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2. Multi-ancestry genome-wide association meta-analysis of Parkinson’s disease

Author

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

Published
2024
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4. A phenome-wide association and Mendelian randomisation study of alcohol use variants in a diverse cohort comprising over 3 million individuals

Author

Aslibekyan, Stella, Auton, Adam, Babalola, Elizabeth, Bell, Robert K., Bielenberg, Jessica, Bryc, Katarzyna, Bullis, Emily, Coker, Daniella, Partida, Gabriel Cuellar, Dhamija, Devika, Das, Sayantan, Elson, Sarah L., Eriksson, Nicholas, Filshtein, Teresa, Fitch, Alison, Fletez-Brant, Kipper, Fontanillas, Pierre, Freyman, Will, Granka, Julie M., Heilbron, Karl, Hernandez, Alejandro, Hicks, Barry, Hinds, David A., Jewett, Ethan M., Jiang, Yunxuan, Kukar, Katelyn, Kwong, Alan, Lin, Keng-Han, Llamas, Bianca A., Lowe, Maya, McCreight, Jey C., McIntyre, Matthew H., Micheletti, Steven J., Moreno, Meghan E., Nandakumar, Priyanka, Nguyen, Dominique T., Noblin, Elizabeth S., O'Connell, Jared, Petrakovitz, Aaron A., Poznik, G. David, Reynoso, Alexandra, Schumacher, Morgan, Shastri, Anjali J., Shelton, Janie F., Shi, Jingchunzi, Shringarpure, Suyash, Su, Qiaojuan Jane, Tat, Susana A., Tchakouté, Christophe Toukam, Tran, Vinh, Tung, Joyce Y., Wang, Xin, Wang, Wei, Weldon, Catherine H., Wilton, Peter, Wong, Corinna D., Jennings, Mariela V., Martínez-Magaña, José Jaime, Courchesne-Krak, Natasia S., Cupertino, Renata B., Vilar-Ribó, Laura, Bianchi, Sevim B., Hatoum, Alexander S., Atkinson, Elizabeth G., Giusti-Rodriguez, Paola, Montalvo-Ortiz, Janitza L., Gelernter, Joel, Artigas, María Soler, Edenberg, Howard J., Palmer, Abraham A., and Sanchez-Roige, Sandra

Published
2024
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5. MUSSEL: Enhanced Bayesian polygenic risk prediction leveraging information across multiple ancestry groups

Author

Aslibekyan, Stella, Auton, Adam, Babalola, Elizabeth, Bell, Robert K., Bielenberg, Jessica, Bryc, Katarzyna, Bullis, Emily, Coker, Daniella, Cuellar Partida, Gabriel, Dhamija, Devika, Das, Sayantan, Elson, Sarah L., Eriksson, Nicholas, Filshtein, Teresa, Fitch, Alison, Fletez-Brant, Kipper, Fontanillas, Pierre, Freyman, Will, Granka, Julie M., Heilbron, Karl, Hernandez, Alejandro, Hicks, Barry, Hinds, David A., Jewett, Ethan M., Jiang, Yunxuan, Kukar, Katelyn, Kwong, Alan, Lin, Keng-Han, Llamas, Bianca A., Lowe, Maya, McCreight, Jey C., McIntyre, Matthew H., Micheletti, Steven J., Moreno, Meghan E., Nandakumar, Priyanka, Nguyen, Dominique T., Noblin, Elizabeth S., O’Connell, Jared, Petrakovitz, Aaron A., Poznik, G. David, Reynoso, Alexandra, Schumacher, Morgan, Shastri, Anjali J., Shelton, Janie F., Shi, Jingchunzi, Shringarpure, Suyash, Su, Qiaojuan Jane, Tat, Susana A., Tchakouté, Christophe Toukam, Tran, Vinh, Tung, Joyce Y., Wang, Xin, Wang, Wei, Weldon, Catherine H., Wilton, Peter, Wong, Corinna D., Jin, Jin, Zhan, Jianan, Zhang, Jingning, Zhao, Ruzhang, Buyske, Steven, Gignoux, Christopher, Haiman, Christopher, Kenny, Eimear E., Kooperberg, Charles, North, Kari, Koelsch, Bertram L., Wojcik, Genevieve, Zhang, Haoyu, and Chatterjee, Nilanjan

Published
2024
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6. Ancestry-independent risk of venous thromboembolism in individuals with sickle cell trait vs factor V Leiden

Author

Aslibekyan, Stella, Auton, Adam, Babalola, Elizabeth, Bell, Robert K., Bielenberg, Jessica, Bowes, Jonathan, Bryc, Katarzyna, Chaudhary, Ninad S., Coker, Daniella, Das, Sayantan, DelloRusso, Emily, Elson, Sarah L., Eriksson, Nicholas, Filshtein, Teresa, Fontanillas, Pierre, Freyman, Will, Fuller, Zach, German, Chris, Granka, Julie M., Heilbron, Karl, Hernandez, Alejandro, Hicks, Barry, Hinds, David A., Jewett, Ethan M., Jiang, Yunxuan, Kukar, Katelyn, Kwong, Alan, Liang, Yanyu, Lin, Keng-Han, Llamas, Bianca A., McIntyre, Matthew H., Micheletti, Steven J., Moreno, Meghan E., Nandakumar, Priyanka, Nguyen, Dominique T., O'Connell, Jared, Petrakovitz, Aaron A., Poznik, G. David, Reynoso, Alexandra, Saini, Shubham, Schumacher, Morgan, Selcer, Leah, Shastri, Anjali J., Shelton, Janie F., Shi, Jingchunzi, Shringarpure, Suyash, Su, Qiaojuan Jane, Tat, Susana A., Tran, Vinh, Tung, Joyce Y., Wang, Xin, Wang, Wei, Weldon, Catherine H., Wilton, Peter, Wong, Corinna D., Bonham, Vence L., and Naik, Rakhi P.

Published
2024
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7. Identification of genetic risk loci and causal insights associated with Parkinson's disease in African and African admixed populations: a genome-wide association study

Author

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

Published
2023
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8. The genomics of adaptation to mutational degradation in hypermutator Pseudomonas aeruginosa

Author

Heilbron, Karl and MacLean, R. Craig

Subjects
616.9
Abstract

Genetic diversity is generated and maintained even in the simplest of environments. Because interactions between pairs of mutations are incredibly common, genetic diversity may interact with incoming beneficial mutations and alter the evolutionary paths that are available to different genotypes. In this thesis I have explored how divergent genotypes respond to evolutionary forces like drift and selection with a particular focus on the initial fitness of these genotypes. In order to generate genetically divergent starting populations, in Chapter 1 I performed a mutation accumulation (MA) experiment using a hypermutator strain of Pseudomonas aeruginosa. This allowed me to characterize the rate and effect of spontaneous mutations in this system, and I found that fitness is strongly influenced by rare mutations of large effect. In Chapter 2 I evolved several replicates of each of these genetically divergent lines under laboratory conditions and sequenced their genomes to determine the genetic mechanisms underpinning adaptation to mutational degradation. Interestingly, acquiring general laboratory adaptation mutations was more important than specifically compensating for the mutations that occurred during MA. Furthermore, fitness of anMA line prior to recovery played a large role in determining the ruggedness of the adaptive landscape experienced by evolving populations. Given the importance of initial fitness in evolution that I observed in Chapter 2, in Chapter 3 I directly tested whether the initial fitness of a strain could influence the fitness effect of incoming mutations in the context of antibiotic resistance evolution. Adaptation to a novel environment could decrease the cost of antibiotic resistance, but there was no systematic relationship between initial fitness and cost. Taken together, my work has contributed to our understanding of how the fitness of a genotype and the nature of incoming mutations (i.e. beneficial or deleterious) interact to influence the outcome of evolution.

Published
2020

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. Multi-Trait Genetic Analysis Identifies Autoimmune Loci Associated with Cutaneous Melanoma

Author

Agee, Michelle, Aslibekyan, Stella, Auton, Adam, Babalola, Elizabeth, Bell, Robert K., Bielenberg, Jessica, Bryc, Katarzyna, Bullis, Emily, Cameron, Briana, Coker, Daniella, Cuellar Partida, Gabriel, Dhamija, Devika, Das, Sayantan, Elson, Sarah L., Filshtein, Teresa, Fletez-Brant, Kipper, Fontanillas, Pierre, Freyman, Will, Gandhi, Pooja M., Heilbron, Karl, Hicks, Barry, Hinds, David A., Huber, Karen E., Jewett, Ethan M., Kleinman, Aaron, Kukar, Katelyn, Lin, Keng-Han, Lowe, Maya, Luff, Marie K., McCreight, Jennifer C., McIntyre, Matthew H., McManus, Kimberly F., Micheletti, Steven J., Moreno, Meghan E., Mountain, Joanna L., Mozaffari, Sahar V., Nandakumar, Priyanka, Noblin, Elizabeth S., O'Connell, Jared, Petrakovitz, Aaron A., Poznik, G. David, Shastri, Anjali J., Shelton, Janie F., Shi, Jingchunzi, Shringarpure, Suyash, Tran, Vinh, Tung, Joyce Y., Wang, Xin, Wang, Wei, Weldon, Catherine H., Wilton, Peter, Liyanage, Upekha E., MacGregor, Stuart, Bishop, D. Timothy, Shi, Jianxin, An, Jiyuan, Ong, Jue Sheng, Han, Xikun, Scolyer, Richard A., Martin, Nicholas G., Medland, Sarah E., Byrne, Enda M., Green, Adèle C., Saw, Robyn P.M., Thompson, John F., Stretch, Jonathan, Spillane, Andrew, Jiang, Yunxuan, Tian, Chao, Gordon, Scott G., Duffy, David L., Olsen, Catherine M., Whiteman, David C., Long, Georgina V., Iles, Mark M., Landi, Maria Teresa, and Law, Matthew H.

Published
2022
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11. Genome-wide association study of REM sleep behavior disorder identifies polygenic risk and brain expression effects

Author

Krohn, Lynne, Heilbron, Karl, Blauwendraat, Cornelis, Reynolds, Regina H., Yu, Eric, Senkevich, Konstantin, Rudakou, Uladzislau, Estiar, Mehrdad A., Gustavsson, Emil K., Brolin, Kajsa, Ruskey, Jennifer A., Freeman, Kathryn, Asayesh, Farnaz, Chia, Ruth, Arnulf, Isabelle, Hu, Michele T. M., Montplaisir, Jacques Y., Gagnon, Jean-François, Desautels, Alex, Dauvilliers, Yves, Gigli, Gian Luigi, Valente, Mariarosaria, Janes, Francesco, Bernardini, Andrea, Högl, Birgit, Stefani, Ambra, Ibrahim, Abubaker, Šonka, Karel, Kemlink, David, Oertel, Wolfgang, Janzen, Annette, Plazzi, Giuseppe, Biscarini, Francesco, Antelmi, Elena, Figorilli, Michela, Puligheddu, Monica, Mollenhauer, Brit, Trenkwalder, Claudia, Sixel-Döring, Friederike, Cochen De Cock, Valérie, Monaca, Christelle Charley, Heidbreder, Anna, Ferini-Strambi, Luigi, Dijkstra, Femke, Viaene, Mineke, Abril, Beatriz, Boeve, Bradley F., Scholz, Sonja W., Ryten, Mina, Bandres-Ciga, Sara, Noyce, Alastair, Cannon, Paul, Pihlstrøm, Lasse, Nalls, Mike A., Singleton, Andrew B., Rouleau, Guy A., Postuma, Ronald B., and Gan-Or, Ziv

Published
2022
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12. Prevalence of Alpha-1 Antitrypsin Deficiency, Self-Reported Behavior Change, and Health Care Engagement Among Direct-to-Consumer Recipients of a Personalized Genetic Risk Report

Author

Agee, Michelle, Aslibekyan, Stella, Auton, Adam, Babalola, Elizabeth, Bell, Robert K., Bielenberg, Jessica, Bryc, Katarzyna, Bullis, Emily, Cameron, Briana, Coker, Daniella, Partida, Gabriel Cuellar, Dhamija, Devika, Das, Sayantan, Elson, Sarah L., Filshtein, Teresa, Fletez-Brant, Kipper, Fontanillas, Pierre, Freyman, Will, Gandhi, Pooja M., Heilbron, Karl, Hicks, Barry, Hinds, David A., Huber, Karen E., Jewett, Ethan M., Jiang, Yunxuan, Kleinman, Aaron, Kukar, Katelyn, Lane, Vanessa A., Lin, Keng-Han, Lowe, Maya, Luff, Marie K., McCreight, Jennifer C., McIntyre, Matthew H., McManus, Kimberly F., Micheletti, Steven J., Moreno, Meghan E., Mountain, Joanna L., Mozaffari, Sahar V., Nandakumar, Priyanka, Noblin, Elizabeth S., O’Connell, Jared, Petrakovitz, Aaron A., Poznik, G. David, Schumacher, Morgan, Shastri, Anjali J., Shelton, Janie F., Shi, Jingchunzi, Shringarpure, Suyash, Tian, Chao, Tran, Vinh, Tung, Joyce Y., Wang, Xin, Wang, Wei, Weldon, Catherine H., Wilton, Peter, Ashenhurst, James R., Nhan, Hoang, Wu, Shirley, and Stoller, James K.

