Biomedical subjects

Mark J Rieder

Publications and source records attributed to Mark J Rieder.

24 records · Page 2Linked to original sources

PubMed2004

Evidence for substantial fine-scale variation in recombination rates across the human genome.

Characterizing fine-scale variation in human recombination rates is important, both to deepen understanding of the recombination process and to aid the design of disease association studies. Current genetic maps show that rates vary on a megabase scale, but studying finer-scale variation using pedigrees is difficult. Sperm-typing experiments have characterized regions where crossovers cluster into 1-2-kb hot spots, but technical difficulties limit the number of studies. An alternative is to use population variation to infer fine-scale characteristics of the recombination process. Several surveys reported 'block-like' patterns of diversity, which may reflect fine-scale recombination rate variation, but limitations of available methods made this impossible to assess. Here, we applied a new statistical method, which overcomes these limitations, to infer patterns of fine-scale recombination rate variation in 74 genes. We found extensive rate variation both within and among genes. In particular, recombination hot spots are a common feature of the human genome: 47% (35 of 74) of genes showed substantive evidence for a hot spot, and many more showed evidence for some rate variation. No primary sequence characteristics are consistently associated with precise hot-spot location, although G+C content and nucleotide diversity are correlated with local recombination rate.

Genome, Human↗

PubMed2004

Haplotype diversity across 100 candidate genes for inflammation, lipid metabolism, and blood pressure regulation in two populations.

Recent studies have suggested that a significant fraction of the human genome is contained in blocks of strong linkage disequilibrium, ranging from ~5 to >100 kb in length, and that within these blocks a few common haplotypes may account for >90% of the observed haplotypes. Furthermore, previous studies have suggested that common haplotypes in candidate genes are generally shared across populations and represent the majority of chromosomes in each population. The conclusions drawn from these preliminary studies, however, are based on an incomplete knowledge of the variation in the regions examined. To bridge this gap in knowledge, we have completely resequenced 100 candidate genes in a population of African descent and one of European descent. Although these genes have been well studied because of their medical importance, we demonstrate that a large amount of sequence variation has not yet been described. We also report that the average number of inferred haplotypes per gene, when complete data is used, is higher than in previous reports and that the number and proportion of all haplotypes represented by common haplotypes per gene is variable. Furthermore, we demonstrate that haplotypes shared between the two populations constitute only a fraction of the total number of haplotypes observed and that these shared haplotypes represent fewer of the African-descent chromosomes than was expected from previous studies. Finally, we show that restricting variation discovery to coding regions does not adequately describe all common haplotypes or the true haplotype block structure observed when all common variation is used to infer haplotypes. These data, derived from complete knowledge of genetic variation in these genes, suggest that the haplotype architecture of candidate genes across the human genome is more complex than previously suggested, with important implications for candidate gene and genomewide association studies.

Africa↗

PubMed2003

Selecting a maximally informative set of single-nucleotide polymorphisms for association analyses using linkage disequilibrium.

Common genetic polymorphisms may explain a portion of the heritable risk for common diseases. Within candidate genes, the number of common polymorphisms is finite, but direct assay of all existing common polymorphism is inefficient, because genotypes at many of these sites are strongly correlated. Thus, it is not necessary to assay all common variants if the patterns of allelic association between common variants can be described. We have developed an algorithm to select the maximally informative set of common single-nucleotide polymorphisms (tagSNPs) to assay in candidate-gene association studies, such that all known common polymorphisms either are directly assayed or exceed a threshold level of association with a tagSNP. The algorithm is based on the r(2) linkage disequilibrium (LD) statistic, because r(2) is directly related to statistical power to detect disease associations with unassayed sites. We show that, at a relatively stringent r(2) threshold (r2>0.8), the LD-selected tagSNPs resolve >80% of all haplotypes across a set of 100 candidate genes, regardless of recombination, and tag specific haplotypes and clades of related haplotypes in nonrecombinant regions. Thus, if the patterns of common variation are described for a candidate gene, analysis of the tagSNP set can comprehensively interrogate for main effects from common functional variation. We demonstrate that, although common variation tends to be shared between populations, tagSNPs should be selected separately for populations with different ancestries.

