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1. Genetic, transcriptomic, histological, and biochemical analysis of progressive supranuclear palsy implicates glial activation and novel risk genes

Author

Kurt Farrell, Jack Humphrey, Timothy Chang, Yi Zhao, Yuk Yee Leung, Pavel P. Kuksa, Vishakha Patil, Wan-Ping Lee, Amanda B. Kuzma, Otto Valladares, Laura B. Cantwell, Hui Wang, Ashvin Ravi, Claudia De Sanctis, Natalia Han, Thomas D. Christie, Robina Afzal, Shrishtee Kandoi, Kristen Whitney, Margaret M. Krassner, Hadley Ressler, SoongHo Kim, Diana Dangoor, Megan A. Iida, Alicia Casella, Ruth H. Walker, Melissa J. Nirenberg, Alan E. Renton, Bergan Babrowicz, Giovanni Coppola, Towfique Raj, Günter U. Höglinger, Ulrich Müller, Lawrence I. Golbe, Huw R. Morris, John Hardy, Tamas Revesz, Tom T. Warner, Zane Jaunmuktane, Kin Y. Mok, Rosa Rademakers, Dennis W. Dickson, Owen A. Ross, Li-San Wang, Alison Goate, Gerard Schellenberg, Daniel H. Geschwind, PSP Genetics Study Group, John F. Crary, and Adam Naj

Subjects
Science
Abstract

Abstract Progressive supranuclear palsy (PSP), a rare Parkinsonian disorder, is characterized by problems with movement, balance, and cognition. PSP differs from Alzheimer’s disease (AD) and other diseases, displaying abnormal microtubule-associated protein tau by both neuronal and glial cell pathologies. Genetic contributors may mediate these differences; however, the genetics of PSP remain underexplored. Here we conduct the largest genome-wide association study (GWAS) of PSP which includes 2779 cases (2595 neuropathologically-confirmed) and 5584 controls and identify six independent PSP susceptibility loci with genome-wide significant (P

Published
2024
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2. Unraveling the complex role of MAPT-containing H1 and H2 haplotypes in neurodegenerative diseases

Author

Chiara Pedicone, Sarah A. Weitzman, Alan E. Renton, and Alison M. Goate

Subjects
17q21.31, Haplotypes, Inversion, Neurodegeneration, SNV, CNV, Neurology. Diseases of the nervous system, RC346-429, Geriatrics, RC952-954.6
Abstract

Abstract A ~ 1 Mb inversion polymorphism exists within the 17q21.31 locus of the human genome as direct (H1) and inverted (H2) haplotype clades. This inversion region demonstrates high linkage disequilibrium, but the frequency of each haplotype differs across ancestries. While the H1 haplotype exists in all populations and shows a normal pattern of genetic variability and recombination, the H2 haplotype is enriched in European ancestry populations, is less frequent in African ancestry populations, and nearly absent in East Asian ancestry populations. H1 is a known risk factor for several neurodegenerative diseases, and has been associated with many other traits, suggesting its importance in cellular phenotypes of the brain and entire body. Conversely, H2 is protective for these diseases, but is associated with predisposition to recurrent microdeletion syndromes and neurodevelopmental disorders such as autism. Many single nucleotide variants and copy number variants define H1/H2 haplotypes and sub-haplotypes, but identifying the causal variant(s) for specific diseases and phenotypes is complex due to the extended linkage equilibrium. In this review, we assess the current knowledge of this inversion region regarding genomic structure, gene expression, cellular phenotypes, and disease association. We discuss recent discoveries and challenges, evaluate gaps in knowledge, and highlight the importance of understanding the effect of the 17q21.31 haplotypes to promote advances in precision medicine and drug discovery for several diseases. Graphical Abstract

Published
2024
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3. Deconstructing pathological tau by biological process in early stages of Alzheimer disease: a method for quantifying tau spatial spread in neuroimagingResearch in context

Author

Stephanie Doering, Austin McCullough, Brian A. Gordon, Charles D. Chen, Nicole McKay, Diana Hobbs, Sarah Keefe, Shaney Flores, Jalen Scott, Hunter Smith, Stephen Jarman, Kelley Jackson, Russ C. Hornbeck, Beau M. Ances, Chengjie Xiong, Andrew J. Aschenbrenner, Jason Hassenstab, Carlos Cruchaga, Alisha Daniels, Randall J. Bateman, John C. Morris, Tammie L.S. Benzinger, James M. Noble, Gregory S. Day, Neill R. Graff-Radford, Jonathan Voglein, Johannes Levin, Ricardo F. Allegri, Patricio Chrem Mendez, Ezequiel Surace, Sarah B. Berman, Snezana Ikonomovic, Neelesh K. Nadkarni, Francisco Lopera, Laura Ramirez, David Aguillon, Yudy Leon, Claudia Ramos, Diana Alzate, Ana Baena, Natalia Londono, Sonia Moreno, Mathias Jucker, Christoph Laske, Elke Kuder-Buletta, Susanne Graber-Sultan, Oliver Preische, Anna Hofmann, Takeshi Ikeuchi, Kensaku Kasuga, Yoshiki Niimi, Kenji Ishii, Michio Senda, Raquel Sanchez-Valle, Pedro Rosa-Neto, Nick C. Fox, Dave Cash, Jae-Hong Lee, Jee Hoon Roh, Stephen Salloway, Meghan C. Riddle, William Menard, Courtney Bodge, Mustafa Surti, Leonel Tadao Takada, Martin Farlow, Jasmeer P. Chhatwal, V.J. Sanchez-Gonzalez, Maribel Orozco-Barajas, Alison M. Goate, Alan E. Renton, Bianca T. Esposito, Celeste M. Karch, Jacob Marsh, Victoria Fernanadez, Anne M. Fagan, Gina Jerome, Elizabeth Herries, Jorge Llibre-Guerra, Allan I. Levey, Erik C.B. Johnson, Nicholas T. Seyfried, Peter R. Schofield, William S. Brooks, Jacob A. Bechara, Randall Bateman, Eric McDade, Richard J. Perrin, Erin E. Franklin, Tammie Benzinger, Allison Chen, Charles Chen, Nelly Friedrichsen, Brian Gordon, Nancy Hantler, Russ Hornbeck, Steve Jarman, Deborah Koudelis, Parinaz Massoumzadeh, Joyce Nicklaus, Christine Pulizos, Qing Wang, Sheetal Mishall, Edita Sabaredzovic, Emily Deng, Madison Candela, Peter Wang, Xiong Xu, Yan Li, Emily Gremminger, Yinjiao Ma, Ryan Bui, Ruijin Lu, Ralph Martins, Ana Luisa Sosa Ortiz, Laura Courtney, Hiroshi Mori, Charlene Supnet-Bell, Jinbin Xu, John Ringman, Nicolas Barthelemy, John Morris, and Jennifer Smith

Subjects
Alzheimer disease, Positron emission tomography, Tau spread, Tau propagation, Medicine, Medicine (General), R5-920
Abstract

Summary: Background: Neuroimaging studies often quantify tau burden in standardized brain regions to assess Alzheimer disease (AD) progression. However, this method ignores another key biological process in which tau spreads to additional brain regions. We have developed a metric for calculating the extent tau pathology has spread throughout the brain and evaluate the relationship between this metric and tau burden across early stages of AD. Methods: 445 cross-sectional participants (aged ≥ 50) who had MRI, amyloid PET, tau PET, and clinical testing were separated into disease-stage groups based on amyloid positivity and cognitive status (older cognitively normal control, preclinical AD, and symptomatic AD). Tau burden and tau spatial spread were calculated for all participants. Findings: We found both tau metrics significantly elevated across increasing disease stages (p

Published
2024
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4. Genome‐Wide Association Study of Cardiovascular Resilience Identifies Protective Variation in the CETP Gene

Author

Chenglong Yu, Andrew Bakshi, Gerald F. Watts, Alan E. Renton, Brian Fulton‐Howard, Alison M. Goate, Pradeep Natarajan, Daniel I. Chasman, Liubov Robman, Robyn L. Woods, Robyn Guymer, Rory Wolfe, Le Thi Phuong Thao, John J. McNeil, Andrew M. Tonkin, Stephen J. Nicholls, and Paul Lacaze

Subjects
aging, cardioprotective variants, cardiovascular disease, genome‐wide association study, lipid metabolism, Diseases of the circulatory (Cardiovascular) system, RC666-701
Abstract

Background The risk of atherosclerotic cardiovascular disease (ASCVD) increases sharply with age. Some older individuals, however, remain unaffected despite high predicted risk. These individuals may carry cardioprotective genetic variants that contribute to resilience. Our aim was to assess whether asymptomatic older individuals without prevalent ASCVD carry cardioprotective genetic variants that contribute to ASCVD resilience. Methods and Results We performed a genome‐wide association study using a 10‐year predicted ASCVD risk score as a quantitative trait, calculated only in asymptomatic older individuals aged ≥70 years without prevalent ASCVD. Our discovery genome‐wide association study of N=12 031 ASCVD event‐free individuals from the ASPREE (Aspirin in Reducing Events in the Elderly) trial identified 2 independent variants, rs9939224 (P

Published
2023
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5. Discovery and validation of dominantly inherited Alzheimer’s disease mutations in populations from Latin America

Author

Leonel Tadao Takada, Carmen Aláez-Verson, Bhagyashri D. Burgute, Ricardo Nitrini, Ana Luisa Sosa, Raphael Machado Castilhos, Marcia Fagundes Chaves, Erika-Mariana Longoria, Karol Carrillo-Sánchez, Sonia Maria Dozzi Brucki, Luis Leonardo Flores-Lagunes, Carolina Molina, Marcos Jimenez Olivares, Ellen Ziegemeier, Jennifer Petranek, Alison M. Goate, Carlos Cruchaga, Alan E. Renton, Maria Victoria Fernández, Gregory S. Day, Eric McDade, Randall J. Bateman, Celeste M. Karch, Jorge J. Llibre-Guerra, and for the Dominantly Inherited Alzheimer Network

Subjects
Dominantly inherited Alzheimer disease, Presenilin 1, Latin America, Early-onset Alzheimer disease, Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571, Neurology. Diseases of the nervous system, RC346-429
Abstract

Abstract Background In fewer than 1% of patients, AD is caused by autosomal dominant mutations in either the presenilin 1 (PSEN1), presenilin 2 (PSEN2), or amyloid precursor protein (APP) genes. The full extent of familial AD and frequency of these variants remains understudied in Latin American (LatAm) countries. Due to the rare nature of these variants, determining the pathogenicity of a novel variant in these genes can be challenging. Here, we use a systematic approach to assign the likelihood of pathogenicity in variants from densely affected families in Latin American populations. Methods Clinical data was collected from LatAm families at risk for DIAD. Symptomatic family members were identified and assessed by local clinicians and referred for genetic counseling and testing. To determine the likelihood of pathogenicity among variants of unknown significance from LatAm populations, we report pedigree information, frequency in control populations, in silico predictions, and cell-based models of amyloid-beta ratios. Results We identified five novel variants in the presenilin1 (PSEN1) gene from Brazilian and Mexican families. The mean age at onset in newly identified families was 43.5 years (range 36–54). PSEN1 p.Val103_Ser104delinsGly, p.Lys395Ile, p.Pro264Se, p.Ala275Thr, and p.Ile414Thr variants have not been reported in PubMed, ClinVar, and have not been reported in dominantly inherited AD (DIAD) families. We found that PSEN1 p.Val103_Ser104delinsGly, p.Lys395Ile, p.Pro264Se, and p.Ala275Thr produce Aβ profiles consistent with known AD pathogenic mutations. PSEN1 p.Ile414Thr did not alter Aβ in a manner consistent with a known pathogenic mutation. Conclusions Our study provides further insights into the genetics of AD in LatAm. Based on our findings, including clinical presentation, imaging, genetic, segregations studies, and cell-based analysis, we propose that PSEN1 p.Val103_Ser104delinsGly, p.Lys395Ile, p.Pro264Se, and p.Ala275Thr are likely pathogenic variants resulting in DIAD, whereas PSEN1 p.Ile414Thr is likely a risk factor. This report is a step forward to improving the inclusion/engagement of LatAm families in research. Family discovery is of great relevance for the region, as new initiatives are underway to extend clinical trials and observational studies to families living with DIAD.

Published
2022
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6. 17q21.31 sub-haplotypes underlying H1-associated risk for Parkinson’s disease are associated with LRRC37A/2 expression in astrocytes

Author

Kathryn R. Bowles, Derian A. Pugh, Yiyuan Liu, Tulsi Patel, Alan E. Renton, Sara Bandres-Ciga, Ziv Gan-Or, Peter Heutink, Ari Siitonen, Sarah Bertelsen, Jonathan D. Cherry, Celeste M. Karch, Steven J. Frucht, Brian H. Kopell, Inga Peter, Y. J. Park, International Parkinson’s Disease Genomics Consortium (IPDGC), Alexander Charney, Towfique Raj, John F. Crary, and A. M. Goate

Subjects
17q21.31, Parkinson’s disease, LRRC37A, Copy number variation, Astrocytes, Neurology. Diseases of the nervous system, RC346-429, Geriatrics, RC952-954.6
Abstract

Abstract Background Parkinson’s disease (PD) is genetically associated with the H1 haplotype of the MAPT 17q.21.31 locus, although the causal gene and variants underlying this association have not been identified. Methods To better understand the genetic contribution of this region to PD and to identify novel mechanisms conferring risk for the disease, we fine-mapped the 17q21.31 locus by constructing discrete haplotype blocks from genetic data. We used digital PCR to assess copy number variation associated with PD-associated blocks, and used human brain postmortem RNA-seq data to identify candidate genes that were then further investigated using in vitro models and human brain tissue. Results We identified three novel H1 sub-haplotype blocks across the 17q21.31 locus associated with PD risk. Protective sub-haplotypes were associated with increased LRRC37A/2 copy number and expression in human brain tissue. We found that LRRC37A/2 is a membrane-associated protein that plays a role in cellular migration, chemotaxis and astroglial inflammation. In human substantia nigra, LRRC37A/2 was primarily expressed in astrocytes, interacted directly with soluble α-synuclein, and co-localized with Lewy bodies in PD brain tissue. Conclusion These data indicate that a novel candidate gene, LRRC37A/2, contributes to the association between the 17q21.31 locus and PD via its interaction with α-synuclein and its effects on astrocytic function and inflammatory response. These data are the first to associate the genetic association at the 17q21.31 locus with PD pathology, and highlight the importance of variation at the 17q21.31 locus in the regulation of multiple genes other than MAPT and KANSL1, as well as its relevance to non-neuronal cell types.

Published
2022
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7. The complex genetic architecture of Alzheimer's disease: novel insights and future directions

Author

Shea J. Andrews, Alan E. Renton, Brian Fulton-Howard, Anna Podlesny-Drabiniok, Edoardo Marcora, and Alison M. Goate

Subjects
Alzheimer's disease, Genome-wide association study, Review, Medicine, Medicine (General), R5-920
Abstract

Summary: Background: Alzheimer's disease (AD) is a complex multifactorial neurodegenerative disorder and the most common form of dementia. AD is highly heritable, with heritability estimates of ∼70% from twin studies. Progressively larger genome-wide association studies (GWAS) have continued to expand our knowledge of AD/dementia genetic architecture. Until recently these efforts had identified 39 disease susceptibility loci in European ancestry populations. Recent developments: Two new AD/dementia GWAS have dramatically expanded the sample sizes and the number of disease susceptibility loci. The first increased total sample size to 1,126,563—with an effective sample size of 332,376—by predominantly including new biobank and population-based dementia datasets. The second, expands on an earlier GWAS from the International Genomics of Alzheimer's Project (IGAP) by increasing the number of clinically-defined AD cases/controls in addition to incorporating biobank dementia datasets, resulting in a total sample size to 788,989 and an effective sample size of 382,472. Collectively both GWAS identified 90 independent variants across 75 AD/dementia susceptibility loci, including 42 novel loci. Pathway analyses indicate the susceptibility loci are enriched for genes involved in amyloid plaque and neurofibrillary tangle formation, cholesterol metabolism, endocytosis/phagocytosis, and the innate immune system. Gene prioritization efforts for the novel loci identified 62 candidate causal genes. Many of the candidate genes from known and newly discovered loci play key roles in macrophages and highlight phagocytic clearance of cholesterol-rich brain tissue debris by microglia (efferocytosis) as a core pathogenetic hub and putative therapeutic target for AD. Where next?: While GWAS in European ancestry populations have substantially enhanced our understanding of AD genetic architecture, heritability estimates from population based GWAS cohorts are markedly smaller than those from twin studies. While this missing heritability is likely due to a combination of factors, it highlights that our understanding of AD genetic architecture and genetic risk mechanisms remains incomplete. These knowledge gaps result from several underexplored areas in AD research. First, rare variants remain understudied due to methodological issues in identifying them and the cost of generating sufficiently powered whole exome/genome sequencing datasets. Second, sample sizes of non-European ancestry populations in AD GWAS remain small. Third, GWAS of AD neuroimaging and cerebrospinal fluid endophenotypes remains limited due to low compliance and high costs associated with measuring amyloid-β and tau levels and other disease-relevant biomarkers. Studies generating sequencing data, including diverse populations, and incorporating blood-based AD biomarkers are set to substantially improve our knowledge of AD genetic architecture.

Published
2023
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8. Beyond association: successes and challenges in linking non-coding genetic variation to functional consequences that modulate Alzheimer’s disease risk

Author

Gloriia Novikova, Shea J. Andrews, Alan E. Renton, and Edoardo Marcora

Subjects
Alzheimer’s disease, Myeloid cells, Functional genomics, Fine-mapping methods, Non-coding variants, Gene prioritization, Neurology. Diseases of the nervous system, RC346-429, Geriatrics, RC952-954.6
Abstract

Abstract Alzheimer’s disease (AD) is the most common type of dementia, affecting millions of people worldwide; however, no disease-modifying treatments are currently available. Genome-wide association studies (GWASs) have identified more than 40 loci associated with AD risk. However, most of the disease-associated variants reside in non-coding regions of the genome, making it difficult to elucidate how they affect disease susceptibility. Nonetheless, identification of the regulatory elements, genes, pathways and cell type/tissue(s) impacted by these variants to modulate AD risk is critical to our understanding of disease pathogenesis and ability to develop effective therapeutics. In this review, we provide an overview of the methods and approaches used in the field to identify the functional effects of AD risk variants in the causal path to disease risk modification as well as describe the most recent findings. We first discuss efforts in cell type/tissue prioritization followed by recent progress in candidate causal variant and gene nomination. We discuss statistical methods for fine-mapping as well as approaches that integrate multiple levels of evidence, such as epigenomic and transcriptomic data, to identify causal variants and risk mechanisms of AD-associated loci. Additionally, we discuss experimental approaches and data resources that will be needed to validate and further elucidate the effects of these variants and genes on biological pathways, cellular phenotypes and disease risk. Finally, we discuss future steps that need to be taken to ensure that AD GWAS functional mapping efforts lead to novel findings and bring us closer to finding effective treatments for this devastating disease.

