Browsing by Author "Dalgard, Clifton L."

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    A locus at 19q13.31 significantly reduces the ApoE ε4 risk for Alzheimer's Disease in African Ancestry
    (Public Library of Science, 2022-07-05) Rajabli, Farid; Beecham, Gary W.; Hendrie, Hugh C.; Baiyewu, Olusegun; Ogunniyi, Adesola; Gao, Sujuan; Kushch, Nicholas A.; Lipkin-Vasquez, Marina; Hamilton-Nelson, Kara L.; Young, Juan I.; Dykxhoorn, Derek M.; Nuytemans, Karen; Kunkle, Brian W.; Wang, Liyong; Jin, Fulai; Liu, Xiaoxiao; Feliciano-Astacio, Briseida E.; Alzheimer’s Disease Sequencing Project; Alzheimer’s Disease Genetic Consortium; Schellenberg, Gerard D.; Dalgard, Clifton L.; Griswold, Anthony J.; Byrd, Goldie S.; Reitz, Christiane; Cuccaro, Michael L.; Haines, Jonathan L.; Pericak-Vance, Margaret A.; Vance, Jeffery M.; Psychiatry, School of Medicine
    African descent populations have a lower Alzheimer disease risk from ApoE ε4 compared to other populations. Ancestry analysis showed that the difference in risk between African and European populations lies in the ancestral genomic background surrounding the ApoE locus (local ancestry). Identifying the mechanism(s) of this protection could lead to greater insight into the etiology of Alzheimer disease and more personalized therapeutic intervention. Our objective is to follow up the local ancestry finding and identify the genetic variants that drive this risk difference and result in a lower risk for developing Alzheimer disease in African ancestry populations. We performed association analyses using a logistic regression model with the ApoE ε4 allele as an interaction term and adjusted for genome-wide ancestry, age, and sex. Discovery analysis included imputed SNP data of 1,850 Alzheimer disease and 4,331 cognitively intact African American individuals. We performed replication analyses on 63 whole genome sequenced Alzheimer disease and 648 cognitively intact Ibadan individuals. Additionally, we reproduced results using whole-genome sequencing of 273 Alzheimer disease and 275 cognitively intact admixed Puerto Rican individuals. A further comparison was done with SNP imputation from an additional 8,463 Alzheimer disease and 11,365 cognitively intact non-Hispanic White individuals. We identified a significant interaction between the ApoE ε4 allele and the SNP rs10423769_A allele, (β = -0.54,SE = 0.12,p-value = 7.50x10-6) in the discovery data set, and replicated this finding in Ibadan (β = -1.32,SE = 0.52,p-value = 1.15x10-2) and Puerto Rican (β = -1.27,SE = 0.64,p-value = 4.91x10-2) individuals. The non-Hispanic Whites analyses showed an interaction trending in the "protective" direction but failing to pass a 0.05 significance threshold (β = -1.51,SE = 0.84,p-value = 7.26x10-2). The presence of the rs10423769_A allele reduces the odds ratio for Alzheimer disease risk from 7.2 for ApoE ε4/ε4 carriers lacking the A allele to 2.1 for ApoE ε4/ε4 carriers with at least one A allele. This locus is located approximately 2 mB upstream of the ApoE locus, in a large cluster of pregnancy specific beta-1 glycoproteins on chromosome 19 and lies within a long noncoding RNA, ENSG00000282943. This study identified a new African-ancestry specific locus that reduces the risk effect of ApoE ε4 for developing Alzheimer disease. The mechanism of the interaction with ApoEε4 is not known but suggests a novel mechanism for reducing the risk for ε4 carriers opening the possibility for potential ancestry-specific therapeutic intervention.
