Analyses of the National Institute on Aging Late-Onset Alzheimer's Disease Family Study

Lee, Joseph H.; Cheng, Rong; Graff‐Radford, Neill R.; Foroud, Tatiana; Mayeux, Richard

doi:10.1001/archneur.65.11.1518

Cited by 130 publications

(110 citation statements)

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“…Data were drawn from the Framingham Heart Study original (FHS) and offspring (FHSO) cohorts (Cupples, Heard‐Costa, Lee & Atwood, 2009), the Cardiovascular Health Study (CHS) (Fried et al., 1991), the Health and Retirement Study (HRS) (Juster & Suzman, 1995), and the NIA Late‐Onset Alzheimer Disease Family Study (LOADFS) (Lee, Cheng, Graff‐Radford, Foroud & Mayeux, 2008) for individuals who identified themselves as of Caucasian ancestry. The LOADFS was designed to ascertain dementias of Alzheimer type in the elderly and recruited cases and controls.…”

Section: Methodsmentioning

confidence: 99%

Apolipoprotein E region molecular signatures of Alzheimer's disease

et al. 2018

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SummaryAlthough the APOE region is the strongest genetic risk factor for Alzheimer's diseases (ADs), its pathogenic role remains poorly understood. Elucidating genetic predisposition to ADs, a subset of age‐related diseases characteristic for postreproductive period, is hampered by the undefined role of evolution in establishing molecular mechanisms of such diseases. This uncertainty is inevitable source of natural‐selection–free genetic heterogeneity in predisposition to ADs. We performed first large‐scale analysis of linkage disequilibrium (LD) structures characterized by 30 polymorphisms from five genes in the APOE 19q13.3 region (BCAM,NECTIN2,TOMM40,APOE, and APOC1) in 2,673 AD‐affected and 16,246 unaffected individuals from five cohorts. Consistent with the undefined role of evolution in age‐related diseases, we found that these structures, being highly heterogeneous, are significantly different in subjects with and without ADs. The pattern of the difference represents molecular signature of AD comprised of single nucleotide polymorphisms (SNPs) from all five genes in the APOE region. Significant differences in LD in subjects with and without ADs indicate SNPs from different genes likely involved in AD pathogenesis. Significant and highly heterogeneous molecular signatures of ADs provide unprecedented insight into complex polygenetic predisposition to ADs in the APOE region. These findings are more consistent with a complex haplotype than with a single genetic variant origin of ADs in this region.

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Section: Methodsmentioning

confidence: 99%

Apolipoprotein E region molecular signatures of Alzheimer's disease

et al. 2018

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“…Previous genome-wide family-based linkage analyses have identified several loci linked to AD [9][10][11][12][13][14][15][16][17][18][19] and confirmed linkage by several groups has been reported to chromosome (chr.) 9p, 9q, 10q, 12p and 19q.…”

Section: Introductionmentioning

confidence: 59%

Linkage to 20p13 including the ANGPT4 gene in families with mixed Alzheimer's disease and vascular dementia

et al. 2010

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This study aimed at identifying novel susceptibility genes for a mixed phenotype of Alzheimer's disease and vascular dementia. Results from a genome scan showed strongest linkage to 20p13 in 18 families, and subsequent fine mapping was performed with both microsatellites and single-nucleotide polymorphisms in 18 selected candidate transcripts in an extended sample set of 30 families. The multipoint linkage peak was located at marker rs2144151 in the ANGPT4 gene, which is a strong candidate gene for vascular disease because of its involvement in angiogenesis. Although the significance of the linkage decreased, we find this result intriguing, considering that we included additional families, and thus the reduced linkage signal may be caused by genetic heterogeneity.

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“…This dataset is described and analyzed in Lee et al [12] . It consists of 6,000 single nucleotide polymorhisms at an average intermarker distance of 0.65 cM.…”

Section: Application To the Load Datamentioning

confidence: 99%

“…Next, in order to investigate the properties of BMA for complex models with multiple interacting loci, we analyze all 100 replicates of the Genetic Analysis Workshop 13 (GAW13) simulated data that were generated to mimic the real data from the Framingham Heart Study [11] . Finally, we apply BMA to the National Institute on Aging's (NIA) Late-Onset Alzheimer's Disease (LOAD) data obtained from NIH's database of genotypes and phenotypes (dbGaP) [12] .…”

Section: Introductionmentioning

confidence: 99%

Accounting for Disease Model Uncertainty in Mapping Heterogeneous Traits – A Bayesian Model Averaging Approach

Biswas

Papachristou

2010

Hum Hered

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Background: Locus heterogeneity, wherein a disease can be caused in different individuals by different genes and/or environmental factors, is a ubiquitous feature of complex traits. A Bayesian approach has been proposed to account for variable rates of heterogeneity across families in a parametric linkage analysis setup [Biswas and Lin: J Am Stat Assoc 2006;101:1341–1351]. As with any parametric approach, its application requires specification of the disease model, which limits its practical utility. Methods: We address this limitation by proposing a Bayesian model averaging (BMA) approach. We consider a finite number of disease models and treat the model as an unknown parameter. In practice, we use simple single-locus disease models as various categories for model. Results: Our simulations as well as analysis of Genetic Analysis Workshop 13 simulated data show that BMA retains at least 80% of the power that is obtained by analyzing under the true disease model. The coverage probability of interval for disease gene is maintained around the nominal level. Finally, we apply BMA to a Late-Onset Alzheimer’s Disease dataset and find evidence for linkage on chromosomes 19, 9, and 21. Conclusion: We conclude that the BMA approach utilizing simple single-locus models for averaging is effective for mapping heterogeneous traits.

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Analyses of the National Institute on Aging Late-Onset Alzheimer's Disease Family Study

Cited by 130 publications

References 50 publications

Apolipoprotein E region molecular signatures of Alzheimer's disease

Apolipoprotein E region molecular signatures of Alzheimer's disease

Linkage to 20p13 including the ANGPT4 gene in families with mixed Alzheimer's disease and vascular dementia

Accounting for Disease Model Uncertainty in Mapping Heterogeneous Traits – A Bayesian Model Averaging Approach

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