Published
2022
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13. Genetic Analysis and Natural History of LRRK2 G2019S Parkinson’s Disease (P11-3.006)

Author

Kmiecik, Matthew, primary, Micheletti, Steven, additional, Coker, Daniella, additional, Heilbron, Karl, additional, Shi, Jingchunzi, additional, Stagaman, Keaton, additional, Sonmez, Teresa Filshtein, additional, Fontanillas, Pierre, additional, Shringarpure, Suyash, additional, Schloetter, Madeleine, additional, Rowbotham, Helen M., additional, Cannon, Paul, additional, Shelton, Janie, additional, Hinds, David A., additional, Tung, Joyce Y., additional, Holmes, Michael V., additional, Aslibekyan, Stella, additional, and Norcliffe-Kaufmann, Lucy, additional

Published
2024
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14. MUSSEL: Enhanced Bayesian polygenic risk prediction leveraging information across multiple ancestry groups

Author

Jin, Jin, primary, Zhan, Jianan, additional, Zhang, Jingning, additional, Zhao, Ruzhang, additional, O’Connell, Jared, additional, Jiang, Yunxuan, additional, Aslibekyan, Stella, additional, Auton, Adam, additional, Babalola, Elizabeth, additional, Bell, Robert K., additional, Bielenberg, Jessica, additional, Bryc, Katarzyna, additional, Bullis, Emily, additional, Coker, Daniella, additional, Cuellar Partida, Gabriel, additional, Dhamija, Devika, additional, Das, Sayantan, additional, Elson, Sarah L., additional, Eriksson, Nicholas, additional, Filshtein, Teresa, additional, Fitch, Alison, additional, Fletez-Brant, Kipper, additional, Fontanillas, Pierre, additional, Freyman, Will, additional, Granka, Julie M., additional, Heilbron, Karl, additional, Hernandez, Alejandro, additional, Hicks, Barry, additional, Hinds, David A., additional, Jewett, Ethan M., additional, Kukar, Katelyn, additional, Kwong, Alan, additional, Lin, Keng-Han, additional, Llamas, Bianca A., additional, Lowe, Maya, additional, McCreight, Jey C., additional, McIntyre, Matthew H., additional, Micheletti, Steven J., additional, Moreno, Meghan E., additional, Nandakumar, Priyanka, additional, Nguyen, Dominique T., additional, Noblin, Elizabeth S., additional, Petrakovitz, Aaron A., additional, Poznik, G. David, additional, Reynoso, Alexandra, additional, Schumacher, Morgan, additional, Shastri, Anjali J., additional, Shelton, Janie F., additional, Shi, Jingchunzi, additional, Shringarpure, Suyash, additional, Su, Qiaojuan Jane, additional, Tat, Susana A., additional, Tchakouté, Christophe Toukam, additional, Tran, Vinh, additional, Tung, Joyce Y., additional, Wang, Xin, additional, Wang, Wei, additional, Weldon, Catherine H., additional, Wilton, Peter, additional, Wong, Corinna D., additional, Buyske, Steven, additional, Gignoux, Christopher, additional, Haiman, Christopher, additional, Kenny, Eimear E., additional, Kooperberg, Charles, additional, North, Kari, additional, Koelsch, Bertram L., additional, Wojcik, Genevieve, additional, Zhang, Haoyu, additional, and Chatterjee, Nilanjan, additional

Published
2024
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15. A genome-wide association study with 1,126,563 individuals identifies new risk loci for Alzheimer’s disease

Author

Wightman, Douglas P., Jansen, Iris E., Savage, Jeanne E., Shadrin, Alexey A., Bahrami, Shahram, Holland, Dominic, Rongve, Arvid, Børte, Sigrid, Winsvold, Bendik S., Drange, Ole Kristian, Martinsen, Amy E., Skogholt, Anne Heidi, Willer, Cristen, Bråthen, Geir, Bosnes, Ingunn, Nielsen, Jonas Bille, Fritsche, Lars G., Thomas, Laurent F., Pedersen, Linda M., Gabrielsen, Maiken E., Johnsen, Marianne Bakke, Meisingset, Tore Wergeland, Zhou, Wei, Proitsi, Petroula, Hodges, Angela, Dobson, Richard, Velayudhan, Latha, Heilbron, Karl, Auton, Adam, Sealock, Julia M., Davis, Lea K., Pedersen, Nancy L., Reynolds, Chandra A., Karlsson, Ida K., Magnusson, Sigurdur, Stefansson, Hreinn, Thordardottir, Steinunn, Jonsson, Palmi V., Snaedal, Jon, Zettergren, Anna, Skoog, Ingmar, Kern, Silke, Waern, Margda, Zetterberg, Henrik, Blennow, Kaj, Stordal, Eystein, Hveem, Kristian, Zwart, John-Anker, Athanasiu, Lavinia, Selnes, Per, Saltvedt, Ingvild, Sando, Sigrid B., Ulstein, Ingun, Djurovic, Srdjan, Fladby, Tormod, Aarsland, Dag, Selbæk, Geir, Ripke, Stephan, Stefansson, Kari, Andreassen, Ole A., and Posthuma, Danielle

Published
2021
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16. Genetic analysis and natural history of Parkinson's disease due to the LRRK2 G2019S variant.

Author

Kmiecik, Matthew J, Micheletti, Steven, Coker, Daniella, Heilbron, Karl, Shi, Jingchunzi, Stagaman, Keaton, Sonmez, Teresa Filshtein, Fontanillas, Pierre, Shringarpure, Suyash, Wetzel, Madeleine, Rowbotham, Helen M, Cannon, Paul, Shelton, Janie F, Hinds, David A, Tung, Joyce Y, Team, 23andMe Research, Holmes, Michael V, Aslibekyan, Stella, and Norcliffe-Kaufmann, Lucy

Subjects
PARKINSON'S disease, DARDARIN, GENETIC risk score, MOVEMENT disorders, RAPID eye movement sleep, BEHAVIOR disorders
Abstract

The LRRK2 G2019S variant is the most common cause of monogenic Parkinson's disease (PD); however, questions remain regarding the penetrance, clinical phenotype and natural history of carriers. We performed a 3.5-year prospective longitudinal online study in a large number of 1286 genotyped LRRK2 G2019S carriers and 109 154 controls, with and without PD, recruited from the 23andMe Research Cohort. We collected self-reported motor and non-motor symptoms every 6 months, as well as demographics, family histories and environmental risk factors. Incident cases of PD (phenoconverters) were identified at follow-up. We determined lifetime risk of PD using accelerated failure time modelling and explored the impact of polygenic risk on penetrance. We also computed the genetic ancestry of all LRRK2 G2019S carriers in the 23andMe database and identified regions of the world where carrier frequencies are highest. We observed that despite a 1 year longer disease duration (P = 0.016), LRRK2 G2019S carriers with PD had similar burden of motor symptoms, yet significantly fewer non-motor symptoms including cognitive difficulties, REM sleep behaviour disorder (RBD) and hyposmia (all P- values ≤ 0.0002). The cumulative incidence of PD in G2019S carriers by age 80 was 49%. G2019S carriers had a 10-fold risk of developing PD versus non-carriers. This rose to a 27-fold risk in G2019S carriers with a PD polygenic risk score in the top 25% versus non-carriers in the bottom 25%. In addition to identifying ancient founding events in people of North African and Ashkenazi descent, our genetic ancestry analyses infer that the G2019S variant was later introduced to Spanish colonial territories in the Americas. Our results suggest LRRK2 G2019S PD appears to be a slowly progressive predominantly motor subtype of PD with a lower prevalence of hyposmia, RBD and cognitive impairment. This suggests that the current prodromal criteria, which are based on idiopathic PD, may lack sensitivity to detect the early phases of LRRK2 PD in G2019S carriers. We show that polygenic burden may contribute to the development of PD in the LRRK2 G2019S carrier population. Collectively, the results should help support screening programmes and candidate enrichment strategies for upcoming trials of LRRK2 inhibitors in early-stage disease. [ABSTRACT FROM AUTHOR]

Published
2024
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17. Gene‐environment interactions for Parkinson's disease

Author

Reynoso, Alexandra, primary, Torricelli, Roberta, additional, Jacobs, Benjamin Meir, additional, Shi, Jingchunzi, additional, Aslibekyan, Stella, additional, Norcliffe‐Kaufmann, Lucy, additional, Noyce, Alastair J, additional, and Heilbron, Karl, additional

Published
2023
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18. Identification of novel risk loci, causal insights, and heritable risk for Parkinson's disease: a meta-analysis of genome-wide association studies