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    Beyond GWAS: Investigating Structural Variants and Their Segregation in Familial Alzheimer’s Disease
    (Wiley, 2025-01-09) Gunasekaran, Tamil Iniyan; Reyes-Dumeyer, Dolly; Corvelo, André; Clarke, Wayne E.; Evani, Uday S.; Byrska-Bishop, Marta S.; Basile, Anna O.; Runnels, Alexi; Musunuri, Rajeeva O.; Narzisi, Giuseppe; Faber, Kelley M.; Goate, Alison M.; Boeve, Brad F.; Cruchaga, Carlos; Pericak-Vance, Margaret A.; Haines, Jonathan L.; Rosenberg, Roger N.; Tsuang, Debby W.; Rivera Mejia, Diones; Medrano, Martin; Lantigua, Rafael A.; Sweet, Robert; Bennett, David A.; Wilson, Robert S.; Foroud, Tatiana M.; Dalgard, Clifton L.; Mayeux, Richard; Zody, Michael; Vardarajan, Badri N.; Medical and Molecular Genetics, School of Medicine
    Background: Late‐Onset Alzheimer’s Disease (LOAD) is characterized by genetic heterogeneity and there is no single model explaining the genetic mode of inheritance. To date, more than 70 genetic loci associated with AD have been identified but they explain only a small proportion of AD heritability. Structural variants (SVs) may explain some of the missing AD heritability, and specifically, their segregation in AD families has yet to be investigated. Method: We analyzed WGS data from 197 NHW families (926 subjects, 58.5% affected) and 214 CH families (1,340 subjects, 59.17% affected). Manta, Absinthe, and MELT were used for large insertions/deletions calling from short‐read WGS, combined with Sniffles2 calls from 4 ONT‐sequenced genomes and an external SV call set from HGSVC on 32 PacBio‐sequenced genomes from the 1000 Genomes Project. Genotyping produced a unified project‐level VCF. We identified 45,251 insertions and 76,566 deletions genome‐wide. Variants were tested for segregation and pathogenicity using Annot‐SV, cadd‐SV, and Variant Effect Predictor. Segregation required SV presence in all affected family members and only in unaffected members five years younger than average disease onset. Result: We identified 453 insertions and 598 deletions segregating in 78.68% and 87.31% of NHW families, respectively. In CH families, 432 insertions and 460 deletions were segregating in 75.23% and 72.90% of the families, respectively. Genes overlapping with the SVs exhibited high expression levels in brain tissues. Notably, around 93% of insertions and 76% of deletions segregating in NHW and CH families were less than 1 kilobase pair (1kbp) in length. A total of 79 insertions and 96 deletions were found to be segregating in both NHW and CH families. Interestingly, a segregating insertion was observed in CH families overlapping within the CACNA2D3 gene, which was previously reported in a CH GWAS for clinical AD. A deletion segregating in NHW overlapped with the PSEN1, and another in a CH family overlapped with the PTK2B gene. Conclusion: Our findings suggested that there are several SVs associated with familial AD across CH and NHW families. Prioritizing the SVs based on their effects on gene function and expression will be helpful in understanding their contributions in AD.
