kimberley, Krohn, Lynne, Hall, Ashley, Díez-Fairen, Mónica, Periñán, María Teresa, Foo, Jia Nee, Sandor, Cynthia, Webber, Caleb, Fiske, Brian K., Gibbs, J. Raphael, Nalls, Mike A., Singleton, Andrew B., Bandres-Ciga, Sara, Reed, Xylena, Blauwendraat, Cornelis, National Institute of Neurological Disorders and Stroke (US), National Institute on Aging (US), National Institute of Environmental Health Sciences (US), Medical Research Council (UK), Alzheimer's Research UK, Alzheimer Society, Cardiff University, European Commission, Welsh Government, National Heart, Lung, and Blood Institute (US), National Institutes of Health (US), Case Western Reserve University, Fondation Leducq, Cleveland Clinic, National Cancer Institute (US), Donald W. Reynolds Foundation, Amgen, Harris Family Foundation, Watkins Foundation, American Heart Association, COPD Foundation, National Human Genome Research Institute (US), Grenn, Francis P., Kim, Jonggeol J., Makarious, Mary B., Iwaki, Hirotaka, Illarionova, Anastasia, Brolin, Kajsa, Kluss, Jillian H., Schumacher‐Schuh, Artur F., Leonard, Hampton, Faghri, Faraz, Billingsley, Kimberley, Krohn, Lynne, Hall, Ashley, Díez-Fairen, Mónica, Periñán, María Teresa, Foo, Jia Nee, Sandor, Cynthia, Webber, Caleb, Fiske, Brian K., Gibbs, J. Raphael, Nalls, Mike A., Singleton, Andrew B., Bandres-Ciga, Sara, Reed, Xylena, and Blauwendraat, Cornelis

Abstract

[Background] Parkinson's disease (PD) is a neurodegenerative disease with an often complex component identifiable by genome‐wide association studies. The most recent large‐scale PD genome‐wide association studies have identified more than 90 independent risk variants for PD risk and progression across more than 80 genomic regions. One major challenge in current genomics is the identification of the causal gene(s) and variant(s) at each genome‐wide association study locus. The objective of the current study was to create a tool that would display data for relevant PD risk loci and provide guidance with the prioritization of causal genes and potential mechanisms at each locus., [Methods] We included all significant genome‐wide signals from multiple recent PD genome‐wide association studies including themost recent PD risk genome‐wide association study, age‐at‐onset genome‐wide association study, progression genome‐wide association study, and Asian population PD risk genome‐wide association study. We gathered data for all genes 1 Mb up and downstream of each variant to allow users to assess which gene(s) are most associated with the variant of interest based on a set of self‐ranked criteria. Multiple databases were queried for each gene to collect additional causal data., [Results] We created a PD genome‐wide association study browser tool (https://pdgenetics.shinyapps.io/GWASBrowser/) to assist the PD research community with the prioritization of genes for follow‐up functional studies to identify potential therapeutic targets., [Conclusions] Our PD genome‐wide association study browser tool provides users with a useful method of identifying potential causal genes at all known PD risk loci from large‐scale PD genome‐wide association studies. We plan to update this tool with new relevant data as sample sizes increase and new PD risk loci are discovered. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. This article has been contributed to by US Government employees and their work is in the public domain in the USA.

