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N Maniatis

Publications and source records attributed to N Maniatis.

10 recordsLinked to original sources
PubMed2006

Refined association mapping for a quantitative trait: weight in the H19-IGF2-INS-TH region.

Previous analyses have provided evidence for one or more loci affecting body weight in the H19-IGF2-INS-TH region on chromosome 11p15. To identify the location of a possible causal locus or loci we applied association analysis by composite likelihood to a large cohort under the Malecot model for body weight. A random sample of 2731 men in the UK were typed for eleven single nucleotide polymorphisms (SNPs) in IGF2, two SNPs in H19, one SNP in INS and one microsatellite marker in the TH genes. Using F tests appropriate to small marker sets, the superiority of regression over correlation was confirmed. All the evidence for association came from IGF2, with P= 0.007 for height-adjusted weight and P= 0.019 for weight additionally adjusted for smoking and alcohol drinking. Although the estimated point location for the suspected causal variant was close to IGF2 ApaI, the 95% confidence and support intervals covered most of IGF2 but none of the other loci. Identification of the causal SNP or SNPs within IGF2 will require typing of more variants in this region.

Body Mass Index↗
PubMed2005

A map of the human genome in linkage disequilibrium units.

Two genetic maps with additive distances contribute information about recombination patterns, recombinogenic sequences, and discovery of genes affecting a particular phenotype. Recombination is measured in morgans (w) over a single generation in a linkage map but may cover thousands of generations in a linkage disequilibrium (LD) map measured in LD units (LDU). We used a subset of single nucleotide polymorphisms from the HapMap Project to create a genome-wide map in LDU. Recombination accounts for 96.8% of the LDU variance in chromosome arms and 92.4% in their deciles. However, deeper analysis shows that LDU/w, an estimate of the effective bottleneck time (t), is significantly variable among chromosome arms because (i) the linkage map is approximated from the Haldane function, then adjusted toward the Kosambi function that is more accurate but still exaggerates w for all chromosomes, especially shorter ones; (ii) the non-pseudoautosomal region of the X chromosome is subject to hemizygous selection; and (iii) at resolution less than approximately 40,000 markers per w, there are indeterminacies (holes) in the LD map reflecting intervals of very high recombination. Selection and stochastic variation in small regions must have effects, which remain to be investigated by comparisons among populations. These considerations suggest an optimal strategy to eliminate holes quickly, greatly enhance the resolution of sex-specific linkage maps, and maximize the gain in association mapping by using LD maps.

Chromosome Mapping↗
PubMed2004

The optimal measure of linkage disequilibrium reduces error in association mapping of affection status.

We have developed a simple yet powerful approach for disease gene association mapping by linkage disequilibrium (LD). This method is unique because it applies a model with evolutionary theory that incorporates a parameter for the location of the causal polymorphism. The method exploits LD maps, which assign a location in LD units (LDU) for each marker. This approach is based on single marker tests within a composite likelihood framework, which avoids the heavy Bonferroni correction through multiple testing. As a proof of principle, we tested an 890 kb region flanking the CYP2D6 gene associated with poor drug-metabolizing activity in order to refine the localization of a causal mutation. Previous LD mapping studies using single markers and haplotypes have identified a 390 kb significant region associated with the poor drug-metabolizing phenotype on chromosome 22. None of the 27 Single nucleotide polymorphisms was within the gene. Using a metric LDU map, the commonest functional polymorphism within the gene was located at 14.9 kb from its true location, surrounded within a 95% confidence interval of 172 kb. The kb map had a relative efficiency of 33% compared with the LDU map. Our findings indicate that the support interval and location error are smaller than any published results. Despite the low resolution and the strong LD in the region, our results provide evidence of the substantial utility of LDU maps for disease gene association mapping. These tests are robust to large numbers of markers and are applicable to haplotypes, diplotypes, whole-genome association or candidate region studies.

Chromosomes, Human, Pair 22↗
PubMed2003

A metric linkage disequilibrium map of a human chromosome.

We used LDMAP (Maniatis et al. 2002) to analyse SNP data spanning chromosome 22 (Dawson et al. 2002), to obtain a whole-chromosome metric LD map. The LD map, with map distances analogous to the centiMorgan scale of linkage maps, identifies regions of high LD as plateaus ('blocks') and characterises steps which define the relationship between these regions. From this map we estimate that block regions comprise between 32% and 55% of the euchromatic portion of chromosome 22 and that increasing marker density within steps may increase block coverage. Steps are regions of low LD which correspond to areas of variable recombination intensity. The intensity of recombination is related to the height of the step and thus intense recombination hot-spots can be distinguished from more randomly distributed historical events. The LD maps are more closely related to the high-resolution linkage map (Kong et al. 2002) than average measures of rho with recombination accounting for between 34% and 52% of the variance in patterns of LD (r=0.58 - 0.71, p=0.0001). Step regions are closely correlated with a range of sequence motifs including GT/CA repeats. The LD map identifies holes in which greater marker density is required and defines the optimal SNP spacing for positional cloning, which suggests that some multiple of around 50,000 SNPs will be required to efficiently screen Caucasian genomes. Further analyses which investigate selection of informative SNPs and the effect of SNP allele frequency and marker density will refine this estimate.