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    Deciphering distinct genetic risk factors for FTLD-TDP pathological subtypes via whole-genome sequencing
    (Springer Nature, 2025-04-25) Pottier, Cyril; Küçükali, Fahri; Baker, Matt; Batzler, Anthony; Jenkins, Gregory D.; van Blitterswijk, Marka; Vicente, Cristina T.; De Coster, Wouter; Wynants, Sarah; Van de Walle, Pieter; Ross, Owen A.; Murray, Melissa E.; Faura, Júlia; Haggarty, Stephen J.; van Rooij, Jeroen G. J.; Mol, Merel O.; Hsiung, Ging-Yuek R.; Graff, Caroline; Öijerstedt, Linn; Neumann, Manuela; Asmann, Yan; McDonnell, Shannon K.; Baheti, Saurabh; Josephs, Keith A.; Whitwell, Jennifer L.; Bieniek, Kevin F.; Forsberg, Leah; Heuer, Hilary; Lago, Argentina Lario; Geier, Ethan G.; Yokoyama, Jennifer S.; Oddi, Alexis P.; Flanagan, Margaret; Mao, Qinwen; Hodges, John R.; Kwok, John B.; Domoto-Reilly, Kimiko; Synofzik, Matthis; Wilke, Carlo; Onyike, Chiadi; Dickerson, Bradford C.; Evers, Bret M.; Dugger, Brittany N.; Munoz, David G.; Keith, Julia; Zinman, Lorne; Rogaeva, Ekaterina; Suh, EunRan; Gefen, Tamar; Geula, Changiz; Weintraub, Sandra; Diehl-Schmid, Janine; Farlow, Martin R.; Edbauer, Dieter; Woodruff, Bryan K.; Caselli, Richard J.; Donker Kaat, Laura L.; Huey, Edward D.; Reiman, Eric M.; Mead, Simon; King, Andrew; Roeber, Sigrun; Nana, Alissa L.; Ertekin-Taner, Nilufer; Knopman, David S.; Petersen, Ronald C.; Petrucelli, Leonard; Uitti, Ryan J.; Wszolek, Zbigniew K.; Ramos, Eliana Marisa; Grinberg, Lea T.; Gorno Tempini, Maria Luisa; Rosen, Howard J.; Spina, Salvatore; Piguet, Olivier; Grossman, Murray; Trojanowski, John Q.; Keene, C. Dirk; Jin, Lee-Way; Prudlo, Johannes; Geschwind, Daniel H.; Rissman, Robert A.; Cruchaga, Carlos; Ghetti, Bernardino; Halliday, Glenda M.; Beach, Thomas G.; Serrano, Geidy E.; Arzberger, Thomas; Herms, Jochen; Boxer, Adam L.; Honig, Lawrence S.; Vonsattel, Jean P.; Lopez, Oscar L.; Kofler, Julia; White, Charles L., III; Gearing, Marla; Glass, Jonathan; Rohrer, Jonathan D.; Irwin, David J.; Lee, Edward B.; Van Deerlin, Vivianna; Castellani, Rudolph; Mesulam, Marsel M.; Tartaglia, Maria C.; Finger, Elizabeth C.; Troakes, Claire; Al-Sarraj, Safa; Dalgard, Clifton L.; Miller, Bruce L.; Seelaar, Harro; Graff-Radford, Neill R.; Boeve, Bradley F.; Mackenzie, Ian Ra; van Swieten, John C.; Seeley, William W.; Sleegers, Kristel; Dickson, Dennis W.; Biernacka, Joanna M.; Rademakers, Rosa; Neurology, School of Medicine
    Frontotemporal lobar degeneration with neuronal inclusions of the TAR DNA-binding protein 43 (FTLD-TDP) is a fatal neurodegenerative disorder with only a limited number of risk loci identified. We report our comprehensive genome-wide association study as part of the International FTLD-TDP Whole-Genome Sequencing Consortium, including 985 patients and 3,153 controls compiled from 26 institutions/brain banks in North America, Europe and Australia, and meta-analysis with the Dementia-seq cohort. We confirm UNC13A as the strongest overall FTLD-TDP risk factor and identify TNIP1 as a novel FTLD-TDP risk factor. In subgroup analyzes, we further identify genome-wide significant loci specific to each of the three main FTLD-TDP pathological subtypes (A, B and C), as well as enrichment of risk loci in distinct tissues, brain regions, and neuronal subtypes, suggesting distinct disease aetiologies in each of the subtypes. Rare variant analysis confirmed TBK1 and identified C3AR1, SMG8, VIPR1, RBPJL, L3MBTL1 and ANO9, as novel subtype-specific FTLD-TDP risk genes, further highlighting the role of innate and adaptive immunity and notch signaling pathway in FTLD-TDP, with potential diagnostic and novel therapeutic implications.