Published
2020

44. Excessive burden of lysosomal storage disorder gene variants in Parkinson's disease

Author

Robak, Laurie A., Jansen, Iris E., Rooij, Jeroen van, Uitterlinden, André G., Kraaij, Robert, Jankovic, Joseph, Heutink, Peter, Shulman, Joshua M., Nalls, Mike A., Plagnol, Vincent, Hernandez, Dena G., Sharma, Manu, Sheerin, Una Marie, Saad, Mohamad, Simón-Sánchez, Javier, Schulte, Claudia, Lesage, Suzanne, Sveinbjörnsdóttir, Sigurlaug, Arepalli, Sampath, Barker, Roger, Ben, Yoav, Berendse, Henk W., Berg, Daniela, Bhatia, Kailash, de Bie, Rob M.A., Biffi, Alessandro, Bloem, Bas, Bochdanovits, Zoltan, Bonin, Michael, Bras, Jose M., Brockmann, Kathrin, Brooks, Janet, Burn, David J., Majounie, Elisa, Charlesworth, Gavin, Lungu, Codrin, Chen, Honglei, Chinnery, Patrick F., Chong, Sean, Clarke, Carl E., Cookson, Mark R., Cooper, J. Mark, Corvol, Jean Christophe, Counsell, Carl, Damier, Philippe, Dartigues, Jean François, Deloukas, Panos, Deuschl, Günther, Dexter, David T., van Dijk, Karin D., Dillman, Allissa, Durif, Frank, Dürr, Alexandra, Edkins, Sarah, Evans, Jonathan R., Foltynie, Thomas, Dong, Jing, Gardner, Michelle, Gibbs, J. Raphael, Goate, Alison, Gray, Emma, Guerreiro, Rita, Harris, Clare, van Hilten, Jacobus J., Hofman, Albert, Hollenbeck, Albert, Holton, Janice, Hu, Michele, Huang, Xuemei, Wurster, Isabel, Mätzler, Walter, Hudson, Gavin, Hunt, Sarah E., Huttenlocher, Johanna, Illig, Thomas, Jónsson, Pálmi V., Lambert, Jean Charles, Langford, Cordelia, Lees, Andrew, Lichtner, Peter, Limousin, Patricia, Lopez, Grisel, Lorenz, Delia, McNeill, Alisdair, Moorby, Catriona, Moore, Matthew, Morris, Huw R., Morrison, Karen E., Escott-Price, Valentina, Mudanohwo, Ese, O’sullivan, Sean S., Pearson, Justin, Perlmutter, Joel S., Pétursson, Hjörvar, Pollak, Pierre, Post, Bart, Potter, Simon, Ravina, Bernard, Revesz, Tamas, Riess, Olaf, Rivadeneira, Fernando, Rizzu, Patrizia, Ryten, Mina, Sawcer, Stephen, Schapira, Anthony, Scheffer, Hans, Shaw, Karen, Shoulson, Ira, Shulman, Joshua, Sidransky, Ellen, Smith, Colin, Spencer, Chris C.A., Stefánsson, Hreinn, Bettella, Francesco, Stockton, Joanna D., Strange, Amy, Talbot, Kevin, Tanner, Carlie M., Tashakkori-Ghanbaria, Avazeh, Tison, François, Trabzuni, Daniah, Traynor, Bryan J., Velseboer, Daan, Vidailhet, Marie, Walker, Robert, Warrenburg, Bart van de, Wickremaratchi, Mirdhu, Williams, Nigel, Williams-Gray, Caroline H., Winder-Rhodes, Sophie, Stefánsson, Kári, Martinez, Maria, Wood, Nicholas W., Hardy, John, Brice, Alexis, Gasser, Thomas, Singleton, Andrew B., Erasmus University Medical Center [Rotterdam] (Erasmus MC), Ctr Life Sci Technol, Div Gen Technol, Tsurumi Ku, RIKEN - Institute of Physical and Chemical Research [Japon] (RIKEN), Neurology, ANS - Neurodegeneration, ANS - Amsterdam Neuroscience, Intensive Care Medicine, ANS - Neuroinfection & -inflammation, Graduate School, ACS - Amsterdam Cardiovascular Sciences, APH - Aging & Later Life, Amsterdam Neuroscience - Neurodegeneration, Human genetics, Internal Medicine, and Erasmus MC other

