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1. Human whole-exome genotype data for Alzheimer’s disease

Author

Yuk Yee Leung, Adam C. Naj, Yi-Fan Chou, Otto Valladares, Michael Schmidt, Kara Hamilton-Nelson, Nicholas Wheeler, Honghuang Lin, Prabhakaran Gangadharan, Liming Qu, Kaylyn Clark, Amanda B. Kuzma, Wan-Ping Lee, Laura Cantwell, Heather Nicaretta, Alzheimer’s Disease Sequencing Project, Jonathan Haines, Lindsay Farrer, Sudha Seshadri, Zoran Brkanac, Carlos Cruchaga, Margaret Pericak-Vance, Richard P. Mayeux, William S. Bush, Anita Destefano, Eden Martin, Gerard D. Schellenberg, and Li-San Wang

Subjects
Science
Abstract

Abstract The heterogeneity of the whole-exome sequencing (WES) data generation methods present a challenge to a joint analysis. Here we present a bioinformatics strategy for joint-calling 20,504 WES samples collected across nine studies and sequenced using ten capture kits in fourteen sequencing centers in the Alzheimer’s Disease Sequencing Project. The joint-genotype called variant-called format (VCF) file contains only positions within the union of capture kits. The VCF was then processed specifically to account for the batch effects arising from the use of different capture kits from different studies. We identified 8.2 million autosomal variants. 96.82% of the variants are high-quality, and are located in 28,579 Ensembl transcripts. 41% of the variants are intronic and 1.8% of the variants are with CADD > 30, indicating they are of high predicted pathogenicity. Here we show our new strategy can generate high-quality data from processing these diversely generated WES samples. The improved ability to combine data sequenced in different batches benefits the whole genomics research community.

Published
2024
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2. Polygenic risk score penetrance & recurrence risk in familial Alzheimer disease

Author

Min Qiao, Annie J. Lee, Dolly Reyes‐Dumeyer, Giuseppe Tosto, Kelley Faber, Alison Goate, Alan Renton, Michael Chao, Brad Boeve, Carlos Cruchaga, Margaret Pericak‐Vance, Jonathan L. Haines, Roger Rosenberg, Debby Tsuang, Robert A. Sweet, David A. Bennett, Robert S. Wilson, Tatiana Foroud, Richard Mayeux, and Badri N. Vardarajan

Subjects
Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571, Neurology. Diseases of the nervous system, RC346-429
Abstract

Abstract Objective To compute penetrance and recurrence risk using a genome‐wide PRS (including and excluding the APOE region) in families with Alzheimer's disease. Methods Genotypes from the National Institute on Aging Late‐Onset Alzheimer's Disease Family‐Based Study and a study of familial Alzheimer's disease in Caribbean Hispanics were used to compute PRS with and without variants in the 2 MB region flanking APOE. PRS was calculated in using clumping/thresholding and Bayesian methods and was assessed for association with Alzheimer's disease and age at onset. Penetrance and recurrence risk for carriers in highest and lowest PRS quintiles were compared separately within APOE‐ε4 carriers and non‐carriers. Results PRS excluding the APOE region was strongly associated with clinical and neuropathological diagnosis of AD. PRS association with AD was similar in participants who did not carry an APOE‐ε4 allele (OR = 1.74 [1.53–1.91]) compared with APOE‐ε4 carriers (1.53 [1.4–1.68]). Compared to the lowest quintile, the highest PRS quintile had a 10% higher penetrance at age 70 (p = 0.0006) and a 20% higher penetrance at age 80 (p

Published
2023
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3. 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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4. A population-specific reference panel empowers genetic studies of Anabaptist populations

Author

Liping Hou, Rachel L. Kember, Jared C. Roach, Jeffrey R. O’Connell, David W. Craig, Maja Bucan, William K. Scott, Margaret Pericak-Vance, Jonathan L. Haines, Michael H. Crawford, Alan R. Shuldiner, and Francis J. McMahon

Subjects
Medicine, Science
Abstract

Abstract Genotype imputation is a powerful strategy for achieving the large sample sizes required for identification of variants underlying complex phenotypes, but imputation of rare variants remains problematic. Genetically isolated populations offer one solution, however population-specific reference panels are needed to assure optimal imputation accuracy and allele frequency estimation. Here we report the Anabaptist Genome Reference Panel (AGRP), the first whole-genome catalogue of variants and phased haplotypes in people of Amish and Mennonite ancestry. Based on high-depth whole-genome sequence (WGS) from 265 individuals, the AGRP contains >12 M high-confidence single nucleotide variants and short indels, of which ~12.5% are novel. These Anabaptist-specific variants were more deleterious than variants with comparable frequencies observed in the 1000 Genomes panel. About 43,000 variants showed enriched allele frequencies in AGRP, consistent with drift. When combined with the 1000 Genomes Project reference panel, the AGRP substantially improved imputation, especially for rarer variants. The AGRP is freely available to researchers through an imputation server.

Published
2017
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5. Genetic assessment of age-associated Alzheimer disease risk: Development and validation of a polygenic hazard score.

Author

Rahul S Desikan, Chun Chieh Fan, Yunpeng Wang, Andrew J Schork, Howard J Cabral, L Adrienne Cupples, Wesley K Thompson, Lilah Besser, Walter A Kukull, Dominic Holland, Chi-Hua Chen, James B Brewer, David S Karow, Karolina Kauppi, Aree Witoelar, Celeste M Karch, Luke W Bonham, Jennifer S Yokoyama, Howard J Rosen, Bruce L Miller, William P Dillon, David M Wilson, Christopher P Hess, Margaret Pericak-Vance, Jonathan L Haines, Lindsay A Farrer, Richard Mayeux, John Hardy, Alison M Goate, Bradley T Hyman, Gerard D Schellenberg, Linda K McEvoy, Ole A Andreassen, and Anders M Dale