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    Genetically programmed alternative splicing of NEMO mediates an autoinflammatory disease phenotype
    (The American Society for Clinical Investigation, 2022) Lee, Younglang; Wessel, Alex W.; Xu, Jiazhi; Reinke, Julia G.; Lee, Eries; Kim, Somin M.; Hsu, Amy P.; Zilberman-Rudenko, Jevgenia; Cao, Sha; Enos, Clinton; Brooks, Stephen R.; Deng, Zuoming; Lin, Bin; de Jesus, Adriana A.; Hupalo, Daniel N.; Piotto, Daniela G.P.; Terreri, Maria T.; Dimitriades, Victoria R.; Dalgard, Clifton L.; Holland, Steven M.; Goldbach-Mansky, Raphaela; Siegel, Richard M.; Hanson, Eric P.; Pediatrics, School of Medicine
    Host defense and inflammation are regulated by the NF-κB essential modulator (NEMO), a scaffolding protein with a broad immune cell and tissue expression profile. Hypomorphic mutations in inhibitor of NF-κB kinase regulatory subunit gamma (IKBKG) encoding NEMO typically present with immunodeficiency. Here, we characterized a pediatric autoinflammatory syndrome in 3 unrelated male patients with distinct X-linked IKBKG germline mutations that led to overexpression of a NEMO protein isoform lacking the domain encoded by exon 5 (NEMO-Δex5). This isoform failed to associate with TANK binding kinase 1 (TBK1), and dermal fibroblasts from affected patients activated NF-κB in response to TNF but not TLR3 or RIG-I-like receptor (RLR) stimulation when isoform levels were high. By contrast, T cells, monocytes, and macrophages that expressed NEMO-Δex5 exhibited increased NF-κB activation and IFN production, and blood cells from these patients expressed a strong IFN and NF-κB transcriptional signature. Immune cells and TNF-stimulated dermal fibroblasts upregulated the inducible IKK protein (IKKi) that was stabilized by NEMO-Δex5, promoting type I IFN induction and antiviral responses. These data revealed how IKBKG mutations that lead to alternative splicing of skipping exon 5 cause a clinical phenotype we have named NEMO deleted exon 5 autoinflammatory syndrome (NDAS), distinct from the immune deficiency syndrome resulting from loss-of-function IKBKG mutations.
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    Genome sequencing analysis identifies new loci associated with Lewy body dementia and provides insights into its genetic architecture
    (Springer Nature, 2021-03) Chia, Ruth; Sabir, Marya S.; Bandres-Ciga, Sara; Saez-Atienzar, Sara; Reynolds, Regina H.; Gustavsson, Emil; Walton, Ronald L.; Ahmed, Sarah; Viollet, Coralie; Ding, Jinhui; Makarious, Mary B.; Diez-Fairen, Monica; Portley, Makayla K.; Shah, Zalak; Abramzon, Yevgeniya; Hernandez, Dena G.; Blauwendraat, Cornelis; Stone, David J.; Eicher, John; Parkkinen, Laura; Ansorge, Olaf; Clark, Lorraine; Honig, Lawrence S.; Marder, Karen; Lemstra, Afina; St. George-Hyslop, Peter; Londos, Elisabet; Morgan, Kevin; Lashley, Tammaryn; Warner, Thomas T.; Jaunmuktane, Zane; Galasko, Douglas; Santana, Isabel; Tienari, Pentti