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Title | Exome Sequencing of Extended Families with Alzheimer's Disease Identifies Novel Genes Implicated in Cell Immunity and Neuronal Function. |
Publication Type | Journal Article |
Year of Publication | 2017 |
Authors | Cukier HN, Kunkle BK, Hamilton KL, Rolati S, Kohli MA, Whitehead PL, Jaworski J, Vance JM, Cuccaro ML, Carney RM, Gilbert JR, Farrer LA, Martin ER, Beecham GW, Haines JL, Pericak-Vance MA |
Journal | J Alzheimers Dis Parkinsonism |
Volume | 7 |
Issue | 4 |
Date Published | 2017 Aug |
ISSN | 2161-0460 |
Abstract | Objective: Alzheimer's disease (AD) is a neurodegenerative disorder for which more than 20 genetic loci have been implicated to date. However, studies demonstrate not all genetic factors have been identified. Therefore, in this study we seek to identify additional rare variants and novel genes potentially contributing to AD.Methods: Whole exome sequencing was performed on 23 multi-generational families with an average of eight affected subjects. Exome sequencing was filtered for rare, nonsynonymous and loss-of-function variants. Alterations predicted to have a functional consequence and located within either a previously reported AD gene, a linkage peak (LOD>2), or clustering in the same gene across multiple families, were prioritized.Results: Rare variants were found in known AD risk genes including and . Three families had five variants of interest in linkage regions with LOD>2. Genes with segregating alterations in these peaks include and , two genes that have both been implicated in immunity, , which encodes a catenin in the cerebral cortex and , a gene that may induce mitochondrial dysfunction and has the potential to damage neurons. Four genes were identified with alterations in more than one family include , a gene that causes Charcot-Marie-Tooth disease and , which promotes synaptogenesis.Conclusion: Utilizing large families with a heavy burden of disease allowed for the identification of rare variants co-segregating with disease. Variants were identified in both known AD risk genes and in novel genes. |
DOI | 10.4172/2161-0460.1000355 |
Alternate Journal | J Alzheimers Dis Parkinsonism |
PubMed ID | 29177109 |
PubMed Central ID | PMC5698805 |
Grant List | R01 AG019085 / AG / NIA NIH HHS / United States U01 AG032984 / AG / NIA NIH HHS / United States P30 AG013846 / AG / NIA NIH HHS / United States R01 AG028786 / AG / NIA NIH HHS / United States U24 AG026395 / AG / NIA NIH HHS / United States R01 AG041797 / AG / NIA NIH HHS / United States R01 AG048927 / AG / NIA NIH HHS / United States P20 MD000546 / MD / NIMHD NIH HHS / United States R01 AG027944 / AG / NIA NIH HHS / United States R01 AG025259 / AG / NIA NIH HHS / United States |