Chromosome Mapping↗
PubMed2003

The impact of data structure on genetic (co)variance components of early growth in sheep, estimated using an animal model with maternal effects.

Several studies have noted high negative correlations between maternal genetic and direct additive effects and their influence on additive and maternal heritability of early growth traits in sheep. Multigeneration data from the Suffolk Sire Reference Scheme (SSRS) were used to investigate the effect of data structure on estimates of direct and maternal (co)variances for lamb 8-wk weight. In all analyses the additive, maternal genetic, maternal environmental, and residual effects were fitted along with the covariance between direct and maternal additive effects. The contributions of particular genetic relationships to the estimates were studied by analyzing subsets of the SSRS data. A further eight subsets were formed having 10% or 50% of the dams with their own records and having one or two, three or four, five or six, and more than six offspring per dam. Analysis of data having only 10% of the dams with their own record and one or two offspring records yielded a high negative correlation (-0.99) between direct and maternal genetic effects. However, the seven other data sets with more records per dam or a higher proportion of dams with their own records produced values of -0.35 to -0.51. Data structure and the number of dams and granddams with records are important determinants of estimated direct and maternal effects in early growth traits.

Analysis of Variance↗
PubMed2002

The first linkage disequilibrium (LD) maps: delineation of hot and cold blocks by diplotype analysis.

Linkage disequilibrium (LD) provides information about positional cloning, linkage, and evolution that cannot be inferred from other evidence, even when a correct sequence and a linkage map based on more than a handful of families become available. We present theory to construct an LD map for which distances are additive and population-specific maps are expected to be approximately proportional. For this purpose, there is only a modest difference in relative efficiency of haplotypes and diplotypes: resolving the latter into 2-locus haplotypes has significant cost or error and increases information by about 50%. LD maps for a cold spot in 19p13.3 and a more typical region in 3q21 are optimized by interval estimates. For a random sample and trustworthy map the value of LD at large distance can be predicted reliably from information over a small distance and does not depend on the evolutionary variance unless the sample size approaches the population size. Values of the association probability that can be distinguished from the value at large distance are determined not by population size but by time since a critical bottleneck. In these examples, omission of markers with significant Hardy-Weinberg disequilibrium does not improve the map, and widely discrepant draft sequences have similar estimates of the genetic parameters. The LD cold spot in 19p13.3 gives an unusually high estimate of time, supporting an argument that this relationship is general. As predicted for a region with ancient haplotypes or uniformly high recombination, there is no clear evidence of LD clustering. On the contrary, the 3q21 region is resolved into alternating blocks of stable and decreasing LD, as expected from crossover clustering. Construction of a genomewide LD map requires data not yet available, which may be complemented but not replaced by a catalog of haplotypes.

Chromosome Mapping↗
PubMed2002

Nuclear, cytoplasmic, and environmental effects on growth, fat, and muscle traits in suffolk lambs from a sire referencing scheme.

Maternal effects are an important source of variation in early growth and body traits in sheep but are often excluded from genetic analyses. Maternal additive genetic, maternal environmental, and cytoplasmic effects were investigated in a large Suffolk breeding scheme using a range of models involving different combinations of these effects with the direct additive genetic effect. Weights at 8 wk of age and at scanning (mean age 146 d) and ultrasonically measured muscle and fat depth were analyzed using an animal model on 55,683 (8-wk weight) and 28,947 (scanning traits) lamb records. Simple additive models always overestimated the heritability of all traits when compared to more complex models. The successive inclusion of maternal environmental, maternal genetic, and the covariance between direct and maternal additive effects in the model significantly improved the fit for almost all models and all traits, as indicated by a likelihood ratio test. Under the full model, the heritability of both weight traits was low (0.14 and 0.20 for 8-wk and scanning weight, respectively). The maternal additive and maternal environmental effects, as a proportion of the phenotypic variance, were similar (0.10 and 0.08 for 8-wk weight and 0.07 and 0.06 for scanning weight). The two scanning traits had higher heritabilities (0.29 and 0.27 for muscle depth and fat depth, respectively) with low levels of maternal genetic and maternal environmental variance. No evidence was found of a cytoplasmic effect on any of the traits studied under the full model. Breeding schemes for early growth and body traits in sheep should account for maternal effects in their genetic evaluations in order to improve their accuracy. The exact model to use will depend on the trait and individual circumstances of the scheme.

Adipose Tissue↗
PubMed2001

Allelic association and disease mapping.

The application of allelic association to map genes for complex traits, particularly using high-density maps of single nucleotide polymorphisms in candidate regions, is an area of very active research. Here we present some aspects of the methodology and applications to both major gene mapping, which illustrates the effectiveness of the method, and oligogenes, where methods are still in flux and for which there have been relatively few successes to date. Several important considerations emerge, including the selection of the optimal metric for measuring association and the importance of modelling the decline in association with distance given the variability in association in a candidate region. The Malecot model of association with distance is shown to have a resolution of greater than 50 kilobases but the available evidence suggests that considerably higher resolution might be achieved with dense single nucleotide polymorphism (SNP) maps.

Alleles↗