Author

Adarmes-Gómez, Astrid D, Aguilar, Miquel, Aitkulova, Akbota, Akhmetzhanov, Vadim, Alcalay, Roy N, Alvarez, Ignacio, Alvarez, Victoria, Bandres-Ciga, Sara, Barrero, Francisco Javier, Bergareche Yarza, Jesús Alberto, Bernal-Bernal, Inmaculada, Billingsley, Kimberley, Blauwendraat, Cornelis, Blazquez, Marta, Bonilla-Toribio, Marta, Botía, Juan A, Boungiorno, María Teresa, Bras, Jose, Brice, Alexis, 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, Corvol, Jean-Christophe, Craig, David W, Danjou, Fabrice, Diez-Fairen, Monica, Dols-Icardo, Oriol, Duarte, Jacinto, Duran, Raquel, Escamilla-Sevilla, Francisco, Escott-Price, Valentina, Ezquerra, Mario, Faghri, Faraz, Feliz, Cici, Fernández, Manel, Fernández-Santiago, Rubén, Finkbeiner, Steven, Foltynie, Thomas, Gan-Or, Ziv, Garcia, Ciara, García-Ruiz, Pedro, Gasser, Thomas, Gibbs, J Raphael, Gomez Heredia, Maria Jose, Gómez-Garre, Pilar, González, Manuel Menéndez, Gonzalez-Aramburu, Isabel, Guelfi, Sebastian, Guerreiro, Rita, Hardy, John, Hassin-Baer, Sharon, Hernandez, Dena G, Heutink, Peter, Hoenicka, Janet, Holmans, Peter, Houlden, Henry, Infante, Jon, Iwaki, Hirotaka, Jesús, Silvia, Jimenez-Escrig, Adriano, Kaishybayeva, Gulnaz, Kaiyrzhanov, Rauan, Karimova, Altynay, Kia, Demis A, Kinghorn, Kerri J, Koks, Sulev, Krohn, Lynne, Kulisevsky, Jaime, Labrador-Espinosa, Miguel A, Leonard, Hampton L, Lesage, Suzanne, Lewis, Patrick, Lopez-Sendon, Jose Luis, Lovering, Ruth, Lubbe, Steven, Lungu, Codrin, Macias, Daniel, Majamaa, Kari, Manzoni, Claudia, Marín, Juan, Marinus, Johan, Marti, Maria Jose, Martinez, Maria, Martínez Torres, Irene, Martínez-Castrillo, Juan Carlos, Mata, Marina, Mencacci, Niccolo E, Méndez-del-Barrio, Carlota, Middlehurst, Ben, Mínguez, Adolfo, Mir, Pablo, Mok, Kin Y, Morris, Huw R, Muñoz, Esteban, Nalls, Mike A, Narendra, Derek, Noyce, Alastair J, Ojo, Oluwadamilola O, Okubadejo, Njideka U, Pagola, Ana Gorostidi, Pastor, Pau, Perez Errazquin, Francisco, Periñán-Tocino, Teresa, Pihlstrom, Lasse, Plun-Favreau, Helene, Quinn, John, R'Bibo, Lea, Reed, Xylena, Rezola, Elisabet Mondragon, Rizig, Mie, Rizzu, Patrizia, Robak, Laurie, Rodriguez, Antonio Sanchez, Rouleau, Guy A, Ruiz-Martínez, Javier, Ruz, Clara, Ryten, Mina, Sadykova, Dinara, Scholz, Sonja W, Schreglmann, Sebastian, Schulte, Claudia, Sharma, Manu, Shashkin, Chingiz, Shulman, Joshua M, Sierra, María, Siitonen, Ari, Simón-Sánchez, Javier, Singleton, Andrew B, Suarez-Sanmartin, Esther, Taba, Pille, Tabernero, Cesar, Tan, Manuela X, Tartari, Juan Pablo, Tejera-Parrado, Cristina, Toft, Mathias, Tolosa, Eduard, Trabzuni, Daniah, Valldeoriola, Francesc, van Hilten, Jacobus J, Van Keuren-Jensen, Kendall, Vargas-González, Laura, Vela, Lydia, Vives, Francisco, Williams, Nigel, Wood, Nicholas W, Zharkinbekova, Nazira, Zharmukhanov, Zharkyn, Zholdybayeva, Elena, Zimprich, Alexander, Ylikotila, Pauli, Shulman, Lisa M., von Coelln, Rainer, Reich, Stephen, Savitt, Joseph, Agee, Michelle, Alipanahi, Babak, Auton, Adam, Bell, Robert K., Bryc, Katarzyna, Elson, Sarah L., Fontanillas, Pierre, Furlotte, Nicholas A., Huber, Karen E., Hicks, Barry, Jewett, Ethan M., Jiang, Yunxuan, Kleinman, Aaron, Lin, Keng-Han, Litterman, Nadia K., McCreight, Jennifer C., McIntyre, Matthew H., McManus, Kimberly F., Mountain, Joanna L., Noblin, Elizabeth S., Northover, Carrie A.M., Pitts, Steven J., Poznik, G. David, Sathirapongsasuti, J. Fah, Shelton, Janie F., Shringarpure, Suyash, Tian, Chao, Tung, Joyce, Vacic, Vladimir, Wang, Xin, Wilson, Catherine H., Anderson, Tim, Bentley, Steven, Dalrymple-Alford, John, Fowdar, Javed, Gratten, Jacob, Halliday, Glenda, Henders, Anjali K., Hickie, Ian, Kassam, Irfahan, Kennedy, Martin, Kwok, John, Lewis, Simon, Mellick, George, Montgomery, Grant, Pearson, John, Pitcher, Toni, Sidorenko, Julia, Silburn, Peter A., Vallerga, Costanza L., Visscher, Peter M., Wallace, Leanne, Wray, Naomi R., Xue, Angli, Yang, Jian, Zhang, Futao, Vallerga, Costanza L, Heilbron, Karl, Chang, Diana, Tan, Manuela, Young, Emily, Pihlstrøm, Lasse, Leonard, Hampton, Botia, Juan A, Jankovic, Joseph, Shulman, Lisa M, Sutherland, Margaret, Tienari, Pentti, Andreassen, Ole A, Bangale, Tushar, Hinds, David A, Hardy, John A, Visscher, Peter M, and Graham, Robert R

Published
2019
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19. Discriminating selection on lateral plate phenotype and its underlying gene, Ectodysplasin, in threespine stickleback.

Author

Rennison, Diana J, Heilbron, Karl, Barrett, Rowan DH, and Schluter, Dolph

Subjects
Genetics, Adaptation, Biological, Animals, Biological Evolution, Ectodysplasins, Gene Frequency, Genetic Linkage, Genotype, Phenotype, Selection, Genetic, Smegmamorpha, genetics of adaptation, natural selection, evolutionary ecology, pleiotropy, correlated response to selection, Biological Sciences, Ecology
Abstract

When a signature of natural selection is discovered on a gene that is pleiotropic or in tight linkage with other genes, it is challenging to determine which of the affected phenotypes is under selection. One way to make progress is to employ methods for analyzing natural selection on correlated traits, including both genotype and phenotype. We used this approach in threespine stickleback to estimate selection on a rapidly evolving trait, lateral armor plates, while controlling for variation at its major underlying gene, Ectodysplasin (Eda), and vice versa. This allowed for independent estimates of selection on lateral plates and on Eda via other traits. Previously, we demonstrated allele frequency changes at Eda in a pond experiment. Here we show that this resulted from selection on both plates and on Eda, implying additional selection on other phenotypic traits affected by the same gene. This represents the first evidence for direct selection on lateral plates independent of selection on the Eda locus and highlights the value of measuring selection on both phenotypes and genotypes in studies of adaptation.

Published
2015

20. Author Correction: A genome-wide association study with 1,126,563 individuals identifies new risk loci for Alzheimer’s disease

Author

Wightman, Douglas P., Jansen, Iris E., Savage, Jeanne E., Shadrin, Alexey A., Bahrami, Shahram, Holland, Dominic, Rongve, Arvid, Børte, Sigrid, Winsvold, Bendik S., Drange, Ole Kristian, Martinsen, Amy E., Skogholt, Anne Heidi, Willer, Cristen, Bråthen, Geir, Bosnes, Ingunn, Nielsen, Jonas Bille, Fritsche, Lars G., Thomas, Laurent F., Pedersen, Linda M., Gabrielsen, Maiken E., Johnsen, Marianne Bakke, Meisingset, Tore Wergeland, Zhou, Wei, Proitsi, Petroula, Hodges, Angela, Dobson, Richard, Velayudhan, Latha, Heilbron, Karl, Auton, Adam, Sealock, Julia M., Davis, Lea K., Pedersen, Nancy L., Reynolds, Chandra A., Karlsson, Ida K., Magnusson, Sigurdur, Stefansson, Hreinn, Thordardottir, Steinunn, Jonsson, Palmi V., Snaedal, Jon, Zettergren, Anna, Skoog, Ingmar, Kern, Silke, Waern, Margda, Zetterberg, Henrik, Blennow, Kaj, Stordal, Eystein, Hveem, Kristian, Zwart, John-Anker, Athanasiu, Lavinia, Selnes, Per, Saltvedt, Ingvild, Sando, Sigrid B., Ulstein, Ingun, Djurovic, Srdjan, Fladby, Tormod, Aarsland, Dag, Selbæk, Geir, Ripke, Stephan, Stefansson, Kari, Andreassen, Ole A., and Posthuma, Danielle

Published
2022
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21. Gene–Environment Interactions for Parkinson's Disease.

Author

Reynoso, Alexandra, Torricelli, Roberta, Jacobs, Benjamin Meir, Shi, Jingchunzi, Aslibekyan, Stella, Norcliffe‐Kaufmann, Lucy, Noyce, Alastair J, and Heilbron, Karl

Subjects
GENETIC risk score, PARKINSON'S disease, TOBACCO use, BODY mass index, MONOGENIC & polygenic inheritance (Genetics)
Abstract

Objective: Parkinson's disease (PD) is a neurodegenerative disorder with complex etiology. Multiple genetic and environmental factors have been associated with PD, but most PD risk remains unexplained. The aim of this study was to test for statistical interactions between PD‐related genetic and environmental exposures in the 23andMe, Inc. research dataset. Methods: Using a validated PD polygenic risk score and common PD‐associated variants in the GBA gene, we explored interactions between genetic susceptibility factors and 7 lifestyle and environmental factors: body mass index (BMI), type 2 diabetes (T2D), tobacco use, caffeine consumption, pesticide exposure, head injury, and physical activity (PA). Results: We observed that T2D, as well as higher BMI, caffeine consumption, and tobacco use, were associated with lower odds of PD, whereas head injury, pesticide exposure, GBA carrier status, and PD polygenic risk score were associated with higher odds. No significant association was observed between PA and PD. In interaction analyses, we found statistical evidence for an interaction between polygenic risk of PD and the following environmental/lifestyle factors: T2D (p = 6.502 × 10−8), PA (p = 8.745 × 10−5), BMI (p = 4.314 × 10−4), and tobacco use (p = 2.236 × 10−3). Although BMI and tobacco use were associated with lower odds of PD regardless of the extent of individual genetic liability, the direction of the relationship between odds of PD and T2D, as well as PD and PA, varied depending on polygenic risk score. Interpretation: We provide preliminary evidence that associations between some environmental and lifestyle factors and PD may be modified by genotype. ANN NEUROL 2024;95:677–687 [ABSTRACT FROM AUTHOR]

Published
2024
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23. Author Correction: A genome-wide association study with 1,126,563 individuals identifies new risk loci for Alzheimer’s disease

Author

Wightman, Douglas P., Jansen, Iris E., Savage, Jeanne E., Shadrin, Alexey A., Bahrami, Shahram, Holland, Dominic, Rongve, Arvid, Børte, Sigrid, Winsvold, Bendik S., Drange, Ole Kristian, Martinsen, Amy E., Skogholt, Anne Heidi, Willer, Cristen, Bråthen, Geir, Bosnes, Ingunn, Nielsen, Jonas Bille, Fritsche, Lars G., Thomas, Laurent F., Pedersen, Linda M., Gabrielsen, Maiken E., Johnsen, Marianne Bakke, Meisingset, Tore Wergeland, Zhou, Wei, Proitsi, Petroula, Hodges, Angela, Dobson, Richard, Velayudhan, Latha, Heilbron, Karl, Auton, Adam, Sealock, Julia M., Davis, Lea K., Pedersen, Nancy L., Reynolds, Chandra A., Karlsson, Ida K., Magnusson, Sigurdur, Stefansson, Hreinn, Thordardottir, Steinunn, Jonsson, Palmi V., Snaedal, Jon, Zettergren, Anna, Skoog, Ingmar, Kern, Silke, Waern, Margda, Zetterberg, Henrik, Blennow, Kaj, Stordal, Eystein, Hveem, Kristian, Zwart, John-Anker, Athanasiu, Lavinia, Selnes, Per, Saltvedt, Ingvild, Sando, Sigrid B., Ulstein, Ingun, Djurovic, Srdjan, Fladby, Tormod, Aarsland, Dag, Selbæk, Geir, Ripke, Stephan, Stefansson, Kari, Andreassen, Ole A., and Posthuma, Danielle