Algorithms↗

PubMed2003

Additional SNPs and linkage-disequilibrium analyses are necessary for whole-genome association studies in humans.

More than 5 million single-nucleotide polymorphisms (SNPs) with minor-allele frequency greater than 10% are expected to exist in the human genome. Some of these SNPs may be associated with risk of developing common diseases. To assess the power of currently available SNPs to detect such associations, we resequenced 50 genes in two ethnic samples and measured patterns of linkage disequilibrium between the subset of SNPs reported in dbSNP and the complete set of common SNPs. Our results suggest that using all 2.7 million SNPs currently in the database would detect nearly 80% of all common SNPs in European populations but only 50% of those common in the African American population and that efficient selection of a minimal subset of SNPs for use in association studies requires measurement of allele frequency and linkage disequilibrium relationships for all SNPs in dbSNP.

Alleles↗

PubMed2003

Novel paraoxonase (PON1) nonsense and missense mutations predicted by functional genomic assay of PON1 status.

Paraoxonase (PON1) has been termed an environmental response enzyme for its function in the detoxification of organophosphate pesticides, nerve agents and pharmaceuticals such as glucocorticoids and statins, as well as its cardioprotective role in breaking down oxidized LDL. PON1(192) genotype can be predicted with high accuracy from an examination of the two-dimensional plot of paraoxon and diazoxon hydrolysis rates [ 1]. Individuals for whom this functional genomic assay failed to predict PON1(192) genotype, or who had a low PON activity relative to others with the same genotype, were predicted to have genetic alterations that explained the inconsistency. Sequencing of the PON1 region of 23 Caucasian individuals detected a nonsense mutation changing amino acid 194 from a Trp to a stop codon (PON1(Trp194stop)). It was predicted that subjects who genotyped as PON1(192QR) but phenotyped as PON1(192QQ) or PON1(192RR) might carry the protein truncation mutation for which the defective product failed to be detected by the phenotyping assay. Screening of the five discordant subjects resulted in the detection of a single Caucasian carrying the stop codon, and determined its phasing on the PON1(192R) allele. Sequencing confirmed the change and revealed an additional subject with a likely deletion of the 5' end of the PON1 gene. Additional sequencing of 25 subjects with low PON1 activities identified two additional previously undescribed PON1 mutations, which may affect PON1 function: PON1(Pro90Leu) associated with the PON1(192Q) allele and PON1(Asp124missplice) associated with the PON1(192R) allele.

Aryldialkylphosphatase↗

PubMedDate not supplied

Mitochondrial genetic variants and Alzheimer disease: a case-control study of the T4336C and G5460A variants.

The T4336C mitochondrial genetic variant was associated with Alzheimer disease in several previous studies. Recent investigations, however, failed to confirm this association. We tested this association in newly diagnosed Alzheimer disease cases and controls of similar age and gender recruited from an established HMO serving Seattle, Washington and surrounding areas. In this, the largest case-control study reported to date, the T4336C variant was not associated with Alzheimer disease overall (present in 6 of 236 cases and 7 of 328 controls; odds ratio = 1.20, 95% CI 0.33 to 4.22). There was evidence of effect modification by Apolipoprotein E (APOE) status--among subjects with an APOE epsilon 4 allele, the T4336C variant was associated with disease (present in 5 of 139 cases and none of 82 controls; odds ratio = infinity, 95% CI 0.73 to infinity). APOE may be an important modifier of the T4336C effect, potentially explaining variable findings across previous studies. Alternatively, the positive findings reported to date may simply reflect the problem of "type I" error inherent in genetic association studies. Substantially larger samples than are currently available would be required to resolve this question. G5460(A/T) variants were also investigated and found not to be associated with Alzheimer disease.

Aged↗