Joseph H Lee1, Rong Cheng2, Badri Vardarajan2, Rafael Lantigua3, Dolly Reyes-Dumeyer4, Ward Ortmann5, Robert R Graham5, Tushar Bhangale5, Timothy W Behrens6, Martin Medrano7, Ivonne Z Jiménez-Velázquez8, Richard Mayeux1. 1. The Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University, New York, New York2Gertrude H. Sergievsky Center, Columbia University, New York, New York3Department of Epidemiology, School of Public Health, Columbia Univer. 2. The Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University, New York, New York2Gertrude H. Sergievsky Center, Columbia University, New York, New York. 3. The Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University, New York, New York4Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, New York. 4. The Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University, New York, New York. 5. Genentech, South San Francisco, California. 6. Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, New York. 7. School of Medicine, Pontificia Universidad Catolica Madre y Maestra, Santiago, Dominican Republic. 8. Department of Internal Medicine, University of Puerto Rico School of Medicine, San Juan, Puerto Rico.
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. OBJECTIVE: To identify genetic variants that modify age at onset of AD. 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. MAIN OUTCOMES AND MEASURES: Age at onset of AD. 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. 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.
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. OBJECTIVE: To identify genetic variants that modify age at onset of AD. 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. MAIN OUTCOMES AND MEASURES: Age at onset of AD. 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. 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.
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