Showing papers by "Gonçalo R. Abecasis published in 2002"

Merlin--rapid analysis of dense genetic maps using sparse gene flow trees.

Abstract: Efforts to find disease genes using high-density single-nucleotide polymorphism (SNP) maps will produce data sets that exceed the limitations of current computational tools. Here we describe a new, efficient method for the analysis of dense genetic maps in pedigree data that provides extremely fast solutions to common problems such as allele-sharing analyses and haplotyping. We show that sparse binary trees represent patterns of gene flow in general pedigrees in a parsimonious manner, and derive a family of related algorithms for pedigree traversal. With these trees, exact likelihood calculations can be carried out efficiently for single markers or for multiple linked markers. Using an approximate multipoint calculation that ignores the unlikely possibility of a large number of recombinants further improves speed and provides accurate solutions in dense maps with thousands of markers. Our multipoint engine for rapid likelihood inference (Merlin) is a computer program that uses sparse inheritance trees for pedigree analysis; it performs rapid haplotyping, genotype error detection and affected pair linkage analyses and can handle more markers than other pedigree analysis packages.

A first-generation linkage disequilibrium map of human chromosome 22.

Abstract: DNA sequence variants in specific genes or regions of the human genome are responsible for a variety of phenotypes such as disease risk or variable drug response. These variants can be investigated directly, or through their non-random associations with neighbouring markers (called linkage disequilibrium (LD)). Here we report measurement of LD along the complete sequence of human chromosome 22. Duplicate genotyping and analysis of 1,504 markers in Centre d'Etude du Polymorphisme Humain (CEPH) reference families at a median spacing of 15 kilobases (kb) reveals a highly variable pattern of LD along the chromosome, in which extensive regions of nearly complete LD up to 804 kb in length are interspersed with regions of little or no detectable LD. The LD patterns are replicated in a panel of unrelated UK Caucasians. There is a strong correlation between high LD and low recombination frequency in the extant genetic map, suggesting that historical and contemporary recombination rates are similar. This study demonstrates the feasibility of developing genome-wide maps of LD.

Powerful regression-based quantitative-trait linkage analysis of general pedigrees.

Abstract: We present a new method of quantitative-trait linkage analysis that combines the simplicity and robustness of regression-based methods and the generality and greater power of variance-components models. The new method is based on a regression of estimated identity-by-descent (IBD) sharing between relative pairs on the squared sums and squared differences of trait values of the relative pairs. The method is applicable to pedigrees of arbitrary structure and to pedigrees selected on the basis of trait value, provided that population parameters of the trait distribution can be correctly specified. Ambiguous IBD sharing (due to incomplete marker information) can be accommodated in the method by appropriate specification of the variance-covariance matrix of IBD sharing between relative pairs. We have implemented this regression-based method and have performed simulation studies to assess, under a range of conditions, estimation accuracy, type I error rate, and power. For normally distributed traits and in large samples, the method is found to give the correct type I error rate and an unbiased estimate of the proportion of trait variance accounted for by the additive effects of the locus—although, in cases where asymptotic theory is doubtful, significance levels should be checked by simulations. In large sibships, the new method is slightly more powerful than variance-components models. The proposed method provides a practical and powerful tool for the linkage analysis of quantitative traits.

Genetic variation in the 22q11 locus and susceptibility to schizophrenia

Abstract: An increased prevalence of microdeletions at the 22q11 locus has been reported in samples of patients with schizophrenia. 22q11 microdeletions represent the highest known genetic risk factor for the development of schizophrenia, second only to that of the monozygotic cotwin of an affected individual or the offspring of two schizophrenic parents. It is therefore clear that a schizophrenia susceptibility locus maps to chromosome 22q11. In light of evidence for suggestive linkage for schizophrenia in this region, we hypothesized that, whereas deletions of chromosome 22q11 may account for only a small proportion of schizophrenia cases in the general population (up to ≈2%), nondeletion variants of individual genes within the 22q11 region may make a larger contribution to susceptibility to schizophrenia in the wider population. By studying a dense collection of markers (average one single nucleotide polymorphism/20 kb over 1.5 Mb) in the vicinity of the 22q11 locus, in both family- and population-based samples, we present here results consistent with this assumption. Moreover, our results are consistent with contribution from more than one gene to the strikingly increased disease risk associated with this locus. Finer-scale haplotype mapping has identified two subregions within the 1.5-Mb locus that are likely to harbor candidate schizophrenia susceptibility genes.