Published
2021
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9. Whole genome sequencing identifies loci specifically associated with thoracic aortic wall defects and abdominal aortic aneurysms in patients with European ancestry

Author

Grace H. Miner, PhD, Alan E. Renton, PhD, Ella Taubenfeld, BS, Rami O. Tadros, MD, Edoardo Marcora, PhD, Robert A. Lookstein, MD, Peter L. Faries, MD, and Michael L. Marin, MD

Subjects
Abdominal aortic aneurysm, Genetic association, Aortic dissection, Genetics, Morphology, Diseases of the circulatory (Cardiovascular) system, RC666-701
Abstract

Objective: The objective of this study was to better understand the pathophysiology and underlying genetic mechanisms behind two abdominal aortic aneurysm (AAA) subtypes using computed tomographic imaging in combination with whole genome sequencing. Methods: Patients with a known AAA and European ancestry were included in this investigation and underwent genetic and image analysis. Patients with AAAs and indications of descending thoracic aortic pathology (aortic dissection, penetrating aortic ulcers, intramural hematoma, atheromas, ulcerative plaque, and intramural ulceration, and intimal flaps/tears) were classified as having thoracic aortic disease, grouped together, and compared with patients with an AAA and a normal descending thoracic aorta. Whole genome sequencing was then performed on the 93 patients who had imaging features consistent with thoracic aortic disease and the 126 patients with a normal descending thoracic aorta. Results: The results of this study suggest one variant-level, four gene-level, and one gene set-level associations in patients with thoracic aortic disease who also had an AAA. The variant rs79508780 located in TSEN54 achieved study-wide significance (P = 1.71E-06). BATF3 and SMLR1 were significantly associated and EFCAB3 and TAF4 were reached suggestive assocation with a diseased descending thoracic aorta (P = 5.23E-26, P = 1.86E-25, P = 1.54E-05, and P = 8.31E-05, respectively). Gene sets were also compiled using MSigDB and trait-based index single nucleotide variation from major genome-wide association studies. GO_DNA_DOUBLE_STRAND_BREAK_PROCESSING, a gene set related to double-stranded DNA break repair, was significantly associated with thoracic aortic disease in AAA patients (P = 1.80E-06). Conclusions: This pilot study provides further evidence that an AAA may be the end result of multiple degenerative pathways. Genetic variations in vitamin D signaling, cholesterol metabolism, extracellular matrix breakdown, and double-stranded DNA break repair pathways were associated with European patients who had an AAA and thoracic aortic disease. Additionally, this study provides support for the application of a radiogenomic approach for the investigation of other potential pathologies that could lead to the development of an AAA or influence future management decisions. (JVS–Vascular Science.) Clinical Relevance: In this study, we provide evidence that abdominal aortic aneurysms (AAAs) may be a result of multiple pathophysiologies rather than a single disease. We have identified genetic variants involved in vitamin D signaling, cholesterol metabolism, extracellular matrix breakdown, and double-stranded DNA break repair associated with structural defects in the aortic wall in patients with AAAs who are of European descent. Patients with AAAs and structural defects in the thoracic aorta have been previously linked to differential behavior after endovascular aneurysm repair. These patients with wall defects exhibited greater sac regression, a marker of surgical success, after endovascular aneurysm repair. Our study demonstrates the usefulness of a radiogenomic approach for elucidating mechanisms behind the formation and future behavior of AAAs that could aid surgeons in making future procedural and management decisions.

Published
2020
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10. Polygenic score modifies risk for Alzheimer's disease in APOE ε4 homozygotes at phenotypic extremes

Author

Aamira J. Huq, Brian Fulton‐Howard, Moeen Riaz, Simon Laws, Robert Sebra, Joanne Ryan, Alzheimer's Disease Genetics Consortium, Alan E. Renton, Alison M. Goate, Colin L. Masters, Elsdon Storey, Raj C. Shah, Anne Murray, John McNeil, Ingrid Winship, Paul A. James, and Paul Lacaze

Subjects
Alzheimer's disease, Alzheimer's disease dementia, apolipoprotein E, dementia resilience, genetic modifiers, polygenic risk score, Neurology. Diseases of the nervous system, RC346-429, Geriatrics, RC952-954.6
Abstract

Abstract Introduction Diversity in cognition among apolipoprotein E (APOE) ε4 homozygotes can range from early‐onset Alzheimer's disease (AD) to a lifetime with no symptoms. Methods We evaluated a phenotypic extreme polygenic risk score (PRS) for AD between cognitively healthy APOE ε4 homozygotes aged ≥75 years (n = 213) and early‐onset APOE ε4 homozygote AD cases aged ≤65 years (n = 223) as an explanation for this diversity. Results The PRS for AD was significantly higher in APOE ε4 homozygote AD cases compared to older cognitively healthy APOE ε4/ε4 controls (odds ratio [OR] 8.39; confidence interval [CI] 2.0–35.2; P = .003). The difference in the same PRS between APOE ε3/ε3 extremes was not as significant (OR 3.13; CI 0.98–9.92; P = .053) despite similar numbers and power. There was no statistical difference in an educational attainment PRS between these age extreme case‐controls. Discussion A PRS for AD contributes to modified cognitive expression of the APOE ε4/ε4 genotype at phenotypic extremes of risk.

Published
2021
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11. Large‐scale sequencing studies expand the known genetic architecture of Alzheimer's disease

Author

Diane Xue, William S. Bush, Alan E. Renton, Edoardo A. Marcora, Joshua C. Bis, Brian W. Kunkle, The Alzheimer's Disease Sequencing Project, Eric Boerwinkle, Anita L. DeStefano, Lindsay Farrer, Alison Goate, Richard Mayeux, Margaret Pericak‐Vance, Gerard Schellenberg, Sudha Seshadri, Ellen Wijsman, Jonathan L. Haines, and Elizabeth E. Blue

Subjects
Alzheimer's disease, genetic architecture, genome, networks, pathways, Neurology. Diseases of the nervous system, RC346-429, Geriatrics, RC952-954.6
Abstract

Abstract Introduction Genes implicated by genome‐wide association studies and family‐based studies of Alzheimer's disease (AD) are largely discordant. We hypothesized that genes identified by sequencing studies like the Alzheimer's Disease Sequencing Project (ADSP) may bridge this gap and highlight shared biological mechanisms. Methods We performed structured literature review of genes prioritized by ADSP studies, genes underlying familial dementias, and genes nominated by genome‐wide association studies. Gene set enrichment analyses of each list identified enriched pathways. Results The genes prioritized by the ADSP, familial dementia studies, and genome‐wide association studies minimally overlapped. Each gene set identified dozens of enriched pathways, several of which were shared (e.g., regulation of amyloid beta clearance). Discussion Alternative study designs provide unique insights into AD genetics. Shared pathways enriched by different genes highlight their relevance to AD pathogenesis, while the patterns of pathway enrichment unique to each gene set provide additional targets for functional studies.

Published
2021
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12. Clinical Characteristics of C9ORF72-Linked Frontotemporal Lobar Degeneration

Author

Anna-Lotta Kaivorinne, Michaela K. Bode, Liisa Paavola, Hannu Tuominen, Mika Kallio, Alan E. Renton, Bryan J. Traynor, Virpi Moilanen, and Anne M. Remes

Subjects
Association study, Clinical features, Frontotemporal dementia, Frontotemporal lobar degeneration, Genetics, Neurology. Diseases of the nervous system, RC346-429, Geriatrics, RC952-954.6
Abstract

Background: The most common genetic cause of frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS) has been linked to a hexanucleotide repeat expansion in the C9ORF72 gene. The frequency of the C9ORF72 expansion in Finland is among the highest in the world. Methods: We assessed 73 Finnish patients with FTLD in order to examine the clinical characteristics associated with the expanded C9ORF72. Demographic and clinical features were evaluated. As a potential disease modifier, the apolipoprotein E (APOE) genotype was also assessed. Neuropathological analysis was available on 2 expansion carriers and 1 non-carrier. Results: The C9ORF72 expansion was present in 20 of 70 (29%) probands. Significant associations with the C9ORF72 expansion were observed for concomitant ALS and positive family history of dementia or ALS. Psychoses were detected in both carriers and non-carriers (21 vs. 10%, p = 0.25). The APOE ε4 allele did not cluster among expansion carriers. Numerous p62-positive neuronal inclusions were detected in the cerebellar cortex of the 2 expansion carriers. Conclusion: In line with the suggested C9ORF72 core phenotype, we also detected a high frequency of neuropsychiatric symptoms; however, these symptoms seem not be specific to C9ORF72-associated FTLD. FTLD should be considered in cases of middle-age-onset psychosis.

Published
2013
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13. Validation of newly derived polygenic risk scores for dementia in a prospective study of older individuals

Author

Chenglong Yu, Joanne Ryan, Suzanne G. Orchard, Catherine Robb, Robyn L. Woods, Rory Wolfe, Alan E. Renton, Alison M. Goate, Amy Brodtmann, Raj C. Shah, Trevor T.‐J. Chong, Kerry Sheets, Christopher Kyndt, Ajay Sood, Elsdon Storey, Anne M. Murray, John J. McNeil, and Paul Lacaze

Subjects
Psychiatry and Mental health, Cellular and Molecular Neuroscience, Developmental Neuroscience, Epidemiology, Health Policy, Neurology (clinical), Geriatrics and Gerontology
Published
2023

14. Genetic associations with age at dementia onset in the PSEN1 E280A Colombian kindred

Author

Jesse Nicholas Cochran, Juliana Acosta‐Uribe, Bianca T. Esposito, Lucia Madrigal, David Aguillón, Margarita M. Giraldo, Jared W. Taylor, Joseph Bradley, Brian Fulton‐Howard, Shea J. Andrews, Natalia Acosta‐Baena, Diana Alzate, Gloria P. Garcia, Francisco Piedrahita, Hugo E. Lopez, Ashlyn G. Anderson, Ivan Rodriguez‐Nunez, Kevin Roberts, null Dominantly Inherited Alzheimer Network, Devin Absher, Richard M. Myers, Gary W. Beecham, Christiane Reitz, Lindsay F. Rizzardi, Maria Victoria Fernandez, Alison M. Goate, Carlos Cruchaga, Alan E. Renton, Francisco Lopera, and Kenneth S. Kosik

Subjects
Psychiatry and Mental health, Cellular and Molecular Neuroscience, Developmental Neuroscience, Epidemiology, Health Policy, Neurology (clinical), Geriatrics and Gerontology
Published
2023

15. Genome-wide structural variant analysis identifies risk loci for non-Alzheimer's dementias

Author

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

Subjects
amyotrophic lateral sclerosis, Neurologie [D14] [Sciences de la santé humaine], genome-wide association study, Neurology [D14] [Human health sciences], case-control study, Non-Alzheimer dementia, resource, Biochemistry, Genetics and Molecular Biology (miscellaneous), frontotemporal dementia, structural variant, Genetics, non–Alzheimer's dementia, Genetics & genetic processes [F10] [Life sciences], Lewy body dementia, Structural variants, Génétique & processus génétiques [F10] [Sciences du vivant]
Abstract

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

Published
2023

16. Discovery and validation of dominantly Inherited Alzheimer’s Disease mutations in populations from Latin America

Author

Jorge J Llibre‐Guerra, Leonel Tadao Takada, Carmen Alaez Verson, Bhagyashri Burgute, Ricardo Nitrini, Ana Luisa Sosa‐Ortiz, Raphael Machado Castilhos, Marcia L Fagundes Chaves, Mariana Longoria Ibarrola, Karol Carrillo‐Sanchez, Sonia Maria Dozzi Brucki, Luis Leonardo Flores‐Lagunes, Carolina Molina, Marcos Jimenez Olivares, Ellen Ziegemeier, Alison M. Goate, Carlos Cruchaga, Alan E. Renton, Maria Victoria Fernandez, Gregory S Day, Eric McDade, Randall J. Bateman, and Celeste M. Karch

Subjects
Psychiatry and Mental health, Cellular and Molecular Neuroscience, Developmental Neuroscience, Epidemiology, Health Policy, Neurology (clinical), Geriatrics and Gerontology
Published
2022

17. Genome-wide association study and functional validation implicates JADE1 in tauopathy

Author

John F. Crary, Katia de Paiva Lopes, Bradley T. Hyman, Manav Kapoor, Gloriia Novikova, Jonathan D. Glass, Valeriy Borukov, Hadley Walsh, Erin E. Franklin, Johannes Attems, Sara Shuldberg, Shea J. Andrews, Thomas J. Montine, Julie A. Schneider, Jonathan D. Cherry, C. Dirk Keene, Towfique Raj, Charles L. White, Thor D. Stein, Evan Udine, Gai Ayalon, Thao Pham, Maria M. Corrada, Weijing Tang, Ann C. McKee, Bess Frost, Marco M. Hefti, Qinwen Mao, Lei Yu, Patrick R. Hof, Peter T. Nelson, Elias M. Gonzalez, Alan E. Renton, Corey T. McMillan, Jack Humphrey, Natalia Han, Margaret E. Flanagan, SoongHo Kim, Etty Cortes, Megan A. Iida, Inma Cobos, Jeff Metcalf, Sandra Weintraub, Julie Hunkapiller, Diana K. Dangoor, Robert A. Rissman, Marcos Otero-Garcia, John Q. Trojanowski, Dushyant P. Purohit, Caitlin S. Latimer, Marla Gearing, Claudia H. Kawas, Kathryn R. Bowles, Wayne W. Poon, Brian Fulton-Howard, Edoardo Marcora, Alison Goate, Alicia Casella, Tushar Bhangale, Richard J. Perrin, Herbert T. Cohen, Bahar Salehi, Gabor G. Kovacs, Andy F. Teich, Mary Sano, Jamie M. Walker, Dennis W. Dickson, Randy Woltjer, Kristen Whitney, M.-Marsel Mesulam, Ricardo Assunção Vialle, Peter Fischer, Kurt Farrell, Jean-Paul Vonsattel, Cheick T. Sissoko, Vahram Haroutunian, Sam Gandy, Mirjam I. Lutz, Matthew P. Frosch, Nigel J. Cairns, Melissa E. Murray, Robert R. Graham, David A. Wolk, Juan C. Troncoso, Garrett Wong, Julia Kofler, Edward B. Lee, Timothy E. Richardson, and Thomas G. Beach

Subjects
Male, Aging, Locus (genetics), Single-nucleotide polymorphism, Genome-wide association study, Biology, Polymorphism, Single Nucleotide, Article, Pathology and Forensic Medicine, Progressive supranuclear palsy, Cohort Studies, Cellular and Molecular Neuroscience, medicine, Animals, Humans, Aged, Genetic association, Aged, 80 and over, Homeodomain Proteins, Tumor Suppressor Proteins, Neurofibrillary tangle, Middle Aged, medicine.disease, Molecular biology, Tauopathies, Drosophila, Female, Neurology (clinical), Tauopathy, Alzheimer's disease, Genome-Wide Association Study
Abstract

Primary age-related tauopathy (PART) is a neurodegenerative pathology with features distinct from but also overlapping with Alzheimer disease (AD). While both exhibit Alzheimer-type temporal lobe neurofibrillary degeneration alongside amnestic cognitive impairment, PART develops independently of amyloid-β (Aβ) plaques. The pathogenesis of PART is not known, but evidence suggests an association with genes that promote tau pathology and others that protect from Aβ toxicity. Here, we performed a genetic association study in an autopsy cohort of individuals with PART (n = 647) using Braak neurofibrillary tangle stage as a quantitative trait. We found some significant associations with candidate loci associated with AD (SLC24A4, MS4A6A, HS3ST1) and progressive supranuclear palsy (MAPT and EIF2AK3). Genome-wide association analysis revealed a novel significant association with a single nucleotide polymorphism on chromosome 4 (rs56405341) in a locus containing three genes, including JADE1 which was significantly upregulated in tangle-bearing neurons by single-soma RNA-seq. Immunohistochemical studies using antisera targeting JADE1 protein revealed localization within tau aggregates in autopsy brains with four microtubule-binding domain repeats (4R) isoforms and mixed 3R/4R, but not with 3R exclusively. Co-immunoprecipitation in post-mortem human PART brain tissue revealed a specific binding of JADE1 protein to four repeat tau lacking N-terminal inserts (0N4R). Finally, knockdown of the Drosophila JADE1 homolog rhinoceros (rno) enhanced tau-induced toxicity and apoptosis in vivo in a humanized 0N4R mutant tau knock-in model, as quantified by rough eye phenotype and terminal deoxynucleotidyl transferase dUTP nick end-labeling (TUNEL) in the fly brain. Together, these findings indicate that PART has a genetic architecture that partially overlaps with AD and other tauopathies and suggests a novel role for JADE1 as a modifier of neurofibrillary degeneration.

Published
2021

18. A quantitative trait rare variant nonparametric linkage method with application to age-at-onset of Alzheimer’s disease

Author

Richard Mayeux, Gao T Wang, Badri N. Vardarajan, Sandra Rodriguez, Alison Goate, Suzanne M. Leal, Alan E. Renton, Zhihui Zhang, and Linhai Zhao

Subjects
Genetics, Linkage (software), Apolipoprotein E, 0303 health sciences, education.field_of_study, 030305 genetics & heredity, Population, Nonparametric statistics, Pedigree chart, Biology, Quantitative trait locus, medicine.disease, 03 medical and health sciences, Locus heterogeneity, medicine, Allele, education, Genetics (clinical)
Abstract

To analyze pedigrees with quantitative trait (QT) and sequence data, we developed a rare variant (RV) quantitative nonparametric linkage (QNPL) method, which evaluates sharing of minor alleles. RV-QNPL has greater power than the traditional QNPL that tests for excess sharing of minor and major alleles. RV-QNPL is robust to population substructure and admixture, locus heterogeneity, and inclusion of nonpathogenic variants and can be readily applied outside of coding regions. When QNPL was used to analyze common variants, it often led to loci mapping to large intervals, e.g., >40 Mb. In contrast, when RVs are analyzed, regions are well defined, e.g., a gene. Using simulation studies, we demonstrate that RV-QNPL is substantially more powerful than applying traditional QNPL methods to analyze RVs. RV-QNPL was also applied to analyze age-at-onset (AAO) data for 107 late-onset Alzheimer’s disease (LOAD) pedigrees of Caribbean Hispanic and European ancestry with whole-genome sequence data. When AAO of AD was analyzed regardless of APOE e4 status, suggestive linkage (LOD = 2.4) was observed with RVs in KNDC1 and nominally significant linkage (p

Published
2020

19. Whole genome sequencing identifies loci specifically associated with thoracic aortic wall defects and abdominal aortic aneurysms in patients with European ancestry

Author

Rami O. Tadros, Edoardo Marcora, Robert A. Lookstein, Grace H. Miner, Ella Taubenfeld, Alan E. Renton, Peter L. Faries, and Michael L. Marin

Subjects
Morphology, medicine.medical_specialty, medicine.medical_treatment, Aortic dissection, Disease, Endovascular aneurysm repair, Internal medicine, medicine.artery, medicine, Genetics, Thoracic aorta, Diseases of the circulatory (Cardiovascular) system, Clinical significance, Genetic association, business.industry, Basic Reserch Study, medicine.disease, Aneurysm, Pathophysiology, Abdominal aortic aneurysm, RC666-701, Cardiology, cardiovascular system, business
Abstract

Objective The objective of this study was to better understand the pathophysiology and underlying genetic mechanisms behind two abdominal aortic aneurysm (AAA) subtypes using computed tomographic imaging in combination with whole genome sequencing. Methods Patients with a known AAA and European ancestry were included in this investigation and underwent genetic and image analysis. Patients with AAAs and indications of descending thoracic aortic pathology (aortic dissection, penetrating aortic ulcers, intramural hematoma, atheromas, ulcerative plaque, and intramural ulceration, and intimal flaps/tears) were classified as having thoracic aortic disease, grouped together, and compared with patients with an AAA and a normal descending thoracic aorta. Whole genome sequencing was then performed on the 93 patients who had imaging features consistent with thoracic aortic disease and the 126 patients with a normal descending thoracic aorta. Results The results of this study suggest one variant-level, four gene-level, and one gene set-level associations in patients with thoracic aortic disease who also had an AAA. The variant rs79508780 located in TSEN54 achieved study-wide significance (P = 1.71E-06). BATF3 and SMLR1 were significantly associated and EFCAB3 and TAF4 were reached suggestive assocation with a diseased descending thoracic aorta (P = 5.23E-26, P = 1.86E-25, P = 1.54E-05, and P = 8.31E-05, respectively). Gene sets were also compiled using MSigDB and trait-based index single nucleotide variation from major genome-wide association studies. GO_DNA_DOUBLE_STRAND_BREAK_PROCESSING, a gene set related to double-stranded DNA break repair, was significantly associated with thoracic aortic disease in AAA patients (P = 1.80E-06). Conclusions This pilot study provides further evidence that an AAA may be the end result of multiple degenerative pathways. Genetic variations in vitamin D signaling, cholesterol metabolism, extracellular matrix breakdown, and double-stranded DNA break repair pathways were associated with European patients who had an AAA and thoracic aortic disease. Additionally, this study provides support for the application of a radiogenomic approach for the investigation of other potential pathologies that could lead to the development of an AAA or influence future management decisions. (JVS–Vascular Science.) Clinical Relevance In this study, we provide evidence that abdominal aortic aneurysms (AAAs) may be a result of multiple pathophysiologies rather than a single disease. We have identified genetic variants involved in vitamin D signaling, cholesterol metabolism, extracellular matrix breakdown, and double-stranded DNA break repair associated with structural defects in the aortic wall in patients with AAAs who are of European descent. Patients with AAAs and structural defects in the thoracic aorta have been previously linked to differential behavior after endovascular aneurysm repair. These patients with wall defects exhibited greater sac regression, a marker of surgical success, after endovascular aneurysm repair. Our study demonstrates the usefulness of a radiogenomic approach for elucidating mechanisms behind the formation and future behavior of AAAs that could aid surgeons in making future procedural and management decisions.

