Intermediate phenotypes identify divergent pathways to Alzheimer's disease.
Recent genetic studies have identified a growing number of loci with suggestive evidence of association with susceptibility to Alzheimer's disease (AD). However, little is known of the role of these candidate genes in influencing intermediate phenotypes associated with a diagnosis of AD, includ...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2010-06-01
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| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC2888589?pdf=render |
| _version_ | 1811269828968710144 |
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| author | Joshua M Shulman Lori B Chibnik Cristin Aubin Julie A Schneider David A Bennett Philip L De Jager |
| author_facet | Joshua M Shulman Lori B Chibnik Cristin Aubin Julie A Schneider David A Bennett Philip L De Jager |
| author_sort | Joshua M Shulman |
| collection | DOAJ |
| description | Recent genetic studies have identified a growing number of loci with suggestive evidence of association with susceptibility to Alzheimer's disease (AD). However, little is known of the role of these candidate genes in influencing intermediate phenotypes associated with a diagnosis of AD, including cognitive decline or AD neuropathologic burden.Thirty-two single nucleotide polymorphisms (SNPs) previously implicated in AD susceptibility were genotyped in 414 subjects with both annual clinical evaluation and completed brain autopsies from the Religious Orders Study and the Rush Memory and Aging Project. Regression analyses evaluated the relation of SNP genotypes to continuous measures of AD neuropathology and cognitive function proximate to death. A SNP in the zinc finger protein 224 gene (ZNF224, rs3746319) was associated with both global AD neuropathology (p = 0.009) and global cognition (p = 0.002); whereas, a SNP at the phosphoenolpyruvate carboxykinase locus (PCK1, rs8192708) was selectively associated with global cognition (p = 3.57 x 10(-4)). The association of ZNF224 with cognitive impairment was mediated by neurofibrillary tangles, whereas PCK1 largely influenced cognition independent of AD pathology, as well as Lewy bodies and infarcts.The findings support the association of several loci with AD, and suggest how intermediate phenotypes can enhance analysis of susceptibility loci in this complex genetic disorder. |
| first_indexed | 2024-04-12T21:49:03Z |
| format | Article |
| id | doaj.art-c80ceed39c8a467d9220472695e65251 |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-04-12T21:49:03Z |
| publishDate | 2010-06-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-c80ceed39c8a467d9220472695e652512022-12-22T03:15:32ZengPublic Library of Science (PLoS)PLoS ONE1932-62032010-06-0156e1124410.1371/journal.pone.0011244Intermediate phenotypes identify divergent pathways to Alzheimer's disease.Joshua M ShulmanLori B ChibnikCristin AubinJulie A SchneiderDavid A BennettPhilip L De JagerRecent genetic studies have identified a growing number of loci with suggestive evidence of association with susceptibility to Alzheimer's disease (AD). However, little is known of the role of these candidate genes in influencing intermediate phenotypes associated with a diagnosis of AD, including cognitive decline or AD neuropathologic burden.Thirty-two single nucleotide polymorphisms (SNPs) previously implicated in AD susceptibility were genotyped in 414 subjects with both annual clinical evaluation and completed brain autopsies from the Religious Orders Study and the Rush Memory and Aging Project. Regression analyses evaluated the relation of SNP genotypes to continuous measures of AD neuropathology and cognitive function proximate to death. A SNP in the zinc finger protein 224 gene (ZNF224, rs3746319) was associated with both global AD neuropathology (p = 0.009) and global cognition (p = 0.002); whereas, a SNP at the phosphoenolpyruvate carboxykinase locus (PCK1, rs8192708) was selectively associated with global cognition (p = 3.57 x 10(-4)). The association of ZNF224 with cognitive impairment was mediated by neurofibrillary tangles, whereas PCK1 largely influenced cognition independent of AD pathology, as well as Lewy bodies and infarcts.The findings support the association of several loci with AD, and suggest how intermediate phenotypes can enhance analysis of susceptibility loci in this complex genetic disorder.http://europepmc.org/articles/PMC2888589?pdf=render |
| spellingShingle | Joshua M Shulman Lori B Chibnik Cristin Aubin Julie A Schneider David A Bennett Philip L De Jager Intermediate phenotypes identify divergent pathways to Alzheimer's disease. PLoS ONE |
| title | Intermediate phenotypes identify divergent pathways to Alzheimer's disease. |
| title_full | Intermediate phenotypes identify divergent pathways to Alzheimer's disease. |
| title_fullStr | Intermediate phenotypes identify divergent pathways to Alzheimer's disease. |
| title_full_unstemmed | Intermediate phenotypes identify divergent pathways to Alzheimer's disease. |
| title_short | Intermediate phenotypes identify divergent pathways to Alzheimer's disease. |
| title_sort | intermediate phenotypes identify divergent pathways to alzheimer s disease |
| url | http://europepmc.org/articles/PMC2888589?pdf=render |
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