Published
2021
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24. Identification of genetic risk loci and causal insights associated with Parkinson's disease in African and African admixed populations: a genome-wide association study

Author

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

Published
2023
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26. Author Correction: Discovery of 42 genome-wide significant loci associated with dyslexia

Author

Doust, Catherine, Fontanillas, Pierre; https://orcid.org/0000-0002-8944-4454, Eising, Else; https://orcid.org/0000-0001-9819-1260, Gordon, Scott D; https://orcid.org/0000-0001-7623-328X, Wang, Zhengjun; https://orcid.org/0000-0003-2326-4167, Alagöz, Gökberk, Molz, Barbara; https://orcid.org/0000-0002-9300-761X, Aslibekyan, Stella, Auton, Adam, Babalola, Elizabeth, Bell, Robert K, Bielenberg, Jessica, Bryc, Katarzyna, Bullis, Emily, Coker, Daniella, Partida, Gabriel Cuellar, Dhamija, Devika, Das, Sayantan, Elson, Sarah L, Filshtein, Teresa, Fletez-Brant, Kipper, Freyman, Will, Gandhi, Pooja M, Heilbron, Karl, Hicks, Barry, Hinds, David A, Jewett, Ethan M, Jiang, Yunxuan, Kukar, Katelyn, Lin, Keng-Han, et al, Doust, Catherine, Fontanillas, Pierre; https://orcid.org/0000-0002-8944-4454, Eising, Else; https://orcid.org/0000-0001-9819-1260, Gordon, Scott D; https://orcid.org/0000-0001-7623-328X, Wang, Zhengjun; https://orcid.org/0000-0003-2326-4167, Alagöz, Gökberk, Molz, Barbara; https://orcid.org/0000-0002-9300-761X, Aslibekyan, Stella, Auton, Adam, Babalola, Elizabeth, Bell, Robert K, Bielenberg, Jessica, Bryc, Katarzyna, Bullis, Emily, Coker, Daniella, Partida, Gabriel Cuellar, Dhamija, Devika, Das, Sayantan, Elson, Sarah L, Filshtein, Teresa, Fletez-Brant, Kipper, Freyman, Will, Gandhi, Pooja M, Heilbron, Karl, Hicks, Barry, Hinds, David A, Jewett, Ethan M, Jiang, Yunxuan, Kukar, Katelyn, Lin, Keng-Han, and et al

Abstract

Correction to: Nature Genetics https://doi.org/10.1038/s41588-022-01192-y. Published online 20 October 2022. In the version of this article originally published, a paragraph was omitted in the Methods section, reading “Genomic control. Top SNPs are reported from the more conservative GWAS results adjusted for genomic control (Fig. 1, Extended Data Figs. 1–4, and Supplementary Tables 1, 2, 9 and 10), whereas downstream analyses (including gene-set analysis, enrichment and heritability partitioning, genetic correlations, polygenic prediction, candidate gene replication) are based on GWAS results without genomic control.” The paragraph has now been included in the HTML and PDF versions of the article.

Published
2023

27. Genome-wide Association Identifies Novel Etiological Insights Associated with Parkinson’s Disease in African and African Admixed Populations

Author

Rizig, Mie, Bandres-Ciga, Sara, Makarious, Mary B, Ojo, Oluwadamilola, Crea, Peter Wild, Abiodun, Oladunni, Levine, Kristin S, Abubakar, Sani, Achoru, Charles, Vitale, Dan, Adeniji, Olaleye, Agabi, Osigwe, Koretsky, Mathew J, Agulanna, Uchechi, Hall, Deborah A., Akinyemi, Rufus, Xie, Tao, Ali, Mohammed, Shamim, Ejaz A., Ani-Osheku, Ifeyinwa, Padmanaban, Mahesh, Arigbodi, Owotemu, Standaert, David G, Bello, Abiodun, Dean, Marissa, Erameh, Cyril, Elsayed, Inas, Farombi, Temitope, Okunoye, Olaitan, Fawale, Michael, Billingsley, Kimberley J, Imarhiagbe, Frank, Jerez, Pilar Alvarez, Iwuozo, Emmanuel, Baker, Breeana, Komolafe, Morenikeji, Malik, Laksh, Nwani, Paul, Daida, Kensuke, Nwazor, Ernest, Miano-Burkhardt, Abigail, Nyandaiti, Yakub, Fang, Zih-Hua, Obiabo, Yahaya, Kluss, Jillian H., Odeniyi, Olanike, Hernandez, Dena, Odiase, Francis, Tayebi, Nahid, Ojini, Francis, Sidranksy, Ellen, Onwuegbuzie, Gerald, D’Souza, Andrea M., Osaigbovo, Godwin, Berhe, Bahafta, Osemwegie, Nosakhare, Reed, Xylena, Oshinaike, Olajumoke, Leonard, Hampton, Otubogun, Folajimi, Alvarado, Chelsea X, Oyakhire, Shyngle, Ozomma, Simon, Samuel, Sarah, Taiwo, Funmilola, Wahab, Kolawole, Zubair, Yusuf, Iwaki, Hirotaka, Kim, Jonggeol Jeffrey, Morris, Huw R, Hardy, John, Nalls, Mike, Heilbron, Karl, Norcliffe-Kaufmann, Lucy, Blauwendraat, Cornelis, Houlden, Henry, Singleton, Andrew, and Okubadejo, Njideka

Subjects
Article
Abstract

BACKGROUND: Understanding the genetic mechanisms underlying diseases in ancestrally diverse populations is a critical step towards the realization of the global application of precision medicine. The African and African admixed populations enable mapping of complex traits given their greater levels of genetic diversity, extensive population substructure, and distinct linkage disequilibrium patterns. METHODS: Here we perform a comprehensive genome-wide assessment of Parkinson’s disease (PD) in 197,918 individuals (1,488 cases; 196,430 controls) of African and African admixed ancestry, characterizing population-specific risk, differential haplotype structure and admixture, coding and structural genetic variation and polygenic risk profiling. FINDINGS: We identified a novel common risk factor for PD and age at onset at the GBA1 locus (risk, rs3115534-G; OR=1.58, 95% CI = 1.37 – 1.80, P=2.397E-14; age at onset, BETA =−2.004, SE =0.57, P = 0.0005), that was found to be rare in non-African/African admixed populations. Downstream short- and long-read whole genome sequencing analyses did not reveal any coding or structural variant underlying the GWAS signal. However, we identified that this signal mediates PD risk via expression quantitative trait locus (eQTL) mechanisms. While previously identified GBA1 associated disease risk variants are coding mutations, here we suggest a novel functional mechanism consistent with a trend in decreasing glucocerebrosidase activity levels. Given the high population frequency of the underlying signal and the phenotypic characteristics of the homozygous carriers, we hypothesize that this variant may not cause Gaucher disease. Additionally, the prevalence of Gaucher’s disease in Africa is low. INTERPRETATION: The present study identifies a novel African-ancestry genetic risk factor in GBA1 as a major mechanistic basis of PD in the African and African admixed populations. This striking result contrasts to previous work in Northern European populations, both in terms of mechanism and attributable risk. This finding highlights the importance of understanding population-specific genetic risk in complex diseases, a particularly crucial point as the field moves toward precision medicine in PD clinical trials and while recognizing the need for equitable inclusion of ancestrally diverse groups in such trials. Given the distinctive genetics of these underrepresented populations, their inclusion represents a valuable step towards insights into novel genetic determinants underlying PD etiology. This opens new avenues towards RNA-based and other therapeutic strategies aimed at reducing lifetime risk.

Published
2023

30. Using a polygenic score in a family design to understand genetic influences on musicality

Author

Wesseldijk, Laura W., Abdellaoui, Abdel, Gordon, Reyna L., Aslibekyan, Stella, Auton, Adam, Babalola, Elizabeth, Bell, Robert K., Bielenberg, Jessica, Bryc, Katarzyna, Bullis, Emily, Coker, Daniella, Partida, Gabriel Cuellar, Dhamija, Devika, Das, Sayantan, Elson, Sarah L., Filshtein, Teresa, Fletez-Brant, Kipper, Fontanillas, Pierre, Freyman, Will, Faaborg, Anna, Fuller, Shirin T., Gandhi, Pooja M., Heilbron, Karl, Hicks, Barry, Jewett, Ethan M., Kukar, Katelyn, Lin, Keng-Han, Lowe, Maya, McCreight, Jey C., McIntyre, Matthew H., Micheletti, Steven J., Moreno, Meghan E., Mountain, Joanna L., Nandakumar, Priyanka, Noblin, Elizabeth S., O’Connell, Jared, Huang, Yunru, Petrakovitz, Aaron A., Lane, Vanessa, Petrakovitz, Aaron, Kim, Joanne S., Poznik, G. David, Schumacher, Morgan, Shastri, Anjali J., Shelton, Janie F., Shi, Jingchunzi, Shringarpure, Suyash, Tran, Vinh, Tung, Joyce Y., Wang, Xin, Wang, Wei, Weldon, Catherine H., Wilton, Peter, Hernandez, Alejandro, Wong, Corinna, Tchakouté, Christophe Toukam, Ullén, Fredrik, Mosing, Miriam A., 23andMe Research Team, Adult Psychiatry, Social Psychology, IBBA, and Biological Psychology

Subjects
Sweden, Multifactorial Inheritance, SDG 16 - Peace, Multidisciplinary, SDG 16 - Peace, Justice and Strong Institutions, Twins, SDG 10 - Reduced Inequalities, Justice and Strong Institutions, Pitch Discrimination, Humans, Multifactorial Inheritance/genetics, Music, Twins/genetics
Abstract

To further our understanding of the genetics of musicality, we explored associations between a polygenic score for self-reported beat synchronization ability (PGSrhythm) and objectively measured rhythm discrimination, as well as other validated music skills and music-related traits. Using family data, we were able to further explore potential pathways of direct genetic, indirect genetic (through passive gene–environment correlation) and confounding effects (such as population structure and assortative mating). In 5648 Swedish twins, we found PGSrhythm to predict not only rhythm discrimination, but also melody and pitch discrimination (betas between 0.11 and 0.16, p p rhythm was not associated with control phenotypes not directly related to music. Associations did not deteriorate within families (N = 243), implying that indirect genetic or confounding effects did not inflate PGSrhythm effects. A correlation (r = 0.05, p rhythm, suggests gene–environment correlation. We conclude that the PGSrhythm captures individuals' general genetic musical propensity, affecting musical behavior more likely direct than through indirect or confounding effects.

