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Elizabeth A Norgard,
Joseph P Jarvis,
Charles C Roseman, Taylor J Maxwell,
Jane P Kenney-Hunt,
Kaitlin E Samocha,
L Susan Pletscher,
Bing Wang,
Gloria L Fawcett,
Christopher J Leatherwood,
Jason B Wolf,
James M Cheverud
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ABSTRACT: Quantitative trait locus (QTL) mapping techniques are frequently used to identify genomic regions associated with variation in phenotypes of interest. However, the F(2) intercross and congenic strain populations usually employed have limited genetic resolution resulting in relatively large confidence intervals that greatly inhibit functional confirmation of statistical results. Here we use the increased resolution of the combined F(9) and F(10) generations (n = 1455) of the LG,SM advanced intercross to fine-map previously identified QTL associated with the lengths of the humerus, ulna, femur, and tibia. We detected 81 QTL affecting long-bone lengths. Of these, 49 were previously identified in the combined F(2)-F(3) population of this intercross, while 32 represent novel contributors to trait variance. Pleiotropy analysis suggests that most QTL affect three to four long bones or serially homologous limb segments. We also identified 72 epistatic interactions involving 38 QTL and 88 novel regions. This analysis shows that using later generations of an advanced intercross greatly facilitates fine-mapping of confidence intervals, resolving three F(2)-F(3) QTL into multiple linked loci and narrowing confidence intervals of other loci, as well as allowing identification of additional QTL. Further characterization of the biological bases of these QTL will help provide a better understanding of the genetics of small variations in long-bone length.
Mammalian Genome 04/2009; 20(4):224-35. · 2.89 Impact Factor
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ABSTRACT: Irinotecan is an important drug for the treatment of solid tumors. Although genes involved in irinotecan pharmacokinetics have been shown to influence toxicity, there are no data on pharmacodynamic genes. CDC45L, NFKB1, PARP1, TDP1, and XRCC1 have been shown to influence the cytotoxic action of camptothecins, including irinotecan. Polymorphisms in the drug target of camptothecins, topoisomerase I (TOP1), and downstream effectors may influence patient outcomes to irinotecan therapy. We undertook a retrospective candidate gene haplotype association study to investigate this hypothesis.
Haplotype compositions of six candidate genes were constructed in European (n = 93), East Asian (n = 94), and West African (n = 95) populations. Haplotype-tagging single nucleotide polymorphisms (htSNP) were selected based on genealogic relationships between haplotypes. DNA samples from 107 European, advanced colorectal cancer patients treated with irinotecan-based regimens were genotyped for htSNPs as well as three coding region SNPs. Associations between genetic variants and toxicity (grade 3/4 diarrhea and neutropenia) or efficacy (objective response) were assessed.
TOP1 and TDP1 htSNPs were related to grade 3/4 neutropenia (P = 0.04) and response (P = 0.04), respectively. Patients homozygous for an XRCC1 haplotype (GGCC-G) were more likely to show an objective response to therapy than other patients (83% versus 30%; P = 0.02). This effect was also seen in a multivariate analysis (odds ratio, 11.9; P = 0.04). No genetic variants were associated with diarrhea.
This is the first comprehensive pharmacogenetic investigation of irinotecan pharmacodynamic factors, and our findings suggest that genetic variation in the pharmacodynamic genes may influence the efficacy of irinotecan-containing therapies in advanced colorectal cancer patients.