Subjects
Medicine
Abstract

BackgroundIdentifying individuals at risk for developing Alzheimer disease (AD) is of utmost importance. Although genetic studies have identified AD-associated SNPs in APOE and other genes, genetic information has not been integrated into an epidemiological framework for risk prediction.Methods and findingsUsing genotype data from 17,008 AD cases and 37,154 controls from the International Genomics of Alzheimer's Project (IGAP Stage 1), we identified AD-associated SNPs (at p < 10-5). We then integrated these AD-associated SNPs into a Cox proportional hazard model using genotype data from a subset of 6,409 AD patients and 9,386 older controls from Phase 1 of the Alzheimer's Disease Genetics Consortium (ADGC), providing a polygenic hazard score (PHS) for each participant. By combining population-based incidence rates and the genotype-derived PHS for each individual, we derived estimates of instantaneous risk for developing AD, based on genotype and age, and tested replication in multiple independent cohorts (ADGC Phase 2, National Institute on Aging Alzheimer's Disease Center [NIA ADC], and Alzheimer's Disease Neuroimaging Initiative [ADNI], total n = 20,680). Within the ADGC Phase 1 cohort, individuals in the highest PHS quartile developed AD at a considerably lower age and had the highest yearly AD incidence rate. Among APOE ε3/3 individuals, the PHS modified expected age of AD onset by more than 10 y between the lowest and highest deciles (hazard ratio 3.34, 95% CI 2.62-4.24, p = 1.0 × 10-22). In independent cohorts, the PHS strongly predicted empirical age of AD onset (ADGC Phase 2, r = 0.90, p = 1.1 × 10-26) and longitudinal progression from normal aging to AD (NIA ADC, Cochran-Armitage trend test, p = 1.5 × 10-10), and was associated with neuropathology (NIA ADC, Braak stage of neurofibrillary tangles, p = 3.9 × 10-6, and Consortium to Establish a Registry for Alzheimer's Disease score for neuritic plaques, p = 6.8 × 10-6) and in vivo markers of AD neurodegeneration (ADNI, volume loss within the entorhinal cortex, p = 6.3 × 10-6, and hippocampus, p = 7.9 × 10-5). Additional prospective validation of these results in non-US, non-white, and prospective community-based cohorts is necessary before clinical use.ConclusionsWe have developed a PHS for quantifying individual differences in age-specific genetic risk for AD. Within the cohorts studied here, polygenic architecture plays an important role in modifying AD risk beyond APOE. With thorough validation, quantification of inherited genetic variation may prove useful for stratifying AD risk and as an enrichment strategy in therapeutic trials.

Published
2017
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6. Common variants at 9p21 and 8q22 are associated with increased susceptibility to optic nerve degeneration in glaucoma.

Author

Janey L Wiggs, Brian L Yaspan, Michael A Hauser, Jae H Kang, R Rand Allingham, Lana M Olson, Wael Abdrabou, Bao J Fan, Dan Y Wang, Wendy Brodeur, Donald L Budenz, Joseph Caprioli, Andrew Crenshaw, Kristy Crooks, Elizabeth Delbono, Kimberly F Doheny, David S Friedman, Douglas Gaasterland, Terry Gaasterland, Cathy Laurie, Richard K Lee, Paul R Lichter, Stephanie Loomis, Yutao Liu, Felipe A Medeiros, Cathy McCarty, Daniel Mirel, Sayoko E Moroi, David C Musch, Anthony Realini, Frank W Rozsa, Joel S Schuman, Kathleen Scott, Kuldev Singh, Joshua D Stein, Edward H Trager, Paul Vanveldhuisen, Douglas Vollrath, Gadi Wollstein, Sachiko Yoneyama, Kang Zhang, Robert N Weinreb, Jason Ernst, Manolis Kellis, Tomohiro Masuda, Don Zack, Julia E Richards, Margaret Pericak-Vance, Louis R Pasquale, and Jonathan L Haines

Subjects
Genetics, QH426-470
Abstract

Optic nerve degeneration caused by glaucoma is a leading cause of blindness worldwide. Patients affected by the normal-pressure form of glaucoma are more likely to harbor risk alleles for glaucoma-related optic nerve disease. We have performed a meta-analysis of two independent genome-wide association studies for primary open angle glaucoma (POAG) followed by a normal-pressure glaucoma (NPG, defined by intraocular pressure (IOP) less than 22 mmHg) subgroup analysis. The single-nucleotide polymorphisms that showed the most significant associations were tested for association with a second form of glaucoma, exfoliation-syndrome glaucoma. The overall meta-analysis of the GLAUGEN and NEIGHBOR dataset results (3,146 cases and 3,487 controls) identified significant associations between two loci and POAG: the CDKN2BAS region on 9p21 (rs2157719 [G], OR = 0.69 [95%CI 0.63-0.75], p = 1.86×10⁻¹⁸), and the SIX1/SIX6 region on chromosome 14q23 (rs10483727 [A], OR = 1.32 [95%CI 1.21-1.43], p = 3.87×10⁻¹¹). In sub-group analysis two loci were significantly associated with NPG: 9p21 containing the CDKN2BAS gene (rs2157719 [G], OR = 0.58 [95% CI 0.50-0.67], p = 1.17×10⁻¹²) and a probable regulatory region on 8q22 (rs284489 [G], OR = 0.62 [95% CI 0.53-0.72], p = 8.88×10⁻¹⁰). Both NPG loci were also nominally associated with a second type of glaucoma, exfoliation syndrome glaucoma (rs2157719 [G], OR = 0.59 [95% CI 0.41-0.87], p = 0.004 and rs284489 [G], OR = 0.76 [95% CI 0.54-1.06], p = 0.021), suggesting that these loci might contribute more generally to optic nerve degeneration in glaucoma. Because both loci influence transforming growth factor beta (TGF-beta) signaling, we performed a genomic pathway analysis that showed an association between the TGF-beta pathway and NPG (permuted p = 0.009). These results suggest that neuro-protective therapies targeting TGF-beta signaling could be effective for multiple forms of glaucoma.

Published
2012
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7. The Peruvian Alzheimer Disease Initiative (PeADI): An international effort model to increase diversity in AD research (S15.002)

Author

Maryenela Illanes-Manrique, Pedro Mena, Karina Milla-Neyra, Larry Adams, Koni Mejia, Julia Rios-Pinto, Rosario Isasi, Angel Medina-Colque, Gary Beecham, Ivan Cornejo-Herrera, Jeffery Vance, Edward Ochoa-Valle, Sheila Castro-Suarez, Michael L. Cuccaro, Elison Sarapura-Castro, Diana Cubas-Montecino, Mario Cornejo Olivas, and Margaret Pericak-Vance

Published
2023

8. The National Institute on Aging Late‐Onset Alzheimer's Disease Family Based Study: A resource for genetic discovery

Author

Dolly, Reyes-Dumeyer, Kelley, Faber, Badri, Vardarajan, Alison, Goate, Alan, Renton, Michael, Chao, Brad, Boeve, Carlos, Cruchaga, Margaret, Pericak-Vance, Jonathan L, Haines, Roger, Rosenberg, Debby, Tsuang, Robert A, Sweet, David A, Bennett, Robert S, Wilson, Tatiana, Foroud, and Richard, Mayeux