Subjects
Male, 0301 basic medicine, Parkinson's disease, Acid Ceramidase, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Organic Anion Transporters, ASAH1 protein, human, Disease, CTSD protein, human, Cathepsin D, genetics [Glucosylceramidase], whole exome sequencing, Cohort Studies, 0302 clinical medicine, genetics [Parkinson Disease], Exome, genetics, Exome sequencing, ComputingMilieux_MISCELLANEOUS, Aged, 80 and over, Genetics, Symporters, [SDV.NEU.PC]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Psychology and behavior, [SDV.NEU.SC]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Cognitive Sciences, genetics [Organic Anion Transporters], Middle Aged, genetics [Lysosomal Storage Diseases], Disorders of movement Donders Center for Medical Neuroscience [Radboudumc 3], Control subjects, sphingomyelin phosphodiesterase 1, human, 3. Good health, sialic acid transport proteins, Sphingomyelin Phosphodiesterase, ASAH1, Glucosylceramidase, Female, Adult, Genotype, Biology, lysosomal storage disorders, 03 medical and health sciences, medicine, Humans, Genetic Predisposition to Disease, ddc:610, Genotyping, Gene, Aged, [SCCO.NEUR]Cognitive science/Neuroscience, Original Articles, medicine.disease, genetics [Symporters], genetics [Acid Ceramidase], nervous system diseases, genetics [Cathepsin D], 030104 developmental biology, Case-Control Studies, Mutation, genetics [Sphingomyelin Phosphodiesterase], Neurology (clinical), Glucocerebrosidase, 030217 neurology & neurosurgery
Abstract

Item does not contain fulltext Mutations in the glucocerebrosidase gene (GBA), which cause Gaucher disease, are also potent risk factors for Parkinson's disease. We examined whether a genetic burden of variants in other lysosomal storage disorder genes is more broadly associated with Parkinson's disease susceptibility. The sequence kernel association test was used to interrogate variant burden among 54 lysosomal storage disorder genes, leveraging whole exome sequencing data from 1156 Parkinson's disease cases and 1679 control subjects. We discovered a significant burden of rare, likely damaging lysosomal storage disorder gene variants in association with Parkinson's disease risk. The association signal was robust to the exclusion of GBA, and consistent results were obtained in two independent replication cohorts, including 436 cases and 169 controls with whole exome sequencing and an additional 6713 cases and 5964 controls with exome-wide genotyping. In secondary analyses designed to highlight the specific genes driving the aggregate signal, we confirmed associations at the GBA and SMPD1 loci and newly implicate CTSD, SLC17A5, and ASAH1 as candidate Parkinson's disease susceptibility genes. In our discovery cohort, the majority of Parkinson's disease cases (56%) have at least one putative damaging variant in a lysosomal storage disorder gene, and 21% carry multiple alleles. Our results highlight several promising new susceptibility loci and reinforce the importance of lysosomal mechanisms in Parkinson's disease pathogenesis. We suggest that multiple genetic hits may act in combination to degrade lysosomal function, enhancing Parkinson's disease susceptibility.

Published
2017

45. Using genome-wide complex trait analysis to quantify ‘missing heritability’ in Parkinsonʼs disease

Author

Keller, Margaux F., Saad, Mohamad, Bras, Jose, Bettella, Francesco, Nicolaou, Nayia, Simón-Sánchez, Javier, Mittag, Florian, Büchel, Finja, Sharma, Manu, Gibbs, J. Raphael, Schulte, Claudia, Moskvina, Valentina, Durr, Alexandra, Holmans, Peter, Kilarski, Laura L., Guerreiro, Rita, Hernandez, Dena G., Brice, Alexis, Ylikotila, Pauli, Stefánsson, Hreinn, Majamaa, Kari, Morris, Huw R., Williams, Nigel, Gasser, Thomas, Heutink, Peter, Wood, Nicholas W., Hardy, John, Martinez, Maria, Singleton, Andrew B., and Nalls, Michael A.

Published
2012
Full Text
View/download PDF

Catalog

Books, media, physical & digital resources
See catalog results