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    ABSTRACT: Homer and others (2008. Resolving individuals contributing trace amounts of DNA to highly complex mixtures using high-density SNP genotyping microarrays. PLoS Genetics 4, e1000167) recently showed that, given allele frequency data for a large number of single nucleotide polymorphisms in a sample together with corresponding population "reference" frequencies, by typing an individual's DNA sample at the same set of loci it can be inferred whether or not the individual was a member of the sample. This observation has been responsible for precautionary removal of large amounts of summary data from public access. This and further work on the problem has followed a frequentist approach. This paper sets out a Bayesian analysis of this problem which clarifies the role of the reference frequencies and allows incorporation of prior probabilities of the individual's membership in the sample.
    Biostatistics 10/2010; 11(4):661-73. DOI:10.1093/biostatistics/kxq035
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    ABSTRACT: The problem of testing for genotype-phenotype association with loci on the X chromosome in mixed-sex samples has received surprisingly little attention. A simple test can be constructed by counting alleles, with males contributing a single allele and females 2. This approach does assume not only Hardy-Weinberg equilibrium in the population from which the study subjects are sampled but also, perhaps, an unrealistic alternative hypothesis. This paper proposes 1 and 2 degree-of-freedom tests for association which do not assume Hardy-Weinberg equilibrium and which treat males as homozygous females. The proposed method remains valid when phenotype varies between sexes, provided the allele frequency does not, and avoids the loss of power resulting from stratification by sex in such circumstances.
    Biostatistics 05/2008; 9(4):593-600. DOI:10.1093/biostatistics/kxn007
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    ABSTRACT: Lymphoblastoid cell lines (LCL) are being actively and extensively used to examine the expression of specific genes and genome-wide expression profiles, including allele specific expression assays. However, it has recently been shown that approximately 10% of human genes exhibit random patterns of monoallelic expression within single clones of LCLs. Consequently allelic imbalance studies could be significantly compromised if bulk populations of donor cells are clonal, or near clonal. Here, using X chromosome inactivation as a readout, we confirm and quantify widespread near monoclonality in two independent sets of cell lines. Consequently, we recommend where possible the use of bulk, non cell line, ex vivo cells for allele specific expression assays.
    PLoS ONE 02/2008; 3(8):e2966. DOI:10.1371/journal.pone.0002966
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    ABSTRACT: We performed linkage and family-based association analysis across chromosomes 1-22 in Replicates 1-5 of the Genetic Analysis Workshop 15 simulated data. Linkage analysis was performed using the Kong and Cox allele-sharing test as implemented in the program Merlin. Association analysis was performed using the transmission/disequilibrium test (TDT). A region on chromosome 6 was consistently highlighted as showing significant linkage to and association with the disease trait. We focused in on this region and performed fine-mapping using stepwise regression approaches using the case/control and family-based data. In this region, we also applied several new methods, implemented in the computer programs LAMP and Graphminer, respectively, that have recently been proposed for association analysis with family and/or case/control data. All methods confirmed the highly significant associations previously observed. Differentiating between potentially causal single nucleotide polymorphisms (SNPs) and other non-causal loci (associated with disease merely due to linkage disequilibrium) proved to be problematic. However, in most replicates we did identify two SNPs (either SNPs 3437 and 3439 from the dense SNP set, or SNPs 153 and 3437 from the combined non-dense/dense SNP set) that together explain most of the observed disease association in the DR/C locus region, and an additional SNP (3931 or 3933) that accounts for the association 5 cM away at locus D.
    BMC proceedings 02/2007; 1 Suppl 1(Suppl 1):S23. DOI:10.1186/1753-6561-1-s1-s23
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    ABSTRACT: Type 1 diabetes is an autoimmune disease influenced by multiple genetic loci. Although more than 20 insulin-dependent diabetes (Idd) loci have been implicated in the nonobese diabetic (NOD) mouse model, few causal gene variants have been identified. Here we show that RNA interference (RNAi) can be used to probe candidate genes in this disease model. Slc11a1 encodes a phagosomal ion transporter, Nramp1, that affects resistance to intracellular pathogens and influences antigen presentation. This gene is the strongest candidate among the 42 genes in the Idd5.2 region; a naturally occurring mutation in the protective Idd5.2 haplotype results in loss of function of the Nramp1 protein. Using lentiviral transgenesis, we generated NOD mice in which Slc11a1 is silenced by RNAi. Silencing reduced the frequency of type 1 diabetes, mimicking the protective Idd5.2 region. Our results demonstrate a role for Slc11a1 in modifying susceptibility to type 1 diabetes and illustrate that RNAi can be used to study causal genes in a mammalian model organism.