Subjects
Genotype, Epidemiology, Health Policy, United States, Psychiatry and Mental health, Cellular and Molecular Neuroscience, Apolipoproteins E, Developmental Neuroscience, Alzheimer Disease, National Institute on Aging (U.S.), Humans, Neurology (clinical), Age of Onset, Geriatrics and Gerontology
Abstract

The 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).Recruitment 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. Apolipoprotein E (APOE) genotypes, genome-wide single nucleotide polymorphism (SNP) arrays, and sequencing was completed in most families.APOE genotype modified the age-at-onset in many large families. Novel variants and known variants associated with early- and late-onset AD and frontotemporal dementia were identified supporting an international effort to solve AD genetics.The NIA-LOAD FBS is the largest collection of familial AD worldwide, and data or samples have been included in 123 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
2022

9. Mitochondrial TXNRD2 and ME3 Genetic Risk Scores Are Associated with Specific Primary Open-Angle Glaucoma Phenotypes

Author

Inas F. Aboobakar, Tyler G. Kinzy, Yan Zhao, Baojian Fan, Louis R. Pasquale, Ayub Qassim, Antonia Kolovos, Joshua M. Schmidt, Jamie E. Craig, Jessica N. Cooke Bailey, Janey L. Wiggs, R. Rand Allingham, Murray Brilliant, Donald L. Budenz, John H. Fingert, Douglas Gaasterland, Teresa Gaasterland, Jonathan L. Haines, Michael A. Hauser, Richard K. Lee, Paul R. Lichter, Yutao Liu, Syoko Moroi, Jonathan Myers, Margaret Pericak-Vance, Anthony Realini, Doug Rhee, Julia E. Richards, Robert Ritch, Joel S. Schuman, William K. Scott, Kuldev Singh, Arthur J. Sit, Douglas Vollrath, Robert N. Weinreb, Gadi Wollstein, and Donald J. Zack

Subjects
Ophthalmology
Published
2023

10. P1‐045: EXOME ARRAY ANALYSIS IDENTIFIES NOVEL RISK VARIANTS FOR ALZHEIMER'S DISEASE WITH ONSET BEFORE 65 YEARS

Author

Adam C. Naj, Carlos Cruchaga, Brian W. Kunkle, Shubhabrata Mukherjee, Robert Graham, Li‐San Wang, Timothy Behrens, Richard Mayeux, Jonathan Haines, Lindsay A. Farrer, Margaret Pericak‐Vance, Gerard D. Schellenberg, and null The Alzheimer's Disease Genetics Consortium

Subjects
Oncology, medicine.medical_specialty, Epidemiology, business.industry, Health Policy, Disease, Psychiatry and Mental health, Cellular and Molecular Neuroscience, Developmental Neuroscience, Internal medicine, medicine, Neurology (clinical), Geriatrics and Gerontology, business, Exome
Published
2014

11. O1‐04‐03: LOW‐FREQUENCY VARIANT IMPUTATION IDENTIFIES NOVEL DISEASE‐ASSOCIATED LOCI IN A GENOME‐WIDE ASSOCIATION STUDY OF LATE‐ONSET ALZHEIMER'S DISEASE

Author

Brian W. Kunkle, Adam C. Naj, Kara Hamilton‐Nelson, William R. Perry, Amanda Partch, Otto Valladares, Jaeyoon Chung, Gyungah Jun, Mike Schmidt, Gary Beecham, Li‐San Wang, Eden Martin, Richard Mayeux, Jonathan Haines, Lindsay A. Farrer, Gerard D. Schellenberg, Margaret Pericak‐Vance, and null The Alzheimer's Disease Genetics Consortium

Subjects
Genetics, Psychiatry and Mental health, Cellular and Molecular Neuroscience, Developmental Neuroscience, Epidemiology, Health Policy, Late onset, Genome-wide association study, Neurology (clinical), Disease, Geriatrics and Gerontology, Biology, Imputation (genetics)
Published
2014

12. Genes—Here Today Gone Tomorrow

Author

Patricia Rieser, Penelope Manasco, and Margaret Pericak-Vance

Subjects
Genetics, Genetic linkage, business.industry, Endocrinology, Diabetes and Metabolism, Medicine, business, Gene, Genetic association
Published
2000

13. O4–06–05: SORL1 is genetically associated with late‐onset Alzheimer's disease in Japanese, Koreans and Caucasians

Author

Ryozo Kuwano, Akinori Miyashita, Asako Koike, Gyungah Jun, Li‐San Wang, Satoshi Takahashi, Jong‐Won Kim, Peter St. George‐Hyslop, Richard Mayeux, Jonathan Haines, Margaret Pericak‐Vance, Makiko Yoshida, Nao Nishida, Katsusi Tokunaga, Ken Yamamoto, Shoji Tsuji, Ichiro Kanazawa, Yasuo Ihara, Gerard Schellenberg, and Lindsay Farrer

Subjects
Psychiatry and Mental health, Cellular and Molecular Neuroscience, Developmental Neuroscience, Epidemiology, Health Policy, Neurology (clinical), Geriatrics and Gerontology
Published
2013

15. P4‐377: Large repeat expansions in the C9ORF72 gene contribute to a spectrum of neurodegenerative disorders including Alzheimer's disease in Caucasians, but not African‐Americans

Author

Margaret Pericak‐Vance, Stephan Zuchner, Martin Kohli, Krista John‐Williams, Adam Naj, Ruchita Rajbhandary, Patrice L. Whitehead, Kara Hamilton‐Nelson, Regina Carney, Clinton Wright, Elizabeth Crocco, Harry Gwirtzman, Rosalyn Lang, Gary Beecham, Eden Martin, John Gilbert, Michael Benatar, Deborah Mash, Goldie Byrd, and Jonathan Haines

Subjects
Genetics, Psychiatry and Mental health, Cellular and Molecular Neuroscience, Developmental Neuroscience, Epidemiology, business.industry, Health Policy, C9orf72 Gene, Medicine, Neurology (clinical), Disease, Geriatrics and Gerontology, business
Published
2012

16. Abstract 535: Stem Cell--Mediated Atherosclerosis Plaque Repair

Author

Zhao-Jun Liu, Yurong Tan, Runxia Tian, Yan Li, Gary W Beecham, David M Seo, Roberto I Vazquez-Padron, Margaret Pericak-Vance, Jeffery M Vance, Pascal J Goldschmidt-Clermont, Alan S Livingstone, and Omaida C Velazquez