J.; Myllykangas, Liisa; Oinas, Minna; Cairns, Nigel J.; Morris, John C.; Halliday, Glenda M.; Van Deerlin, Vivianna M.; Trojanowski, John Q.; Grassano, Maurizio; Calvo, Andrea; Mora, Gabriele; Canosa, Antonio; Floris, Gianluca; Bohannan, Ryan C.; Brett, Francesca; Gan-Or, Ziv; Geiger, Joshua T.; Moore, Anni; May, Patrick; Krüger, Rejko; Goldstein, David S.; Lopez, Grisel; Tayebi, Nahid; Sidransky, Ellen; Norcliffe-Kaufmann, Lucy; Palma, Jose-Alberto; Kaufmann, Horacio; Shakkottai, Vikram G.; Perkins, Matthew; Newell, Kathy L.; Gasser, Thomas; Schulte, Claudia; Landi, Francesco; Salvi, Erika; Cusi, Daniele; Masliah, Eliezer; Kim, Ronald C.; Caraway, Chad A.; Monuki, Edwin S.; Brunetti, Maura; Dawson, Ted M.; Rosenthal, Liana S.; Albert, Marilyn S.; Pletnikova, Olga; Troncoso, Juan C.; Flanagan, Margaret E.; Mao, Qinwen; Bigio, Eileen H.; Rodríguez-Rodríguez, Eloy; Infante, Jon; Lage, Carmen; González-Aramburu, Isabel; Sanchez-Juan, Pascual; Ghetti, Bernardino; Keith, Julia; Black, Sandra E.; Masellis, Mario; Rogaeva, Ekaterina; Duyckaerts, Charles; Brice, Alexis; Lesage, Suzanne; Xiromerisiou, Georgia; Barrett, Matthew J.; Tilley, Bension S.; Gentleman, Steve; Logroscino, Giancarlo; Serrano, Geidy E.; Beach, Thomas G.; McKeith, Ian G.; Thomas, Alan J.; Attems, Johannes; Morris, Christopher M.; Palmer, Laura; Love, Seth; Troakes, Claire; Al-Sarraj, Safa; Hodges, Angela K.; Aarsland, Dag; Klein, Gregory; Kaiser, Scott M.; Woltjer, Randy; Pastor, Pau; Bekris, Lynn M.; Leverenz, James B.; Besser, Lilah M.; Kuzma, Amanda; Renton, Alan E.; Goate, Alison; Bennett, David A.; Scherzer, Clemens R.; Morris, Huw R.; Ferrari, Raffaele; Albani, Diego; Pickering-Brown, Stuart; Faber, Kelley; Kukull, Walter A.; Morenas-Rodriguez, Estrella; Lleó, Alberto; Fortea, Juan; Alcolea, Daniel; Clarimon, Jordi; Nalls, Mike A.; Ferrucci, Luigi; Resnick, Susan M.; Tanaka, Toshiko; Foroud, Tatiana M.; Graff-Radford, Neill R.; Wszolek, Zbigniew K.; Ferman, Tanis; Boeve, Bradley F.; Hardy, John A.; Topol, Eric J.; Torkamani, Ali; Singleton, Andrew B.; Ryten, Mina; Dickson, Dennis W.; Chiò, Adriano; Ross, Owen A.; Gibbs, J. Raphael; Dalgard, Clifton L.; Traynor, Bryan J.; Scholz, Sonja W.; Pathology and Laboratory Medicine, School of Medicine
    The genetic basis of Lewy body dementia (LBD) is not well understood. Here, we performed whole-genome sequencing in large cohorts of LBD cases and neurologically healthy controls to study the genetic architecture of this understudied form of dementia, and to generate a resource for the scientific community. Genome-wide association analysis identified five independent risk loci, whereas genome-wide gene-aggregation tests implicated mutations in the gene GBA. Genetic risk scores demonstrate that LBD shares risk profiles and pathways with Alzheimer's disease and Parkinson's disease, providing a deeper molecular understanding of the complex genetic architecture of this age-related neurodegenerative condition.
