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Published, Version of Record (VoR)Open Access (License Unspecified), Open
Journal article
Role of common and rare APP DNA sequence variants in Alzheimer disease
Neurology, v 78(16), pp 1250-1257
01 Apr 2012
PMID: 22491860
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
Objectives: More than 30 different rare mutations, including copy number variants (CNVs), in the amyloid precursor protein gene (APP) cause early-onset familial Alzheimer disease (EOFAD), whereas the contribution of common APP variants to disease risk remains controversial. In this study we systematically assessed the role of both rare and common APP DNA variants in Alzheimer disease (AD) families.
Methods: Families with EOFAD genetically linked to the APP region were screened for missense mutations and locus duplications of APP. Further, using genome-wide DNA microarray data, we examined the APP locus for CNVs in a total of 797 additional early-and late-onset AD pedigrees. Finally, 423 single nucleotide polymorphisms (SNPs) in the APP locus, including 2 promoter polymorphisms previously associated with AD risk, were tested in up to 4,200 individuals from multiplex AD families.
Results: Analyses of 8 21q21-linked families revealed one family carrying a nonsynonymous mutation in exon 17 (Val717Leu) and another family with a partially penetrant 3.5-Mb locus duplication encompassing APP. CNV analysis in the APP locus revealed an additional family carrying a fully penetrant 380-kb duplication, merely spanning APP. Last, contrary to previous reports, association analyses of more than 400 different SNPs in or near APP failed to show significant effects on AD risk.
Conclusion: Our study shows that APP mutations and locus duplications are a very rare cause of EOFAD and that the contribution of common APP variants to AD susceptibility is insignificant. Furthermore, duplications of APP may not be fully penetrant, possibly indicating the existence of hitherto unknown protective genetic factors. Neurology (R) 2012;78:1250-1257
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- Title
- Role of common and rare APP DNA sequence variants in Alzheimer disease
- Creators
- B. V. Hooli - Massachusetts General HospitalG. Mohapatra - Massachusetts Gen Hosp, Mol Pathol Unit, Charlestown, MA USAM. Mattheisen - Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USAA. R. Parrado - Massachusetts Gen Hosp, Genet & Aging Res Unit, Charlestown, MA USAJ. T. Roehr - Max Planck Inst Mol Genet, Dept Vertebrate Genom, Neuropsychiat Genet Grp, D-14195 Berlin, GermanyY. Shen - Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USAJ. F. Gusella - Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USAR. Moir - Massachusetts Gen Hosp, Genet & Aging Res Unit, Charlestown, MA USAA. J. Saunders - Drexel Univ, Dept Biol, Philadelphia, PA 19104 USAC. Lange - Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USAR. E. Tanzi - Massachusetts Gen Hosp, Genet & Aging Res Unit, Charlestown, MA USAL. Bertram - Neuropsychiatric Genetics (Lars Bertram), Dept. of Vertebrate Genomics (Head: Hans Lehrach), Max Planck Institute for Molecular Genetics, Max Planck Society
- Publication Details
- Neurology, v 78(16), pp 1250-1257
- Publisher
- Lippincott Williams & Wilkins
- Number of pages
- 8
- Grant note
- Simons Foundation Autism Research Initiative Children's Tumor Foundation NIH; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA NIH/NINDS; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Neurological Disorders & Stroke (NINDS) 5R37-MH60009 / NIMH; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Mental Health (NIMH) NINDS; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Neurological Disorders & Stroke (NINDS) Huntington's Disease Society of America R01NS057295 / NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Neurological Disorders & Stroke (NINDS) Cure Alzheimer Fund CHDI Foundation Inc. Helmsley Foundation NICHD; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD) R37MH060009 / NATIONAL INSTITUTE OF MENTAL HEALTH; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Mental Health (NIMH) Autism Speaks 5R01-AG23667 / NIA; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute on Aging (NIA) Cure Alzheimer's Fund NIGMS; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of General Medical Sciences (NIGMS) NIH/NIMH; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Mental Health (NIMH) U24AG021886 / NATIONAL INSTITUTE ON AGING; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute on Aging (NIA)
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Biology; Obstetrics and Gynecology
- Web of Science ID
- WOS:000302933200012
- Scopus ID
- 2-s2.0-84860764162
- Other Identifier
- 991019167531504721
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- Collaboration types
- Domestic collaboration
- International collaboration
- Web of Science research areas
- Clinical Neurology