Subjects
Cardiology and Cardiovascular Medicine
Abstract

Objectives: Notch Signaling is known to regulate the biology of stem cells and the embryonic development of the aorta, but its role in atherosclerosis has received limited investigation. We recently reported that several Notch pathway components are activated in atherosclerotic plaques and result in endothelial inflammation and senescence. We investigate if differential Notch expression plays a role in the balance between plaque repair versus progression as a putative determinant of overall plaque burden. Methods: We assessed Notch expression in Bone Marrow Stem Cells of atherosclerosis-predisposed ApoE -/- mice (N=5) by PCRArray. We queried our data base of 1179 human blood samples (patients phenotyped by cardiac catherization and genotyped by Genome-Wide Human SNP Array) to determine if circulating mononuclear cells in patients with severe coronary artery disease (CAD) show variant genetic patterns within the family of Notch genes. Results: The Notch pathway was significantly activated in bone marrow-derived Endothelial Progenitor Cells (EPC) and Mesenchymal Stem Cells (MSC) from young ApoE -/- mice before initiation of high-fat diet and before aortic development of atherosclerosis plaque (some components such as Hes-1 and Hey-1 increased by up to 6.6- and 8.2-fold, respectively P Conclusions: Notch signaling may be linked to CAD risk by modulating the biology of bone marrow-derived progenitor/stem cell pools. These findings, together with our prior findings that Notch signaling is activated in atherosclerotic plaques and results in endothelial inflammation and senescence, strongly implicate the involvement of Notch in atherosclerosis pathogenesis.

Published
2012

17. P1‐250: Genome‐Wide Association Study of Late‐Onset Alzheimer Disease Identifies Disease‐Associated Variants in MS4A4/MS4A6E, CD2AP, CD33, and EPHA1

Author

Adam Naj, Gyungah Jun, Jacqueline Buros, Paul Gallins, Lindsay Farrer, Jonathan Haines, Margaret Pericak‐Vance, Gerard Schellenberg, and null The Alzheimer's Disease Genetics Consortium

Subjects
Genetics, Psychiatry and Mental health, Cellular and Molecular Neuroscience, Developmental Neuroscience, Epidemiology, Health Policy, CD33, Late Onset Alzheimer Disease, Genome-wide association study, Neurology (clinical), Disease, Geriatrics and Gerontology, Biology
Published
2011

18. P1‐272: The ADGC genome browser

Author

Li‐San Wang, Otto Valladares, Chiao‐Feng Lin, Jacqueline Buros, Adam Naj, Lindsay Farrer, Margaret Pericak‐Vance, Gerard Schellenberg, and null The Alzheimer's Disease Genetics Consortium

Subjects
Psychiatry and Mental health, Cellular and Molecular Neuroscience, Developmental Neuroscience, Epidemiology, Health Policy, Neurology (clinical), Genome browser, Computational biology, Geriatrics and Gerontology, Biology
Published
2011

19. P1‐242: Comprehensive Variant Discovery in the Late‐Onset Alzheimer's Disease Susceptibility Gene MTHFD1L Using Next Generation Sequencing Technology

Author

Martin Kohli, Adam Naj, Jessica Van Baaren, William Hulme, Gary Beecham, Joseph Buxbaum, Stephan Zuchner, Jonathan Haines, John Gilbert, and Margaret Pericak‐Vance

Subjects
Psychiatry and Mental health, Cellular and Molecular Neuroscience, Developmental Neuroscience, Epidemiology, Health Policy, Neurology (clinical), Geriatrics and Gerontology
Published
2011

20. P1‐268: Discovery and Replication of Gene‐Gene Interactions in Multiple Independent Datasets from the Alzheimer Disease Genetics Consortium

Author

Tricia Thornton‐Wells, Eric Torstenson, Scott Dudek, Marylyn Ritchie, Eden Martin, Margaret Pericak‐Vance, Jonathan Haines, and null The Alzheimer's Disease Genetics Consortium

Subjects
Genetics, Epidemiology, Health Policy, Biology, medicine.disease, Psychiatry and Mental health, Cellular and Molecular Neuroscience, Developmental Neuroscience, Replication (statistics), medicine, Neurology (clinical), Geriatrics and Gerontology, Alzheimer's disease, Gene
Published
2011

21. Inflammation, stem cells and atherosclerosis genetics

Author

Pascal J, Goldschmidt-Clermont, David M, Seo, Liyong, Wang, Gary W, Beecham, Zhao Jun, Liu, Roberto I, Vazquez-Padron, Chunming, Dong, Joshua M, Hare, Michael S, Kapiloff, Nanette H, Bishopric, Margaret, Pericak-Vance, Jeffery M, Vance, and Omaida C, Velazquez

Subjects
Inflammation, Gene Expression Regulation, Models, Genetic, Stem Cells, Endothelial Cells, Humans, Genetic Predisposition to Disease, Atherosclerosis, Polymorphism, Single Nucleotide, Genome-Wide Association Study
Abstract

Atherosclerosis and its associated complications remain the primary cause of death in humans. Aging is the main contributor to atherosclerosis, compared with any other risk factor, yet the specific manner in which age increases risk (the 'aging-risk' mechanism) remains elusive. A novel concept for atherosclerosis risk implicates a lack of endothelial progenitor cell (EPC)-dependent arterial repair in the development of the disease that is secondary to exhaustion of repair-competent EPCs. Molecular evidence derived from genetic techniques indicates atherosclerotic lesions may begin to form as arterial repair fails, rather than merely following arterial injury. Thus, chronic arterial injury may overwhelm the ability of EPCs to maintain arterial homeostasis, particularly when EPCs capable of arterial repair become exhausted. Recent studies have reported genes identified using non-biased approaches (ie, genetic linkage studies and genome-wide association studies) that are associated with susceptibility for atherosclerosis and related thromboembolic disorders; these genes may be implicated in the control of arterial wall inflammation and EPC-mediated tissue repair. Most of the genes identified by using non-biased genomic techniques are associated with inflammation, immune response and stem cells. This review focuses on new genetic data in the field of atherosclerosis and arterial homeostasis.