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    Genome-wide structural variant analysis identifies risk loci for non-Alzheimer's dementias
    (Elsevier, 2023-05-04) Kaivola, Karri; Chia, Ruth; Ding, Jinhui; Rasheed, Memoona; Fujita, Masashi; Menon, Vilas; Walton, Ronald L.; Collins, Ryan L.; Billingsley, Kimberley; Brand, Harrison; Talkowski, Michael; Zhao, Xuefang; Dewan, Ramita; Stark, Ali; Ray, Anindita; Solaiman, Sultana; Alvarez Jerez, Pilar; Malik, Laksh; Dawson, Ted M.; Rosenthal, Liana S.; Albert, Marilyn S.; Pletnikova, Olga; Troncoso, Juan C.; Masellis, Mario; Keith, Julia; Black, Sandra E.; Ferrucci, Luigi; Resnick, Susan M.; Tanaka, Toshiko; American Genome Center; International LBD Genomics Consortium; International ALS/FTD Consortium; PROSPECT Consortium; Topol, Eric; Torkamani, Ali; Tienari, Pentti; Foroud, Tatiana M.; Ghetti, Bernardino; Landers, John E.; Ryten, Mina; Morris, Huw R.; Hardy, John A.; Mazzini, Letizia; D'Alfonso, Sandra; Moglia, Cristina; Calvo, Andrea; Serrano, Geidy E.; Beach, Thomas G.; Ferman, Tanis; Graff-Radford, Neill R.; Boeve, Bradley F.; Wszolek, Zbigniew K.; Dickson, Dennis W.; Chiò, Adriano; Bennett, David A.; De Jager, Philip L.; Ross, Owen A.; Dalgard, Clifton L.; Gibbs, J. Raphael; Traynor, Bryan J.; Scholz, Sonja W.; Medical and Molecular Genetics, School of Medicine
    We characterized the role of structural variants, a largely unexplored type of genetic variation, in two non-Alzheimer's dementias, namely Lewy body dementia (LBD) and frontotemporal dementia (FTD)/amyotrophic lateral sclerosis (ALS). To do this, we applied an advanced structural variant calling pipeline (GATK-SV) to short-read whole-genome sequence data from 5,213 European-ancestry cases and 4,132 controls. We discovered, replicated, and validated a deletion in TPCN1 as a novel risk locus for LBD and detected the known structural variants at the C9orf72 and MAPT loci as associated with FTD/ALS. We also identified rare pathogenic structural variants in both LBD and FTD/ALS. Finally, we assembled a catalog of structural variants that can be mined for new insights into the pathogenesis of these understudied forms of dementia.
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    Peptide ancestry informative markers in uterine neoplasms from women of European, African, and Asian ancestry
    (Elsevier, 2021-12-23) Bateman, Nicholas W.; Tarney, Christopher M.; Abulez, Tamara S.; Hood, Brian L.; Conrads, Kelly A.; Zhou, Ming; Soltis, Anthony R.; Teng, Pang-Ning; Jackson, Amanda; Tian, Chunqiao; Dalgard, Clifton L.; Wilkerson, Matthew D.; Kessler, Michael D.; Goecker, Zachary; Loffredo, Jeremy; Shriver, Craig D.; Hu, Hai; Cote, Michele; Parker, Glendon J.; Segars, James; Al-Hendy, Ayman; Risinger, John I.; Phippen, Neil T.; Casablanca, Yovanni; Darcy, Kathleen M.; Maxwell, G. Larry; Conrads, Thomas P.; O'Connor, Timothy D.; Medicine, School of Medicine
    Characterization of ancestry-linked peptide variants in disease-relevant patient tissues represents a foundational step to connect patient ancestry with disease pathogenesis. Nonsynonymous single-nucleotide polymorphisms encoding missense substitutions within tryptic peptides exhibiting high allele frequencies in European, African, and East Asian populations, termed peptide ancestry informative markers (pAIMs), were prioritized from 1000 genomes. In silico analysis identified that as few as 20 pAIMs can determine ancestry proportions similarly to >260K SNPs (R2 = 0.99). Multiplexed proteomic analysis of >100 human endometrial cancer cell lines and uterine leiomyoma tissues combined resulted in the quantitation of 62 pAIMs that correlate with patient race and genotype-confirmed ancestry. Candidates include a D451E substitution in GC vitamin D-binding protein previously associated with altered vitamin D levels in African and European populations. pAIMs will support generalized proteoancestry assessment as well as efforts investigating the impact of ancestry on the human proteome and how this relates to the pathogenesis of uterine neoplasms.