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Objectives: Describe the inflation in nonparametric multipoint LOD scores due to inter-marker linkage disequilibrium (LD) across many markers with varied allele frequencies. Method: Using simulated two-generation families with and without parents, we conducted nonparametric multipoint linkage analysis with 2 to 10 markers with minor allele frequencies (MAF) of 0.5 and 0.1. Results: Misspecification of population haplotype frequencies by assuming linkage equilibrium caused inflated multipoint LOD scores due to inter-marker LD when parental genotypes were not included. Inflation increased as more markers in LD were included and decreased as markers in equilibrium were added. When marker allele frequencies were unequal, the r2 measure of LD was a better predictor of inflation than D′. Conclusion: This observation strongly supports the evaluation of LD in multipoint linkage analyses, and further suggests that unaccounted for LD may be suspected when two-point and multipoint linkage analyses show a marked disparity in regions with elevated r2 measures of LD. Given the increasing popularity of high-density genome-wide SNP screens, inter-marker LD should be a concern in future linkage studies. Copyright © 2005 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Autistic disorder (AD) is a complex neurodevelopmental disorder. The role of genetics in AD etiology is well established, and it is postulated that anywhere from 2 to 10 genes could be involved. As part of a larger study to identify these genetic effects we have ascertained a series of AD families: Sporadic (SP, 1 known AD case per family and no known history of AD) and multiplex (MP, ≥2 cases per family). The underlying etiology of both family types is unknown. It is possible that MP families may constitute a unique subset of families in which the disease phenotype is more likely due to genetic factors. Clinical differences between the two family types could represent underlying genetic heterogeneity. We examined ADI-R data for 69 probands from MP families and 88 from SP families in order to compare and contrast the clinical phenotypes for each group as a function of verbal versus nonverbal status. Multivariate analysis controlling for covariates of age at examination, gender, and race (MANCOVA) revealed no differences between either the verbal or nonverbal MP and SP groups for the three ADI-R area scores: social interaction, communication, and restricted/repetitive interests or behaviors. These data failed to find clinical heterogeneity between MP and SP family types. This supports previous work that indicated that autism features are not useful as tools to index genetic heterogeneity. Thus, although there may be different underlying etiologic mechanisms in the SP and MP probands, there are no distinct behavioral patterns associated with probands from MP families versus SP families. These results suggests the possibility that common etiologic mechanisms, either genetic and/or environmental, could underlie all of AD. [ABSTRACT FROM AUTHOR]

Presents a study to identify genetic risk factors for late-onset Alzheimer disease. Design; Setting; Patients; Main outcome measures; Results; Conclusions.

The low-density lipoprotein receptor-related protein gene ( LRP1) is often mentioned as a candidate gene for Alzheimer disease (AD) because of its role as a receptor for apolipoprotein E (apoE), a major genetic risk factor for late-onset familial and sporadic AD. A recent association study of a tetranucleotide repeat polymorphism located 5′ to the LRP1 gene detected an increase in the 87 base pair allele in AD cases compared to unaffected controls. Additionally, an independent study involving a genomic screen for genes associated with late-onset AD identified a region as a possible location of a late-onset AD gene on chromosome 12p between D12S373 and D12S390, about 10 cM proximal to LRP1. We examined 144 late-onset multiplex AD families, 436 sporadic AD cases, and 240 controls and found no evidence of linkage or association of LRP1 and AD. Our data indicate that genetic variation of the LRP1 gene is not a major risk factor in the etiology of AD. [ABSTRACT FROM AUTHOR]