Published
2022

31. Genome-wide analysis of 53,400 people with irritable bowel syndrome highlights shared genetic pathways with mood and anxiety disorders

Author

Eijsbouts, Chris, Zheng, Tenghao, Kennedy, Nicholas A., Bonfiglio, Ferdinando, Anderson, Carl A., Moutsianas, Loukas, Holliday, Joanne, Shi, Jingchunzi, Shringarpure, Suyash, Voda, Alexandru-Ioan, Farrugia, Gianrico, Franke, Andre, H��benthal, Matthias, Abecasis, Gon��alo, Zawistowski, Matthew, Skogholt, Anne Heidi, Ness-Jensen, Eivind, Hveem, Kristian, Esko, T��nu, Teder-Laving, Maris, Zhernakova, Alexandra, Camilleri, Michael, Boeckxstaens, Guy, Whorwell, Peter J., Spiller, Robin, McVean, Gil, D���Amato, Mauro, Jostins, Luke, Parkes, Miles, Agee, Michelle, Aslibekyan, Stella, Auton, Adam, Bell, Robert K., Bryc, Katarzyna, Clark, Sarah K., Elson, Sarah L., Fletez-Brant, Kipper, Fontanillas, Pierre, Furlotte, Nicholas A., Gandhi, Pooja M., Heilbron, Karl, Hicks, Barry, Hinds, David A., Huber, Karen E., Jewett, Ethan M., Jiang, Yunxuan, Kleinman, Aaron, Lin, Keng-Han, Litterman, Nadia K., Luff, Marie K., McCreight, Jey C., McIntyre, Matthew H., McManus, Kimberly F., Mountain, Joanna L., Mozaffari, Sahar V., Nandakumar, Priyanka, Noblin, Elizabeth S., Northover, Carrie A. M., O���Connell, Jared, Petrakovitz, Aaron A., Pitts, Steven J., Poznik, G. David, Sathirapongsasuti, J. Fah, Shastri, Anjali J., Shelton, Janie F., Tian, Chao, Tung, Joyce Y., Tunney, Robert J., Vacic, Vladimir, Wang, Xin, Zare, Amir S., Kashyap, Purna, Chang, Lin, Mayer, Emeran, Heitkemper, Margaret, Sayuk, Gregory S., Ringel-Kulka, Tamar, Ringel, Yehuda, Chey, William D., Eswaran, Shanti, Merchant, Juanita L., Shulman, Robert J., Bujanda, Luis, Garcia-Etxebarria, Koldo, Dlugosz, Aldona, Lindberg, Greger, Schmidt, Peter T., Karling, Pontus, Ohlsson, Bodil, Walter, Susanna, Faresj��, ��shild O., Simren, Magnus, Halfvarson, Jonas, Portincasa, Piero, Barbara, Giovanni, Usai-Satta, Paolo, Neri, Matteo, Nardone, Gerardo, Cuomo, Rosario, Galeazzi, Francesca, Bellini, Massimo, Latiano, Anna, Houghton, Lesley, Jonkers, Daisy, Kurilshikov, Alexander, Weersma, Rinse K., Netea, Mihai, Tesarz, Jonas, Gauss, Annika, Goebel-Stengel, Miriam, Andresen, Viola, Frieling, Thomas, Pehl, Christian, Schaefert, Rainer, Niesler, Beate, Lieb, Wolfgang, Hanevik, Kurt, Langeland, Nina, Wensaas, Knut-Arne, Litleskare, Sverre, Gabrielsen, Maiken E., Thomas, Laurent, Thijs, Vincent, Lemmens, Robin, Van Oudenhove, Lukas, Wouters, Mira, Eijsbouts C., Zheng T., Kennedy N.A., Bonfiglio F., Anderson C.A., Moutsianas L., Holliday J., Shi J., Shringarpure S., Agee M., Aslibekyan S., Auton A., Bell R.K., Bryc K., Clark S.K., Elson S.L., Fletez-Brant K., Fontanillas P., Furlotte N.A., Gandhi P.M., Heilbron K., Hicks B., Hinds D.A., Huber K.E., Jewett E.M., Jiang Y., Kleinman A., Lin K.-H., Litterman N.K., Luff M.K., McCreight J.C., McIntyre M.H., McManus K.F., Mountain J.L., Mozaffari S.V., Nandakumar P., Noblin E.S., Northover C.A.M., O'Connell J., Petrakovitz A.A., Pitts S.J., Poznik G.D., Sathirapongsasuti J.F., Shastri A.J., Shelton J.F., Tian C., Tung J.Y., Tunney R.J., Vacic V., Wang X., Zare A.S., Voda A.-I., Kashyap P., Chang L., Mayer E., Heitkemper M., Sayuk G.S., Ringel-Kulka T., Ringel Y., Chey W.D., Eswaran S., Merchant J.L., Shulman R.J., Bujanda L., Garcia-Etxebarria K., Dlugosz A., Lindberg G., Schmidt P.T., Karling P., Ohlsson B., Walter S., Faresjo A.O., Simren M., Halfvarson J., Portincasa P., Barbara G., Usai-Satta P., Neri M., Nardone G., Cuomo R., Galeazzi F., Bellini M., Latiano A., Houghton L., Jonkers D., Kurilshikov A., Weersma R.K., Netea M., Tesarz J., Gauss A., Goebel-Stengel M., Andresen V., Frieling T., Pehl C., Schaefert R., Niesler B., Lieb W., Hanevik K., Langeland N., Wensaas K.-A., Litleskare S., Gabrielsen M.E., Thomas L., Thijs V., Lemmens R., Van Oudenhove L., Wouters M., Farrugia G., Franke A., Hubenthal M., Abecasis G., Zawistowski M., Skogholt A.H., Ness-Jensen E., Hveem K., Esko T., Teder-Laving M., Zhernakova A., Camilleri M., Boeckxstaens G., Whorwell P.J., Spiller R., McVean G., D'Amato M., Jostins L., Parkes M., Eijsbouts, Chris [0000-0001-5179-0653], Anderson, Carl A. [0000-0003-1719-7009], Moutsianas, Loukas [0000-0001-5453-345X], Holliday, Joanne [0000-0003-4568-7320], Shringarpure, Suyash [0000-0001-6464-2668], Voda, Alexandru-Ioan [0000-0003-2974-6992], Farrugia, Gianrico [0000-0003-3473-5235], Hübenthal, Matthias [0000-0002-5956-3006], Abecasis, Gonçalo [0000-0003-1509-1825], Zawistowski, Matthew [0000-0002-3005-083X], Ness-Jensen, Eivind [0000-0001-6005-0729], Teder-Laving, Maris [0000-0002-5872-1850], Camilleri, Michael [0000-0001-6472-7514], Whorwell, Peter J. [0000-0002-5220-8474], Spiller, Robin [0000-0001-6371-4500], McVean, Gil [0000-0002-5012-4162], D’Amato, Mauro [0000-0003-2743-5197], Jostins, Luke [0000-0002-2475-3969], Parkes, Miles [0000-0002-6467-0631], Apollo - University of Cambridge Repository, Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Translational Immunology Groningen (TRIGR), Eijsbouts, C., Zheng, T., Kennedy, N. A., Bonfiglio, F., Anderson, C. A., Moutsianas, L., Holliday, J., Shi, J., Shringarpure, S., Agee, M., Aslibekyan, S., Auton, A., Bell, R. K., Bryc, K., Clark, S. K., Elson, S. L., Fletez-Brant, K., Fontanillas, P., Furlotte, N. A., Gandhi, P. M., Heilbron, K., Hicks, B., Hinds, D. A., Huber, K. E., Jewett, E. M., Jiang, Y., Kleinman, A., Lin, K. -H., Litterman, N. K., Luff, M. K., Mccreight, J. C., Mcintyre, M. H., Mcmanus, K. F., Mountain, J. L., Mozaffari, S. V., Nandakumar, P., Noblin, E. S., Northover, C. A. M., O'Connell, J., Petrakovitz, A. A., Pitts, S. J., Poznik, G. D., Sathirapongsasuti, J. F., Shastri, A. J., Shelton, J. F., Tian, C., Tung, J. Y., Tunney, R. J., Vacic, V., Wang, X., Zare, A. S., Voda, A. -I., Kashyap, P., Chang, L., Mayer, E., Heitkemper, M., Sayuk, G. S., Ringel-Kulka, T., Ringel, Y., Chey, W. D., Eswaran, S., Merchant, J. L., Shulman, R. J., Bujanda, L., Garcia-Etxebarria, K., Dlugosz, A., Lindberg, G., Schmidt, P. T., Karling, P., Ohlsson, B., Walter, S., Faresjo, A. O., Simren, M., Halfvarson, J., Portincasa, P., Barbara, G., Usai-Satta, P., Neri, M., Nardone, G., Cuomo, R., Galeazzi, F., Bellini, M., Latiano, A., Houghton, L., Jonkers, D., Kurilshikov, A., Weersma, R. K., Netea, M., Tesarz, J., Gauss, A., Goebel-Stengel, M., Andresen, V., Frieling, T., Pehl, C., Schaefert, R., Niesler, B., Lieb, W., Hanevik, K., Langeland, N., Wensaas, K. -A., Litleskare, S., Gabrielsen, M. E., Thomas, L., Thijs, V., Lemmens, R., Van Oudenhove, L., Wouters, M., Farrugia, G., Franke, A., Hubenthal, M., Abecasis, G., Zawistowski, M., Skogholt, A. H., Ness-Jensen, E., Hveem, K., Esko, T., Teder-Laving, M., Zhernakova, A., Camilleri, M., Boeckxstaens, G., Whorwell, P. J., Spiller, R., Mcvean, G., D'Amato, M., Jostins, L., and Parkes, M.

Subjects
Male, Molecular Chaperone, Mood Disorder, 631/208/205/2138, Biology, 692/699/1503/1502/2071, Bioinformatics, Polymorphism, Single Nucleotide, Genetic pathways, 38/43, Irritable Bowel Syndrome, Cytoskeletal Protein, Genetics, medicine, Genetic predisposition, Aged, Anxiety Disorders, CD56 Antigen, Cell Adhesion Molecules, Cytoskeletal Proteins, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Guanine Nucleotide Exchange Factors, Homeodomain Proteins, Humans, Middle Aged, Molecular Chaperones, Mood Disorders, United Kingdom, Polymorphism, 692/699/476, Irritable bowel syndrome, Depression (differential diagnoses), article, Homeodomain Protein, Single Nucleotide, Guanine Nucleotide Exchange Factor, medicine.disease, Neuroticism, Biobank, Mood, Cell Adhesion Molecule, Anxiety, medicine.symptom, Anxiety Disorder, Human
Abstract

Funder: Kennedy Trust Rheumatology Research Prize Studentship, Funder: DFG Cluster of Excellence ���Precision Medicine in Chronic In-flammation��� (PMI; ID: EXC2167), Funder: EC | EC Seventh Framework Programm | FP7 Ideas: European Research Council (FP7-IDEAS-ERC - Specific Programme: ���Ideas��� Implementing the Seventh Framework Programme of the European Community for Research, Technological Development and Demonstration Activities (2007 to 2013)); doi: https://doi.org/10.13039/100011199; Grant(s): 715772, Funder: NWO-VIDI grant 016.178.056, the Netherlands Heart Foundation CVON grant 2018-27, and NWO Gravitation grant ExposomeNL, Funder: Li Ka Shing Foundation (Li Ka Shing Foundation Limited); doi: https://doi.org/10.13039/100007421, Irritable bowel syndrome (IBS) results from disordered brain���gut interactions. Identifying susceptibility genes could highlight the underlying pathophysiological mechanisms. We designed a digestive health questionnaire for UK Biobank and combined identified cases with IBS with independent cohorts. We conducted a genome-wide association study with 53,400 cases and 433,201 controls and replicated significant associations in a 23andMe panel (205,252 cases and 1,384,055 controls). Our study identified and confirmed six genetic susceptibility loci for IBS. Implicated genes included NCAM1, CADM2, PHF2/FAM120A, DOCK9, CKAP2/TPTE2P3 and BAG6. The first four are associated with mood and anxiety disorders, expressed in the nervous system, or both. Mirroring this, we also found strong genome-wide correlation between the risk of IBS and anxiety, neuroticism and depression (rg > 0.5). Additional analyses suggested this arises due to shared pathogenic pathways rather than, for example, anxiety causing abdominal symptoms. Implicated mechanisms require further exploration to help understand the altered brain���gut interactions underlying IBS.

