Genome scan in familial late-onset Alzheimer's disease: a locus on chromosome 6 contributes to age-at-onset.

Alzheimer's disease (AD) is a common, genetically complex, fatal neurodegenerative disorder of late life. Although several genes are known to play a role in early-onset AD, identification of the genetic basis of late onset AD (LOAD) has been challenging, with only the APOE gene known to have a high contribution to both AD risk and age-at-onset. Here, we present the first genome-scan analysis of the complete, well-characterized University of Washington LOAD sample of 119 pedigrees, using age-at-onset as the trait of interest.

Estimation and visualization of identity-by-descent within pedigrees simplifies interpretation of complex trait analysis.

Linkage analysis identifies markers that appear to be co-inherited with a trait within pedigrees. The inheritance of a chromosomal segment may be probabilistically reconstructed, with missing data complicating inference. Inheritance patterns are further obscured in the analysis of complex traits, where variants in one or more genes may contribute to phenotypic variation within a pedigree.

Genome scan of age-at-onset in the NIMH Alzheimer disease sample uncovers multiple loci, along with evidence of both genetic and sample heterogeneity.

Alzheimer's disease (AD) is a common neurodegenerative disorder of late life with a complex genetic basis. Although several genes are known to play a role in rare early onset AD, only the APOE gene is known to have a high contribution to risk of the common late-onset form of the disease (LOAD, onset >60 years). APOE genotypes vary in their AD risk as well as age-at-onset distributions, and it is likely that other loci will similarly affect AD age-at-onset.

The N141I mutation in PSEN2: implications for the quintessential case of Alzheimer disease.

Objective: To connect a new family with early-onset Alzheimer disease (EOAD) in Germany to the American Volga German pedigrees.

Design: Pedigree molecular genetic analysis.

Setting: University Medical Centers in Fulda and Giessen, Germany, and in Seattle, Washington.

Evidence for three loci modifying age-at-onset of Alzheimer's disease in early-onset PSEN2 families.

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.

Contrasting identity-by-descent estimators, association studies, and linkage analyses using the Framingham Heart Study data.

We explored the utility of population- and pedigree-based analyses using the Framingham Heart Study genome-wide 50 k single-nucleotide polymorphism marker data provided for Genetic Analysis Workshop 16. Our aims were: 1) to compare identity-by-descent sharing estimates from variable amounts of data; 2) to apply each of these estimates to a case-control association study designed to control for relatedness among samples; and 3) to contrast these results to those obtained using model-based and model-free linkage analysis methods.

Combining information from linkage and association methods.

Group 12 evaluated approaches to incorporate outside information or otherwise optimize traditional linkage and association analyses. The abundance of available data allowed exploration of identity-by-descent (IBD) estimation, score statistics, formal combination of linkage and association testing, significance estimation, and replication. We observed that IBD estimation can be optimized with a subset of marker data while estimation of inheritance vectors can provide both IBD estimates and a measure of their uncertainty.

Estimating the age of retrotransposon subfamilies using maximum likelihood.

We present a maximum likelihood model to estimate the age of retrotransposon subfamilies. This method is designed around a master gene model which assumes a constant retrotransposition rate. The statistical properties of this model and an ad hoc estimation procedure are compared using two simulated data sets.

Culture creates genetic structure in the Caucasus: autosomal, mitochondrial, and Y-chromosomal variation in Daghestan.

Background: Near the junction of three major continents, the Caucasus region has been an important thoroughfare for human migration. While the Caucasus Mountains have diverted human traffic to the few lowland regions that provide a gateway from north to south between the Caspian and Black Seas, highland populations have been isolated by their remote geographic location and their practice of patrilocal endogamy. We investigate how these cultural and historical differences between highland and lowland populations have affected patterns of genetic diversity.