Published
2020

20. Assessing Variant-Dependent Heterogeneity in β-Amyloid Burden in Autosomal Dominant Alzheimer’s Disease: a cross-sectional and longitudinal study

Author

Jasmeer P Chhatwal, Stephanie A Schultz, Eric McDade, Aaron P Schultz, Lei Liu, Bernard J Hanseeuw, Nelly Joseph-Mathurin, Rebecca Feldman, Colleen D Fitzpatrick, Kathryn P Sparks, Johannes Levin, Sarah B Berman, Alan E Renton, Bianca T Esposito, Maria Vitoria Fernandez, Yun Ju Sung, Jae Hong Lee, William E Klunk, Anna Hofmann, James M Noble, Neill Graff-Radford, Hiroshi Mori, Steven M Salloway, Colin L Masters, Ralph Martins, Celeste M Karch, Chengjie Xiong, Carlos Cruchaga, Richard J Perrin, Brian A Gordon, Tammie L S Benzinger, Nick C Fox, Peter R Schofield, Anne M Fagan, Alison M Goate, John C Morris, Randall J Bateman, Keith A Johnson, Reisa A Sperling, and UCL - SSS/IONS/NEUR - Clinical Neuroscience

Subjects
Heterozygote, Amyloid beta-Peptides, Adolescent, metabolism [Amyloid beta-Peptides], genetics [Alzheimer Disease], Article, Diagnosis, Differential, Cross-Sectional Studies, Alzheimer Disease, Positron-Emission Tomography, genetics [Amyloid beta-Peptides], Humans, ddc:610, Neurology (clinical), diagnostic imaging [Alzheimer Disease], metabolism [Alzheimer Disease], Biomarkers
Abstract

BackgroundInsights gained from studying individuals with autosomal dominant Alzheimer's disease have broadly influenced mechanistic hypotheses, biomarker development, and clinical trials in both sporadic and dominantly inherited Alzheimer's disease. Although pathogenic variants causing autosomal dominant Alzheimer's disease are highly penetrant, there is substantial heterogeneity in levels of amyloid β (Aβ) between individuals. We aimed to examine whether this heterogeneity is related to disease progression and to investigate the association with mutation location within PSEN1, PSEN2, or APP.MethodsWe did cross-sectional and longitudinal analyses of data from the Dominantly Inherited Alzheimer's Network (DIAN) observational study, which enrols individuals from families affected by autosomal dominant Alzheimer's disease. 340 participants in the DIAN study who were aged 18 years or older, had a history of autosomal dominant Alzheimer's disease in their family, and who were enrolled between September, 2008, and June, 2019, were included in our analysis. 206 participants were carriers of pathogenic mutations in PSEN1, PSEN2, or APP, and 134 were non-carriers. 62 unique pathogenic variants were identified in the cohort and were grouped in two ways. First, we sorted variants in PSEN1, PSEN2, or APP by the affected protein domain. Second, we divided PSEN1 variants according to position before or after codon 200. We examined variant-dependent variability in Aβ biomarkers, specifically Pittsburgh-Compound-B PET (PiB-PET) signal, levels of CSF Aβ1-42 (Aβ42), and levels of Aβ1-40 (Aβ40).FindingsCortical and striatal PiB-PET signal showed striking variant-dependent variability using both grouping approaches (p0·7), and CSF Aβ42 levels (codon-based grouping: p=0·49; domain-based grouping: p=0·095). Longitudinal PiB-PET signal also varied across codon-based groups, mirroring cross-sectional analyses.InterpretationAutosomal dominant Alzheimer's disease pathogenic variants showed highly differential temporal and regional patterns of PiB-PET signal, despite similar functional progression. These findings suggest that although increased PiB-PET signal is generally seen in autosomal dominant Alzheimer's disease, higher levels of PiB-PET signal at an individual level might not reflect more severe or more advanced disease. Our results have high relevance for ongoing clinical trials in autosomal dominant Alzheimer's disease, including those using Aβ PET as a surrogate marker of disease progression. Additionally, and pertinent to both sporadic and autosomal dominant Alzheimer's disease, our results suggest that CSF and PET measures of Aβ levels are not interchangeable and might reflect different Aβ-driven pathobiological processes.FundingNational Institute on Aging, Doris Duke Charitable Foundation, German Center for Neurodegenerative Diseases, Japanese Agency for Medical Research and Development.

Published
2022

21. Systematic validation of variants of unknown significance in PSEN1

Author

Bhagyashri Burgute, Alan E. Renton, Ellen Ziegemeier, Carlos Cruchaga, Alison M. Goate, Eric McDade, Jorge J Llibre‐Guerra, and Celeste M. Karch

Subjects
Psychiatry and Mental health, Cellular and Molecular Neuroscience, Developmental Neuroscience, Epidemiology, Health Policy, Neurology (clinical), Geriatrics and Gerontology
Published
2021

22. Genome-wide association study and functional validation implicates JADE1 in tauopathy

Author

Kurt Farrell, SoongHo Kim, Natalia Han, Megan A. Iida, Elias Gonzalez, Marcos Otero-Garcia, Jamie Walker, Tim Richardson, Alan E. Renton, Shea J. Andrews, Brian Fulton-Howard, Jack Humphrey, Ricardo A. Vialle, Kathryn R. Bowles, Kristen Whitney, Diana K. Dangoor, Edoardo Marcora, Marco M. Hefti, Alicia Casella, Cheick Sissoko, Manav Kapoor, Gloriia Novikova, Evan Udine, Garrett Wong, Weijing Tang, Tushar Bhangale, Julie Hunkapiller, Gai Ayalon, Rob Graham, Jonathan D. Cherry, Etty Cortes, Valeriy Borukov, Ann C. McKee, Thor D. Stein, Jean-Paul Vonsattel, Andy F. Teich, Marla Gearing, Jonathan Glass, Juan C. Troncoso, Matthew P. Frosch, Bradley T. Hyman, Dennis W. Dickson, Melissa E. Murray, Johannes Attems, Margaret E. Flanagan, Qinwen Mao, M-Marsel Mesulam, Sandra Weintraub, Randy Woltjer, Thao Pham, Julia Kofler, Julie A. Schneider, Lei Yu, Dushyant P. Purohit, Vahram Haroutunian, Patrick R. Hof, Sam Gandy, Mary Sano, Thomas G. Beach, Wayne Poon, Claudia Kawas, María Corrada, Robert A. Rissman, Jeff Metcalf, Sara Shuldberg, Bahar Salehi, Peter T. Nelson, John Q. Trojanowski, Edward B. Lee, David A. Wolk, Corey T. McMillan, Dirk C. Keene, Thomas J. Montine, Gabor G. Kovacs, Mirjam I. Lutz, Peter Fischer, Richard J. Perrin, Nigel Cairns, Erin E. Franklin, Herbert T. Cohen, Maria Inmaculada Cobos Sillero, Bess Frost, Towfique Raj, Alison Goate, Charles L. White, and John F. Crary

Subjects
medicine, Neurofibrillary tangle, Genome-wide association study, Single-nucleotide polymorphism, Tauopathy, Alzheimer's disease, Biology, medicine.disease, Molecular biology, Phenotype, Genetic association, Progressive supranuclear palsy
Abstract

Primary age-related tauopathy (PART) is a neurodegenerative tauopathy with features distinct from but also overlapping with Alzheimer disease (AD). While both exhibit Alzheimer-type temporal lobe neurofibrillary degeneration alongside amnestic cognitive impairment, PART develops independently of amyloid-β (Aβ) deposition in plaques. The pathogenesis of PART is unknown, but evidence suggests it is associated with genes that promote tau pathology as well as others that protect from Aβ toxicity. Here, we performed a genetic association study in an autopsy cohort of individuals with PART (n=647) using Braak neurofibrillary tangle stage as a quantitative trait adjusting for sex, age, genotyping platform, and principal components. We found significant associations with some candidate loci associated with AD and progressive supranuclear palsy, a primary tauopathy (SLC24A4, MS4A6A, HS3ST1, MAPT and EIF2AK3). Genome-wide association analysis revealed a novel significant association with a single nucleotide polymorphism on chromosome 4 (rs56405341) in a locus containing three genes, including JADE1 which was significantly upregulated in tangle-bearing neurons by single-soma RNA-seq. Immunohistochemical studies using antisera targeting JADE1 protein revealed localization within tau aggregates in autopsy brain from tauopathies containing isoforms with four microtubule-binding domain repeats (4R) and mixed 3R/4R, but not with 3R exclusively. Co-immunoprecipitation revealed a direct and specific binding of JADE1 protein to tau containing four (4R) and no N-terminal inserts (0N4R) in post-mortem human PART brain tissue. Finally, knockdown of the Drosophila JADE1 homolog rhinoceros (rno) enhanced tau-induced toxicity and apoptosis in vivo in a humanized 0N4R mutant tau knock-in model as quantified by rough eye phenotype and terminal deoxynucleotidyl transferase dUTP nick end-labeling (TUNEL) in the fly brain. Together, these findings indicate that PART has a genetic architecture that partially overlaps with AD and other tauopathies and suggests a novel role for JADE1 as a mediator of neurofibrillary degeneration.

Published
2021

23. A Rare Variant Nonparametric Linkage Method for Nuclear and Extended Pedigrees with Application to Late-Onset Alzheimer Disease via WGS Data

Author

Linhai Zhao, Richard Mayeux, Di Zhang, Gao Wang, Badri N. Vardarajan, Suzanne M. Leal, Zongxiao He, Alan E. Renton, Michael Nothnagel, and Alison Goate

Subjects
Male, 0301 basic medicine, Genetic Linkage, SORL1, Population, Pedigree chart, 030105 genetics & heredity, Biology, Article, 03 medical and health sciences, Alzheimer Disease, Locus heterogeneity, Genetics, medicine, Humans, Allele, education, Genetics (clinical), Genetic association, Linkage (software), education.field_of_study, Whole Genome Sequencing, Family aggregation, medicine.disease, Pedigree, 030104 developmental biology, Female
Abstract

To analyze family-based whole-genome sequence (WGS) data for complex traits, we developed a rare variant (RV) non-parametric linkage (NPL) analysis method, which has advantages over association methods. The RV-NPL differs from the NPL in that RVs are analyzed, and allele sharing among affected relative-pairs is estimated only for minor alleles. Analyzing families can increase power because causal variants with familial aggregation usually have larger effect sizes than those underlying sporadic diseases. Differing from association analysis, for NPL only affected individuals are analyzed, which can increase power, since unaffected family members can be susceptibility variant carriers. RV-NPL is robust to population substructure and admixture, inclusion of nonpathogenic variants, as well as allelic and locus heterogeneity and can readily be applied outside of coding regions. In contrast to analyzing common variants using NPL, where loci localize to large genomic regions (e.g., >50 Mb), mapped regions are well defined for RV-NPL. Using simulation studies, we demonstrate that RV-NPL is substantially more powerful than applying traditional NPL methods to analyze RVs. The RV-NPL was applied to analyze 107 late-onset Alzheimer disease (LOAD) pedigrees of Caribbean Hispanic and European ancestry with WGS data, and statistically significant linkage (LOD ≥ 3.8) was found with RVs in PSMF1 and PTPN21 which have been shown to be involved in LOAD etiology. Additionally, nominally significant linkage was observed with RVs in ABCA7, ACE, EPHA1, and SORL1, genes that were previously reported to be associated with LOAD. RV-NPL is an ideal method to elucidate the genetic etiology of complex familial diseases.

Published
2019

24. Editorial: Multifaceted Genes in Amyotrophic Lateral Sclerosis-Frontotemporal Dementia

Author

Henry Houlden, Francesca Luisa Conforti, and Alan E. Renton

Subjects
amyotrophic lateral sclerosis, business.industry, General Neuroscience, ALS - Amyotrophic lateral sclerosis, Neurosciences. Biological psychiatry. Neuropsychiatry, ALS-FTD spectrum, medicine.disease, Omics, omics, genomics, medicine, genetics, Amyotrophic lateral sclerosis, business, Gene, Neuroscience, RC321-571, Frontotemporal dementia
Published
2021

25. The National Institute on Aging Late Onset Alzheimer’s Disease Family Based Study: A Critical Component of the International Effort to Understand Alzheimer’s Disease

Author

Debby W. Tsuang, Robert S. Wilson, Michael J. Chao, Alan E. Renton, Kelley Faber, Tatiana Foroud, Richard Mayeux, Allison Goate, Dolly Reyes-Dumeyer, Robert A. Sweet, Badri N. Vardarajan, David A. Bennett, Roger N. Rosenberg, Margaret A. Pericak-Vance, B. F. Boeve, Carlos Cruchaga, and Haines Jl

Subjects
Apolipoprotein E, Gerontology, business.industry, Genetic heterogeneity, Medicine, Dementia, SNP, Neuropathology, Disease, First-degree relatives, business, medicine.disease, Frontotemporal dementia
Abstract

INTRODUCTIONThe National Institute on Aging Late-Onset Alzheimer’s Disease Family Based Study (NIA-LOAD FBS) was established to study the genetic etiology of Alzheimer’s disease (AD).METHODSRecruitment focused on families with two living affected siblings and a third first degree relative similar in age with or without dementia. Uniform assessments were completed, DNA was obtained as was neuropathology, when possible. APOE genotypes, genome-wide SNP arrays and sequencing was completed in the majority of families.RESULTSA wide range in the age-at-onset in many large families was related to APOE genotype, but not in all. Variants typically associated with early-onset AD and frontotemporal dementia were also found.DISCUSSIONThe NIA-LOAD FBS is the largest collection of familial AD worldwide, and data or samples have been included in 126 publications addressing the genetic etiology of AD. Genetic heterogeneity and variability in the age-at-onset provides opportunities to investigate the complexity of familial AD.

Published
2021

26. Polygenic score modifies risk for Alzheimer's disease in APOE ε4 homozygotes at phenotypic extremes

Author

John McNeil, Robert Sebra, Ingrid Winship, Paul A. James, Alan E. Renton, Brian Fulton-Howard, Elsdon Storey, Moeen Riaz, Joanne Ryan, Anne Murray, Alison Goate, Simon M. Laws, Colin L. Masters, Raj C. Shah, Paul Lacaze, and Aamira Huq

Subjects
Oncology, Apolipoprotein E, medicine.medical_specialty, Alzheimer's disease dementia, Genome-wide association study, Disease, Internal medicine, Genotype, medicine, Dementia, Allele, RC346-429, apolipoprotein E, dementia resilience, business.industry, RC952-954.6, Odds ratio, Alzheimer's disease, genetic modifiers, medicine.disease, Confidence interval, Psychiatry and Mental health, Geriatrics, polygenic risk score, Neurology. Diseases of the nervous system, Neurology (clinical), business
Abstract

Introduction Diversity in cognition among apolipoprotein E (APOE) ε4 homozygotes can range from early‐onset Alzheimer's disease (AD) to a lifetime with no symptoms. Methods We evaluated a phenotypic extreme polygenic risk score (PRS) for AD between cognitively healthy APOE ε4 homozygotes aged ≥75 years (n = 213) and early‐onset APOE ε4 homozygote AD cases aged ≤65 years (n = 223) as an explanation for this diversity. Results The PRS for AD was significantly higher in APOE ε4 homozygote AD cases compared to older cognitively healthy APOE ε4/ε4 controls (odds ratio [OR] 8.39; confidence interval [CI] 2.0–35.2; P = .003). The difference in the same PRS between APOE ε3/ε3 extremes was not as significant (OR 3.13; CI 0.98–9.92; P = .053) despite similar numbers and power. There was no statistical difference in an educational attainment PRS between these age extreme case‐controls. Discussion A PRS for AD contributes to modified cognitive expression of the APOE ε4/ε4 genotype at phenotypic extremes of risk.

Published
2021

27. Genetic studies of Alzheimer's disease risk implicate clearance of lipid rich debris in myeloid cells

Author

Anastasia M. Efthymiou, Panos Roussos, Ke Hao, Alan E. Renton, Wayne W. Poon, Jaroslav Bendl, Haoxiang M. Cheng, Alison Goate, Edoardo Marcora, Julia T.C.W., John F. Fullard, Gloriia Novikova, Manav Kapoor, and Edsel M. Abud

Subjects
Epidemiology, business.industry, Health Policy, Debris, Psychiatry and Mental health, Cellular and Molecular Neuroscience, Developmental Neuroscience, Myeloid cells, Immunology, Disease risk, Medicine, Neurology (clinical), Geriatrics and Gerontology, business
Published
2020

28. Functional molecular network models for the genetic risk factors of Alzheimer’s disease

Author

Bin Zhang, Erming Wang, Alan E. Renton, Minghui Wang, Alison Goate, Edoardo Marcora, and Chen Ming

Subjects
Epidemiology, Health Policy, Systems biology, Disease, Computational biology, Biology, Omics, Psychiatry and Mental health, Cellular and Molecular Neuroscience, Molecular network, Developmental Neuroscience, Neurology (clinical), Geriatrics and Gerontology, Genetic risk
Published
2020

29. Integration of Alzheimer’s disease genetics and myeloid genomics reveals novel disease risk mechanisms

Author

John F. Fullard, Alison Goate, Anastasia M. Efthymiou, Wayne W. Poon, Gloriia Novikova, Julia Tcw, Manav Kapoor, Ke Hao, Jaroslav Bendl, Edoardo Marcora, Haoxiang M. Cheng, Panos Roussos, Edsel M. Abud, and Alan E. Renton

Subjects
Myeloid, Epidemiology, business.industry, Health Policy, Genomics, Computational biology, Disease, Psychiatry and Mental health, Cellular and Molecular Neuroscience, medicine.anatomical_structure, Developmental Neuroscience, medicine, Disease risk, Neurology (clinical), Geriatrics and Gerontology, business
Published
2020

