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Genetic Modifiers of Age at Onset in Carriers of the G206A Mutation in PSEN1 With Familial Alzheimer Disease Among Caribbean Hispanics.
- Source :
-
JAMA neurology [JAMA Neurol] 2015 Sep; Vol. 72 (9), pp. 1043-51. - Publication Year :
- 2015
-
Abstract
- Importance: The present study identified potential genetic modifiers that may delay or accelerate age at onset of familial Alzheimer disease (AD) by examining age at onset in PSEN1 mutation carrier families, and further investigation of these modifiers may provide insight into the pathobiology of AD and potential therapeutic measures.<br />Objective: To identify genetic variants that modify age at onset of AD.<br />Design, Setting, and Participants: Using a subset of Caribbean Hispanic families that carry the PSEN1 p.G206A mutation, we performed a 2-stage genome study. The mutation carrier families from an ongoing genetic study served as a discovery set, and the cohort of those with LOAD served as a confirmation set. To identify candidate loci, we performed linkage analysis using 5 p.G206A carrier families (n = 56), and we also performed whole-exome association analysis using 31 p.G206A carriers from 26 families. To confirm the genetic modifiers identified from the p.G206A carrier families, we analyzed the GWAS data for 2888 elderly individuals with LOAD. All study participants were Caribbean Hispanics.<br />Main Outcomes and Measures: Age at onset of AD.<br />Results: Linkage analysis of AD identified the strongest linkage support at 4q35 (LOD [logarithm of odds] score, 3.69), and the GWAS of age at onset identified variants on 1p13.1, 2q13, 4q25, and 17p11. In the confirmation stage, genewise analysis identified SNX25, PDLIM3, and 3 SH3 domain genes (SORBS2, SH3RF3, and NPHP1) to be significantly associated with LOAD. Subsequent allelic association analysis confirmed SNX25, PDLIM3, and SORBS2 as genetic modifiers of age at onset of EOAD and LOAD and provided modest support for SH3RF3 and NPHP1.<br />Conclusions and Relevance: Our 2-stage analysis revealed that SNX25, PDLIM3, and SORBS2 may serve as genetic modifiers of age at onset in both EOAD and LOAD.<br />Competing Interests: Disclosures: Drs Ortmann, Graham, Bhangale, and Behrens reported being full-time employees of Genentech, Inc. No other disclosures were reported.
- Subjects :
- Adaptor Proteins, Signal Transducing
Age of Onset
Aged
Caribbean Region epidemiology
Caribbean Region ethnology
Computational Biology
Female
Genetic Association Studies
Hispanic or Latino genetics
Homeodomain Proteins genetics
Humans
LIM Domain Proteins genetics
Male
Meta-Analysis as Topic
Microfilament Proteins genetics
Middle Aged
RNA-Binding Proteins
Sorting Nexins genetics
Alzheimer Disease genetics
Genetic Predisposition to Disease genetics
Polymorphism, Single Nucleotide genetics
Presenilin-1 genetics
Subjects
Details
- Language :
- English
- ISSN :
- 2168-6157
- Volume :
- 72
- Issue :
- 9
- Database :
- MEDLINE
- Journal :
- JAMA neurology
- Publication Type :
- Academic Journal
- Accession number :
- 26214276
- Full Text :
- https://doi.org/10.1001/jamaneurol.2015.1424