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Title | Evidence for three loci modifying age-at-onset of Alzheimer's disease in early-onset PSEN2 families. |
Publication Type | Journal Article |
Year of Publication | 2010 |
Authors | Marchani EE, Bird TD, Steinbart EJ, Rosenthal E, Yu C-E, Schellenberg GD, Wijsman EM |
Journal | Am J Med Genet B Neuropsychiatr Genet |
Volume | 153B |
Issue | 5 |
Pagination | 1031-41 |
Date Published | 2010 Jul |
ISSN | 1552-485X |
Keywords | Adult, Age of Onset, Aged, Aged, 80 and over, Alzheimer Disease, Chromosome Segregation, Chromosomes, Human, European Continental Ancestry Group, Family, Genetic Linkage, Genetic Loci, Genetic Markers, Genome, Human, Germany, Humans, Middle Aged, Presenilin-2, Quantitative Trait Loci |
Abstract | Families with early-onset Alzheimer's disease (AD) sharing a single PSEN2 mutation exhibit a wide range of age-at-onset, suggesting that modifier loci segregate within these families. While APOE is known to be an age-at-onset modifier, it does not explain all of this variation. We performed a genome scan within nine such families for loci influencing age-at-onset, while simultaneously controlling for variation in the primary PSEN2 mutation (N141I) and APOE. We found significant evidence of linkage between age-at-onset and chromosome 1q23.3 (P < 0.001) when analysis included all families, and to chromosomes 1q23.3 (P < 0.001), 17p13.2 (P = 0.0002), 7q33 (P = 0.017), and 11p14.2 (P = 0.017) in a single large pedigree. Simultaneous analysis of these four chromosomes maintained strong evidence of linkage to chromosomes 1q23.3 and 17p13.2 when all families were analyzed, and to chromosomes 1q23.3, 7q33, and 17p13.2 within the same single pedigree. Inclusion of major gene covariates proved essential to detect these linkage signals, as all linkage signals dissipated when PSEN2 and APOE were excluded from the model. The four chromosomal regions with evidence of linkage all coincide with previous linkage signals, associated SNPs, and/or candidate genes identified in independent AD study populations. This study establishes several candidate regions for further analysis and is consistent with an oligogenic model of AD risk and age-at-onset. More generally, this study also demonstrates the value of searching for modifier loci in existing datasets previously used to identify primary causal variants for complex disease traits. |
DOI | 10.1002/ajmg.b.31072 |
Alternate Journal | Am. J. Med. Genet. B Neuropsychiatr. Genet. |
PubMed ID | 20333730 |
PubMed Central ID | PMC3022037 |
Grant List | T32 AG000258 / AG / NIA NIH HHS / United States R37 GM046255-17 / GM / NIGMS NIH HHS / United States T32 AG000258-11 / AG / NIA NIH HHS / United States R01 GM046255 / GM / NIGMS NIH HHS / United States P50 AG005136 / AG / NIA NIH HHS / United States P50 AG005136-20 / AG / NIA NIH HHS / United States T32 AG000258-12 / AG / NIA NIH HHS / United States GM46255 / GM / NIGMS NIH HHS / United States T32 AG000258-13 / AG / NIA NIH HHS / United States R37 GM046255 / GM / NIGMS NIH HHS / United States R37 GM046255-18 / GM / NIGMS NIH HHS / United States P50 AG005136-19 / AG / NIA NIH HHS / United States P50 AG005136-21 / AG / NIA NIH HHS / United States Z01 AG000258 / ImNIH / Intramural NIH HHS / United States AG05136 / AG / NIA NIH HHS / United States |