30. Pathogenic huntingtin repeat expansions in patients with frontotemporal dementia and amyotrophic lateral sclerosis

Author

Ramita Dewan, Ruth Chia, Jinhui Ding, Richard A. Hickman, Thor D. Stein, Yevgeniya Abramzon, Sarah Ahmed, Marya S. Sabir, Makayla K. Portley, Arianna Tucci, Kristina Ibáñez, F.N.U. Shankaracharya, Pamela Keagle, Giacomina Rossi, Paola Caroppo, Fabrizio Tagliavini, Maria L. Waldo, Per M. Johansson, Christer F. Nilsson, James B. Rowe, Luisa Benussi, Giuliano Binetti, Roberta Ghidoni, Edwin Jabbari, Coralie Viollet, Jonathan D. Glass, Andrew B. Singleton, Vincenzo Silani, Owen A. Ross, Mina Ryten, Ali Torkamani, Toshiko Tanaka, Luigi Ferrucci, Susan M. Resnick, Stuart Pickering-Brown, Christopher B. Brady, Neil Kowal, John A. Hardy, Vivianna Van Deerlin, Jean Paul Vonsattel, Matthew B. Harms, Huw R. Morris, Raffaele Ferrari, John E. Landers, Adriano Chiò, J. Raphael Gibbs, Clifton L. Dalgard, Sonja W. Scholz, Bryan J. Traynor, Adelani Adeleye, Camille Alba, Dagmar Bacikova, Daniel N. Hupalo, Elisa McGrath Martinez, Harvey B. Pollard, Gauthaman Sukumar, Anthony R. Soltis, Meila Tuck, Xijun Zhang, Matthew D. Wilkerson, Bradley N. Smith, Nicola Ticozzi, Claudia Fallini, Athina Soragia Gkazi, Simon D. Topp, Jason Kost, Emma L. Scotter, Kevin P. Kenna, Jack W. Miller, Cinzia Tiloca, Caroline Vance, Eric W. Danielson, Claire Troakes, Claudia Colombrita, Safa Al-Sarraj, Elizabeth A. Lewis, Andrew King, Daniela Calini, Viviana Pensato, Barbara Castellotti, Jacqueline de Belleroche, Frank Baas, Anneloor L.M.A. ten Asbroek, Peter C. Sapp, Diane McKenna-Yasek, Russell L. McLaughlin, Meraida Polak, Seneshaw Asress, Jesús Esteban-Pérez, José Luis Muñoz-Blanco, Zorica Stevic, Sandra D’Alfonso, Letizia Mazzini, Giacomo P. Comi, Roberto Del Bo, Mauro Ceroni, Stella Gagliardi, Giorgia Querin, Cinzia Bertolin, Wouter van Rheenen, Frank P. Diekstra, Rosa Rademakers, Marka van Blitterswijk, Kevin B. Boylan, Giuseppe Lauria, Stefano Duga, Stefania Corti, Cristina Cereda, Lucia Corrado, Gianni Sorarù, Kelly L. Williams, Garth A. Nicholson, Ian P. Blair, Claire Leblond-Manry, Guy A. Rouleau, Orla Hardiman, Karen E. Morrison, Jan H. Veldink, Leonard H. van den Berg, Ammar Al-Chalabi, Hardev Pall, Pamela J. Shaw, Martin R. Turner, Kevin Talbot, Franco Taroni, Alberto García-Redondo, Zheyang Wu, Cinzia Gellera, Antonia Ratti, Robert H. Brown, Christopher E. Shaw, John C. Ambrose, Prabhu Arumugam, Emma L. Baple, Marta Bleda, Freya Boardman-Pretty, Jeanne M. Boissiere, Christopher R. Boustred, H. Brittain, Mark J. Caulfield, Georgia C. Chan, Clare E.H. Craig, Louise C. Daugherty, Anna de Burca, Andrew Devereau, Greg Elgar, Rebecca E. Foulger, Tom Fowler, Pedro Furió-Tarí, Joanne M. Hackett, Dina Halai, Angela Hamblin, Shirley Henderson, James E. Holman, Tim J.P. Hubbard, Rob Jackson, Louise J. Jones, Dalia Kasperaviciute, Melis Kayikci, Lea Lahnstein, Kay Lawson, Sarah E.A. Leigh, Ivonne U.S. Leong, Javier F. Lopez, Fiona Maleady-Crowe, Joanne Mason, Ellen M. McDonagh, Loukas Moutsianas, Michael Mueller, Nirupa Murugaesu, Anna C. Need, Chris A. Odhams, Christine Patch, Daniel Perez-Gil, Dimitris Polychronopoulos, John Pullinger, Tahrima Rahim, Augusto Rendon, Pablo Riesgo-Ferreiro, Tim Rogers, Kevin Savage, Kushmita Sawant, Richard H. Scott, Afshan Siddiq, Alexander Sieghart, Damian Smedley, Katherine R. Smith, Alona Sosinsky, William Spooner, Helen E. Stevens, Alexander Stuckey, Razvan Sultana, Ellen R.A. Thomas, Simon R. Thompson, Carolyn Tregidgo, Emma Walsh, Sarah A. Watters, Matthew J. Welland, Eleanor Williams, Katarzyna Witkowska, Suzanne M. Wood, Magdalena Zarowiecki, Sampath Arepalli, Pavan Auluck, Robert H. Baloh, Robert Bowser, Alexis Brice, James Broach, William Camu, John Cooper-Knock, Philippe Corcia, Carsten Drepper, Vivian E. Drory, Travis L. Dunckley, Faraz Faghri, Jennifer Farren, Eva Feldman, Mary Kay Floeter, Pietro Fratta, Glenn Gerhard, Summer B. Gibson, Stephen A. Goutman, Terry D. Heiman-Patterson, Dena G. Hernandez, Ben Hoover, Lilja Jansson, Freya Kamel, Janine Kirby, Neil W. Kowall, Hannu Laaksovirta, Francesco Landi, Isabelle Le Ber, Serge Lumbroso, Daniel JL. MacGowan, Nicholas J. Maragakis, Gabriele Mora, Kevin Mouzat, Liisa Myllykangas, Mike A. Nalls, Richard W. Orrell, Lyle W. Ostrow, Roger Pamphlett, Erik Pioro, Stefan M. Pulst, John M. Ravits, Alan E. Renton, Wim Robberecht, Ian Robey, Ekaterina Rogaeva, Jeffrey D. Rothstein, Michael Sendtner, Katie C. Sidle, Zachary Simmons, David J. Stone, Pentti J. Tienari, John Q. Trojanowski, Juan C. Troncoso, Miko Valori, Philip Van Damme, Ludo Van Den Bosch, Lorne Zinman, Diego Albani, Barbara Borroni, Alessandro Padovani, Amalia Bruni, Jordi Clarimon, Oriol Dols-Icardo, Ignacio Illán-Gala, Alberto Lleó, Adrian Danek, Daniela Galimberti, Elio Scarpini, Maria Serpente, Caroline Graff, Huei-Hsin Chiang, Behzad Khoshnood, Linn Öijerstedt, Christopher M. Morris, Benedetta Nacmias, Sandro Sorbi, Jorgen E. Nielsen, Lynne E. Hjermind, Valeria Novelli, Annibale A. Puca, Pau Pastor, Ignacio Alvarez, Monica Diez-Fairen, Miquel Aguilar, Robert Perneczky, Janine Diehl-Schimd, Mina Rossi, Agustin Ruiz, Mercè Boada, Isabel Hernández, Sonia Moreno-Grau, Johannes C. Schlachetzki, Dag Aarsland, Marilyn S. Albert, Johannes Attems, Matthew J. Barrett, Thomas G. Beach, Lynn M. Bekris, David A. Bennett, Lilah M. Besser, Eileen H. Bigio, Sandra E. Black, Bradley F. Boeve, Ryan C. Bohannan, Francesca Brett, Maura Brunetti, Chad A. Caraway, Jose-Alberto Palma, Andrea Calvo, Antonio Canosa, Dennis Dickson, Charles Duyckaerts, Kelley Faber, Tanis Ferman, Margaret E. Flanagan, Gianluca Floris, Tatiana M. Foroud, Juan Fortea, Ziv Gan-Or, Steve Gentleman, Bernardino Ghetti, Jesse Raphael Gibbs, Alison Goate, David Goldstein, Isabel González-Aramburu, Neill R. Graff-Radford, Angela K. Hodges, Heng-Chen Hu, Daniel Hupalo, Jon Infante, Alex Iranzo, Scott M. Kaiser, Horacio Kaufmann, Julia Keith, Ronald C. Kim, Gregory Klein, Rejko Krüger, Walter Kukull, Amanda Kuzma, Carmen Lage, Suzanne Lesage, James B. Leverenz, Giancarlo Logroscino, Grisel Lopez, Seth Love, Qinwen Mao, Maria Jose Marti, Elisa Martinez-McGrath, Mario Masellis, Eliezer Masliah, Patrick May, Ian McKeith, Marek-Marsel Mesulam, Edwin S. Monuki, Kathy L. Newell, Lucy Norcliffe-Kaufmann, Laura Palmer, Matthew Perkins, Olga Pletnikova, Laura Molina-Porcel, Regina H. Reynolds, Eloy Rodríguez-Rodríguez, Jonathan D. Rohrer, Pascual Sanchez-Juan, Clemens R. Scherzer, Geidy E. Serrano, Vikram Shakkottai, Ellen Sidransky, Nahid Tayebi, Alan J. Thomas, Bension S. Tilley, Ronald L. Walton, Randy Woltjer, Zbigniew K. Wszolek, Georgia Xiromerisiou, Chiara Zecca, Hemali Phatnani, Justin Kwan, Dhruv Sareen, James R. Broach, Ximena Arcila-Londono, Edward B. Lee, Neil A. Shneider, Ernest Fraenkel, Noah Zaitlen, James D. Berry, Andrea Malaspina, Gregory A. Cox, Leslie M. Thompson, Steve Finkbeiner, Efthimios Dardiotis, Timothy M. Miller, Siddharthan Chandran, Suvankar Pal, Eran Hornstein, Daniel J. MacGowan, Terry Heiman-Patterson, Molly G. Hammell, Nikolaos.A. Patsopoulos, Oleg Butovsky, Joshua Dubnau, Avindra Nath, Matt Harms, Eleonora Aronica, Mary Poss, Jennifer Phillips-Cremins, John Crary, Nazem Atassi, Dale J. Lange, Darius J. Adams, Leonidas Stefanis, Marc Gotkine, Suma Babu, Towfique Raj, Sabrina Paganoni, Ophir Shalem, Colin Smith, Bin Zhang, Brent Harris, Iris Broce, Vivian Drory, John Ravits, Corey McMillan, Vilas Menon, Lani Wu, Steven Altschuler, Khaled Amar, Neil Archibald, Oliver Bandmann, Erica Capps, Alistair Church, Jan Coebergh, Alyssa Costantini, Peter Critchley, Boyd CP. Ghosh, Michele T.M. Hu, Christopher Kobylecki, P. Nigel Leigh, Carl Mann, Luke A. Massey, Uma Nath, Nicola Pavese, Dominic Paviour, Jagdish Sharma, Jenny Vaughan, HUS Neurocenter, Neurologian yksikkö, Department of Neurosciences, Clinicum, Pentti Tienari / Principal Investigator, Parkinson's UK, Human Genetics, ARD - Amsterdam Reproduction and Development, ANS - Complex Trait Genetics, Pathology, ANS - Cellular & Molecular Mechanisms, AII - Inflammatory diseases, Universidad de Cantabria, Rowe, James [0000-0001-7216-8679], and Apollo - University of Cambridge Repository

Subjects
0301 basic medicine, Huntington's Disease, Pathology, amyotrophic lateral sclerosis, Huntingtin, Neurology, 1702 Cognitive Sciences, International ALS/FTD Genomics Consortium, Neurodegenerative, frontotemporal dementia, 3124 Neurology and psychiatry, 0302 clinical medicine, Medicine, 2.1 Biological and endogenous factors, Psychology, Amyotrophic lateral sclerosis, Aetiology, Alzheimer's Disease Related Dementias (ADRD), NYGC ALS Consortium, Huntingtin Protein, DNA Repeat Expansion, General Neuroscience, Frontotemporal Dementia (FTD), International FTD Genetics Consortium, whole-genome sequencing, Frontotemporal Dementia, Neurological, Cognitive Sciences, Lewy body dementia, huntingtin, repeat expansions, Amyotrophic Lateral Sclerosis, Humans, Mutation, Whole Genome Sequencing, Frontotemporal dementia, Huntington’s disease, medicine.medical_specialty, congenital, hereditary, and neonatal diseases and abnormalities, FALS Sequencing Consortium, Article, 03 medical and health sciences, Atrophy, Rare Diseases, American Genome Center, Clinical Research, mental disorders, Genetics, Acquired Cognitive Impairment, Dementia, PROSPECT Consortium, Neurology & Neurosurgery, Lewy body, business.industry, International LBD Genomics Consortium, Neurosciences, 3112 Neurosciences, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), nutritional and metabolic diseases, medicine.disease, Brain Disorders, nervous system diseases, 030104 developmental biology, Genomics England Research Consortium, 1701 Psychology, ALS, business, 1109 Neurosciences, 030217 neurology & neurosurgery
Abstract

Hannu Laaksovirta konsortion jäsenenä. The Genomics England Research Consortium, The International ALS/FTD Genomics Consortium (iAFGC), The International FTD Genetics Consortium (IFGC), The International LBD Genomics Consortium (iLBDGC), The NYGC ALS Consortium, The PROSPECT Consortium,17 James B. Rowe,17 Luisa Benussi,18 Giuliano Binetti,18,19 Roberta Ghidoni,18 Edwin Jabbari,20,21 Coralie Viollet,22 Jonathan D. Glass,23 Andrew B. Singleton,24 Vincenzo Silani,25,26 Owen A. Ross,27 Mina Ryten,8,28,29 Ali Torkamani,30 Toshiko Tanaka,31 Luigi Ferrucci,31 Susan M. Resnick,32 We examined the role of repeat expansions in the pathogenesis of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) by analyzing whole-genome sequence data from 2,442 FTD/ALS patients, 2,599 Lewy body dementia (LBD) patients, and 3,158 neurologically healthy subjects. Pathogenic expansions (range, 40?64 CAG repeats) in the huntingtin (HTT) gene were found in three (0.12%) patients diagnosed with pure FTD/ALS syndromes but were not present in the LBD or healthy cohorts. We replicated our findings in an independent collection of 3,674 FTD/ALS patients. Postmortem evaluations of two patients revealed the classical TDP-43 pathology of FTD/ALS, as well as huntingtin-positive, ubiquitin-positive aggregates in the frontal cortex. The neostriatal atrophy that pathologically defines Huntington?s disease was absent in both cases. Our findings reveal an etiological relationship between HTT repeat expansions and FTD/ALS syndromes and indicate that genetic screening of FTD/ALS patients for HTT repeat expansions should be considered. We examined the role of repeat expansions in the pathogenesis of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) by analyzing whole-genome sequence data from 2,442 FTD/ALS patients, 2,599 Lewy body dementia (LBD) patients, and 3,158 neurologically healthy subjects. Pathogenic expansions (range, 40?64 CAG repeats) in the huntingtin (HTT) gene were found in three (0.12%) patients diagnosed with pure FTD/ALS syndromes but were not present in the LBD or healthy cohorts. We replicated our findings in an independent collection of 3,674 FTD/ALS patients. Postmortem evaluations of two patients revealed the classical TDP-43 pathology of FTD/ALS, as well as huntingtin-positive, ubiquitin-positive aggregates in the frontal cortex. The neostriatal atrophy that pathologically defines Huntington?s disease was absent in both cases. Our findings reveal an etiological relationship between HTT repeat expansions and FTD/ALS syndromes and indicate that genetic screening of FTD/ALS patients for HTT repeat expansions should be considered.

Published
2020

31. Beyond association: successes and challenges in linking non-coding genetic variation to functional consequences that modulate Alzheimer's disease risk

Author

Gloriia Novikova, Edoardo Marcora, Shea J. Andrews, and Alan E. Renton

Subjects
0301 basic medicine, Epigenomics, Risk, Genome-wide association study, Disease, Computational biology, Review, Biology, Polymorphism, Single Nucleotide, 03 medical and health sciences, Cellular and Molecular Neuroscience, 0302 clinical medicine, Alzheimer Disease, medicine, Dementia, Humans, Age of Onset, Non-coding variants, RC346-429, Molecular Biology, Genetic association, Gene Editing, Models, Genetic, Fine-mapping methods, Variant prioritization, RC952-954.6, Bayes Theorem, Molecular Sequence Annotation, Functional genomics, Evidence-based medicine, medicine.disease, Chromatin, Causality, 030104 developmental biology, Gene Expression Regulation, Geriatrics, Myeloid cells, Gene prioritization, Identification (biology), Neurology (clinical), Neurology. Diseases of the nervous system, CRISPR-Cas Systems, Transcriptome, Alzheimer’s disease, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract

Alzheimer’s disease (AD) is the most common type of dementia, affecting millions of people worldwide; however, no disease-modifying treatments are currently available. Genome-wide association studies (GWASs) have identified more than 40 loci associated with AD risk. However, most of the disease-associated variants reside in non-coding regions of the genome, making it difficult to elucidate how they affect disease susceptibility. Nonetheless, identification of the regulatory elements, genes, pathways and cell type/tissue(s) impacted by these variants to modulate AD risk is critical to our understanding of disease pathogenesis and ability to develop effective therapeutics. In this review, we provide an overview of the methods and approaches used in the field to identify the functional effects of AD risk variants in the causal path to disease risk modification as well as describe the most recent findings. We first discuss efforts in cell type/tissue prioritization followed by recent progress in candidate causal variant and gene nomination. We discuss statistical methods for fine-mapping as well as approaches that integrate multiple levels of evidence, such as epigenomic and transcriptomic data, to identify causal variants and risk mechanisms of AD-associated loci. Additionally, we discuss experimental approaches and data resources that will be needed to validate and further elucidate the effects of these variants and genes on biological pathways, cellular phenotypes and disease risk. Finally, we discuss future steps that need to be taken to ensure that AD GWAS functional mapping efforts lead to novel findings and bring us closer to finding effective treatments for this devastating disease.

Published
2020

32. Effect of APOE and a polygenic risk score on incident dementia and cognitive decline in a healthy older population

Author

Raj C. Shah, Anne M. Murray, Eric E. Schadt, Robert Sebra, John J McNeil, Jessica E. Lockery, Joanne Ryan, Moeen Riaz, Suzanne G Orchard, Robyn L. Woods, Alan E. Renton, Paul Lacaze, Elsdon Storey, Rory Wolfe, Alison Goate, Aamira Huq, Jane Tiller, and Amy Brodtmann

Subjects
Psychomotor learning, Apolipoprotein E, education.field_of_study, business.industry, Population, Cognition, medicine.disease, Relative risk, medicine, Dementia, Cumulative incidence, Cognitive decline, education, business, Demography
Abstract

ImportanceFew studies have measured the effect of genetic factors on dementia and cognitive decline in a population of healthy older individuals followed prospectively.ObjectiveTo examine the effect of Apolipoprotein E (APOE) genotypes and a polygenic risk score (PRS) on incident dementia and cognitive decline in a longitudinal cohort of healthy older people.Design, Setting and ParticipantsPost-hoc genetic analysis of a randomized clinical trial population - the ASPirin in Reducing Events in the Elderly (ASPREE) trial. At enrollment, participants had no history of diagnosed dementia, atherothrombotic cardiovascular disease, or permanent physical disability and were without cognitive impairment.Main Outcomes and MeasuresDementia (adjudicated trial endpoint) and cognitive decline, defined as a >1.5 standard deviation decline in test score for either global cognition, episodic memory, language/executive function or psychomotor speed, versus baseline scores. Cumulative incidence curves for all-cause dementia and cognitive decline were calculated with mortality as a competing event, stratified by APOE genotypes and tertiles of a PRS based on 23 common non-APOE variants.Results12,978 participants with European ancestry were included; 54.8% were female, and average age at baseline was 75 years (range 70 to 96). During a median 4.5 years of follow-up, 324 (2.5%) participants developed dementia and 503 (3.8%) died. Cumulative incidence of dementia to age 85 years was estimated to be 7.4% in all participants, 12.6% in APOE ε4 heterozygotes, 26.6% in ε4 homozygotes, 9.6% in the high PRS tertile, and 7.3% in the low PRS tertile. APOE ε4 heterozygosity/homozygosity was associated with a 2.5/6.3-fold increased risk of dementia and a 1.4/1.8-fold increased risk of cognitive decline, versus ε3/ε3 (PConclusions and RelevanceIncidence of dementia among healthy older individuals is low across all genotypes; however, APOE ε4 and high PRS increase relative risk. APOE ε4 is associated with cognitive decline, but PRS is not.KEY POINTSQuestionHow do genetic factors influence the risk of dementia and cognitive decline among healthy older individuals?FindingsWe studied cumulative incidence of dementia and cognitive decline in 12,978 healthy older individuals without cardiovascular disease or cognitive impairment at enrollment, stratified by APOE genotype and a polygenic risk score (PRS). APOE ε4 and PRS increased the relative risk of dementia, but cumulative incidence was low across all genotypes. APOE genotypes were associated with cognitive decline, but PRS was not.MeaningIncidence of dementia is low among healthy older individuals; however, genetic factors still increase relative risk.