Published
2010

22. Findings from a community education needs assessment to facilitate the integration of genomic medicine into primary care

Author

Carol A, Christianson, Karen Potter, Powell, Susan Estabrooks, Hahn, Deborah, Bartz, Tiese, Roxbury, Susan H, Blanton, Jeffery M, Vance, Margaret, Pericak-Vance, Joseph, Telfair, Vincent C, Henrich, and Astrid, Agbaje

Subjects
Adult, medicine.medical_specialty, Community education, Risk management tools, Risk Assessment, Health Services Accessibility, Interviews as Topic, medicine, Genetic predisposition, North Carolina, Humans, Genetic Predisposition to Disease, Genetic Testing, Family history, Genetic discrimination, Health Education, Genetics (clinical), Genetic testing, Family Health, medicine.diagnostic_test, Primary Health Care, Knowledge level, Genomics, Family medicine, Needs assessment, Psychology, Needs Assessment
Abstract

Purpose: To assess the lay public's knowledge of, and beliefs about, genetics and genetic testing to create an educational initiative that promotes acceptance and utilization of genomic medicine in primary health care. Methods: A telephone survey of English-speaking adults in Guilford County, North Carolina was conducted in 2006 to identify community members' educational needs regarding genetics and genetic testing. Results: Most respondents recognized the connection between family history and disease risk. A majority did not appear to know about: (1) basic principles of inheritance, (2) laws prohibiting genetic discrimination, and (3) the availability and limitations of genetic tests. About 25% thought that they could not reduce their risk if they have a genetic predisposition for disease. Knowledge level was affected by education, experience, age, and race. Conclusion: If primary care providers use family history as a risk assessment tool, community education programs must address (1) the collection of family health history, (2) legislation regarding genetic nondiscrimination, (3) benefits and limitations of existing genetic tests, and (4) genetic determinism. Programs emphasizing practical, “how to” information can be targeted to individuals likely to collect family history information and address misperceptions about discrimination, testing, and determinism.

Published
2010

23. Juvenile bilateral lens dislocation and glaucoma associated with a novel mutation in the fibrillin 1 gene

Author

Pratap, Challa, Michael Arthur, Hauser, Coralia Catalina, Luna, Sharon Fridovich, Freedman, Margaret, Pericak-Vance, Jun, Yang, Marie Theresa, McDonald, and R Rand, Allingham

Subjects
Adult, Male, Genetic Linkage, Fibrillin-1, Microfilament Proteins, Mutation, Missense, Glaucoma, Exons, Syndrome, Lens Subluxation, Middle Aged, Fibrillins, Corneal Diseases, Pedigree, Amino Acid Substitution, Child, Preschool, Serine, Humans, Female, Cysteine, Lod Score, Child, Aged
Abstract

To describe the clinical, ocular, and genetic findings in multiple members of a family with early-onset and bilateral lens dislocation, clinical corneal guttae, and glaucoma.All family members underwent complete physical and ophthalmic examinations. After informed consent was given, DNA was obtained from eleven family members, eight of whom were affected. Three polymorphic markers near the fibrillin 1 (FBN1) locus were genotyped and the results analyzed using the VITESSE program. Amplification of the 65 exons and flanking intronic sequences of FBN1 was performed using polymerase chain reaction (PCR), followed by conformation sensitive gel electrophoresis (CSGE). Then, all fragments with mobility variations were sequenced.Pedigree analysis revealed a three generation family with eight of eleven individuals affected by early onset lens dislocation, high myopia, typical facies, frontal bossing, flexion contractures, proximal interphalangeal (PIP) joint thickening, clinical corneal guttae, and glaucoma. Genetic linkage analysis using polymorphic markers near FBN1 demonstrated an LOD score of 1.78 (maximum possible LOD score 1.78). Conformation sequence gel electrophoresis analysis suggested a sequence variation in exon 3. Sequencing revealed a C965G substitution, resulting in an S322C coding change. This sequence variant segregated with affection status and was not identified in 154 control chromosomes.This syndrome is consistent with a novel mutation in the FBN1 gene. FBN1 mutations have been previously described as causative for Marfan syndrome. The early-onset of complete lens dislocation, progressive corneal guttae, and glaucoma is unusual for Marfan syndrome. This study expands the Marfan phenotype and demonstrates a possible link between guttae, glaucoma, and fibrillin 1 disorders.

Published
2006

24. Erratum: A genome-wide search for linkage to asthma phenotypes in the genetics of asthma international network families: evidence for a major susceptibility locus on chromosome 2p

Author

John H. Riley, John Tsanakas, Andrea von Berg, Margaret Pericak-Vance, Wayne H. Anderson, Marcy Speer, Peter D. Sly, Jorrit Gerritsen, Karin C. Lødrup Carlsen, Daniel K. Burns, John S. Sundy, Peter J Helms, Warren Lenney, Mathias Chiano, Shela Varsani, S. Brewster, Jeffery M. Vance, Michael Silverman, Nicola J. White, Michael A. Hauser, Kathleen C. Barnes, Sreekumar G. Pillai, Moira K. B. Whyte, Lefkos T. Middleton, and Paul Skelding

Subjects
Linkage (software), Genetics, International network, Asthma phenotypes, Chromosome, Biology, medicine.disease, Genome, Evolutionary biology, Susceptibility locus, medicine, Genetics (clinical), Asthma
Published
2007

25. Genetic Studies in Familial Dementia

Author

Case Western Reserve University, Columbia University, Wake Forest University, National Institute on Aging (NIA), and Margaret Pericak-Vance, Professor