    Nature Genetics 05/2006; 38(4):479-83. DOI:10.1038/ng1766
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    ABSTRACT: Costimulation blockade induces prolonged rat islet and skin xenograft survival in C57BL/6 mice. Nonobese diabetic (NOD) mice, which are used to model human autoimmune diabetes, are resistant to costimulation blockade-induced allograft tolerance. We tested the hypothesis that NOD mice would also be resistant to costimulation blockade-induced rat xenograft tolerance. We report that rat islet xenograft survival is short in spontaneously diabetic NOD mice treated with a tolerizing regimen of donor-specific transfusion and anti-CD154 antibody. Rat islet xenograft survival is only marginally longer in chemically diabetic NOD mice treated with costimulation blockade but is prolonged further in NOD Idd congenic mice bearing C57-derived chromosome 3 loci. Reciprocally, the presence of NOD-derived chromosome 3 loci shortens islet xenograft survival in tolerized C57BL/6 mice. Islet xenograft survival is longer in tolerized NOD.CD4a(-/-) and (NOD x C57BL/6)F1 mice than in NOD mice but still much shorter than in C57BL/6 mice. Skin xenograft survival in (NOD x C57BL/6)F1 mice treated with costimulation blockade is short, suggesting a strong genetic resistance to skin xenograft tolerance induction. We conclude that the resistance of NOD mice to xenograft tolerance induction involves some mechanisms that also participate in the expression of autoimmunity and other mechanisms that are distinct.
    Diabetes 02/2005; 54(1):107-15. DOI:10.2337/diabetes.54.1.107
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    ABSTRACT: It is usually assumed that detection of a disease susceptability gene via marker polymorphisms in linkage disequilibrium with it is facilitated by consideration of marker haplotypes. However, capture of the marker haplotype information requires resolution of gametic phase, and this must usually be inferred statistically. Recently, we questioned the value of the marker haplotype information, and suggested that certain analyses of multivariate marker data, not based on haplotypes explicitly and not requiring resolution of gametic phase, are often more powerful than analyses based on haplotypes. Here, we review this work and assess more carefully the situations in which our conclusions might apply. We also relate these analyses to alternative approaches to haplotype analysis, namely those based on haplotype similarity and those inspired by cladistics.
    Genetic Epidemiology 12/2004; 27(4):415-28. DOI:10.1002/gepi.20032
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    ABSTRACT: Vitamin D is known to modulate the immune system, and its administration has been associated with reduced risk of type 1 diabetes. Vitamin D acts via its receptor (VDR). Four single nucleotide polymorphisms (SNPs) of the VDR gene have been commonly studied, and evidence of association with type 1 diabetes has been reported previously. We sequenced the VDR gene region and developed its SNP map. Here we analyzed association of the 98 VDR SNPs in up to 3,763 type 1 diabetic families. First, we genotyped all 98 SNPs in a minimum of 458 U.K. families with two affected offspring. We further tested eight SNPs, including four SNPs associated with P < 0.05 in the first set and the four commonly studied SNPs, in up to 3,305 additional families from the U.K., Finland, Norway, Romania, and U.S. We only found weak evidence of association (P = 0.02-0.05) of the rs4303288, rs12721366, and rs2544043 SNPs. We then tested these three SNPs in an independent set of 1,587 patients and 1,827 control subjects from the U.K. and found no evidence of association. Overall, our results indicate that common sequence variation in the VDR gene has no major effect in type 1 diabetes in the populations tested.
    Diabetes 10/2004; 53(10):2709-12. DOI:10.2337/diabetes.53.10.2709
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    ABSTRACT: Prior data associating the expression of lymphocyte-specific protein tyrosine kinase (LCK) with type 1 diabetes, its critical function in lymphocytes, and the linkage of the region to diabetes in the nonobese diabetic (NOD) mouse model make LCK a premier candidate for a susceptibility gene. Resequencing of LCK in 32 individuals detected seven single nucleotide polymorphisms (SNPs) with allele frequencies >3%, including four common SNPs previously reported. These and six other SNPs from dbSNP were genotyped in a two-stage strategy using 2,430 families and were all shown not to be significantly associated with type 1 diabetes. We conclude that a major role for the common LCK polymorphisms in type 1 diabetes is unlikely. However, we cannot rule out the possibility of there being a causal variant outside the exonic, intronic, and untranslated regions studied.
    Diabetes 09/2004; 53(9):2479-82. DOI:10.2337/diabetes.53.9.2479
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    ABSTRACT: Type 1 diabetes susceptibility at the IDDM2 locus was previously mapped to a variable number tandem repeat (VNTR) 5' of the insulin gene (INS). However, the observation of associated markers outside a 4.1-kb interval, previously considered to define the limits of IDDM2 association, raised the possibility that the VNTR association might result from linkage disequilibrium (LD) with an unknown polymorphism. We therefore identified a total of 177 polymorphisms and obtained genotypes for 75 of these in up to 434 pedigrees. We found that, whereas disease susceptibility did map to within the 4.1-kb region, there were two equally likely candidates for the causal variant, -23HphI and +1140A/C, in addition to the VNTR. Further analyses in 2,960 pedigrees did not support the difference in association between VNTR lineages that had previously enabled the exclusion of these two polymorphisms. Therefore, we were unable to rule out -23HphI and +1140A/C having an etiological effect. Our mapping results using robust regression methods show how precisely a variant for a common disease can be mapped, even within a region of strong LD, and specifically that IDDM2 maps to one or more of three common variants in a approximately 2-kb region of chromosome 11p15.
    Diabetes 08/2004; 53(7):1884-9. DOI:10.2337/diabetes.53.7.1884
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