Published
2021

32. Genome-wide association study of musical beat synchronization demonstrates high polygenicity

Author

Niarchou, Maria, Gustavson, Daniel E., Sathirapongsasuti, J. Fah, Anglada-Tort, Manuel, Eising, Else, Bell, Eamonn, McArthur, Evonne, Straub, Peter, Aslibekyan, Stella, Auton, Adam, Bell, Robert K., Bryc, Katarzyna, Clark, Sarah K., Elson, Sarah L., Fletez-Brant, Kipper, Fontanillas, Pierre, Furlotte, Nicholas A., Gandhi, Pooja M., Heilbron, Karl, Hicks, Barry, Huber, Karen E., Jewett, Ethan M., Jiang, Yunxuan, Kleinman, Aaron, Lin, Keng-Han, Litterman, Nadia K., McCreight, Jey C., McIntyre, Matthew H., McManus, Kimberly F., Mountain, Joanna L., Mozaffari, Sahar V., Nandakumar, Priyanka, Noblin, Elizabeth S., Northover, Carrie A. M., O’Connell, Jared, Pitts, Steven J., Poznik, G. David, Shastri, Anjali J., Shelton, Janie F., Shringarpure, Suyash, Tian, Chao, Tung, Joyce Y., Tunney, Robert J., Vacic, Vladimir, Wang, Xin, McAuley, J. Devin, Capra, John A., Ullén, Fredrik, Creanza, Nicole, Mosing, Miriam A., Hinds, David A., Davis, Lea K., Jacoby, Nori, Gordon, Reyna L., and The 23andMe Research Team

Subjects
Multifactorial Inheritance, Behavioral Neuroscience, Social Psychology, Nucleotides, Humans, Experimental and Cognitive Psychology, Polymorphism, Single Nucleotide, Music, Genome-Wide Association Study
Abstract

Moving in synchrony to the beat is a fundamental component of musicality. Here, we conducted a genome-wide association study (GWAS) to identify common genetic variants associated with beat synchronization in 606,825 individuals. Beat synchronization exhibited a highly polygenic architecture, with sixty-nine loci reaching genome-wide significance (p

Published
2022

34. Multi-Trait Genetic Analysis Identifies Autoimmune Loci Associated with Cutaneous Melanoma

Author

Liyanage, Upekha E., primary, MacGregor, Stuart, additional, Bishop, D. Timothy, additional, Shi, Jianxin, additional, An, Jiyuan, additional, Ong, Jue Sheng, additional, Han, Xikun, additional, Scolyer, Richard A., additional, Martin, Nicholas G., additional, Medland, Sarah E., additional, Byrne, Enda M., additional, Green, Adèle C., additional, Saw, Robyn P.M., additional, Thompson, John F., additional, Stretch, Jonathan, additional, Spillane, Andrew, additional, Jiang, Yunxuan, additional, Tian, Chao, additional, Gordon, Scott G., additional, Duffy, David L., additional, Olsen, Catherine M., additional, Whiteman, David C., additional, Long, Georgina V., additional, Iles, Mark M., additional, Landi, Maria Teresa, additional, Law, Matthew H., additional, Agee, Michelle, additional, Aslibekyan, Stella, additional, Auton, Adam, additional, Babalola, Elizabeth, additional, Bell, Robert K., additional, Bielenberg, Jessica, additional, Bryc, Katarzyna, additional, Bullis, Emily, additional, Cameron, Briana, additional, Coker, Daniella, additional, Cuellar Partida, Gabriel, additional, Dhamija, Devika, additional, Das, Sayantan, additional, Elson, Sarah L., additional, Filshtein, Teresa, additional, Fletez-Brant, Kipper, additional, Fontanillas, Pierre, additional, Freyman, Will, additional, Gandhi, Pooja M., additional, Heilbron, Karl, additional, Hicks, Barry, additional, Hinds, David A., additional, Huber, Karen E., additional, Jewett, Ethan M., additional, Kleinman, Aaron, additional, Kukar, Katelyn, additional, Lin, Keng-Han, additional, Lowe, Maya, additional, Luff, Marie K., additional, McCreight, Jennifer C., additional, McIntyre, Matthew H., additional, McManus, Kimberly F., additional, Micheletti, Steven J., additional, Moreno, Meghan E., additional, Mountain, Joanna L., additional, Mozaffari, Sahar V., additional, Nandakumar, Priyanka, additional, Noblin, Elizabeth S., additional, O'Connell, Jared, additional, Petrakovitz, Aaron A., additional, Poznik, G. David, additional, Shastri, Anjali J., additional, Shelton, Janie F., additional, Shi, Jingchunzi, additional, Shringarpure, Suyash, additional, Tran, Vinh, additional, Tung, Joyce Y., additional, Wang, Xin, additional, Wang, Wei, additional, Weldon, Catherine H., additional, and Wilton, Peter, additional

Published
2022
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36. Association of Essential Tremor With Novel Risk Loci

Author

Liao, Calwing, Castonguay, Charles-Etienne, Heilbron, Karl, Vuokila, Veikko, Medeiros, Miranda, Houle, Gabrielle, Akçimen, Fulya, Ross, Jay P., Catoire, Helene, Diez-Fairen, Monica, Kang, Jooeun, Mueller, Stefanie H., Girard, Simon L., Hopfner, Franziska, Lorenz, Delia, Clark, Lorraine N., Soto-Beasley, Alexandra I., Klebe, Stephan, Hallett, Mark, Wszolek, Zbigniew K., Pendziwiat, Manuela, Lorenzo-Betancor, Oswaldo, Seppi, Klaus, Berg, Daniela, Vilariño-Güell, Carles, Postuma, Ronald B., Bernard, Geneviève, Dupré, Nicolas, Jankovic, Joseph, Testa, Claudia M., Ross, Owen A., Arzberger, Thomas, Chouinard, Sylvain, Louis, Elan D., Mandich, Paola, Vitale, Carmine, Barone, Paolo, García-Martín, Elena, Alonso-Navarro, Hortensia, Agúndez, José A. G., Jiménez-Jiménez, Félix Javier, Pastor, Pau, Rajput, Alex, Deuschl, Günther, Kuhlenbaümer, Gregor, Meijer, Inge A., Dion, Patrick A., and Rouleau, Guy A.

Subjects
Research, Online First, Comments, Original Investigation
Abstract

Key Points Question Can common genetic variants associated with essential tremor (ET) be identified? Findings In this genome-wide association study and meta-analysis including genetic data on 483 054 individuals, 5 genome-wide significant loci were associated with risk of ET and common variants were associated with approximately 18% of ET heritability. Meaning Findings of this study may help identify new genes and inform ET biology., This genome-wide association study identifies common variants associated with risk of essential tremor., Importance Essential tremor (ET) is one of the most common movement disorders, affecting 5% of the general population older than 65 years. Common variants are thought to contribute toward susceptibility to ET, but no variants have been robustly identified. Objective To identify common genetic factors associated with risk of ET. Design, Setting, and Participants Case-control genome-wide association study. Inverse-variance meta-analysis was used to combine cohorts. Multicenter samples collected from European populations were collected from January 2010 to September 2019 as part of an ongoing study. Included patients were clinically diagnosed with or reported having ET. Control individuals were not diagnosed with or reported to have ET. Of 485 250 individuals, data for 483 054 passed data quality control and were used. Main Outcomes and Measures Genotypes of common variants associated with risk of ET. Results Of the 483 054 individuals included, there were 7177 with ET (3693 [51.46%] female; mean [SD] age, 62.66 [15.12] years), and 475 877 control individuals (253 785 [53.33%] female; mean [SD] age, 56.40 [17.6] years). Five independent genome-wide significant loci and were identified and were associated with approximately 18% of ET heritability. Functional analyses found significant enrichment in the cerebellar hemisphere, cerebellum, and axonogenesis pathways. Genetic correlation (r), which measures the degree of genetic overlap, revealed significant common variant overlap with Parkinson disease (r, 0.28; P = 2.38 × 10−8) and depression (r, 0.12; P = 9.78 × 10−4). A separate fine-mapping of transcriptome-wide association hits identified genes such as BACE2, LRRN2, DHRS13, and LINC00323 in disease-relevant brain regions, such as the cerebellum. Conclusions and Relevance The results of this genome-wide association study suggest that a portion of ET heritability can be explained by common genetic variation and can help identify new common genetic risk factors for ET.

Published
2022

37. Prevalence of Alpha-1 Antitrypsin Deficiency, Self-Reported Behavior Change, and Health Care Engagement Among Direct-to-Consumer Recipients of a Personalized Genetic Risk Report

Author

Ashenhurst, James R., primary, Nhan, Hoang, additional, Shelton, Janie F., additional, Wu, Shirley, additional, Tung, Joyce Y., additional, Elson, Sarah L., additional, Stoller, James K., additional, Agee, Michelle, additional, Aslibekyan, Stella, additional, Auton, Adam, additional, Babalola, Elizabeth, additional, Bell, Robert K., additional, Bielenberg, Jessica, additional, Bryc, Katarzyna, additional, Bullis, Emily, additional, Cameron, Briana, additional, Coker, Daniella, additional, Partida, Gabriel Cuellar, additional, Dhamija, Devika, additional, Das, Sayantan, additional, Filshtein, Teresa, additional, Fletez-Brant, Kipper, additional, Fontanillas, Pierre, additional, Freyman, Will, additional, Gandhi, Pooja M., additional, Heilbron, Karl, additional, Hicks, Barry, additional, Hinds, David A., additional, Huber, Karen E., additional, Jewett, Ethan M., additional, Jiang, Yunxuan, additional, Kleinman, Aaron, additional, Kukar, Katelyn, additional, Lane, Vanessa A., additional, Lin, Keng-Han, additional, Lowe, Maya, additional, Luff, Marie K., additional, McCreight, Jennifer C., additional, McIntyre, Matthew H., additional, McManus, Kimberly F., additional, Micheletti, Steven J., additional, Moreno, Meghan E., additional, Mountain, Joanna L., additional, Mozaffari, Sahar V., additional, Nandakumar, Priyanka, additional, Noblin, Elizabeth S., additional, O’Connell, Jared, additional, Petrakovitz, Aaron A., additional, Poznik, G. David, additional, Schumacher, Morgan, additional, Shastri, Anjali J., additional, Shi, Jingchunzi, additional, Shringarpure, Suyash, additional, Tian, Chao, additional, Tran, Vinh, additional, Wang, Xin, additional, Wang, Wei, additional, Weldon, Catherine H., additional, and Wilton, Peter, additional

Published
2022
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38. A new transcriptional role for matrix metalloproteinase-12 in antiviral immunity

Author

Marchant, David J., Bellac, Caroline L., Moraes, Theo J., Wadsworth, Samuel J., Dufour, Antoine, Butler, Georgina S., Bilawchuk, Leanne M., Hendry, Reid G., Robertson, A. Gordon, Cheung, Caroline T., Ng, Julie, Ang, Lisa, Luo, Zongshu, Heilbron, Karl, Norris, Michael J., Duan, Wenming, Bucyk, Taylor, Karpov, Andrei, Devel, Laurent, Georgiadis, Dimitris, Hegele, Richard G., Luo, Honglin, Granville, David J., Dive, Vincent, McManus, Bruce M., and Overall, Christopher M.