Published
2020

33. Genome sequencing analysis identifies new loci associated with Lewy body dementia and provides insights into the complex genetic architecture

Author

Pentti J. Tienari, James B. Leverenz, Nahid Tayebi, Gabriele Mora, Bradley F. Boeve, Laura Palmer, Steve M. Gentleman, Ellen Sidransky, Pau Pastor, Liana S. Rosenthal, G. Xiromerisiou, Sara Saez-Atienzar, Francesco Landi, Scott M. Kaiser, Qinwen Mao, Claire Troakes, Peter St George-Hyslop, Andrea Calvo, Suzanne Lesage, Mario Masellis, Randy Woltjer, Marilyn S. Albert, Thomas T. Warner, Lorraine N. Clark, Gregory Klein, Charles Duyckaerts, Seth Love, Ed Monuki, Lawrence S. Honig, Kelley Faber, Dennis W. Dickson, Lucy Norcliffe-Kaufmann, Cornelis Blauwendraat, Ronald C. Kim, Kevin Morgan, Clifton L. Dalgard, Joshua T. Geiger, Ali Torkamani, Jinhui Ding, Juan Fortea, Eliezer Masliah, Ekaterina Rogaeva, Matthew H. Perkins, Clemens R. Scherzer, John Q. Trojanowski, Zbigniew K. Wszolek, Glenda M. Halliday, Jordi Clarimón, Sonja W. Scholz, Olaf Ansorge, Makayla K. Portley, Toshiko Tanaka, Mary B. Makarious, Safa Al-Sarraj, Giancarlo Logroscino, John D. Eicher, Neill R. Graff-Radford, Carmen Lage, Ziv Gan-Or, Francesca Brett, Alison Goate, Raffaele Ferrari, John C. Morris, J. Raphael Gibbs, Lynn M. Bekris, Jose-Alberto Palma, Angela K. Hodges, Regina H. Reynolds, Alexis Brice, Monica Diez-Fairen, Coralie Viollet, Patrick May, Minna Oinas, Erika Salvi, Vivianna M. Van Deerlin, Estrella Morenas-Rodríguez, Anni Moore, Zane Jaunmuktane, Eileen H. Bigio, Daniele Cusi, Douglas Galasko, Ruth Chia, Kathy L. Newell, Isabel Santana, Claudia Schulte, David Goldstein, Thomas Gasser, Owen A. Ross, Walter A. Kukull, Tatiana Foroud, Chad A. Caraway, David A. Bennett, Samreen Ahmed, Lilah M. Besser, Antonio Canosa, Daniel Alcolea, Yevgeniya Abramzon, Elisabet Londos, Laura Parkkinen, Sandra E. Black, Eric Topol, Marya S. Sabir, Olga Pletnikova, Grisel Lopez, Tanis J. Ferman, Johannes Attems, Matthew J. Barrett, Margaret E. Flanagan, Horacio Kaufmann, Stuart Pickering Brown, Jon Infante, Ryan C. Bohannan, Alberto Lleó, Eloy Rodríguez-Rodríguez, Huw R. Morris, Gianluca Floris, Ted M. Dawson, Maura Brunetti, Alan E. Renton, Andrew B. Singleton, Karen Marder, Alan J. Thomas, Pascual Sanchez-Juan, Adriano Chiò, Nigel J. Cairns, David J. Stone, Tammaryn Lashley, Mike A. Nalls, Bernardino Ghetti, Sara Bandres-Ciga, Zalak Shah, Ian G. McKeith, Susan M. Resnick, Julia Keith, Liisa Myllykangas, Diego Albani, Christopher M. Morris, Vikram Shakkottai, M. Ryten, Ronald L. Walton, Isabel González-Aramburu, Luigi Ferrucci, Bryan J. Traynor, Amanda B. Kuzma, Afina W. Lemstra, Thomas G. Beach, Juan C. Troncoso, Emil K. Gustavsson, Maurizio Grassano, John Hardy, Geidy E. Serrano, Rejko Krüger, Dag Aarsland, Bension S. Tilley, and Dena G. Hernandez

Subjects
0303 health sciences, Lewy body, Disease, Computational biology, Biology, medicine.disease, DNA sequencing, Genetic architecture, 03 medical and health sciences, 0302 clinical medicine, medicine, Dementia, Genetic risk, Gene, 030217 neurology & neurosurgery, 030304 developmental biology, Genetic association
Abstract

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

Published
2020

34. 17q21.31 Sub-Haplotypes Underlying H1-Associated Risk for Parkinson's Disease and Progressive Supranuclear Palsy Converge on Altered Glial Regulation

Author

Kathryn Bowles, Derian A. Pugh, Kurt Farrell, Natalia Han, Julia TCW, Y. Liu, Shiang An Liang, Lu Qian, Jaroslav Bendl, John F. Fullard, Alan E. Renton, Alicia Casella, Megan A. Iida, Sara Bandres-Ciga, Ziv Gan-Or, Peter Heutink, Ari Siitonen, Sarah Bertelsen, Celeste M. Karch, Steven J. Frucht, Brian H. Kopell, Inga Peter, You Jeong Park, PK Crane, John SK Kauwe, Kevin L. Boehme, Guenter U. Hoglinger, PART Working Group, International Parkinson’s Disease G Consortium (IPDGC), Progressive Supranuclear Palsy Gene Consortium, Alexander Charney, Panagiotis Roussos, JC Wang, Wayne W. Poon, Towfique Raj, John F. Crary, and Alison M. Goate

Subjects
Structural variation, Genetics, Parkinson's disease, Movement disorders, Haplotype, medicine, Locus (genetics), Disease, Tauopathy, medicine.symptom, Biology, medicine.disease, Progressive supranuclear palsy
Abstract

Parkinson’s disease (PD) and progressive supranuclear palsy (PSP) are clinically similar neurodegenerative movement disorders that display unique neuropathological features (i.e. Lewy body pathology and Tau pathology, respectively). While each disorder has distinct clinical and genetic risk factors, both are associated with the MAPT 17q.21.31 locus H1 haplotype. This suggests a pleiotropic effect of this genomic region. To better understand the genetic contribution of this region to these diseases, we fine-mapped the apparent pleiotropy of this locus. Our study indicates that PD and PSP are associated with different sub-haplotypes of the H1 clade. PD-associated sub-haplotypes were associated with altered LRRC37A copy number and expression, which, like other PD risk-associated genes, we hypothesize to be most relevant to astroglial function. In contrast, PSP was associated with grossly altered LD structure across the 17q21.31 locus, and risk-associated variants were found to impact chromatin structure in both neurons and microglia. We conclude that the contribution of the 17q21.31 locus to multiple disorders is a result of its structural and haplotypic complexity, which in turn impacts the regulation of multiple genes and neural cell types. This raises the possibility of novel disease-specific pathogenic mechanisms driven by 17q21.31 structural variation and altered epigenetic regulation that appear to converge on glial function and gene expression. By fine-mapping the association of H1 with PD and PSP, we have begun to untangle the apparent pleiotropy of this locus, and gain better insight into the mechanism of each disease, which will guide future functional analyses and disease models for PD and PSP.

Published
2020

35. Whole exome sequencing study identifies novel rare and common Alzheimer’s-Associated variants involved in immune response and transcriptional regulation

Author

Joshua C. Bis, Li-San Wang, Waleed Nasser, Giuseppe Tosto, Jean-Charles Lambert, Gary W. Beecham, Lucinda Fulton, Eric Boerwinkle, Reinhold Schmidt, Kara L. Hamilton-Nelson, Josée Dupuis, Cornelia M. van Duijn, Yuning Chen, Stéphanie Debette, Devanshi Patel, Philippe Amouyel, Gaël Nicolas, Farid Rajabli, Mark J. Daly, Richard Redon, Hilkka Soininen, Anita L. DeStefano, Aki S. Havulinna, Weixin Wang, Margaret A. Pericak-Vance, Chloé Sarnowski, Gerard D. Schellenberg, William S. Bush, Eden R. Martin, John J. Farrell, Richard A. Gibbs, Richard Mayeux, Emmanuelle Génin, Yi Zhao, Kwangsik Nho, Céline Bellenguez, Kari Mattila, Jean-François Deleuze, William J Salerno, Alzheimer’s Disease Sequencing, Brian W. Kunkle, Dominique Campion, Mikko Hiltunen, Richard K. Wilson, Sudha Seshadri, Paul K. Crane, Otto Valladares, Jennifer E. Below, Adam C. Naj, Timothy A. Thornton, Stacey Gabriel, Jan Konrad, Markus Perola, Mark Lathrop, Namrata Gupta, Badri N. Vardarajan, Bruce M. Psaty, Seppo Helisalmi, Jonathan L. Haines, Yiyi Ma, Honghuang Lin, Laura B. Cantwell, Carlos Cruchaga, Alan E. Renton, Terho Lehtimäki, Anne M. Remes, Michael A. Schmidt, Benjamin M. Neale, M. Arfan Ikram, Lindsay A. Farrer, Myriam Fornage, Daniel P. Howrigan, Ellen M. Wijsman, Mitja I. Kurki, Helena Schmidt, Aarno Palotie, Daniel Lancour, Camille Charbonnier, Daniela Witten, Liming Qu, Najaf Amin, Eric S. Lander, Alison Goate, Donna M. Muzny, Kathryn L. Lunetta, Jaakko Kaprio, Edoardo Marcora, Amanda B. Kuzma, Sven J. van der Lee, Shahzad Ahmad, Kim C. Worley, Christophe Tzourio, Benjamin Grenier-Boley, Jean-François Dartigues, L. Adrienne Cupples, Veikko Salomaa, Jaeyoon Chung, Christiane Reitz, Xueqiu Jian, Xiaoling Zhang, Olivier Quenez, Medicum, Institute for Molecular Medicine Finland, Complex Disease Genetics, University of Helsinki, Centre of Excellence in Complex Disease Genetics, Research Programs Unit, Aarno Palotie / Principal Investigator, Genomics of Neurological and Neuropsychiatric Disorders, HUS Helsinki and Uusimaa Hospital District, Facteurs de Risque et Déterminants Moléculaires des Maladies liées au Vieillissement - U 1167 (RID-AGE), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Génomique et Médecine Personnalisée du Cancer et des Maladies Neuropsychiatriques (GPMCND), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Rouen, Normandie Université (NU), Bordeaux population health (BPH), Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Bordeaux [Bordeaux], Centre National de Recherche en Génomique Humaine (CNRGH), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Génétique, génomique fonctionnelle et biotechnologies (UMR 1078) (GGB), EFS-Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO), Unité de recherche de l'institut du thorax (ITX-lab), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO)-Université de Brest (UBO)-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM), unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and Epidemiology

Subjects
Male, 0301 basic medicine, DYSBINDIN GENE DTNBP1, Transcription, Genetic, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, SORL1, PROTEIN, Diseases, Genome-wide association study, SUSCEPTIBILITY, [SDV.IMM.II]Life Sciences [q-bio]/Immunology/Innate immunity, DISEASE, ABCA7, 0302 clinical medicine, Exome sequencing, Aged, 80 and over, Genetics, RISK, 3. Good health, Psychiatry and Mental health, [SDV.IMM.IA]Life Sciences [q-bio]/Immunology/Adaptive immunology, Female, RNA, Long Noncoding, Alzheimer's disease, Immunoglobulin gene, EXPRESSION, Kruppel-Like Transcription Factors, Biology, Article, CODING MUTATIONS, 03 medical and health sciences, Cellular and Molecular Neuroscience, Apolipoproteins E, Alzheimer Disease, Exome Sequencing, medicine, Humans, GENOME-WIDE ASSOCIATION, Molecular Biology, Gene, Genotyping, Aged, Amyloid beta-Peptides, Polymorphism, Genetic, [SDV.GEN.GPO]Life Sciences [q-bio]/Genetics/Populations and Evolution [q-bio.PE], Haplotype, Immunity, 3112 Neurosciences, Correction, medicine.disease, 030104 developmental biology, Gene Expression Regulation, Haplotypes, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Immunoglobulin G, 3111 Biomedicine, 030217 neurology & neurosurgery
Abstract

The Alzheimer’s Disease Sequencing Project (ADSP) undertook whole exome sequencing in 5,740 late-onset Alzheimer disease (AD) cases and 5,096 cognitively normal controls primarily of European ancestry (EA), among whom 218 cases and 177 controls were Caribbean Hispanic (CH). An age-, sex- and APOE based risk score and family history were used to select cases most likely to harbor novel AD risk variants and controls least likely to develop AD by age 85 years. We tested ~1.5 million single nucleotide variants (SNVs) and 50,000 insertion-deletion polymorphisms (indels) for association to AD, using multiple models considering individual variants as well as gene-based tests aggregating rare, predicted functional, and loss of function variants. Sixteen single variants and 19 genes that met criteria for significant or suggestive associations after multiple-testing correction were evaluated for replication in four independent samples; three with whole exome sequencing (2,778 cases, 7,262 controls) and one with genome-wide genotyping imputed to the Haplotype Reference Consortium panel (9,343 cases, 11,527 controls). The top findings in the discovery sample were also followed-up in the ADSP whole-genome sequenced family-based dataset (197 members of 42 EA families and 501 members of 157 CH families). We identified novel and predicted functional genetic variants in genes previously associated with AD. We also detected associations in three novel genes: IGHG3 (p = 9.8 × 10−7), an immunoglobulin gene whose antibodies interact with β-amyloid, a long non-coding RNA AC099552.4 (p = 1.2 × 10−7), and a zinc-finger protein ZNF655 (gene-based p = 5.0 × 10−6). The latter two suggest an important role for transcriptional regulation in AD pathogenesis.

Published
2018

36. Functional annotation of genomic variants in studies of late-onset Alzheimer’s disease

Author

Alan E. Renton, Yuk Yee Leung, Amanda B. Kuzma, Edoardo Marcora, Daniel C. Koboldt, Li-San Wang, Jonathan L. Haines, Mariusz Butkiewicz, Elizabeth E. Blue, William S. Bush, and Xueqiu Jian

Subjects
0301 basic medicine, Statistics and Probability, Sequence analysis, Computer science, Genomics, Disease, Computational biology, Polymorphism, Single Nucleotide, Biochemistry, Genome, 03 medical and health sciences, Annotation, Alzheimer Disease, Databases, Genetic, Humans, Genetic Predisposition to Disease, Potential analysis, Molecular Biology, Gene, Molecular Sequence Annotation, Sequence Analysis, DNA, Genome Analysis, Original Papers, Computer Science Applications, Computational Mathematics, ComputingMethodologies_PATTERNRECOGNITION, 030104 developmental biology, Computational Theory and Mathematics, Functional annotation, Software
Abstract

Motivation Annotation of genomic variants is an increasingly important and complex part of the analysis of sequence-based genomic analyses. Computational predictions of variant function are routinely incorporated into gene-based analyses of rare-variants, though to date most studies use limited information for assessing variant function that is often agnostic of the disease being studied. Results In this work, we outline an annotation process motivated by the Alzheimer’s Disease Sequencing Project, illustrate the impact of including tissue-specific transcript sets and sources of gene regulatory information and assess the potential impact of changing genomic builds on the annotation process. While these factors only impact a small proportion of total variant annotations (∼5%), they influence the potential analysis of a large fraction of genes (∼25%). Availability and implementation Individual variant annotations are available via the NIAGADS GenomicsDB, at https://www.niagads.org/genomics/ tools-and-software/databases/genomics-database. Annotations are also available for bulk download at https://www.niagads.org/datasets. Annotation processing software is available at http://www.icompbio.net/resources/software-and-downloads/. Supplementary information Supplementary data are available at Bioinformatics online.

Published
2018

37. A common haplotype lowers PU.1 expression in myeloid cells and delays onset of Alzheimer's disease

Author

Towfique Raj, Sven J. van der Lee, Julie Williams, Anna A. Pimenova, Benjamin Grenier-Boley, Laura Ibanez, Annette L. Fitzpatrick, Jorge L. Del-Aguila, Benjamin P. Fairfax, Gerard D. Schellenberg, Edoardo Marcora, Anita L. DeStefano, Sarah Bertelsen, Hieab H.H. Adams, Manav Kapoor, Valentina Escott-Price, Carlos Cruchaga, Cornelia M. van Duijn, Alan E. Renton, Richard Mayeux, Céline Bellenguez, Jean-Charles Lambert, Lindsay A. Farrer, Vincent Chouraki, Rebecca Sims, Kuan-lin Huang, Margaret A. Pericak-Vance, Bin Zhang, M. Arfan Ikram, Antonio Fabio Di Narzo, Maria Victoria Fernandez, Philippe Amouyel, Alison Goate, Ingrid B. Borecki, Sheng Chih Jin, Albert V. Smith, Yuetiva Deming, Joshua C. Bis, Jonathan L. Haines, Andrew M. McKenzie, Sudha Seshadri, Lenore J. Launer, John S. K. Kauwe, Oscar Harari, Jake Czajkowski, Ke Hao, John P. Budde, and Epidemiology

Subjects
0301 basic medicine, Male, Linkage disequilibrium, Myeloid, Locus (genetics), Biology, Polymorphism, Single Nucleotide, Linkage Disequilibrium, Article, 03 medical and health sciences, Mice, Alzheimer Disease, Risk Factors, Proto-Oncogene Proteins, Gene expression, medicine, Animals, Humans, Genetic Predisposition to Disease, Allele, Gene, Alleles, SPI1, General Neuroscience, 030104 developmental biology, medicine.anatomical_structure, Cistrome, Haplotypes, Immunology, Cancer research, Trans-Activators, Female, Genome-Wide Association Study, Transcription Factors
Abstract

A genome-wide survival analysis of 14,406 Alzheimer's disease (AD) cases and 25,849 controls identified eight previously reported AD risk loci and 14 novel loci associated with age at onset. Linkage disequilibrium score regression of 220 cell types implicated the regulation of myeloid gene expression in AD risk. The minor allele of rs1057233 (G), within the previously reported CELF1 AD risk locus, showed association with delayed AD onset and lower expression of SPI1 in monocytes and macrophages. SPI1 encodes PU.1, a transcription factor critical for myeloid cell development and function. AD heritability was enriched within the PU.1 cistrome, implicating a myeloid PU.1 target gene network in AD. Finally, experimentally altered PU.1 levels affected the expression of mouse orthologs of many AD risk genes and the phagocytic activity of mouse microglial cells. Our results suggest that lower SPI1 expression reduces AD risk by regulating myeloid gene expression and cell function.

Published
2017

38. 17q21.31 sub-haplotypes underlying H1-associated risk for Parkinson’s disease are associated with LRRC37A/2 expression in astrocytes

Author

Towfique Raj, Alison Goate, Ari Siitonen, Celeste M. Karch, Sarah Bertelsen, Alan E. Renton, John F. Crary, Ziv Gan-Or, Yiyuan Liu, Kathryn R. Bowles, Inga Peter, Steven J. Frucht, Alexander W. Charney, Ipdgc, Peter Heutink, Derian A. Pugh, Sara Bandres-Ciga, Brian H. Kopell, You Jeong Park, and Günter U. Höglinger

Subjects
Genetics, Candidate gene, Cell type, Parkinson's disease, Haplotype, medicine, Locus (genetics), Substantia nigra, Biology, medicine.disease, Gene, Genetic association
Abstract

Parkinson’s disease (PD) is genetically associated with the H1 haplotype of the MAPT 17q.21.31 locus, although the causal gene and variants underlying this association have not been identified. To better understand the genetic contribution of this region to PD, we fine-mapped the 17q21.31 locus in order to identify novel mechanisms conferring risk for the disease. We identified three novel H1 sub-haplotype blocks across the 17q21.31 locus associated with PD risk. Protective sub-haplotypes were associated with increased LRRC37A/2 copy number and expression in human brain tissue. We found that LRRC37A/2 is a membrane-associated protein that plays a role in cellular migration, chemotaxis and astroglial inflammation. In human substantia nigra, LRRC37A/2 was primarily expressed in astrocytes, interacted directly with soluble α-synuclein, and co-localized with Lewy bodies in PD brain tissue. These data indicate that a novel candidate gene, LRRC37A/2, contributes to the association between the 17q21.31 locus and PD via its interaction with α-synuclein and its effects on astrocytic function and inflammatory response. These data are the first to associate the genetic association at the 17q21.31 locus with PD pathology, and highlight the importance of variation at the 17q21.31 locus in the regulation of multiple genes other than MAPT and KANSL1, as well as its relevance to non-neuronal cell types.