Published
2023

26. Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism

Author

Gail E. Herman, Jennifer Reichert, Camilla Stoltenberg, Stephen Sanders, Menachem Fromer, Branko Aleksic, Julian Maller, Rachel Nguyen, Utku Norman, J. Jay Gargus, Donna M. Werling, David J. Cutler, Silvia De Rubeis, Kathryn Roeder, Ryan N. Doan, Sherif Gerges, Joseph D. Buxbaum, Per Magnus, Patrick Turley, Moyra Smith, Isaac N. Pessah, Rebecca J. Schmidt, Chiara Fallerini, Michael E. Talkowski, Carla Lintas, Pål Surén, Paige M. Siper, Duncan S. Palmer, Timothy W. Yu, Michael S. Breen, Sven Sandin, Esben Agerbo, Rich Belliveau, Antonio M. Persico, Elaine Cristina Zachi, Matthew W. State, Karoline Teufel, Margaret A. Pericak-Vance, Caitlin E. Carey, Ryan Collins, Lambertus Klei, Lara Tang, Mads V. Hollegaard, Ole Mors, Iuliana Ionita-Laza, Elisa Giorgio, Astanand Jugessur, Gerry Schellenberg, Christopher A. Walsh, A. Ercument Cicek, Caroline Dias, Gun Peggy Knudsen, Louise Gallagher, Elise B. Robinson, Abraham Reichenberg, Judith Miller, Ashley Dumont, Flora Tassone, Grace Schwartz, Peter Szatmari, Jacqueline I. Goldstein, Evelise Riberi, Brian H.Y. Chung, Stephen W. Scherer, Fátima Lopes, Jesslyn Jamison, Thomas Werge, Mara Parellada, Gabriela Soares, Hilary Coon, Shan Dong, Terho Lehtimäki, Norio Ozaki, Lauren A. Weiss, Susan L. Santangelo, F. Kyle Satterstrom, Daniel P. Howrigan, Emily Hansen-Kiss, Anders D. Børglum, Vivek Appadurai, Maria Rita Passos-Bueno, Hailiang Huang, Marcus C.Y. Chan, Eric M. Morrow, Stephen J. Guter, Catalina Betancur, Ditte Demontis, Matthew W. Mosconi, Pierandrea Muglia, Joanna Martin, Jack A. Kosmicki, Christine M. Freitag, Suma Jacob, W. Ian Lipkin, Angel Carracedo, Mark J. Daly, Andreas G. Chiocchetti, Eduarda Montenegro M. de Souza, Carsten Bøcker Pedersen, Isabela Maya Wahys Silva, Elizabeth E. Guerrero, Mafalda Barbosa, A. Jeremy Willsey, Maureen Mulhern, Claire Churchhouse, Raymond K. Walters, Timothy Poterba, Alessandra Renieri, Emilie M. Wigdor, Lauren M. Schmitt, Jennifer L. Moran, Mullin H.C. Yu, Edwin H. Cook, Jiebiao Wang, Behrang Mahjani, Kaitlin E. Samocha, Kaija Puura, Xin He, Ezra Susser, Aarno Palotie, Bernardo Dalla Bernardina, Montserrat Fernández-Prieto, Thomas Damm Als, Mykyta Artomov, Emma Wilkinson, Mads E. Hauberg, Enrico Domenici, Joon Yong An, Christine Søholm Hansen, Somer L. Bishop, Idan Menashe, So Lun Lee, Marianne Giørtz Pedersen, Alfredo Brusco, Nancy J. Minshew, Michael E. Zwick, Jesper Buchhave Poulsen, Elaine T. Lim, Benjamin M. Neale, Harrison Brand, Danielle Halpern, Elisabetta Trabetti, Alexander Kolevzon, Christine Stevens, Aurora Currò, Miia Kaartinen, Gal Meiri, Richard Anney, Søren Dalsgaard, Minshi Peng, Kimberly Chambert, Brooke Sheppard, Yunin Ludena, James S. Sutcliffe, Marie Bækvad-Hansen, Xinyi Xu, Audrey Thurm, Itaru Kushima, Michael Gill, Irva Hertz-Picciotto, Jonatan Pallesen, Stephan Ripke, Dara S. Manoach, Giovanni Battista Ferrero, Nell Maltman, Michael L. Cuccaro, David M. Hougaard, Javier González-Peñas, Wesley K. Thompson, Felecia Cerrato, Danielle de Paula Moreira, Jonas Bybjerg-Grauholm, Alicia R. Martin, Merete Nordentoft, John A. Sweeney, Alfonso Buil, Tarjinder Singh, Bernie Devlin, Jakob Grove, Daniel H. Geschwind, Manuel Mattheisen, Patrícia Maciel, Preben Bo Mortensen, Andrew J. Schork, Ryan Yuen, Christina M. Hultman, Maria del Pilar Trelles, Aparna Bhaduri, Sabine Schlitt, Diego Lopergolo, Broad Institute of MIT and Harvard (BROAD INSTITUTE), Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston], Massachusetts General Hospital [Boston], Harvard Medical School [Boston] (HMS), Carnegie Mellon University [Pittsburgh] (CMU), Icahn School of Medicine at Mount Sinai [New York] (MSSM), University of California [San Francisco] (UCSF), University of California, Korea University [Seoul], The Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH), Aarhus University [Aarhus], Center for Genomics and Personalized Medicine [Aarhus, Denmark] (CGPM), University of Pittsburgh School of Medicine, Pennsylvania Commonwealth System of Higher Education (PCSHE), Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research [San Francisco, CA, USA], Bilkent University [Ankara], University of California [Irvine] (UCI), Medical Investigation of Neurodevelopmental Disorders Institute [Davis, CA, USA] (MIND), University of California [Davis] (UC Davis), University of California-University of California, Boston Children's Hospital, Génétique de l'autisme = Genetics of Autism (NPS-01), Neurosciences Paris Seine (NPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Biologie Paris Seine (IBPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Biologie Paris Seine (IBPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), University of Illinois [Chicago] (UIC), University of Illinois System, Trinity College Dublin, Vanderbilt University School of Medicine [Nashville], National Institute of Mental Health (NIMH), Emory University School of Medicine, Emory University [Atlanta, GA], Institute for Molecular Medicine Finland [Helsinki] (FIMM), Helsinki Institute of Life Science (HiLIFE), University of Helsinki-University of Helsinki, Autism Sequencing Consortium : Branko Aleksic, Richard Anney, Mafalda Barbosa, Somer Bishop, Alfredo Brusco, Jonas Bybjerg-Grauholm, Angel Carracedo, Marcus C.Y. Chan, Andreas G. Chiocchetti, Brian H.Y. Chung, Hilary Coon, Michael L. Cuccaro, Aurora Curro´ , Bernardo Dalla Bernardina, Ryan Doan, Enrico Domenici, Shan Dong, Chiara Fallerini, Montserrat Ferna´ ndez-Prieto, Giovanni Battista Ferrero, Christine M. Freitag, Menachem Fromer, J. Jay Gargus, Daniel Geschwind, Elisa Giorgio, Javier Gonza´ lez-Pen˜ as, Stephen Guter, Danielle Halpern, Emily HansenKiss, Xin He, Gail E. Herman, Irva Hertz-Picciotto, David M. Hougaard, Christina M. Hultman, Iuliana Ionita-Laza, Suma Jacob, Jesslyn Jamison, Astanand Jugessur, Miia Kaartinen, Gun Peggy Knudsen, Alexander Kolevzon, Itaru Kushima, So Lun Lee, Terho Lehtima¨ ki, Elaine T. Lim, Carla Lintas, W. Ian Lipkin, Diego Lopergolo, Fa´ tima Lopes, Yunin Ludena, Patricia Maciel, Per Magnus, Behrang Mahjani, Nell Maltman, Dara S. Manoach, Gal Meiri, Idan Menashe, Judith Miller, Nancy Minshew, Eduarda M.S. Montenegro, Danielle Moreira, Eric M. Morrow, Ole Mors, Preben Bo Mortensen, Matthew Mosconi, Pierandrea Muglia, Benjamin M. Neale, Merete Nordentoft, Norio Ozaki, Aarno Palotie, Mara Parellada, Maria Rita Passos-Bueno, Margaret Pericak-Vance, Antonio M. Persico, Isaac Pessah, Kaija Puura, Abraham Reichenberg, Alessandra Renieri, Evelise Riberi, Elise B. Robinson, Kaitlin E. Samocha, Sven Sandin, Susan L. Santangelo, Gerry Schellenberg, Stephen W. Scherer, Sabine Schlitt, Rebecca Schmidt, Lauren Schmitt, Isabela M.W. Silva, Tarjinder Singh, Paige M. Siper, Moyra Smith, Gabriela Soares, Camilla Stoltenberg, Pa˚ l Suren, Ezra Susser, John Sweeney, Peter Szatmari, Lara Tang, Flora Tassone, Karoline Teufel, Elisabetta Trabetti, Maria del Pilar Trelles, Christopher A. Walsh, Lauren A. Weiss, Thomas Werge, Donna M. Werling, Emilie M. Wigdor, Emma Wilkinson, A. Jeremy Willsey, Timothy W. Yu, Mullin H.C. Yu, Ryan Yuen, and Elaine Zachi. and iPSYCH-Broad Consortium : e Esben Agerbo, Thomas Damm Als, Vivek Appadurai, Marie Bækvad-Hansen, Rich Belliveau, Alfonso Buil, Caitlin E. Carey, Felecia Cerrato, Kimberly Chambert, Claire Churchhouse, Søren Dalsgaard, Ditte Demontis, Ashley Dumont, Jacqueline Goldstein, Christine S. Hansen, Mads Engel Hauberg, Mads V. Hollegaard, Daniel P. Howrigan, Hailiang Huang, Julian Maller, Alicia R. Martin, Joanna Martin, Manuel Mattheisen, Jennifer Moran, Jonatan Pallesen, Duncan S. Palmer, Carsten Bøcker Pedersen, Marianne Giørtz Pedersen, Timothy Poterba, Jesper Buchhave Poulsen, Stephan Ripke, Andrew J. Schork, Wesley K. Thompson, Patrick Turley, and Raymond K. Walters., Norman, Utku, Çicek, A. Ercüment, Betancur, Catalina, University of California [San Francisco] (UC San Francisco), University of California (UC), University of California [Irvine] (UC Irvine), University of California (UC)-University of California (UC), Neuroscience Paris Seine (NPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), and Helsingin yliopisto = Helsingfors universitet = University of Helsinki-Helsingin yliopisto = Helsingfors universitet = University of Helsinki