Subjects
Proteases -- Research -- Analysis -- Physiological aspects, Immunity -- Research -- Analysis, Biological sciences, Health
Abstract

Interferon-α (IFN-α) is essential for antiviral immunity, but in the absence of matrix metalloproteinase-12 (MMP-12) or IκBα (encoded by NFKBIA) we show that IFN-α is retained in the cytosol of virus-infected cells and is not secreted. Our findings suggest that activated IκBα mediates the export of IFN-α from virus-infected cells and that the inability of cells in [Mmp12.sup.-/-] but not wild-type mice to express IκBα and thus export IFN-α makes coxsackievirus type B3 infection lethal and renders respiratory syncytial virus more pathogenic. We show here that after macrophage secretion, MMP-12 is transported into virus-infected cells. In HeLa cells MMP-12 is also translocated to the nucleus, where it binds to the NFKBIA promoter, driving transcription. We also identified dual-regulated substrates that are repressed both by MMP-12 binding to the substrate's gene exons and by MMP-12-mediated cleavage of the substrate protein itself. Whereas intracellular MMP-12 mediates NFKBIA transcription, leading to IFN-α secretion and host protection, extra cellular MMP-12 cleaves off the IFN-α receptor 2 binding site of systemic IFN-α, preventing an unchecked immune response. Consistent with an unexpected role for MMP-12 in clearing systemic IFN-α, treatment of coxsackievirus type B3-infected wild-type mice with a membrane-impermeable MMP-12 inhibitor elevates systemic IFN-α levels and reduces viral replication in pancreas while sparing intracellular MMP-12. These findings suggest that inhibiting extra cellular MMP-12 could be a new avenue for the development of antiviral treatments., Interferons (1) and macrophages are important in antiviral immunity (2). MMP-12 (ref. 3; also known as macrophage metalloelastase) is a secreted protease that degrades extra cellular matrix during inflammatory tissue [...]

Published
2014
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39. Genome-wide association analysis and replication in 810,625 individuals with varicose veins.

Author

Ahmed, Waheed-Ul-Rahman, Kleeman, Sam, Ng, Michael, Wang, Wei, Auton, Adam, 23andMe Research Team, Agee, Michelle, Aslibekyan, Stella, Bell, Robert K., Bryc, Katarzyna, Clark, Sarah K., Elson, Sarah L., Fletez-Brant, Kipper, Fontanillas, Pierre, Furlotte, Nicholas A., Gandhi, Pooja M., Heilbron, Karl, Hicks, Barry, Hinds, David A., and Huber, Karen E.

Subjects
VARICOSE veins, GENOME-wide association studies, GENE targeting, DISEASE risk factors, VASCULAR smooth muscle, COMPRESSION stockings
Abstract

Varicose veins affect one-third of Western society, with a significant subset of patients developing venous ulceration, costing $14.9 billion annually in the USA. Current management consists of either compression stockings, or surgical ablation for more advanced disease. Most varicose veins patients report a positive family history, and heritability is ~17%. We describe the largest two-stage genome-wide association study of varicose veins in 401,656 individuals from UK Biobank, and replication in 408,969 individuals from 23andMe (total 135,514 cases and 675,111 controls). Forty-nine signals at 46 susceptibility loci were discovered. We map 237 genes to these loci, several of which are biologically plausible and tractable to therapeutic targeting. Pathway analysis identified enrichment in extracellular matrix biology, inflammation, (lymph)angiogenesis, vascular smooth muscle cell migration, and apoptosis. Using a polygenic risk score (PRS) derived in an independent cohort, we demonstrate its predictive utility and correlation with varicose veins surgery. Although varicose veins are a common condition, the genetic basis is not well understood. Here, the authors find genetic variants associated with varicose veins and show that a higher polygenic risk score for varicose veins correlates with a greater likelihood of patients undergoing surgical treatment. [ABSTRACT FROM AUTHOR]

Published
2022
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41. Avoiding dynastic, assortative mating, and population stratification biases in Mendelian randomization through within-family analyses

Author

Heilbron, Karl, Howe, Laura D., Hughes, Amanda, Boomsma, Dorret I., Hopper, John, Pedersen, Nancy L., Reynolds, Chandra A., Tucker-Drob, Elliot M., Howe, Laurence, Li, Shuai, Auton, Adam, Windmeijer, Frank, Chen, Wei-Min, Bjørngaard, Johan Håkon, Hveem, Kristian, Davey Smith, George, Åsvold, Bjørn Olav, Brumpton, Ben, Sanderson, Eleanor, Hartwig, Fernando Pires, Harrison, Sean, Vie, Gunnhild Åberge, Cho, Yoonsu, Havdahl, Alexandra, Neale, Michael, Nivard, Michel G., Grotzinger, Andrew, Morris, Tim, Willer, Cristen, Evans, David M., Kaprio, Jaakko, Smith, George Davey, Hemani, Gibran, Davies, Neil M., Brumpton, Ben [0000-0002-3058-1059], Sanderson, Eleanor [0000-0001-5188-5775], Hartwig, Fernando Pires [0000-0003-3729-0710], Harrison, Sean [0000-0002-7966-0700], Vie, Gunnhild Åberge [0000-0003-1552-5291], Cho, Yoonsu [0000-0001-6118-6652], Havdahl, Alexandra [0000-0002-9268-0423], Neale, Michael [0000-0003-4887-659X], Nivard, Michel G. [0000-0003-2015-1888], Grotzinger, Andrew [0000-0001-7852-9244], Morris, Tim [0000-0001-8178-6815], Willer, Cristen [0000-0001-5645-4966], Evans, David M. [0000-0003-0663-4621], Kaprio, Jaakko [0000-0002-3716-2455], Davey Smith, George [0000-0002-1407-8314], Hemani, Gibran [0000-0003-0920-1055], Davies, Neil M. [0000-0002-2460-0508], and Apollo - University of Cambridge Repository

Subjects
631/208, 692/308, 692/308/2056, 45/43, article, 692/308/174, 692/499
Abstract

Estimates from Mendelian randomization studies of unrelated individuals can be biased due to uncontrolled confounding from familial effects. Here we describe methods for within-family Mendelian randomization analyses and use simulation studies to show that family-based analyses can reduce such biases. We illustrate empirically how familial effects can affect estimates using data from 61,008 siblings from the Nord-Trøndelag Health Study and UK Biobank and replicated our findings using 222,368 siblings from 23andMe. Both Mendelian randomization estimates using unrelated individuals and within family methods reproduced established effects of lower BMI reducing risk of diabetes and high blood pressure. However, while Mendelian randomization estimates from samples of unrelated individuals suggested that taller height and lower BMI increase educational attainment, these effects were strongly attenuated in within-family Mendelian randomization analyses. Our findings indicate the necessity of controlling for population structure and familial effects in Mendelian randomization studies.

Published
2020

42. SMPD1 variants do not have a major role in REM sleep behavior disorder

Author

Rudakou, Uladzislau, Futhey, Naomi C., Krohn, Lynne M., Ruskey, Jennifer A., Heilbron, Karl, Cannon, Paul, Alam, Armaghan, Arnulf, Isabelle, Hu, Michele T.M., Montplaisir, Jacques Y., Gagnon, Jean-François, Desautels, Alex, Dauvilliers, Yves, Toffoli, Marco, Gigli, Gian Luigi, Valente, Mariarosaria, Högl, Birgit, Stefani, Ambra, Holzknecht, Evi, Sonka, Karel, Kemlink, David, Oertel, Wolfgang, Janzen, Annette, Plazzi, Giuseppe, Antelmi, Elena, Figorilli, Michela, Puligheddu, Monica, Mollenhauer, Brit, Trenkwalder, Claudia, Sixel-Döring, Friederike, Cochen De Cock, Valérie, Monaca, Christelle Charley, Heidbreder, Anna, Ferini-Strambi, Luigi, Dijkstre, Femke, Viaene, Mineke, Beatriz, Abril, Boeve, Bradley F., Postuma, Ronald B., Rouleau, Guy, and Gan-Or, Ziv

Abstract

Mutations in the sphingomyelin phosphodiesterase 1 (SMPD1) gene were reported to be associated with Parkinson disease (PD) and dementia with Lewy bodies (DLB). The majority of patients with isolated rapid eye movement sleep behavior disorder (iRBD) develop PD or DLB later in life, suggesting that iRBD is a prodromal phase of these two conditions. In the current study we aimed to evaluate the role of SMPD1 variants in iRBD. SMPD1 and its untranslated regions were sequenced using targeted next-generation sequencing in 959 iRBD patients and 1,287 controls from European descent. Logistic regression adjusted for sex and age showed no significant associations with two common variants and iRBD (rs1050239 and rs8164). The frequency of all rare nonsynonymous SMPD1 variants (minor allele frequency p=0.09) but there was no statistically significant burden (p=0.64). Our study reports no statistically significant association of SMPD1 variants and iRBD. It is hence unlikely that SMPD1 plays a major role in iRBD.

Published
2020

43. Genome-wide Study Identifies Association between HLA-B∗55:01 and Self-Reported Penicillin Allergy

Author

Krebs, Kristi, primary, Bovijn, Jonas, additional, Zheng, Neil, additional, Lepamets, Maarja, additional, Censin, Jenny C., additional, Jürgenson, Tuuli, additional, Särg, Dage, additional, Abner, Erik, additional, Laisk, Triin, additional, Luo, Yang, additional, Skotte, Line, additional, Geller, Frank, additional, Feenstra, Bjarke, additional, Wang, Wei, additional, Auton, Adam, additional, Raychaudhuri, Soumya, additional, Esko, Tõnu, additional, Metspalu, Andres, additional, Laur, Sven, additional, Roden, Dan M., additional, Wei, Wei-Qi, additional, Holmes, Michael V., additional, Lindgren, Cecilia M., additional, Phillips, Elizabeth J., additional, Mägi, Reedik, additional, Milani, Lili, additional, Fadista, João, additional, Agee, Michelle, additional, Aslibekyan, Stella, additional, Bell, Robert K., additional, Bryc, Katarzyna, additional, Clark, Sarah K., additional, Elson, Sarah L., additional, Fletez-Brant, Kipper, additional, Fontanillas, Pierre, additional, Furlotte, Nicholas A., additional, Gandhi, Pooja M., additional, Heilbron, Karl, additional, Hicks, Barry, additional, Hinds, David A., additional, Huber, Karen E., additional, Jewett, Ethan M., additional, Jiang, Yunxuan, additional, Kleinman, Aaron, additional, Lin, Keng-Han, additional, Litterman, Nadia K., additional, Luff, Marie K., additional, McCreight, Jennifer C., additional, McIntyre, Matthew H., additional, McManus, Kimberly F., additional, Mountain, Joanna L., additional, Mozaffari, Sahar V., additional, Nandakumar, Priyanka, additional, Noblin, Elizabeth S., additional, Northover, Carrie A.M., additional, O’Connell, Jared, additional, Petrakovitz, Aaron A., additional, Pitts, Steven J., additional, Poznik, G. David, additional, Sathirapongsasuti, J. Fah, additional, Shastri, Anjali J., additional, Shelton, Janie F., additional, Shringarpure, Suyash, additional, Tian, Chao, additional, Tung, Joyce Y., additional, Tunney, Robert J., additional, Vacic, Vladimir, additional, Wang, Xin, additional, and Zare, Amir S., additional

Published
2020
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44. Parkinson’s disease determinants, prediction and gene–environment interactions in the UK Biobank

Author

Jacobs, Benjamin Meir, primary, Belete, Daniel, additional, Bestwick, Jonathan, additional, Blauwendraat, Cornelis, additional, Bandres-Ciga, Sara, additional, Heilbron, Karl, additional, Dobson, Ruth, additional, Nalls, Mike A, additional, Singleton, Andrew, additional, Hardy, John, additional, Giovannoni, Gavin, additional, Lees, Andrew John, additional, Schrag, Anette-Eleonore, additional, and Noyce, Alastair J, additional

Published
2020
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45. SMPD1 variants do not have a major role in rapid eye movement sleep behavior disorder

Author

Rudakou, Uladzislau, primary, Futhey, Naomi C., additional, Krohn, Lynne, additional, Ruskey, Jennifer A., additional, Heilbron, Karl, additional, Cannon, Paul, additional, Alam, Armaghan, additional, Arnulf, Isabelle, additional, Hu, Michele T.M., additional, Montplaisir, Jacques Y., additional, Gagnon, Jean-François, additional, Desautels, Alex, additional, Dauvilliers, Yves, additional, Toffoli, Marco, additional, Gigli, Gian Luigi, additional, Valente, Mariarosaria, additional, Högl, Birgit, additional, Stefani, Ambra, additional, Holzknecht, Evi, additional, Sonka, Karel, additional, Kemlink, David, additional, Oertel, Wolfang, additional, Janzen, Annette, additional, Plazzi, Giuseppe, additional, Antelmi, Elena, additional, Figorilli, Michela, additional, Puligheddu, Monica, additional, Mollenhauer, Brit, additional, Trenkwalder, Claudia, additional, Sixel-Döring, Friederike, additional, De Cock, Valérie Cochen, additional, Monaca, Christelle Charley, additional, Heidbreder, Anna, additional, Ferini-Strambi, Luigi, additional, Dijkstra, Femke, additional, Viaene, Mineke, additional, Abril, Beatriz, additional, Boeve, Bradley F., additional, Postuma, Ronald B., additional, Rouleau, Guy A., additional, and Gan-Or, Ziv, additional

Published
2020
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46. Unhealthy Behaviours and Risk of Parkinson's Disease: A Mendelian Randomisation Study.