Published
2019

39. A quantitative trait rare variant nonparametric linkage method with application to age-at-onset of Alzheimer's disease

Author

Linhai, Zhao, Zhihui, Zhang, Sandra M Barral, Rodriguez, Badri N, Vardarajan, Alan E, Renton, Alison M, Goate, Richard, Mayeux, Gao T, Wang, and Suzanne M, Leal

Subjects
Male, Polymorphism, Genetic, Genetic Linkage, Quantitative Trait Loci, Comment, Apolipoproteins E, ADAMTS1 Protein, Alzheimer Disease, Humans, ATP-Binding Cassette Transporters, Female, ras Guanine Nucleotide Exchange Factors, Age of Onset, Algorithms, Genome-Wide Association Study
Abstract

To analyze pedigrees with quantitative trait (QT) and sequence data, we developed a rare variant (RV) quantitative nonparametric linkage (QNPL) method, which evaluates sharing of minor alleles. RV-QNPL has greater power than the traditional QNPL that tests for excess sharing of minor and major alleles. RV-QNPL is robust to population substructure and admixture, locus heterogeneity, and inclusion of nonpathogenic variants and can be readily applied outside of coding regions. When QNPL was used to analyze common variants, it often led to loci mapping to large intervals, e.g.,40 Mb. In contrast, when RVs are analyzed, regions are well defined, e.g., a gene. Using simulation studies, we demonstrate that RV-QNPL is substantially more powerful than applying traditional QNPL methods to analyze RVs. RV-QNPL was also applied to analyze age-at-onset (AAO) data for 107 late-onset Alzheimer's disease (LOAD) pedigrees of Caribbean Hispanic and European ancestry with whole-genome sequence data. When AAO of AD was analyzed regardless of APOE ε4 status, suggestive linkage (LOD = 2.4) was observed with RVs in KNDC1 and nominally significant linkage (p 0.05) was observed with RVs in LOAD genes ABCA7 and IQCK. When AAO of AD was analyzed for APOE ε4 positive family members, nominally significant linkage was observed with RVs in APOE, while when AAO of AD was analyzed for APOE ε4 negative family members, nominal significance was observed for IQCK and ADAMTS1. RV-QNPL provides a powerful resource to analyze QTs in families to elucidate their genetic etiology.

Published
2019

40. Empirical design of a variant quality control pipeline for whole genome sequencing data using replicate discordance

Author

Nir Barzilai, Peter Davies, Robert P. Adelson, Alan E. Renton, Alison Goate, Yun Freudenberg-Hua, Gil Atzmon, and Wentian Li

Subjects
Quality Control, Genotype, Genotyping Techniques, Pipeline (computing), Concordance, lcsh:Medicine, Datasets as Topic, Computational biology, Biology, Genome, Polymorphism, Single Nucleotide, Article, 03 medical and health sciences, 0302 clinical medicine, Databases, Genetic, Humans, Genetic variation, lcsh:Science, Alleles, 030304 developmental biology, Whole genome sequencing, 0303 health sciences, Multidisciplinary, Whole Genome Sequencing, lcsh:R, High-Throughput Nucleotide Sequencing, Reproducibility of Results, Replicate, Empirical design, Sample size determination, Next-generation sequencing, lcsh:Q, 030217 neurology & neurosurgery
Abstract

The success of next-generation sequencing depends on the accuracy of variant calls. Few objective protocols exist for QC following variant calling from whole genome sequencing (WGS) data. After applying QC filtering based on Genome Analysis Tool Kit (GATK) best practices, we used genotype discordance of eight samples that were sequenced twice each to evaluate the proportion of potentially inaccurate variant calls. We designed a QC pipeline involving hard filters to improve replicate genotype concordance, which indicates improved accuracy of genotype calls. Our pipeline analyzes the efficacy of each filtering step. We initially applied this strategy to well-characterized variants from the ClinVar database, and subsequently to the full WGS dataset. The genome-wide biallelic pipeline removed 82.11% of discordant and 14.89% of concordant genotypes, and improved the concordance rate from 98.53% to 99.69%. The variant-level read depth filter most improved the genome-wide biallelic concordance rate. We also adapted this pipeline for triallelic sites, given the increasing proportion of multiallelic sites as sample sizes increase. For triallelic sites containing only SNVs, the concordance rate improved from 97.68% to 99.80%. Our QC pipeline removes many potentially false positive calls that pass in GATK, and may inform future WGS studies prior to variant effect analysis.

Published
2019

41. Mutations in the SPTLC1 gene are a cause of juvenile amyotrophic lateral sclerosis that may be amenable to serine supplementation

Author

Pentti J. Tienari, Al-Saif H, Ruth Chia, Jinhui Ding, Janel O. Johnson, Claire Troakes, Maura Brunetti, Emily Bonkowski, Mark R. Cookson, Gabriele Mora, Pamela J. Shaw, Adriano Chiò, Simon Topp, Mike A. Nalls, Ammar Al-Chalabi, Bryan J. Traynor, Christopher Shaw, Carol Dobson-Stone, Natalie Landeck, Leigh F, Nada Alahmady, Nathan A. Smith, Olga Pletnikova, David J. Stone, Ian P. Blair, Robert H. Brown, Chang Ij, Thomas O. Crawford, Silani, Marc Gotkine, Alfredo Iacoangeli, Juan C. Troncoso, Karen E. Morrison, Ian A. Glass, Sarah A. Ahmed, Gibbs, Alan E. Renton, Marya S. Sabir, Aleksey Shatunov, Sonja W. Scholz, Li R, Bradley N. Smith, John Landers, Ravindran Kumaran, John B.J. Kwok, Ashley R. Jones, Andrea Calvo, Danny E. Miller, C. Gellera, Faraz Faghri, Hannah A. Pliner, England Bk, Nicola Ticozzi, Yevgeniya Abramzon, Al Khleifat A, Seth J. Perlman, and Clifton L. Dalgard

Subjects
0303 health sciences, Mutation, business.industry, Serine C-palmitoyltransferase, Motor neuron, medicine.disease, medicine.disease_cause, 3. Good health, Pathogenesis, Serine, 03 medical and health sciences, 0302 clinical medicine, medicine.anatomical_structure, medicine, Cancer research, Amyotrophic lateral sclerosis, SPTLC1, business, 030217 neurology & neurosurgery, Exome sequencing, 030304 developmental biology
Abstract

SPTLC1 encodes a critical subunit of serine palmitoyltransferase, the enzyme catalyzing the first and rate-limiting step in de novo sphingolipid biosynthesis, and mutations in this gene are known to cause hereditary sensory autonomic neuropathy, type 1A . Using exome sequencing, we identified a de novo variant in SPTLC1 resulting in a p.Ala20Ser amino acid change in an individual diagnosed with juvenile-onset amyotrophic lateral sclerosis (ALS) and confirmed its pathogenicity by showing elevated plasma levels of neurotoxic deoxymethyl-sphinganine. A second case of juvenile-onset ALS arising again from a p.Ala20Ser mutation was later identified, confirming the association of SPTLC1 with this form of motor neuron disease. We also found SPTLC1 mutations in 0.34% of 5,607 ALS cases, and immunohistochemically confirmed the expression of SPTLC1 in spinal cord motor neurons, supporting their role in the pathogenesis of this fatal neurological disease. We corrected the toxicity of deoxymethyl-sphinganine in HEK293FT cells using L-serine supplementation. Our data broaden the phenotype associated with SPTLC1 and suggest that nutritional supplementation with serine may be beneficial if instituted at an early stage among patients carrying mutations in SPTLC1 .

Published
2019

42. The innate immunity protein IFITM3 modulates γ-secretase in Alzheimer's disease

Author

Pengju Nie, Katherine R. Sadleir, Yujia Zhai, Bianca T. Esposito, Andrew M. McKenzie, Christina J. Crump, Eitan Wong, Douglas S. Johnson, Julia Tcw, Eliezer Masliah, Ji-Yeun Hur, Paul Greengard, Yotam Sagi, Chen Ming, Yong Kim, Jen Chyong Wang, Si Jia Pan, Marília A. S. Barros, Bin Zhang, Xianzhong Wu, Robert A. Rissman, Lei Guo, Thomas Li, Georgia R. Frost, Yue-Ming Li, Alison Goate, Minghui Wang, Robert Vassar, Xianxiao Zhou, Ivy Trinh, and Alan E. Renton

Subjects
0301 basic medicine, Male, Aging, Amyloid plaques, Amyloid beta-Protein Precursor, Mice, 0302 clinical medicine, Catalytic Domain, Γ-secretase, Age of Onset, Aged, 80 and over, Innate immunity, Multidisciplinary, RNA-Binding Proteins, Transmembrane protein, Cell biology, Up-Regulation, IFITM3, Female, medicine.symptom, Alzheimer’s disease, Genetically modified mouse, Risk, Inflammation, Mice, Transgenic, Biology, Photo-crosslinking, Interferon-induced transmembrane protein, Article, Presenilin, Proinflammatory cytokine, 03 medical and health sciences, Immunity, Alzheimer Disease, Nicastrin, medicine, Presenilin-1, Animals, Humans, Neuroinflammation, Innate immune system, Membrane Proteins, Immunity, Innate, Mice, Inbred C57BL, Disease Models, Animal, 030104 developmental biology, HEK293 Cells, Astrocytes, Commentary, Interferons, Amyloid Precursor Protein Secretases, 030217 neurology & neurosurgery
Abstract

Innate immunity is associated with Alzheimer’s disease1, but the influence of immune activation on the production of amyloid-β is unknown2,3. Here we identify interferon-induced transmembrane protein 3 (IFITM3) as a γ-secretase modulatory protein, and establish a mechanism by which inflammation affects the generation of amyloid-β. Inflammatory cytokines induce the expression of IFITM3 in neurons and astrocytes, which binds to γ-secretase and upregulates its activity, thereby increasing the production of amyloid-β. The expression of IFITM3 is increased with ageing and in mouse models that express familial Alzheimer’s disease genes. Furthermore, knockout of IFITM3 reduces γ-secretase activity and the formation of amyloid plaques in a transgenic mouse model (5xFAD) of early amyloid deposition. IFITM3 protein is upregulated in tissue samples from a subset of patients with late-onset Alzheimer’s disease that exhibit higher γ-secretase activity. The amount of IFITM3 in the γ-secretase complex has a strong and positive correlation with γ-secretase activity in samples from patients with late-onset Alzheimer’s disease. These findings reveal a mechanism in which γ-secretase is modulated by neuroinflammation via IFITM3 and the risk of Alzheimer’s disease is thereby increased. The IFITM3 innate immunity protein directly binds presenilin near the active site and upregulates γ-secretase activity and the production of amyloid-β, and IFITM3 is upregulated in patients with late-onset Alzheimer’s disease.

Published
2019

43. Whole Genome Sequencing Identifies Loci Specifically Associated With Thoracic Aortic Wall Defects in Patients With Abdominal Aortic Aneurysms

Author

Peter L. Faries, Rami O. Tadros, Ella Taubenfeld, Robert A. Lookstein, Grace H. Miner, Edoardo Marcora, Michael L. Marin, and Alan E. Renton

Subjects
Whole genome sequencing, Pathology, medicine.medical_specialty, Thoracic aortic wall, business.industry, Medicine, Surgery, In patient, Cardiology and Cardiovascular Medicine, business
Published
2020

44. C9orf72 hexanucleotide repeat length in older population: normal variation and effects on cognition

Author

Anna Kiviharju, Pentti J. Tienari, Johan G. Eriksson, Ville Rantalainen, Timo E. Strandberg, Lilja Jansson, Alan E. Renton, Liisa Myllykangas, Hannu Laaksovirta, Karri Kaivola, Bryan J. Traynor, Neurologian yksikkö, University of Helsinki, HUS Neurocenter, Research Programs Unit, Department of Psychology and Logopedics, Developmental Psychology Research Group, Clinicum, Department of General Practice and Primary Health Care, HUS Internal Medicine and Rehabilitation, Timo Strandberg / Principal Investigator, Department of Medicine, University Management, Department of Neurosciences, HUSLAB, Department of Pathology, and Medicum

Subjects
0301 basic medicine, Male, Aging, BIRTH, CHILDREN, Disease, Biology, 3124 Neurology and psychiatry, Article, Cohort Studies, 03 medical and health sciences, AGE, 0302 clinical medicine, Cognition, C9orf72, Genetics, medicine, Dementia, Humans, Allele, Amyotrophic lateral sclerosis, Aged, Aged, 80 and over, DNA Repeat Expansion, C9orf72 Protein, DEMENTIA, General Neuroscience, Amyotrophic Lateral Sclerosis, EXPANSION, ASSOCIATION, Alzheimer's disease, Middle Aged, medicine.disease, ALZHEIMERS-DISEASE, SIZE, 030104 developmental biology, Frontotemporal Dementia, HUNTINGTONS-DISEASE, GROWTH, Female, Neurology (clinical), Geriatrics and Gerontology, Trinucleotide repeat expansion, 030217 neurology & neurosurgery, Developmental Biology, Frontotemporal dementia
Abstract

The hexanucleotide repeat expansion in C9orf72 is a common cause of amyotrophic lateral sclerosis/frontotemporal dementia and also rarely found in other psychiatric and neurodegenerative conditions. Alleles with >30 repeats are often considered an expansion, but the pathogenic repeat length threshold is still unclear. It is also unclear whether intermediate repeat length alleles (often defined either as 7-30 or 20-30 repeats) have clinically significant effects. We determined the C9orf72 repeat length distribution in 3142 older Finns (aged 60-104 years). The longest nonexpanded allele was 45 repeats. We found 7-45 repeats in 1036/3142 (33%) individuals, 20-45 repeats in 56/3142 (1.8%), 30-45 repeats in 12/3142 (0.38%), and expansion (>45 repeats) in 6/3142 (0.19%). There was no apparent clustering of neurodegenerative or psychiatric diseases in individuals with 30-45 repeats indicating that 30-45 repeats are not pathogenic. None of the 6 expansion carriers had a diagnosis of amyotrophic lateral sclerosis/frontotemporal dementia but 4 had a diagnosis of a neurodegenerative or psychiatric disease. Intermediate length alleles (categorized as 7-45 and 20-45 repeats) did not associate with Alzheimer's disease or cognitive impairment. (C) 2019 The Author(s). Published by Elsevier Inc.

Published
2018

45. Melatonin receptor type 1A gene linked to Alzheimer’s disease in old age

Author

Tuomo Polvikoski, David J. Stone, Raimo Sulkava, Terhi Peuralinna, Hanna Ollila, Hilkka Soininen, Pentti J. Tienari, Alan E. Renton, Sonja Sulkava, Pranuthi Muggalla, Henri J. Huttunen, Seppo Helisalmi, Karri Kaivola, Tiina Paunio, Bryan J. Traynor, Alberto M. Rivera, Mikko Hiltunen, and Liisa Myllykangas

Subjects
Male, 0301 basic medicine, Receptors, Melatonin, Plaque, Amyloid, Cohort Studies, Amyloid beta-Protein Precursor, 0302 clinical medicine, Amyloid precursor protein, melatonin receptor, Finland, Melatonin, Aged, 80 and over, Neurons, education.field_of_study, biology, Neurodegeneration, Brain, Neurofibrillary Tangles, Circadian Rhythm, genetic association study, Female, Alzheimer’s disease, medicine.drug, medicine.medical_specialty, Amyloid beta, Population, In Vitro Techniques, Neurological Disorders, Melatonin receptor, Neuroprotection, 03 medical and health sciences, Alzheimer Disease, Physiology (medical), Internal medicine, medicine, Humans, Genetic Predisposition to Disease, education, Amyloid beta-Peptides, business.industry, Receptor, Melatonin, MT1, Case-control study, medicine.disease, amyloid beta, Editor's Choice, 030104 developmental biology, Endocrinology, Case-Control Studies, gene expression, biology.protein, Neurology (clinical), business, 030217 neurology & neurosurgery
Abstract

Disruption of the circadian rhythms is a frequent preclinical and clinical manifestation of Alzheimer’s disease. Furthermore, it has been suggested that shift work is a risk factor for Alzheimer’s disease. Previously, we have reported association of intolerance to shift work (job-related exhaustion in shift workers) with a variant rs12506228A, which is situated close to melatonin receptor type 1A gene (MTNR1A) and linked to MTNR1A brain expression levels. Here, we studied association of that variant with clinical and neuropathological Alzheimer’s disease in a Finnish whole-population cohort Vantaa 85+ (n = 512, participants over 85 years) and two follow-up cohorts. Rs12506228A was associated with clinical Alzheimer’s disease (p = 0.000073). Analysis of post-mortem brain tissues showed association with higher amount of neurofibrillary tangles (p = 0.0039) and amyloid beta plaques (p = 0.0041). We then followed up the associations in two independent replication samples. Replication for the association with clinical Alzheimer’s disease was detected in Kuopio 75+ (p = 0.012, n = 574), but not in the younger case-control sample (n = 651 + 669). While melatonin has been established in regulation of circadian rhythms, an independent role has been also shown for neuroprotection and specifically for anti-amyloidogenic effects. Indeed, in vitro, RNAi mediated silencing of MTNR1A increased the amyloidogenic processing of amyloid precursor protein (APP) in neurons, whereas overexpression decreased it. Our findings suggest variation close to MTNR1A as a shared genetic risk factor for intolerance to shift work and Alzheimer’s disease in old age. The genetic associations are likely to be mediated by differences in MTNR1A expression, which, in turn, modulate APP metabolism.