Subjects
Male, INTELLECTUAL DISABILITY, genetic structures, MESH: Neurons, Genome-wide association study, [SDV.GEN] Life Sciences [q-bio]/Genetics, Whole Exome Sequencing, Cohort Studies, 0302 clinical medicine, Gene Frequency, Neurobiology, MESH: Gene Expression Regulation, Developmental, Spectrum disorder, Exome, Developmental, genetics, Copy-number variation, excitatory-inhibitory balance, MESH: Cohort Studies, Exome sequencing, Genetics, Cerebral Cortex, Neurons, 0303 health sciences, MESH: Exome, autism spectrum disorder, cell type, cytoskeleton, excitatory neurons, exome sequencing, inhibitory neurons, liability, neurodevelopment, MESH: Genetic Predisposition to Disease, MESH: Case-Control Studies, Phenotype, Autism spectrum disorder, Female, Single-Cell Analysis, AGED 8 YEARS, MESH: Autistic Disorder, UNITED-STATES, GENETIC RISK, Biology, MESH: Phenotype, behavioral disciplines and activities, SAND DOMAIN, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, Sex Factors, MESH: Sex Factors, MESH: Whole Exome Sequencing, MESH: Neurobiology, mental disorders, medicine, MESH: Gene Frequency, Humans, Cell Lineage, Genetic Predisposition to Disease, GENOME-WIDE ASSOCIATION, Autistic Disorder, Allele frequency, Case-Control Studies, Mutation, Missense, Gene Expression Regulation, Developmental, SPECTRUM DISORDER, COPY NUMBER VARIATION, 030304 developmental biology, MESH: Mutation, Missense, [SDV.GEN]Life Sciences [q-bio]/Genetics, MESH: Humans, MESH: Cell Lineage, medicine.disease, MESH: Male, MESH: Cerebral Cortex, DISABILITIES MONITORING NETWORK, Gene Expression Regulation, DE-NOVO MUTATIONS, Mutation, Autism, Missense, MESH: Female, 030217 neurology & neurosurgery, MESH: Single-Cell Analysis
Abstract

International audience; We present the largest exome sequencing study of autism spectrum disorder (ASD) to date (n = 35,584 total samples, 11,986 with ASD). Using an enhanced analytical framework to integrate de novo and case-control rare variation, we identify 102 risk genes at a false discovery rate of 0.1 or less. Of these genes, 49 show higher frequencies of disruptive de novo variants in individuals ascertained to have severe neurodevelopmental delay, whereas 53 show higher frequencies in individuals ascertained to have ASD; comparing ASD cases with mutations in these groups reveals phenotypic differences. Expressed early in brain development, most risk genes have roles in regulation of gene expression or neuronal communication (i.e., mutations effect neurodevelopmental and neurophysiological changes), and 13 fall within loci recurrently hit by copy number variants. In cells from the human cortex, expression of risk genes is enriched in excitatory and inhibitory neuronal lineages, consistent with multiple paths to an excitatory-inhibitory imbalance underlying ASD.