Author

Heilbron, Karl, Jensen, Melanie P., Bandres-Ciga, Sara, Fontanillas, Pierre, Blauwendraat, Cornelis, Nalls, Mike A., Singleton, Andrew B., Smith, George Davey, Cannon, Paul, and Noyce, Alastair J.

Subjects
*PARKINSON'S disease, *GENOME-wide association studies, *SMOKING statistics, *GENETIC variation, *SINGLE nucleotide polymorphisms, *SMOKING
Abstract

Background: Tobacco smoking and alcohol intake have been identified in observational studies as potentially protective factors against developing Parkinson's disease (PD); the impact of body mass index (BMI) on PD risk is debated. Whether such epidemiological associations are causal remains unclear. Mendelian randomsation (MR) uses genetic variants to explore the effects of exposures on outcomes; potentially reducing bias from residual confounding and reverse causation. Objective: Using MR, we examined relationships between PD risk and three unhealthy behaviours: tobacco smoking, alcohol intake, and higher BMI. Methods: 19,924 PD cases and 2,413,087 controls were included in the analysis. We performed genome-wide association studies to identify single nucleotide polymorphisms associated with tobacco smoking, alcohol intake, and BMI. MR analysis of the relationship between each exposure and PD was undertaken using a split-sample design. Results: Ever-smoking reduced the risk of PD (OR 0.955; 95%confidence interval [CI] 0.921–0.991; p = 0.013). Higher daily alcohol intake increased the risk of PD (OR 1.125, 95%CI 1.025–1.235; p = 0.013) and a 1 kg/m2 higher BMI reduced the risk of PD (OR 0.988, 95%CI 0.979–0.997; p = 0.008). Sensitivity analyses did not suggest bias from horizontal pleiotropy or invalid instruments. Conclusion: Using split-sample MR in over 2.4 million participants, we observed a protective effect of smoking on risk of PD. In contrast to observational data, alcohol consumption appeared to increase the risk of PD. Higher BMI had a protective effect on PD, but the effect was small. [ABSTRACT FROM AUTHOR]

Published
2021
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47. Characterizing the Genetic Architecture of Parkinson's Disease in Latinos.

Author

Loesch, Douglas P., Horimoto, Andrea R. V. R., Heilbron, Karl, Sarihan, Elif I., Inca‐Martinez, Miguel, Mason, Emily, Cornejo‐Olivas, Mario, Torres, Luis, Mazzetti, Pilar, Cosentino, Carlos, Sarapura‐Castro, Elison, Rivera‐Valdivia, Andrea, Medina, Angel C., Dieguez, Elena, Raggio, Victor, Lescano, Andres, Tumas, Vitor, Borges, Vanderci, Ferraz, Henrique B., and Rieder, Carlos R.

Subjects
PARKINSON'S disease, GENOME-wide association studies, NATIVE Americans, CHROMOSOMES
Abstract

Objective: This work was undertaken in order to identify Parkinson's disease (PD) risk variants in a Latino cohort, to describe the overlap in the genetic architecture of PD in Latinos compared to European‐ancestry subjects, and to increase the diversity in PD genome‐wide association (GWAS) data. Methods: We genotyped and imputed 1,497 PD cases and controls recruited from nine clinical sites across South America. We performed a GWAS using logistic mixed models; variants with a p‐value <1 × 10−5 were tested in a replication cohort of 1,234 self‐reported Latino PD cases and 439,522 Latino controls from 23andMe, Inc. We also performed an admixture mapping analysis where local ancestry blocks were tested for association with PD status. Results: One locus, SNCA, achieved genome‐wide significance (p‐value <5 × 10−8); rs356182 achieved genome‐wide significance in both the discovery and the replication cohorts (discovery, G allele: 1.58 OR, 95% CI 1.35–1.86, p‐value 2.48 × 10−8; 23andMe, G allele: 1.26 OR, 95% CI 1.16–1.37, p‐value 4.55 × 10−8). In our admixture mapping analysis, a locus on chromosome 14, containing the gene STXBP6, achieved significance in a joint test of ancestries and in the Native American single‐ancestry test (p‐value <5 × 10−5). A second locus on chromosome 6, containing the gene RPS6KA2, achieved significance in the African single‐ancestry test (p‐value <5 × 10−5). Interpretation: This study demonstrated the importance of the SNCA locus for the etiology of PD in Latinos. By leveraging the demographic history of our cohort via admixture mapping, we identified two potential PD risk loci that merit further study. ANN NEUROL 2021;90:353–365 [ABSTRACT FROM AUTHOR]

Published
2021
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48. Evaluating Lipid‐Lowering Drug Targets for Parkinson's Disease Prevention with Mendelian Randomization.

Author

Williams, Dylan M., Bandres‐Ciga, Sara, Heilbron, Karl, Hinds, David, and Noyce, Alastair J.

Subjects
PARKINSON'S disease, ANTILIPEMIC agents, DRUG target, PREVENTIVE medicine, ETIOLOGY of diseases
Abstract

Long‐term exposure to lipid‐lowering drugs might affect Parkinson's disease (PD) risk. We conducted Mendelian randomization analyses where genetic variants indexed expected effects of modulating lipid‐lowering drug targets on PD. Statin exposure was not predicted to increase PD risk, although results were not precise enough to support benefits for prevention clearly (odds ratio [OR] = 0.83; 95% confidence interval [CI] = 0.65, 1.07). Other target results were null, except for variants indicating Apolipoprotein‐A5 or Apolipoprotein‐C3 inhibition might confer protection. These findings suggest peripheral lipid variation may not have a prominent role in PD etiology, but some related drug targets could influence PD via alternate pathways. ANN NEUROL 2020;88:1043–1047 [ABSTRACT FROM AUTHOR]

Published
2020
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49. Avoiding dynastic, assortative mating, and population stratification biases in Mendelian randomization through within-family analyses.

Author

Brumpton, Ben, Sanderson, Eleanor, Heilbron, Karl, Hartwig, Fernando Pires, Harrison, Sean, Vie, Gunnhild Åberge, Cho, Yoonsu, Howe, Laura D., Hughes, Amanda, Boomsma, Dorret I., Havdahl, Alexandra, Hopper, John, Neale, Michael, Nivard, Michel G., Pedersen, Nancy L., Reynolds, Chandra A., Tucker-Drob, Elliot M., Grotzinger, Andrew, Howe, Laurence, and Morris, Tim

Subjects
ASSORTATIVE mating, RANDOMIZATION (Statistics), HYPERTENSION, EDUCATIONAL attainment
Abstract

Estimates from Mendelian randomization studies of unrelated individuals can be biased due to uncontrolled confounding from familial effects. Here we describe methods for within-family Mendelian randomization analyses and use simulation studies to show that family-based analyses can reduce such biases. We illustrate empirically how familial effects can affect estimates using data from 61,008 siblings from the Nord-Trøndelag Health Study and UK Biobank and replicated our findings using 222,368 siblings from 23andMe. Both Mendelian randomization estimates using unrelated individuals and within family methods reproduced established effects of lower BMI reducing risk of diabetes and high blood pressure. However, while Mendelian randomization estimates from samples of unrelated individuals suggested that taller height and lower BMI increase educational attainment, these effects were strongly attenuated in within-family Mendelian randomization analyses. Our findings indicate the necessity of controlling for population structure and familial effects in Mendelian randomization studies. Family-based study designs have been applied to resolve confounding by population stratification, dynastic effects and assortative mating in genetic association analyses. Here, Brumpton et al. describe theory and simulations for overcoming such biases in Mendelian randomization through within-family studies. [ABSTRACT FROM AUTHOR]

Published
2020
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50. Fine-Mapping of SNCA in Rapid Eye Movement Sleep Behavior Disorder and Overt Synucleinopathies.

Author

Krohn, Lynne, Wu, Richard Y. J., Heilbron, Karl, Ruskey, Jennifer A., Laurent, Sandra B., Blauwendraat, Cornelis, Alam, Armaghan, Arnulf, Isabelle, Hu, Michele T. M., Dauvilliers, Yves, Högl, Birgit, Toft, Mathias, Bjørnarå, Kari Anne, Stefani, Ambra, Holzknecht, Evi, Monaca, Christelle Charley, Abril, Beatriz, Plazzi, Giuseppe, Antelmi, Elena, and Ferini‐Strambi, Luigi

Subjects
RAPID eye movement sleep, BEHAVIOR disorders, SLEEP disorders, LEWY body dementia, BONFERRONI correction
Abstract

Objective: Rapid eye movement sleep behavior disorder (RBD) is a prodromal synucleinopathy, as >80% will eventually convert to overt synucleinopathy. We performed an in-depth analysis of the SNCA locus to identify RBD-specific risk variants.Methods: Full sequencing and genotyping of SNCA was performed in isolated/idiopathic RBD (iRBD, n = 1,076), Parkinson disease (PD, n = 1,013), dementia with Lewy bodies (DLB, n = 415), and control subjects (n = 6,155). The iRBD cases were diagnosed with RBD prior to neurodegeneration, although some have since converted. A replication cohort from 23andMe of PD patients with probable RBD (pRBD) was also analyzed (n = 1,782 cases; n = 131,250 controls). Adjusted logistic regression models and meta-analyses were performed. Effects on conversion rate were analyzed in 432 RBD patients with available data using Kaplan-Meier survival analysis.Results: A 5'-region SNCA variant (rs10005233) was associated with iRBD (odds ratio [OR] = 1.43, p = 1.1E-08), which was replicated in pRBD. This variant is in linkage disequilibrium (LD) with other 5' risk variants across the different synucleinopathies. An independent iRBD-specific suggestive association (rs11732740) was detected at the 3' of SNCA (OR = 1.32, p = 4.7E-04, not statistically significant after Bonferroni correction). Homozygous carriers of both iRBD-specific SNPs were at highly increased risk for iRBD (OR = 5.74, p = 2E-06). The known top PD-associated variant (3' variant rs356182) had an opposite direction of effect in iRBD compared to PD.Interpretation: There is a distinct pattern of association at the SNCA locus in RBD as compared to PD, with an opposite direction of effect at the 3' of SNCA. Several 5' SNCA variants are associated with iRBD and with pRBD in overt synucleinopathies. ANN NEUROL 2020;87:584-598. [ABSTRACT FROM AUTHOR]

Published
2020
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