Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 4 de 4
Filter
Add more filters










Database
Language
Publication year range
1.
Am J Hum Genet ; 83(5): 623-32, 2008 Nov.
Article in English | MEDLINE | ID: mdl-18976728

ABSTRACT

Alzheimer's disease (AD) is a genetically complex and heterogeneous disorder. To date four genes have been established to either cause early-onset autosomal-dominant AD (APP, PSEN1, and PSEN2(1-4)) or to increase susceptibility for late-onset AD (APOE5). However, the heritability of late-onset AD is as high as 80%, (6) and much of the phenotypic variance remains unexplained to date. We performed a genome-wide association (GWA) analysis using 484,522 single-nucleotide polymorphisms (SNPs) on a large (1,376 samples from 410 families) sample of AD families of self-reported European descent. We identified five SNPs showing either significant or marginally significant genome-wide association with a multivariate phenotype combining affection status and onset age. One of these signals (p = 5.7 x 10(-14)) was elicited by SNP rs4420638 and probably reflects APOE-epsilon4, which maps 11 kb proximal (r2 = 0.78). The other four signals were tested in three additional independent AD family samples composed of nearly 2700 individuals from almost 900 families. Two of these SNPs showed significant association in the replication samples (combined p values 0.007 and 0.00002). The SNP (rs11159647, on chromosome 14q31) with the strongest association signal also showed evidence of association with the same allele in GWA data generated in an independent sample of approximately 1,400 AD cases and controls (p = 0.04). Although the precise identity of the underlying locus(i) remains elusive, our study provides compelling evidence for the existence of at least one previously undescribed AD gene that, like APOE-epsilon4, primarily acts as a modifier of onset age.


Subject(s)
Alzheimer Disease/genetics , Apolipoproteins E/genetics , Genetic Predisposition to Disease , Genome-Wide Association Study , Age of Onset , Algorithms , Alleles , Bayes Theorem , Case-Control Studies , Chromosomes, Human, Pair 14 , Genetic Markers , Humans , Linear Models , Linkage Disequilibrium , Pedigree , Polymorphism, Single Nucleotide , Sialic Acid Binding Ig-like Lectin 3/genetics , White People
2.
Am J Hum Genet ; 79(1): 13-22, 2006 Jul.
Article in English | MEDLINE | ID: mdl-16773561

ABSTRACT

Array-based comparative genomic hybridization (arrayCGH) is a microarray-based comparative genomic hybridization technique that has been used to compare tumor genomes with normal genomes, thus providing rapid genomic assays of tumor genomes in terms of copy-number variations of those chromosomal segments that have been gained or lost. When properly interpreted, these assays are likely to shed important light on genes and mechanisms involved in the initiation and progression of cancer. Specifically, chromosomal segments, deleted in one or both copies of the diploid genomes of a group of patients with cancer, point to locations of tumor-suppressor genes (TSGs) implicated in the cancer. In this study, we focused on automatic methods for reliable detection of such genes and their locations, and we devised an efficient statistical algorithm to map TSGs, using a novel multipoint statistical score function. The proposed algorithm estimates the location of TSGs by analyzing segmental deletions (hemi- or homozygous) in the genomes of patients with cancer and the spatial relation of the deleted segments to any specific genomic interval. The algorithm assigns, to an interval of consecutive probes, a multipoint score that parsimoniously captures the underlying biology. It also computes a P value for every putative TSG by using concepts from the theory of scan statistics. Furthermore, it can identify smaller sets of predictive probes that can be used as biomarkers for diagnosis and therapeutics. We validated our method using different simulated artificial data sets and one real data set, and we report encouraging results. We discuss how, with suitable modifications to the underlying statistical model, this algorithm can be applied generally to a wider class of problems (e.g., detection of oncogenes).


Subject(s)
Genes, Tumor Suppressor , Gene Deletion , Genome, Human , Humans , Neoplasms/genetics , Nucleic Acid Hybridization
3.
BMC Genet ; 7: 39, 2006 Jun 15.
Article in English | MEDLINE | ID: mdl-16776843

ABSTRACT

BACKGROUND: The mapping of complex diseases is one of the most important problems in human genetics today. The rapid development of technology for genetic research has led to the discovery of millions of polymorphisms across the human genome, making it possible to conduct genome-wide association studies with hundreds of thousands of markers. Given the large number of markers to be tested in such studies, a two-stage strategy may be a reasonable and powerful approach: in the first stage, a small subset of promising loci is identified using single-locus testing, and, in the second stage, multi-locus methods are used while taking into account the loci selected in the first stage. In this report, we investigate and compare two possible two-stage strategies for genome-wide association studies: a conditional approach and a simultaneous approach. RESULTS: We investigate the power of both the conditional and the simultaneous approach to detect the disease loci for a range of two-locus disease models in a case-control study design. Our results suggest that, overall, the conditional approach is more robust and more powerful than the simultaneous approach; the conditional approach can greatly outperform the simultaneous approach when one of the two disease loci has weak marginal effect, but interacts strongly with the other, stronger locus (easily detectable using single-locus methods in the first stage). CONCLUSION: Genome-wide association studies hold the promise of finding new genes implicated in complex diseases. Two-stage strategies are likely to be employed in these large-scale studies. Therefore we compared two natural two-stage approaches: the conditional approach and the simultaneous approach. Our power studies suggest that, when doing genome-wide association studies, a two-stage conditional approach is likely to be more powerful than a two-stage simultaneous approach.


Subject(s)
Chromosome Mapping , Genetic Markers , Genetic Predisposition to Disease , Models, Genetic , Quantitative Trait Loci , Alleles , Gene Frequency , Genetic Linkage , Humans
4.
Hum Hered ; 60(4): 227-40, 2005.
Article in English | MEDLINE | ID: mdl-16424672

ABSTRACT

OBJECTIVE: The conventional affected sib pair methods evaluate the linkage information at a locus by considering only marginal information. We describe a multilocus linkage method that uses both the marginal information and information derived from the possible interactions among several disease loci, thereby increasing the significance of loci with modest effects. METHODS: Our method is based on a statistic that quantifies the linkage information contained in a set of markers. By a marker selection-reduction process, we screen a set of polymorphisms and select a few that seem linked to disease. RESULTS: We test our approach on genome scan data for inflammatory bowel disease (InfBD) and on simulated data. On real data we detect 6 of the 8 known InfBD loci; on simulated data we obtain improvements in power of up to 40% compared to a conventional single-locus method. CONCLUSION: Our extensive simulations and the results on real data show that our method is in general more powerful than single-locus methods in detecting disease loci responsible for complex traits. A further advantage of our approach is that it can be extended to make use of both the linkage and the linkage disequilibrium between disease loci and nearby markers.


Subject(s)
Genetic Linkage/genetics , Genome, Human/genetics , Inflammatory Bowel Diseases/genetics , Models, Genetic , Quantitative Trait Loci/genetics , Sequence Analysis, DNA , Genetic Markers , Humans , Sequence Analysis, DNA/methods
SELECTION OF CITATIONS
SEARCH DETAIL
...