A New Biophysical Metric for Interrogating the Information Content in Human Genome Sequence Variation: Proof of Concept

Various studies have shown an association between single nucleotide polymorphisms (SNPs) and common disease. We hypothesize that information encoded in the structure of SNP haploblock variation illumines molecular pathways and cellular mechanisms involved in the regulation of host adaptation to the environment. We developed and utilized the normalized information content (NIC), a novel metric based on SNP haploblock variation. We found that all SNP haploblocks with statistically low information content contained putative transcription factor binding sites and microRNA motifs. We were able to translate a biophysical, mathematical measure of common variants into a deeper understanding of the life sciences through analysis of biochemical patterns associated with SNP haploblock variation. We submit that this new metric, NIC, may be useful in decoding the functional significance of common variation in the human genome and in analyzing the regulation of molecular pathways involved in host adaptation to environmental pathogens.Comment: 13 page

Development of admixture mapping panels for African Americans from commercial high-density SNP arrays

<p>Abstract</p> <p>Background</p> <p>Admixture mapping is a powerful approach for identifying genetic variants involved in human disease that exploits the unique genomic structure in recently admixed populations. To use existing published panels of ancestry-informative markers (AIMs) for admixture mapping, markers have to be genotyped <it>de novo </it>for each admixed study sample and samples representing the ancestral parental populations. The increased availability of dense marker data on commercial chips has made it feasible to develop panels wherein the markers need not be predetermined.</p> <p>Results</p> <p>We developed two panels of AIMs (~2,000 markers each) based on the Affymetrix Genome-Wide Human SNP Array 6.0 for admixture mapping with African American samples. These two AIM panels had good map power that was higher than that of a denser panel of ~20,000 random markers as well as other published panels of AIMs. As a test case, we applied the panels in an admixture mapping study of hypertension in African Americans in the Washington, D.C. metropolitan area.</p> <p>Conclusions</p> <p>Developing marker panels for admixture mapping from existing genome-wide genotype data offers two major advantages: (1) no <it>de novo </it>genotyping needs to be done, thereby saving costs, and (2) markers can be filtered for various quality measures and replacement markers (to minimize gaps) can be selected at no additional cost. Panels of carefully selected AIMs have two major advantages over panels of random markers: (1) the map power from sparser panels of AIMs is higher than that of ~10-fold denser panels of random markers, and (2) clusters can be labeled based on information from the parental populations. With current technology, chip-based genome-wide genotyping is less expensive than genotyping ~20,000 random markers. The major advantage of using random markers is the absence of ascertainment effects resulting from the process of selecting markers. The ability to develop marker panels informative for ancestry from SNP chip genotype data provides a fresh opportunity to conduct admixture mapping for disease genes in admixed populations when genome-wide association data exist or are planned.</p

Meta-analysis of genome-wide association studies of asthma in ethnically diverse North American populations.

Asthma is a common disease with a complex risk architecture including both genetic and environmental factors. We performed a meta-analysis of North American genome-wide association studies of asthma in 5,416 individuals with asthma (cases) including individuals of European American, African American or African Caribbean, and Latino ancestry, with replication in an additional 12,649 individuals from the same ethnic groups. We identified five susceptibility loci. Four were at previously reported loci on 17q21, near IL1RL1, TSLP and IL33, but we report for the first time, to our knowledge, that these loci are associated with asthma risk in three ethnic groups. In addition, we identified a new asthma susceptibility locus at PYHIN1, with the association being specific to individuals of African descent (P = 3.9 × 10(-9)). These results suggest that some asthma susceptibility loci are robust to differences in ancestry when sufficiently large samples sizes are investigated, and that ancestry-specific associations also contribute to the complex genetic architecture of asthma

Regressive logistic models for ordered and unordered polychotomous traits: Application to affective disorders

Regressive models are extended to disease phenotypes with two or more affection classes through the use of polychotomous logistic regression. The classes of affection may be ordered (ranked as on a liability continuum), or unordered. Data on affective disorders are used for illustration. Copyright © 1989 Wiley‐Liss, Inc., A Wiley Compan

Association of HLA and autoantibody in transfused sickle cell disease patients

This study evaluates autoantibody production in sickle cell disease patients and determines whether genes in the major histocompatibility complex are associated with autoantibody responses. Rheumatoid factor was significantly increased for both male and female patients and was less prevalent in highly transfused patients. Significant increases were also detected in the incidences of antinuclear antibody for females and antismooth muscle antibody for males. Low incidence of antinuclear antibody was significantly associated with HLA‐DR3. Significant associations were also found between the incidence of antinuclear antibody and both HLA‐A28 and B15. Copyright © 1986 Wiley‐Liss, Inc., A Wiley Compan

CYP17 promoter variant associated with prostate cancer aggressiveness in African Americans

Androgens play an important role in the etiology of prostate cancer. The CYP17 gene encodes the cytochrome P450c17α enzyme, which is the rate-limiting enzyme in androgen biosynthesis. A T to C polymorphism in the 5′ promoter region has recently been associated with prostate cancer. However, contradictory data exists concerning the risk allele. To investigate further the involvement of the CYP17 variant with prostate cancer, we typed the polymorphism in three different populations and evaluated its association with prostate cancer and clinical presentation in African Americans. We genotyped the CYP17 polymorphism in Nigerian (n = 56), European-American (n = 74), and African-American (n = 111) healthy male volunteers, along with African-American men affected with prostate cancer (n = 71), using pyrosequencing. Genotype and allele frequencies did not differ significantly across the different control populations. African-American men with the CC CYP17 genotype had an increased risk of prostate cancer (odds ratio, 2.8; 95% confidence interval, 1.0-7.4) compared with those with the TT genotype. A similar trend was observed between the homozygous variant genotype in African-American prostate cancer patients and clinical presentation. The CC genotype was significantly associated with higher grade and stage of prostate cancer (odds ratio, 7.1; 95% confidence interval, 1.4-36, 1). The risk did not differ significantly by family history or age. Our results suggest that the C allele of the CYP17 polymorphism is significantly associated with increased prostate cancer risk and clinically advanced disease in African Americans