Age at Onset in Two Common Neurodegenerative Diseases Is Genetically Controlled

Li, Yi-Ju; Scott, William K.; Hedges, Dale J.; Zhang, Fengyu; Gaskell, P. C.; Nance, Martha; Watts, Ray L.; Hubble, Jean; Koller, William C.; Pahwa, Rajesh; Stern, Matthew B.; Hiner, Bradley C.; Jankovic, Joseph; Allen, Fred H.; Goetz, Christopher G.; Mastaglia, Frank; Stajich, Jeffrey M.; Gibson, Rachel A.; Middleton, Lefkos; Saunders, Ann M.; Scott, Burton L.; Small, Gary W.; Nicodemus, Kristin K.; Reed, Allison D.; Schmechel, Donald E.; Welsh‐Bohmer, Kathleen A.; Conneally, P. Michael; Roses, Allen D.; Gilbert, John R.; Vance, Jeffery M.; Haines, Jonathan L.; Pericak‐Vance, Margaret A.

doi:10.1086/339815

Cited by 290 publications

(251 citation statements)

References 34 publications

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“…However, Li et al [14,40] argued that the age-atonset of disease is equally important because the "regulation of onset could make it possible to delay onset beyond an individual's normal life span." Indeed, allelic variation in APOE profoundly affects risk by lowering the age-at-onset of AD between three to five years with each copy of the ε4 variant [6,8,9].…”

Section: Discussionmentioning

confidence: 99%

“…Indeed, analyses using age-at-onset of disease as a quantitative trait have yielded multiple putative loci on chromosomes 2, 7, 9, 14, 15, 20 and 21, and some of these loci were also found to be significant in the analyses of AD phenotype [13][14][15][16][17][18][19]. However, most of these analyses lack independent confirmation, with the exception of the locus at 14q32 [16] which is of interest because of its location near PSEN 1.…”

Section: Introductionmentioning

confidence: 99%

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Age-at-onset linkage analysis in Caribbean Hispanics with familial late-onset Alzheimer’s disease

et al. 2007

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The aim of the study was to identify chromosomal regions containing putative genetic variants influencing age-at-onset in familial late-onset Alzheimer's disease. Data from a genome-wide scan that included genotyping of APOE was analyzed in 1,161 individuals from 209 families of Caribbean Hispanic ancestry with a mean age-at-onset of 73.3 years multiply affected by late-onset Alzheimer's disease. Two-point and multipoint analyses were conducted using variance component methods from 376 microsatellite markers with an average inter-marker distance of 9.3 cM. Family-based test of association were also conducted for the same set of markers. Age-at-onset of symptoms among affected individuals was used as the quantitative trait. Our results showed that the presence of APOE-ε4 lowered the age-at-onset by three years. Using linkage analysis strategy, the highest LOD scores were obtained using a conservative definition of LOAD at 5q15 (LOD 3.1) 17q25.1 (LOD=2.94) and 14q32.12 (LOD=2.36) and 7q36.3 (LOD=2.29) in covariate adjusted models that included APOE-ε4. Both linkage and family-based association identified 17p13 as a candidate region. In addition, family-based association analysis showed markers at 12q13 (p=0.00002), 13q (p=0.00043) and 14q23 (p=0.00046) to be significantly associated with age at onset. The current study supports the hypothesis that there are additional genetic loci that could influence age-at-onset of late onset

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Age-at-onset linkage analysis in Caribbean Hispanics with familial late-onset Alzheimer’s disease

et al. 2007

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“…Identified by linkage of a population-based register of PD patients and a nation-wide genealogical database in Iceland, these families had typical PD with average age of onset 66 years. The PARK10 locus was also linked to age at onset for PD in a US sample [248]. Association between SNPs in the candidate gene ELAVL4 and age at onset for PD or susceptibility to PD were reported in Caucasian populations [249][250][251], but have not been confirmed in other populations.…”

Section: Park10mentioning

confidence: 94%

Epidemiology and etiology of Parkinson’s disease: a review of the evidence

et al. 2011

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“…Linkage studies have identified several promising chromosomal regions to harbor additional AD genes, including chromosomes 12, 10, 9 and 6 [reviewed in 7]. A broad linkage peak encompassing >60 cM region between chromosome 10q21 and 10q25 that influence both AD risk and AAO has been suggested [2,4,10,13]. There are more than 300 genes in this broad genomic region of chromosome 10 and thus the task of identifying the chromosome 10 candidate gene is daunting.…”

Section: Introductionmentioning

confidence: 99%

Genetic variation in the choline acetyltransferase (CHAT) gene may be associated with the risk of Alzheimer's disease

Öztürk

DeKosky

Kamboh

2006

Neurobiology of Aging

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Several independent linkage studies have mapped a broad susceptibility region for Alzheimer's disease (AD) on the long arm of chromosome 10. There are several biological candidate genes in this region, including choline acetyltransferase (CHAT). A number of studies have examined the role of CHAT genetic variants with AD risk and age-at-onset (AAO), but the results are equivocal. We examined the association of three Single Nucleotide Polymorphisms (SNPs) in the CHAT gene in 1001 white sporadic late-onset AD (LOAD) cases and 708 white controls. We also examined the role of these three SNP with quantitative traits of AD including AAO, disease duration, and MiniMental State Examination (MMSE) score. We observed both allelic and genotypic associations of the intron 9 SNP with AD risk in the total sample (p=0.029 for genotype and p=0.028 for allele frequency differences) as well as among non-APOE*4 carriers (p=0.007 for genotype and p=0.006 for allele frequency differences). Three-site haplotype analysis confirmed that haplotypes determined by the intron 9 SNP were associated with either risk (p=0.0009) or protective (p=0.0082) effects among non-APOE*4 carriers. The three CHAT SNPs also showed a modest association with MMSE score. Our data suggest that genetic variation in the CHAT gene may be associated with AD risk and quantitative traits related to AD.

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Age at Onset in Two Common Neurodegenerative Diseases Is Genetically Controlled

Cited by 290 publications

References 34 publications

Age-at-onset linkage analysis in Caribbean Hispanics with familial late-onset Alzheimer’s disease

Age-at-onset linkage analysis in Caribbean Hispanics with familial late-onset Alzheimer’s disease

Epidemiology and etiology of Parkinson’s disease: a review of the evidence

Genetic variation in the choline acetyltransferase (CHAT) gene may be associated with the risk of Alzheimer's disease

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