Insomnia Associated With Thalamic Involvement in E200K Creutzfeldt-Jakob Disease

Abstract: Background: Insomnia with predominant thalamic involvement and minor cortical and cerebellar pathologic changes is not characteristic of familial Creutzfeldt–Jakob disease (CJD) but is a hallmark of fatal familial insomnia. Objective: To report a 53-year-old woman with intractable insomnia as her initial symptom of disease. Methods: The authors characterized clinical, pathologic, and molecular features of the disease using EEG, polysomnography, neurohistology, Western blotting, protein sequencing, and prion protein (PrP) gene ( PRNP ) analysis. Results: The patient developed dysgraphia, dysarthria, bulimia, myoclonus, memory loss, visual hallucinations, and opisthotonos, as well as pyramidal, extrapyramidal, and cerebellar signs. Polysomnographic studies showed an absence of stages 3 and 4, and REM. She died 8 months after onset. On neuropathologic examination, there was major thalamic involvement characterized by neuronal loss, spongiform changes, and prominent gliosis. The inferior olivary nuclei exhibited chromatolysis, neuronal loss, and gliosis. Spongiform changes were mild in the neocortex and not evident in the cerebellum. PrP immunopositivity was present in these areas as well as in the thalamus. PRNP analysis showed the haplotype E200K-129M. Western blot analysis showed the presence of proteinase K (PK)–resistant PrP (PrP sc ) with the nonglycosylated isoform of approximately 21 kd, corresponding in size to that of type 1 PrP sc . N -terminal protein sequencing demonstrated PK cleavage sites at glycine (G) 82 and G78, as previously reported in CJD with the E200K-129 M haplotype. Conclusions: Insomnia may be a prominent early symptom in cases of CJD linked to the E200K-129M haplotype in which the thalamus is severely affected.

Positive association to IgE levels and a physical map of the 13q14 atopy locus

Abstract: Linkage of atopy and associated traits to a locus on chromosome 13q14 has been identified by several studies in diverse populations. We have previously shown the putative atopy gene to be contained within an interval of approximately 5 Mb flanked by D13S328 and D13S1269 and centred on D13S273. We have now extended this work using a top-down approach to physical mapping. A YAC contig was constructed covering the D13S328 and D13S1269 interval. Thirty-one ESTs were mapped to the contig. We constructed a BAC and PAC contig flanking D13S273 by approximately 750 kb in either direction. The interval contained 27 of the 31 ESTS from the YAC contig. Seven previously unknown microsatellites were recovered and then typed in two subject panels. A positive association between the total serum Immunoglobulin E concentration and the novel USAT24G1 microsatellite was discovered (P(corrected)<0.005) and replicated in a second panel of families. The discovery of a region of positive association within the BAC/PAC contig will permit identification of the atopy gene from this locus.

Mapping quantitative effects of oligogenes by allelic association.

Abstract: summary Regression analysis of a quantitative trait as a function of a single diallelic polymorphism has been extended to allelic association by composite likelihood under the Malecot model for multiple markers. We applied the method to 10 single nucleotide polymorphisms (SNPs) spanning 27 kb of the angiotensin-I converting enzyme (ACE) gene in British families, localising a causal SNP between G2530A and 4656(CT)3}2 in the 3« region, at a distance of 21‐6‡0‐9 kb from the most proximal SNP T-5491C. Neither they nor the I}D polymorphism is causal. To clarify genetic parameters we applied combined segregation, linkage and association analysis. Stronger evidence for the 3« region was obtained, with significant evidence of a lesser 5« eect as reported in French and Nigerian families. However, rigorous confirmation requires that the causal SNPs be identified. Both Malecot and parametric analysis appear to have high power by comparison with alternative methods for localizing oligogenes and their causal polymorphisms.