Published
2018

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

Author

Aude Nicolas, Kevin P. Kenna, Alan E. Renton, Nicola Ticozzi, Faraz Faghri, Ruth Chia, Janice A. Dominov, Brendan J. Kenna, Mike A. Nalls, Pamela Keagle, Alberto M. Rivera, Wouter van Rheenen, Natalie A. Murphy, Joke J.F.A. van Vugt, Joshua T. Geiger, Rick A. Van der Spek, Hannah A. Pliner, null Shankaracharya, Bradley N. Smith, Giuseppe Marangi, Simon D. Topp, Yevgeniya Abramzon, Athina Soragia Gkazi, John D. Eicher, Aoife Kenna, Gabriele Mora, Andrea Calvo, Letizia Mazzini, Nilo Riva, Jessica Mandrioli, Claudia Caponnetto, Stefania Battistini, Paolo Volanti, Vincenzo La Bella, Francesca L. Conforti, Giuseppe Borghero, Sonia Messina, Isabella L. Simone, Francesca Trojsi, Fabrizio Salvi, Francesco O. Logullo, Sandra D’Alfonso, Lucia Corrado, Margherita Capasso, Luigi Ferrucci, Cristiane de Araujo Martins Moreno, Sitharthan Kamalakaran, David B. Goldstein, Aaron D. Gitler, Tim Harris, Richard M. Myers, Hemali Phatnani, Rajeeva Lochan Musunuri, Uday Shankar Evani, Avinash Abhyankar, Michael C. Zody, Julia Kaye, Steven Finkbeiner, Stacia K. Wyman, Alex LeNail, Leandro Lima, Ernest Fraenkel, Clive N. Svendsen, Leslie M. Thompson, Jennifer E. Van Eyk, James D. Berry, Timothy M. Miller, Stephen J. Kolb, Merit Cudkowicz, Emily Baxi, Michael Benatar, J. Paul Taylor, Evadnie Rampersaud, Gang Wu, Joanne Wuu, Giuseppe Lauria, Federico Verde, Isabella Fogh, Cinzia Tiloca, Giacomo P. Comi, Gianni Sorarù, Cristina Cereda, Philippe Corcia, Hannu Laaksovirta, Liisa Myllykangas, Lilja Jansson, Miko Valori, John Ealing, Hisham Hamdalla, Sara Rollinson, Stuart Pickering-Brown, Richard W. Orrell, Katie C. Sidle, Andrea Malaspina, John Hardy, Andrew B. Singleton, Janel O. Johnson, Sampath Arepalli, Peter C. Sapp, Diane McKenna-Yasek, Meraida Polak, Seneshaw Asress, Safa Al-Sarraj, Andrew King, Claire Troakes, Caroline Vance, Jacqueline de Belleroche, Frank Baas, Anneloor L.M.A. ten Asbroek, José Luis Muñoz-Blanco, Dena G. Hernandez, Jinhui Ding, J. Raphael Gibbs, Sonja W. Scholz, Mary Kay Floeter, Roy H. Campbell, Francesco Landi, Robert Bowser, Stefan M. Pulst, John M. Ravits, Daniel J.L. MacGowan, Janine Kirby, Erik P. Pioro, Roger Pamphlett, James Broach, Glenn Gerhard, Travis L. Dunckley, Christopher B. Brady, Neil W. Kowall, Juan C. Troncoso, Isabelle Le Ber, Kevin Mouzat, Serge Lumbroso, Terry D. Heiman-Patterson, Freya Kamel, Ludo Van Den Bosch, Robert H. Baloh, Tim M. Strom, Thomas Meitinger, Aleksey Shatunov, Kristel R. Van Eijk, Mamede de Carvalho, Maarten Kooyman, Bas Middelkoop, Matthieu Moisse, Russell L. McLaughlin, Michael A. Van Es, Markus Weber, Kevin B. Boylan, Marka Van Blitterswijk, Rosa Rademakers, Karen E. Morrison, A. Nazli Basak, Jesús S. Mora, Vivian E. Drory, Pamela J. Shaw, Martin R. Turner, Kevin Talbot, Orla Hardiman, Kelly L. Williams, Jennifer A. Fifita, Garth A. Nicholson, Ian P. Blair, Guy A. Rouleau, Jesús Esteban-Pérez, Alberto García-Redondo, Ammar Al-Chalabi, Ekaterina Rogaeva, Lorne Zinman, Lyle W. Ostrow, Nicholas J. Maragakis, Jeffrey D. Rothstein, Zachary Simmons, Johnathan Cooper-Knock, Alexis Brice, Stephen A. Goutman, Eva L. Feldman, Summer B. Gibson, Franco Taroni, Antonia Ratti, Cinzia Gellera, Philip Van Damme, Wim Robberecht, Pietro Fratta, Mario Sabatelli, Christian Lunetta, Albert C. Ludolph, Peter M. Andersen, Jochen H. Weishaupt, William Camu, John Q. Trojanowski, Vivianna M. Van Deerlin, Robert H. Brown, Leonard H. van den Berg, Jan H. Veldink, Matthew B. Harms, Jonathan D. Glass, David J. Stone, Pentti Tienari, Vincenzo Silani, Adriano Chiò, Christopher E. Shaw, Bryan J. Traynor, John E. Landers, Isabella Simone, Giancarlo Logroscino, Ilaria Bartolomei, Maria Rita Murru, Emanuela Costantino, Carla Pani, Roberta Puddu, Carla Caredda, Valeria Piras, Stefania Tranquilli, Stefania Cuccu, Daniela Corongiu, Maurizio Melis, Antonio Milia, Francesco Marrosu, Maria Giovanna Marrosu, Gianluca Floris, Antonino Cannas, Gianluigi Mancardi, Paola Origone, Paola Mandich, Sebastiano Cavallaro, Kalliopi Marinou, Riccardo Sideri, Silvana Penco, Lorena Mosca, Giuseppe Lauria Pinter, Massimo Corbo, Paola Carrera, Nicola Fini, Antonio Fasano, Lucio Tremolizzo, Alessandro Arosio, Carlo Ferrarese, Gioacchino Tedeschi, Maria Rosaria Monsurrò, Giovanni Piccirillo, Cinzia Femiano, Anna Ticca, Enzo Ortu, Rossella Spataro, Tiziana Colletti, Marcella Zollino, Amelia Conte, Marco Luigetti, Serena Lattante, Marialuisa Santarelli, Antonio Petrucci, Maura Pugliatti, Angelo Pirisi, Leslie D. Parish, Patrizia Occhineri, Fabio Giannini, Claudia Ricci, Michele Benigni, Tea B. Cau, Daniela Loi, Cristina Moglia, Maura Brunetti, Marco Barberis, Gabriella Restagno, Federico Casale, Giuseppe Marrali, Giuseppe Fuda, Irene Ossola, Stefania Cammarosano, Antonio Canosa, Antonio Ilardi, Umberto Manera, Maurizio Grassano, Raffaella Tanel, Fabrizio Pisano, Neil A. Shneider, Stephen Goutman, Siddharthan Chandran, Suvankar Pal, George Manousakis, Stanley H. Appel, Ericka Simpson, Leo Wang, Summer Gibson, Richard Bedlack, David Lacomis, Dhruv Sareen, Alexander Sherman, Lucie Bruijn, Michelle Penny, Andrew S. Allen, Stanley Appel, Richard S. Bedlack, Braden E. Boone, Robert Brown, John P. Carulli, Alessandra Chesi, Wendy K. Chung, Elizabeth T. Cirulli, Gregory M. Cooper, Julien Couthouis, Aaron G. Day-Williams, Patrick A. Dion, Yujun Han, Sebastian D. Hayes, Angela L. Jones, Jonathan Keebler, Brian J. Krueger, Brittany N. Lasseigne, Shawn E. Levy, Yi-Fan Lu, Tom Maniatis, Slavé Petrovski, Alya R. Raphael, Zhong Ren, Katherine B. Sims, John F. Staropoli, Lindsay L. Waite, Quanli Wang, Jack R. Wimbish, Winnie W. Xin, Justin Kwan, James R. Broach, Ximena Arcila-Londono, Edward B. Lee, Noah Zaitlen, Gregory A. Cox, Steve Finkbeiner, Efthimios Dardiotis, Eran Hornstein, Daniel J. MacGowan, Terry Heiman-Patterson, Molly G. Hammell, Nikolaos A. Patsopoulos, Joshua Dubnau, Avindra Nath, Stacia Wyman, Alexander LeNail, Jenny Van Eyk, Stephan Züchner, Rebecca Schule, Jacob McCauley, Sumaira Hussain, Anne Cooley, Marielle Wallace, Christine Clayman, Richard Barohn, Jeffrey Statland, John Ravits, Andrea Swenson, Carlayne Jackson, Jaya Trivedi, Shaida Khan, Jonathan Katz, Liberty Jenkins, Ted Burns, Kelly Gwathmey, James Caress, Corey McMillan, Lauren Elman, Erik Pioro, Jeannine Heckmann, Yuen So, David Walk, Samuel Maiser, Jinghui Zhang, Fabiola De Marchi, Stefania Corti, Mauro Ceroni, Gabriele Siciliano, Massimiliano Filosto, Maurizio Inghilleri, Silvia Peverelli, Claudia Colombrita, Barbara Poletti, Luca Maderna, Roberto Del Bo, Stella Gagliardi, Giorgia Querin, Cinzia Bertolin, Viviana Pensato, Barbara Castellotti, Vincent Meininger, Gérard Besson, Emmeline Lagrange, Pierre Clavelou, Nathalie Guy, Philippe Couratier, Patrick Vourch, Véronique Danel, Emilien Bernard, Gwendal Lemasson, Ahmad Al Kheifat, Peter Andersen, Adriano Chio, Jonathan Cooper-Knock, Annelot Dekker, Vivian Drory, Alberto Garcia Redondo, Marc Gotkine, Winston Hide, Alfredo Iacoangeli, Jonathan Glass, Kevin Kenna, Matthew Kiernan, John Landers, Russell McLaughlin, Jonathan Mill, Miguel Mitne Neto, Mattieu Moisse, Jesus Mora Pardina, Karen Morrison, Stephen Newhouse, Susana Pinto, Sara Pulit, Pamela Shaw, Chris Shaw, William Sproviero, Gijs Tazelaar, Philip van Damme, Leonard van den Berg, Rick van der Spek, Kristel van Eijk, Michael van Es, Joke van Vugt, Jan Veldink, Mayana Zatz, Denis C. Bauer, Natalie A. Twine, Department of Neurosciences, Pentti Tienari / Principal Investigator, Neurologian yksikkö, Research Programs Unit, Clinicum, Research Programme for Molecular Neurology, University of Helsinki, Medicum, Department of Pathology, HUS Neurocenter, Nicolas A., Kenna K.P., Renton A.E., Ticozzi N., Faghri F., Chia R., Dominov J.A., Kenna B.J., Nalls M.A., Keagle P., Rivera A.M., van Rheenen W., Murphy N.A., van Vugt J.J.F.A., Geiger J.T., Van der Spek R.A., Pliner H.A., Shankaracharya, Smith B.N., Marangi G., Topp S.D., Abramzon Y., Gkazi A.S., Eicher J.D., Kenna A., Logullo F.O., Simone I.L., Logroscino G., Salvi F., Bartolomei I., Borghero G., Murru M.R., Costantino E., Pani C., Puddu R., Caredda C., Piras V., Tranquilli S., Cuccu S., Corongiu D., Melis M., Milia A., Marrosu F., Marrosu M.G., Floris G., Cannas A., Capasso M., Caponnetto C., Mancardi G., Origone P., Mandich P., Conforti F.L., Cavallaro S., Mora G., Marinou K., Sideri R., Penco S., Mosca L., Lunetta C., Pinter G.L., Corbo M., Riva N., Carrera P., Volanti P., Mandrioli J., Fini N., Fasano A., Tremolizzo L., Arosio A., Ferrarese C., Trojsi F., Tedeschi G., Monsurro M.R., Piccirillo G., Femiano C., Ticca A., Ortu E., La Bella V., Spataro R., Colletti T., Sabatelli M., Zollino M., Conte A., Luigetti M., Lattante S., Santarelli M., Petrucci A., Pugliatti M., Pirisi A., Parish L.D., Occhineri P., Giannini F., Battistini S., Ricci C., Benigni M., Cau T.B., Loi D., Calvo A., Moglia C., Brunetti M., Barberis M., Restagno G., Casale F., Marrali G., Fuda G., Ossola I., Cammarosano S., Canosa A., Ilardi A., Manera U., Grassano M., Tanel R., Pisano F., Mazzini L., Messina S., D'Alfonso S., Corrado L., Ferrucci L., Harms M.B., Goldstein D.B., Shneider N.A., Goutman S.A., Simmons Z., Miller T.M., Chandran S., Pal S., Manousakis G., Appel S.H., Simpson E., Wang L., Baloh R.H., Gibson S.B., Bedlack R., Lacomis D., Sareen D., Sherman A., Bruijn L., Penny M., Moreno C.D.A.M., Kamalakaran S., Allen A.S., Boone B.E., Brown R.H., Carulli J.P., Chesi A., Chung W.K., Cirulli E.T., Cooper G.M., Couthouis J., Day-Williams A.G., Dion P.A., Gitler A.D., Glass J.D., Han Y., Harris T., Hayes S.D., Jones A.L., Keebler J., Krueger B.J., Lasseigne B.N., Levy S.E., Lu Y.-F., Maniatis T., McKenna-Yasek D., Myers R.M., Petrovski S., Pulst S.M., Raphael A.R., Ravits J.M., Ren Z., Rouleau G.A., Sapp P.C., Sims K.B., Staropoli J.F., Waite L.L., Wang Q., Wimbish J.R., Xin W.W., Phatnani H., Kwan J., Broach J., Arcila-Londono X., Lee E.B., Van Deerlin V.M., Fraenkel E., Ostrow L.W., Baas F., Zaitlen N., Berry J.D., Malaspina A., Fratta P., Cox G.A., Thompson L.M., Finkbeiner S., Dardiotis E., Hornstein E., MacGowan D.J.L., Heiman-Patterson T., Hammell M.G., Patsopoulos N.A., Dubnau J., Nath A., Musunuri R.L., Evani U.S., Abhyankar A., Zody M.C., Kaye J., Wyman S.K., LeNail A., Lima L., Rothstein J.D., Svendsen C.N., Van Eyk J.E., Maragakis N.J., Kolb S.J., Cudkowicz M., Baxi E., Benatar M., Taylor J.P., Wu G., Rampersaud E., Wuu J., Rademakers R., Zuchner S., Schule R., McCauley J., Hussain S., Cooley A., Wallace M., Clayman C., Barohn R., Statland J., Swenson A., Jackson C., Trivedi J., Khan S., Katz J., Jenkins L., Burns T., Gwathmey K., Caress J., McMillan C., Elman L., Pioro E.P., Heckmann J., So Y., Walk D., Maiser S., Zhang J., Silani V., Gellera C., Ratti A., Taroni F., Lauria G., Verde F., Fogh I., Tiloca C., Comi G.P., Soraru G., Cereda C., De Marchi F., Corti S., Ceroni M., Siciliano G., Filosto M., Inghilleri M., Peverelli S., Colombrita C., Poletti B., Maderna L., Del Bo R., Gagliardi S., Querin G., Bertolin C., Pensato V., Castellotti B., Camu W., Mouzat K., Lumbroso S., Corcia P., Meininger V., Besson G., Lagrange E., Clavelou P., Guy N., Couratier P., Vourch P., Danel V., Bernard E., Lemasson G., Laaksovirta H., Myllykangas L., Jansson L., Valori M., Ealing J., Hamdalla H., Rollinson S., Pickering-Brown S., Orrell R.W., Sidle K.C., Hardy J., Singleton A.B., Johnson J.O., Arepalli S., Polak M., Asress S., Al-Sarraj S., King A., Troakes C., Vance C., de Belleroche J., ten Asbroek A.L.M.A., Munoz-Blanco J.L., Hernandez D.G., Ding J., Gibbs J.R., Scholz S.W., Floeter M.K., Campbell R.H., Landi F., Bowser R., Kirby J., Pamphlett R., Gerhard G., Dunckley T.L., Brady C.B., Kowall N.W., Troncoso J.C., Le Ber I., Heiman-Patterson T.D., Kamel F., Van Den Bosch L., Strom T.M., Meitinger T., Shatunov A., Van Eijk K.R., de Carvalho M., Kooyman M., Middelkoop B., Moisse M., McLaughlin R.L., Van Es M.A., Weber M., Boylan K.B., Van Blitterswijk M., Morrison K.E., Basak A.N., Mora J.S., Drory V.E., Shaw P.J., Turner M.R., Talbot K., Hardiman O., Williams K.L., Fifita J.A., Nicholson G.A., Blair I.P., Esteban-Perez J., Garcia-Redondo A., Al-Chalabi A., Al Kheifat A., Andersen P.M., Chio A., Cooper-Knock J., Dekker A., Redondo A.G., Gotkine M., Hide W., Iacoangeli A., Kiernan M., Landers J.E., Mill J., Neto M.M., Pardina J.M., Newhouse S., Pinto S., Pulit S., Robberecht W., Shaw C., Sproviero W., Tazelaar G., Van Damme P., van den Berg L.H., van Vugt J., Veldink J.H., Zatz M., Bauer D.C., Twine N.A., Rogaeva E., Zinman L., Brice A., Feldman E.L., Ludolph A.C., Weishaupt J.H., Trojanowski J.Q., Stone D.J., Tienari P., Shaw C.E., Traynor B.J., ITALSGEN Consortium, Genomic Translation ALS Care GTAC, ALS Sequencing Consortium, NYGC ALS Consortium, Answer ALS Fdn, Clinical Res ALS Related Disorders, SLAGEN Consortium, French ALS Consortium, Project MinE ALS Sequencing Consor, Medical Research Council (MRC), ANS - Complex Trait Genetics, Human Genetics, ARD - Amsterdam Reproduction and Development, Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), Università cattolica del Sacro Cuore [Roma] (Unicatt), Centre référent Sclérose Latérale Amyotrophique [CHRU Montpellier] (SLA CHRU Montpellier), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Université Montpellier 1 (UM1), Lunar and Planetary Laboratory [Tucson] (LPL), University of Arizona, Università degli studi di Torino (UNITO), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS), New York Genome Center [New York], New York Genome Center, Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS), St Jude Children's Research Hospital, Howard Hughes Medical Institute [Chevy Chase] (HHMI), Howard Hughes Medical Institute (HHMI), Centre de compétence de la Sclérose Latérale Amyotrophique [CHRU Tours] (SLA CHRU Tours), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), University College of London [London] (UCL), Synchrotron SOLEIL (SSOLEIL), Centre National de la Recherche Scientifique (CNRS), King‘s College London, University of New Haven [Connecticut], Princeton University, Laboratoire de Biochimie [CHRU Nîmes], Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Institut des Neurosciences de Montpellier - Déficits sensoriels et moteurs (INM), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM), Helmholtz-Zentrum München (HZM), University Medical Center [Utrecht], Deutsches Forschungszentrum für Künstliche Intelligenz GmbH = German Research Center for Artificial Intelligence (DFKI), Mayo Clinic [Jacksonville], Trinity College Dublin, Maurice Wohl Clinical Neuroscience Institut, Tanz Center Research in Neurodegenerative Diseases [Toronto], University of Toronto, Neurologie et thérapeutique expérimentale, Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR70-Université Pierre et Marie Curie - Paris 6 (UPMC), Repositório da Universidade de Lisboa, Nicolas, A, Kenna, K, Renton, A, Ticozzi, N, Faghri, F, Chia, R, Dominov, J, Kenna, B, Nalls, M, Keagle, P, Rivera, A, van Rheenen, W, Murphy, N, van Vugt, J, Geiger, J, van der Spek, R, Pliner, H, Shankaracharya, N, Smith, B, Marangi, G, Topp, S, Abramzon, Y, Gkazi, A, Eicher, J, Kenna, A, Logullo, F, Simone, I, Logroscino, G, Salvi, F, Bartolomei, I, Borghero, G, Murru, M, Costantino, E, Pani, C, Puddu, R, Caredda, C, Piras, V, Tranquilli, S, Cuccu, S, Corongiu, D, Melis, M, Milia, A, Marrosu, F, Marrosu, M, Floris, G, Cannas, A, Capasso, M, Caponnetto, C, Mancardi, G, Origone, P, Mandich, P, Conforti, F, Cavallaro, S, Mora, G, Marinou, K, Sideri, R, Penco, S, Mosca, L, Lunetta, C, Pinter, G, Corbo, M, Riva, N, Carrera, P, Volanti, P, Mandrioli, J, Fini, N, Fasano, A, Tremolizzo, L, Arosio, A, Ferrarese, C, Trojsi, F, Tedeschi, G, Monsurrò, M, Piccirillo, G, Femiano, C, Ticca, A, Ortu, E, La Bella, V, Spataro, R, Colletti, T, Sabatelli, M, Zollino, M, Conte, A, Luigetti, M, Lattante, S, Santarelli, M, Petrucci, A, Pugliatti, M, Pirisi, A, Parish, L, Occhineri, P, Giannini, F, Battistini, S, Ricci, C, Benigni, M, Cau, T, Loi, D, Calvo, A, Moglia, C, Brunetti, M, Barberis, M, Restagno, G, Casale, F, Marrali, G, Fuda, G, Ossola, I, Cammarosano, S, Canosa, A, Ilardi, A, Manera, U, Grassano, M, Tanel, R, Pisano, F, Mazzini, L, Messina, S, D'Alfonso, S, Corrado, L, Ferrucci, L, Harms, M, Goldstein, D, Shneider, N, Goutman, S, Simmons, Z, Miller, T, Chandran, S, Pal, S, Manousakis, G, Appel, S, Simpson, E, Wang, L, Baloh, R, Gibson, S, Bedlack, R, Lacomis, D, Sareen, D, Sherman, A, Bruijn, L, Penny, M, Moreno, C, Kamalakaran, S, Allen, A, Boone, B, Brown, R, Carulli, J, Chesi, A, Chung, W, Cirulli, E, Cooper, G, Couthouis, J, Day-Williams, A, Dion, P, Gitler, A, Glass, J, Han, Y, Harris, T, Hayes, S, Jones, A, Keebler, J, Krueger, B, Lasseigne, B, Levy, S, Lu, Y, Maniatis, T, McKenna-Yasek, D, Myers, R, Petrovski, S, Pulst, S, Raphael, A, Ravits, J, Ren, Z, Rouleau, G, Sapp, P, Sims, K, Staropoli, J, Waite, L, Wang, Q, Wimbish, J, Xin, W, Phatnani, H, Kwan, J, Broach, J, Arcila-Londono, X, Lee, E, Van Deerlin, V, Fraenkel, E, Ostrow, L, Baas, F, Zaitlen, N, Berry, J, Malaspina, A, Fratta, P, Cox, G, Thompson, L, Finkbeiner, S, Dardiotis, E, Hornstein, E, Macgowan, D, Heiman-Patterson, T, Hammell, M, Patsopoulos, N, Dubnau, J, Nath, A, Musunuri, R, Evani, U, Abhyankar, A, Zody, M, Kaye, J, Wyman, S, Lenail, A, Lima, L, Rothstein, J, Svendsen, C, Van Eyk, J, Maragakis, N, Kolb, S, Cudkowicz, M, Baxi, E, Benatar, M, Taylor, J, Wu, G, Rampersaud, E, Wuu, J, Rademakers, R, Züchner, S, Schule, R, Mccauley, J, Hussain, S, Cooley, A, Wallace, M, Clayman, C, Barohn, R, Statland, J, Swenson, A, Jackson, C, Trivedi, J, Khan, S, Katz, J, Jenkins, L, Burns, T, Gwathmey, K, Caress, J, Mcmillan, C, Elman, L, Pioro, E, Heckmann, J, So, Y, Walk, D, Maiser, S, Zhang, J, Silani, V, Gellera, C, Ratti, A, Taroni, F, Lauria, G, Verde, F, Fogh, I, Tiloca, C, Comi, G, Sorarù, G, Cereda, C, De Marchi, F, Corti, S, Ceroni, M, Siciliano, G, Filosto, M, Inghilleri, M, Peverelli, S, Colombrita, C, Poletti, B, Maderna, L, Del Bo, R, Gagliardi, S, Querin, G, Bertolin, C, Pensato, V, Castellotti, B, Camu, W, Mouzat, K, Lumbroso, S, Corcia, P, Meininger, V, Besson, G, Lagrange, E, Clavelou, P, Guy, N, Couratier, P, Vourch, P, Danel, V, Bernard, E, Lemasson, G, Laaksovirta, H, Myllykangas, L, Jansson, L, Valori, M, Ealing, J, Hamdalla, H, Rollinson, S, Pickering-Brown, S, Orrell, R, Sidle, K, Hardy, J, Singleton, A, Johnson, J, Arepalli, S, Polak, M, Asress, S, Al-Sarraj, S, King, A, Troakes, C, Vance, C, de Belleroche, J, ten Asbroek, A, Muñoz-Blanco, J, Hernandez, D, Ding, J, Gibbs, J, Scholz, S, Floeter, M, Campbell, R, Landi, F, Bowser, R, Kirby, J, Pamphlett, R, Gerhard, G, Dunckley, T, Brady, C, Kowall, N, Troncoso, J, Le Ber, I, Kamel, F, Van Den Bosch, L, Strom, T, Meitinger, T, Shatunov, A, Van Eijk, K, de Carvalho, M, Kooyman, M, Middelkoop, B, Moisse, M, Mclaughlin, R, Van Es, M, Weber, M, Boylan, K, Van Blitterswijk, M, Morrison, K, Basak, A, Mora, J, Drory, V, Shaw, P, Turner, M, Talbot, K, Hardiman, O, Williams, K, Fifita, J, Nicholson, G, Blair, I, Esteban-Pérez, J, García-Redondo, A, Al-Chalabi, A, Al Kheifat, A, Andersen, P, Chio, A, Cooper-Knock, J, Dekker, A, Redondo, A, Gotkine, M, Hide, W, Iacoangeli, A, Kiernan, M, Landers, J, Mill, J, Neto, M, Pardina, J, Newhouse, S, Pinto, S, Pulit, S, Robberecht, W, Shaw, C, Sproviero, W, Tazelaar, G, van Damme, P, van den Berg, L, van Eijk, K, van Es, M, Veldink, J, Zatz, M, Bauer, D, Twine, N, Rogaeva, E, Zinman, L, Brice, A, Feldman, E, Ludolph, A, Weishaupt, J, Trojanowski, J, Stone, D, Tienari, P, Chiò, A, Traynor, B, Nicolas, Aude, Kenna, Kevin P, Renton, Alan E, Ticozzi, Nicola, Faghri, Faraz, Chia, Ruth, Dominov, Janice A, Kenna, Brendan J, Nalls, Mike A, Keagle, Pamela, Rivera, Alberto M, van Rheenen, Wouter, Murphy, Natalie A, van Vugt, Joke J F A, Geiger, Joshua T, Van der Spek, Rick A, Pliner, Hannah A, Shankaracharya, Null, Smith, Bradley N, Marangi, Giuseppe, Topp, Simon D, Abramzon, Yevgeniya, Gkazi, Athina Soragia, Eicher, John D, Kenna, Aoife, Mora, Gabriele, Calvo, Andrea, Mazzini, Letizia, Riva, Nilo, Mandrioli, Jessica, Caponnetto, Claudia, Battistini, Stefania, Volanti, Paolo, La Bella, Vincenzo, Conforti, Francesca L, Borghero, Giuseppe, Messina, Sonia, Simone, Isabella L, Trojsi, Francesca, Salvi, Fabrizio, Logullo, Francesco O, D'Alfonso, Sandra, Corrado, Lucia, Capasso, Margherita, Ferrucci, Luigi, Logullo, Fo, Murru, Mr, Marrosu, Mg, Conforti, Fl, Pinter, Gl, Tedeschi, Gioacchino, Monsurrò, Maria Rosaria, Parish, Ld, Cau, Tb, Moreno, Cristiane de Araujo Martin, Kamalakaran, Sitharthan, Goldstein, David B, Gitler, Aaron D, Harris, Tim, Myers, Richard M, Phatnani, Hemali, Musunuri, Rajeeva Lochan, Evani, Uday Shankar, Abhyankar, Avinash, Zody, Michael C, Kaye, Julia, Finkbeiner, Steven, Wyman, Stacia K, Lenail, Alex, Lima, Leandro, Fraenkel, Ernest, Svendsen, Clive N, Thompson, Leslie M, Van Eyk, Jennifer E, Berry, James D, Miller, Timothy M, Kolb, Stephen J, Cudkowicz, Merit, Baxi, Emily, Benatar, Michael, Taylor, J Paul, Rampersaud, Evadnie, Wu, Gang, Wuu, Joanne, Lauria, Giuseppe, Verde, Federico, Fogh, Isabella, Tiloca, Cinzia, Comi, Giacomo P, Sorarù, Gianni, Cereda, Cristina, Corcia, Philippe, Laaksovirta, Hannu, Myllykangas, Liisa, Jansson, Lilja, Valori, Miko, Ealing, John, Hamdalla, Hisham, Rollinson, Sara, Pickering-Brown, Stuart, Orrell, Richard W, Sidle, Katie C, Malaspina, Andrea, Hardy, John, Singleton, Andrew B, Johnson, Janel O, Arepalli, Sampath, Sapp, Peter C, McKenna-Yasek, Diane, Polak, Meraida, Asress, Seneshaw, Al-Sarraj, Safa, King, Andrew, Troakes, Claire, Vance, Caroline, de Belleroche, Jacqueline, Baas, Frank, Ten Asbroek, Anneloor L M A, Muñoz-Blanco, José Lui, Hernandez, Dena G, Ding, Jinhui, Gibbs, J Raphael, Scholz, Sonja W, Floeter, Mary Kay, Campbell, Roy H, Landi, Francesco, Bowser, Robert, Pulst, Stefan M, Ravits, John M, Macgowan, Daniel J L, Kirby, Janine, Pioro, Erik P, Pamphlett, Roger, Broach, Jame, Gerhard, Glenn, Dunckley, Travis L, Brady, Christopher B, Kowall, Neil W, Troncoso, Juan C, Le Ber, Isabelle, Mouzat, Kevin, Lumbroso, Serge, Heiman-Patterson, Terry D, Kamel, Freya, Van Den Bosch, Ludo, Baloh, Robert H, Strom, Tim M, Meitinger, Thoma, Shatunov, Aleksey, Van Eijk, Kristel R, de Carvalho, Mamede, Kooyman, Maarten, Middelkoop, Ba, Moisse, Matthieu, Mclaughlin, Russell L, Van Es, Michael A, Weber, Marku, Boylan, Kevin B, Van Blitterswijk, Marka, Rademakers, Rosa, Morrison, Karen E, Basak, A Nazli, Mora, Jesús S, Drory, Vivian E, Shaw, Pamela J, Turner, Martin R, Talbot, Kevin, Hardiman, Orla, Williams, Kelly L, Fifita, Jennifer A, Nicholson, Garth A, Blair, Ian P, Rouleau, Guy A, Esteban-Pérez, Jesú, García-Redondo, Alberto, Al-Chalabi, Ammar, Rogaeva, Ekaterina, Zinman, Lorne, Ostrow, Lyle W, Maragakis, Nicholas J, Rothstein, Jeffrey D, Simmons, Zachary, Cooper-Knock, Johnathan, Brice, Alexi, Goutman, Stephen A, Feldman, Eva L, Gibson, Summer B, Taroni, Franco, Ratti, Antonia, Gellera, Cinzia, Van Damme, Philip, Robberecht, Wim, Fratta, Pietro, Sabatelli, Mario, Lunetta, Christian, Ludolph, Albert C, Andersen, Peter M, Weishaupt, Jochen H, Camu, William, Trojanowski, John Q, Van Deerlin, Vivianna M, Brown, Robert H, van den Berg, Leonard H, Veldink, Jan H, Harms, Matthew B, Glass, Jonathan D, Stone, David J, Tienari, Pentti, Silani, Vincenzo, Chiò, Adriano, Shaw, Christopher E, Traynor, Bryan J, Landers, John E, Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Régional Universitaire de Tours (CHRU TOURS), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)