Published
2020

27. Rates, distribution and implications of postzygotic mosaic mutations in autism spectrum disorder

Author

Lim, Elaine T., Uddin, Mohammed, De Rubeis, Silvia, Chan, Yingleong, Kamumbu, Anne S., Zhang, Xiaochang, D'Gama, Alissa M., Kim, Sonia N., Hill, Robert Sean, Goldberg, Arthur P., Poultney, Christopher, Minshew, Nancy J., Kushima, Itaru, Aleksic, Branko, Ozaki, Norio, Parellada, Mara, Arango, Celso, Penzol, Maria J., Carracedo, Angel, Kolevzon, Alexander, Hultman, Christina M., Weiss, Lauren A., Fromer, Menachem, Chiocchetti, Andreas G., Freitag, Christine M., Church, George M., Scherer, Stephen W., Buxbaum, Joseph D., Walsh, Christopher A, Aleksic, B, Anney, R, Barbosa, M, Barrett, J, Betancur, C, Bishop, S, Brusco, A, Buxbaum, Jd, Carracedo, A, Chiocchetti, Ag, Chung, Bhy, Cook, E, Coon, H, Cutler, Dj, Daly, M, De Rubeis, S, Doan, R, Fernández-Prieto, M, Ferrero, Gb, Freitag, Cm, Fromer, M, Gargus, J, Geschwind, D, Gill, M, Gómez-Guerrero, L, Hansen-Kiss, E, He, X, Herman, G, Hertz-Picciotto, I, Hultman, C, Iliadou, B, Ionita-Laza, I, Jugessur, A, Knudsen, Gp, Kolevzon, A, Kosmicki, J, Kushima, I, Lee, Sl, Lehner, T, Lennertz, S, Lim, E, Maciel, P, Magnus, P, Manoach, D, Minshew, N, Morrow, E, Mulle, J, Neale, B, Ozaki, N, Palotie, A, Parellada, M, Passos-Bueno, Mr, Pericak-Vance, M, Persico, A, Pessah, I, Reichenberg, A, Reichert, J, Renieri, A, Robinson, E, Samocha, K, Sanders, S, Sandin, S, Santangelo, Sl, Satterstrom, K, Schafer, C, Schellenberg, G, Scherer, S, Senthil, G, Silva, M, Singh, T, Siper, Pm, Soares, G, Stevens, C, Stoltenberg, C, Surén, P, Sutcliffe, Js, Szatmari, P, Tassone, F, Thurm, A, Walsh, C, Weiss, L, Werling, D, Willsey, J, Xu, X, Yu, Tw, Yuen, R, Zwick, Me., Howard Hughes Medical Institute [Boston] (HHMI), Howard Hughes Medical Institute (HHMI)-Harvard Medical School [Boston] (HMS), Boston Children's Hospital, Harvard Medical School [Boston] (HMS), Broad Institute of MIT and Harvard (BROAD INSTITUTE), Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston], Harvard University [Cambridge], Mohammed Bin Rashid University of Medicine and Health Sciences (MBRU), Icahn School of Medicine at Mount Sinai [New York] (MSSM), University of Pittsburgh (PITT), Pennsylvania Commonwealth System of Higher Education (PCSHE), Nagoya University, Hospital General Universitario 'Gregorio Marañón' [Madrid], Universidad Complutense de Madrid = Complutense University of Madrid [Madrid] (UCM), Centro de Investigación Biomédica en Red Salud Mental [Madrid] (CIBER-SAM), Universidade de Santiago de Compostela [Spain] (USC ), CIBER de Enfermedades Raras (CIBERER), Fundación Pública Galega Medicina Xenómica - SERGAS [Santiago de Compostela, Spain] (Grupo de Medicina Xenómica), CIBER de Enfermedades Raras (CIBERER)-Universidade de Santiago de Compostela [Spain] (USC ), King Abdulaziz University, Karolinska Institutet [Stockholm], University of California [San Francisco] (UCSF), University of California, Goethe-University Frankfurt am Main, Génétique de l'autisme = Genetics of Autism (NPS-01), Neurosciences Paris Seine (NPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), The Hospital for sick children [Toronto] (SickKids), University of Toronto, McLaughlin Centre for Population Health Risk Assessment, University of Ottawa [Ottawa], Autism Sequencing Consortium: Branko Aleksic, Richard Anney, Mafalda Barbosa, Jeffrey Barrett, Catalina Betancur, Somer Bishop, Alfredo Brusco, Joseph D Buxbaum, Angel Carracedo, Andreas G Chiocchetti, Brian H Y Chung, Edwin Cook, Hilary Coon, David J Cutler, Mark Daly, Silvia De Rubeis, Ryan Doan, Montserrat Fernández-Prieto, Giovanni Battista Ferrero, Christine M Freitag, Menachem Fromer, Jay Gargus, Dan Geschwind, Michael Gill, Lorena Gómez-Guerrero, Emily Hansen-Kiss, Xin He, Gail Herman, Irva Hertz-Picciotto, Christina Hultman, Bozenna Iliadou, Iuliana Ionita-Laza, Anil Jugessur, Gun Peggy Knudsen, Alexander Kolevzon, Jack Kosmicki, Itaru Kushima, S L Lee, Thomas Lehner, Savannah Lennertz, Elaine Lim, Patricia Maciel, Per Magnus, Dara Manoach, Nancy Minshew, Eric Morrow, Jennifer Mulle, Benjamin Neale, Norio Ozaki, Aarno Palotie, Mara Parellada, Maria Rita Passos-Bueno, Margaret Pericak-Vance, Antonio Persico, Isaac Pessah, Avi Reichenberg, Jennifer Reichert, Alessandra Renieri, Elise Robinson, Kaitlin Samocha, Stephan Sanders, Sven Sandin, Susan L Santangelo, Kyle Satterstrom, Chad Schafer, Gerry Schellenberg, Stephen Scherer, Geetha Senthil, Marisol Silva, Tarjinder Singh, Paige M Siper, Gabriela Soares, Christine Stevens, Camilla Stoltenberg, Pål Surén, James S Sutcliffe, Peter Szatmari, Flora Tassone, Audrey Thurm, Christopher Walsh, Lauren Weiss, Donna Werling, Jeremy Willsey, Xinyi Xu, Timothy W Yu, Ryan Yuen, Michael E Zwick., University of California [San Francisco] (UC San Francisco), University of California (UC), Neuroscience Paris Seine (NPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), and Betancur, Catalina

Subjects
0301 basic medicine, Proband, Nonsynonymous substitution, Autism Spectrum Disorder, Databases, Genetic, Genetic Predisposition to Disease, Genetic Variation, Humans, Mosaicism, Mutation, Missense, Zygote, Neuroscience (all), Mutation, Missense, Epigenetics of autism, Biology, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, medicine.disease_cause, Article, 03 medical and health sciences, Genetic variation, mental disorders, Databases, Genetic, medicine, Missense mutation, Heritability of autism, MESH: Genetic Variation, MESH: Databases, Genetic, Genetics, MESH: Autism Spectrum Disorder, MESH: Mutation, Missense, [SDV.GEN]Life Sciences [q-bio]/Genetics, MESH: Humans, General Neuroscience, MESH: Genetic Predisposition to Disease, medicine.disease, 030104 developmental biology, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Autism spectrum disorder, MESH: Zygote, MESH: Mosaicism
Abstract

International audience; We systematically analyzed postzygotic mutations (PZMs) in whole-exome sequences from the largest collection of trios (5,947) with autism spectrum disorder (ASD) available, including 282 unpublished trios, and performed resequencing using multiple independent technologies. We identified 7.5% of de novo mutations as PZMs, 83.3% of which were not described in previous studies. Damaging, nonsynonymous PZMs within critical exons of prenatally expressed genes were more common in ASD probands than controls (P < 1 × 10-6), and genes carrying these PZMs were enriched for expression in the amygdala (P = 5.4 × 10-3). Two genes (KLF16 and MSANTD2) were significantly enriched for PZMs genome-wide, and other PZMs involved genes (SCN2A, HNRNPU and SMARCA4) whose mutation is known to cause ASD or other neurodevelopmental disorders. PZMs constitute a significant proportion of de novo mutations and contribute importantly to ASD risk.

Published
2017

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