Clinical Cancer Research 04/2008; 14(6):1788-96. · 7.74 Impact Factor
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Petra Nowotny,
Anthony L Hinrichs,
Scott Smemo,
John S K Kauwe, Taylor Maxwell,
Peter Holmans,
Marian Hamshere,
Dragana Turic,
Luke Jehu,
Paul Hollingworth, [......],
Chris M Morris,
Leon Thal,
John C Morris,
Michael C O'Donovan,
Simon Lovestone,
Andrew Grupe,
John Hardy,
Michael J Owen,
Julie Williams,
Alison Goate
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ABSTRACT: Linkage studies have suggested there is a susceptibility gene for late onset Alzheimer's disease (LOAD) in a broad region of chromosome 10. A strong positional and biological candidate is the gene encoding the insulin-degrading enzyme (IDE), a protease involved in the catabolism of Abeta. However, previous association studies have produced inconsistent results. To systematically evaluate the role of variation in IDE in the risk for LOAD, we genotyped 18 SNPs spanning a 276 kb region in and around IDE, including three "tagging" SNPs identified in an earlier study. We used four case-control series with a total of 1,217 cases and 1,257 controls. One SNP (IDE_7) showed association in two samples (P-value = 0.0066, and P = 0.026, respectively), but this result was not replicated in the other two series. None of the other SNPs showed association with LOAD in any of the tested samples. Haplotypes, constructed from the three tagging SNPs, showed no globally significant association. In the UK2 series, the CTA haplotype was over-represented in cases (P = 0.046), and in the combined data set, the CCG haplotype was more frequent in controls (P = 0.015). However, these weak associations observed in our series were in the opposite direction to the results in previous studies. Although our results are not universally negative, we were unable to replicate the results of previous studies and conclude that common variants or haplotypes of these variants in IDE are not major risk factors for LOAD.
American Journal of Medical Genetics Part B Neuropsychiatric Genetics 08/2005; 136B(1):62-8. · 3.70 Impact Factor
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ABSTRACT: We use evolutionary trees of haplotypes to study phenotypic associations by exhaustively examining all possible biallelic partitions of the tree, a technique we call tree scanning. If the first scan detects significant associations, additional rounds of tree scanning are used to partition the tree into three or more allelic classes. Two worked examples are presented. The first is a reanalysis of associations between haplotypes at the Alcohol Dehydrogenase locus in Drosophila melanogaster that was previously analyzed using a nested clade analysis, a more complicated technique for using haplotype trees to detect phenotypic associations. Tree scanning and the nested clade analysis yield the same inferences when permutation testing is used with both approaches. The second example is an analysis of associations between variation in various lipid traits and genetic variation at the Apolipoprotein E (APOE) gene in three human populations. Tree scanning successfully identified phenotypic associations expected from previous analyses. Tree scanning for the most part detected more associations and provided a better biological interpretative framework than single SNP analyses. We also show how prior information can be incorporated into the tree scan by starting with the traditional three electrophoretic alleles at APOE. Tree scanning detected genetically determined phenotypic heterogeneity within all three electrophoretic allelic classes. Overall, tree scanning is a simple, powerful, and flexible method for using haplotype trees to detect phenotype/genotype associations at candidate loci.
Genetics 02/2005; 169(1):441-53. · 4.01 Impact Factor
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Alex Coventry,
Lara Bull-Otterson,
Xiaoming Liu,
Andrew Clark, Taylor Maxwell,
Jacy Crosby,
James Hixson,
Thomas Rea,
Alan R Templeton,
Eric Boerwinkle,
Richard Gibbs,
Charles Sing
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ABSTRACT: Resequencing genes in an exceptionally large sample of individuals is the only way to obtain an unbiased sample of rare human genetic variants. Historical records and anthropological studies show that human population growth has been accelerating for the last several millenia, and this has driven an inordinate excess of rare variation. Given that their role in heritable disease risk is probably substantial, accurately determining the distribution of rare variants is an important goal for human genetics, but resequencing of a sample large enough for this purpose has been infeasible until now. Here we applied Sanger sequencing of genomic PCR amplicons to resequence the diabetes-associated genes KCNJ11 and HHEX in 13,715 individuals from the Atherosclerosis Risk in Communities (ARIC) study, then validated amplicons potentially harboring rare variants using 454 pyrosequencing. The validation directly confirmed 216 variant sites, and was used to calibrate the accuracy of our other predictions. We observed that there are over 550 variant sites in the two loci combined, many of which are predicted to disrupt protein function. This is far more variation than would have been predicted on the basis of earlier surveys, which could only capture the distribution of common variants. By comparison with earlier demographic estimates based on common variants (which mostly arose earlier in human history than the bulk of the variants we identified), we were able to detect a clear genetic signal of accelerating population growth. This explosive growth underlies the emerging reality that humanity harbors a myriad of rare, deleterious variants, and suggests that disease risk and the burden of disease in contemporary populations is heavily influenced by the distribution of rare variants.
Nature Precedings.