Subjects
Male, Als gene, Genome-wide association study, FAMILIAL ALS, ALS, axonal transport, cargo, GWAS, KIF5A, WES, WGS, 0302 clinical medicine, 80 and over, Psychology, Aetiology, Aged, 80 and over, 0303 health sciences, French ALS Consortium, Kinesin, KINESIN HEAVY-CHAIN, Cognitive Sciences, Human, Hereditary spastic paraplegia, Neuroscience(all), Single-nucleotide polymorphism, TARGETED DISRUPTION, Article, 03 medical and health sciences, Genetics, Humans, Amino Acid Sequence, Loss function, Aged, HEXANUCLEOTIDE REPEAT, Neuroscience (all), MUTATIONS, Amyotrophic Lateral Sclerosis, 3112 Neurosciences, 1702 Cognitive Science, medicine.disease, ITALSGEN Consortium, Answer ALS Foundation, 030104 developmental biology, ALS Sequencing Consortium, Human medicine, 1109 Neurosciences, 030217 neurology & neurosurgery, 0301 basic medicine, [SDV]Life Sciences [q-bio], Kinesins, Neurodegenerative, Genetic analysis, Genome, AMYOTROPHIC-LATERAL-SCLEROSIS, 3124 Neurology and psychiatry, Cohort Studies, Pathogenesis, Loss of Function Mutation, Missense mutation, 2.1 Biological and endogenous factors, Amyotrophic lateral sclerosis, NYGC ALS Consortium, General Neuroscience, ALS, axonal transport, cargo, GWAS, KIF5A, WES, WGS, Middle Aged, Phenotype, Settore MED/26 - NEUROLOGIA, Neurological, Project MinE ALS Sequencing Consortium, Female, Adult, Biology, GENOTYPE IMPUTATION, Genome-Wide Association Study, Young Adult, NO, Rare Diseases, medicine, SLAGEN Consortium, Gene, 030304 developmental biology, Clinical Research in ALS and Related Disorders for Therapeutic Development (CReATe) Consortium, Neurology & Neurosurgery, Human Genome, Neurosciences, AXONAL-TRANSPORT, Brain Disorders, Family member, DNA-DAMAGE, MOTOR-NEURONS, 3111 Biomedicine, Cohort Studie, Genomic Translation for ALS Care (GTAC) Consortium, Amyotrophic Lateral Sclerosi
Abstract

© 2018 Elsevier Inc., To identify novel genes associated with ALS, we undertook two lines of investigation. We carried out a genome-wide association study comparing 20,806 ALS cases and 59,804 controls. Independently, we performed a rare variant burden analysis comparing 1,138 index familial ALS cases and 19,494 controls. Through both approaches, we identified kinesin family member 5A (KIF5A) as a novel gene associated with ALS. Interestingly, mutations predominantly in the N-terminal motor domain of KIF5A are causative for two neurodegenerative diseases: hereditary spastic paraplegia (SPG10) and Charcot-Marie-Tooth type 2 (CMT2). In contrast, ALS-associated mutations are primarily located at the C-terminal cargo-binding tail domain and patients harboring loss-of-function mutations displayed an extended survival relative to typical ALS cases. Taken together, these results broaden the phenotype spectrum resulting from mutations in KIF5A and strengthen the role of cytoskeletal defects in the pathogenesis of ALS.

Published
2018

47. Genetics of Dementia

Author

Alan E. Renton and Alison M. Goate

Abstract

The genetic architecture of dementia is polygenic and complex, with risk alleles spanning frequency–effect size space. Despite significant progress, most genes influencing these disorders await discovery. Known risk loci implicate perturbed pathways that coalesce around recurring mechanistic themes, notably the autophagosome-lysosome system, the cytoskeleton, endocytosis, innate immunity, lipid metabolism, mitochondria, and the ubiquitin-proteasome system. Phenotypic and pathophysiological pleiotropy suggests some conditions form continuous clinicopathogenetic disease spectra blurring classical diagnoses. Future large-scale genome sequencing of global populations will significantly elucidate etiopathogenesis and is likely to reframe nosology. Furthermore integrative prospective cohort studies have the potential to revolutionize our understanding of dementia.

Published
2017

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

Author

Hannah Andersen Pliner, Christophe Tzourio, Christina Lill, Jean-christophe Corvol, Anthony Schapira, Maria Martinez, Demetrios Vassilatis, Nicholas Wood, Irene Litvan, Günther Deuschl, Claudia Schulte, Karen Elaine Morrison, Nathan Pankratz, Gavin Hudson, Thomas Gasser, Christopher Letson, Michele Hu, Javier Simón Sánchez, Katie Lunnon, Jose Bras, J. Raphael Gibbs, Panos Deloukas, Cornelia Van Duijn, Eleanna Kara, Patrick Chinnery, Georgios Koutsis, Caroline Williams-Gray, Rita Guerreiro, John Hardy, Jean-Charles Lambert, Daniela Berg, Francis Walker, Vincent Plagnol, Honglei Chen, Peter Heutink, Sudha Seshadri, Jing Dong, Alexis Brice, Sarah Edkins, Alan E. Renton, Human genetics, NCA - neurodegeneration, Radiology & Nuclear Medicine, Erasmus MC other, Neuroscience Campus Amsterdam - Neurodegeneration, Amsterdam Neuroscience, Neurology, Graduate School, and Experimental Immunology

Subjects
Aging, Genotyping, Genotyping Techniques, Parkinson's, Clinical Sciences, Genome-wide association study, Computational biology, Neurodegenerative, Article, Rare Diseases, Clinical Research, Genetic variation, Methods, Genetics, Medicine, Genetic Predisposition to Disease, Genetic variability, Genetic Testing, Neurodegeneration, Exome, Alleles, Genetic Association Studies, Parkinson's Disease meta-analysis consortium, Oligonucleotide Array Sequence Analysis, Imputation, Neurology & Neurosurgery, business.industry, General Neuroscience, Human Genome, Neurosciences, Genetic Variation, Neurodegenerative Diseases, SDG 10 - Reduced Inequalities, Disorders of movement Donders Center for Medical Neuroscience [Radboudumc 3], Data sharing, Meta-analysis, Costs and Cost Analysis, Neurology (clinical), Geriatrics and Gerontology, business, Imputation (genetics), Developmental Biology, International Parkinson's Disease Genomics Consortium
Abstract

Contains fulltext : 153490.pdf (Publisher’s version ) (Closed access) Our objective was to design a genotyping platform that would allow rapid genetic characterization of samples in the context of genetic mutations and risk factors associated with common neurodegenerative diseases. The platform needed to be relatively affordable, rapid to deploy, and use a common and accessible technology. Central to this project, we wanted to make the content of the platform open to any investigator without restriction. In designing this array we prioritized a number of types of genetic variability for inclusion, such as known risk alleles, disease-causing mutations, putative risk alleles, and other functionally important variants. The array was primarily designed to allow rapid screening of samples for disease-causing mutations and large population studies of risk factors. Notably, an explicit aim was to make this array widely available to facilitate data sharing across and within diseases. The resulting array, NeuroX, is a remarkably cost and time effective solution for high-quality genotyping. NeuroX comprises a backbone of standard Illumina exome content of approximately 240,000 variants, and over 24,000 custom content variants focusing on neurologic diseases. Data are generated at approximately $50-$60 per sample using a 12-sample format chip and regular Infinium infrastructure; thus, genotyping is rapid and accessible to many investigators. Here, we describe the design of NeuroX, discuss the utility of NeuroX in the analyses of rare and common risk variants, and present quality control metrics and a brief primer for the analysis of NeuroX derived data.

Published
2015

49. A common haplotype lowers PU.1 expression in myeloid cells and delays onset of Alzheimer’s disease

Author

Julie Williams, Jonathan L. Haines, Jean-Charles Lambert, Anna A. Pimenova, M. Arfan Ikram, Antonio Fabio Di Narzo, Kuan-lin Huang, Laura Ibanez, Alison Goate, Anita L. DeStefano, Ingrid B. Borecki, Hieab H.H. Adams, Alan E. Renton, Jake Czajkowski, Cornelia M. van Duijn, Vincent Chouraki, Ke Hao, Yuetiva Deming, Philippe Amouyel, Lindsay A. Farrer, Towfique Raj, John P. Budde, Richard Mayeux, Céline Bellenguez, Lenore J. Launer, Benjamin Grenier-Boley, Sven J. van der Lee, Joshua C. Bis, Jorge L. Del-Aguila, Andrew M. McKenzie, Albert V. Smith, Manav Kapoor, Sheng Chih Jin, Edoardo Marcora, Rebecca Sims, Oscar Harari, Gerard D. Schellenberg, Bin Zhang, Carlos Cruchaga, John S. K. Kauwe, Maria Victoria Fernandez, Margaret A. Pericak-Vance, Benjamin P. Fairfax, Annette L. Fitzpatrick, Sudha Seshadri, Sarah Bertelsen, and Valentina Escott-Price

Subjects
0303 health sciences, Cell type, SPI1, Myeloid, Locus (genetics), Biology, Minor allele frequency, 03 medical and health sciences, 0302 clinical medicine, medicine.anatomical_structure, Cistrome, Gene expression, Immunology, medicine, Gene, 030217 neurology & neurosurgery, 030304 developmental biology
Abstract

A genome-wide survival analysis of 14,406 Alzheimer’s disease (AD) cases and 25,849 controls identified eight previously reported AD risk loci and fourteen novel loci associated with age at onset. LD score regression of 220 cell types implicated regulation of myeloid gene expression in AD risk. In particular, the minor allele of rs1057233 (G), within the previously reported CELF1 AD risk locus, showed association with delayed AD onset and lower expression of SPI1 in monocytes and macrophages. SPI1 encodes PU.1, a transcription factor critical for myeloid cell development and function. AD heritability is enriched within the PU.1 cistrome, implicating a myeloid PU.1 target gene network in AD. Finally, experimentally altered PU.1 levels affect the expression of mouse orthologs of many AD risk genes and the phagocytic activity of mouse microglial cells. Our results suggest that lower SPI1 expression reduces AD risk by regulating myeloid gene expression and cell function.

Published
2017
Full Text
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50. P4-487: BRAIN SOMATIC MOSAICISM IN 17Q21.31 MAPT H1-ASSOCIATED ALZHEIMER'S DISEASE

Author

Alexander W. Charney, Yiyuan Liu, Minghui Wang, Bin Zhang, Alan E. Renton, Carlos Cruchaga, Maria Victoria Fernandez, Alison Goate, and John F. Crary

Subjects
Pathology, medicine.medical_specialty, Epidemiology, business.industry, Health Policy, Disease, Psychiatry and Mental health, Cellular and Molecular Neuroscience, Developmental Neuroscience, Somatic mosaicism, Medicine, Neurology (clinical), Geriatrics and Gerontology, business
Published
2019

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