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Richard Cooper

Publications and source records attributed to Richard Cooper.

At least 19 recordsLinked to original sources
PubMed2026

Long-read Sequences Mapped to a Complete Reference Genome Uncover Uncaptured Structural Variants across the Beta-globin Cluster in Africans with Sickle Cell Disease.

African genomes are marked by extensive complexity in the number and distribution of variants, yet remain under-represented in genetic databases and the human reference genome. This gap in representation limits the broad application of genomic medicine. Sickle cell disease (SCD) - one of the most common monogenic diseases - has its highest prevalence in Africa, and variation in disease severity has consistently been linked to the beta-globin locus, including levels of fetal hemoglobin (HbF). Modulation of HbF is central to current SCD gene therapies; however, the inherent complexity and variation at the locus in African genomes presents a challenge to translating these advances to Africa. Here, we align long-read single molecule sequences (LRS) targeted to the beta-globin region to the hg38 and T2T-CHM13v2 genome references in 40 individuals with SCD, predominantly recruited from three African countries. We demonstrate that the expanded T2T-CHM13v2 reference sequence at this locus reduces Structural Variant (SV) calls by 70% and uncovers uncaptured single nucleotide variants (SNVs). Across the cluster we report 343 SVs and 196 SNVs that have not been previously reported, including in LRS data from the All of Us project. By including African populations from ethnolinguistic groups that have not been previously surveyed we improve variant resolution and bolster evidence for observed variation. Finally, we identify a common ∼4kb insertion locus overlapping the HBB promoter among individuals with high HbF. These results demonstrate the utility of combining a comprehensive reference genome with LRS in African populations to uncover genomic variation at disease-associated loci.

SNV↗
PubMed2006

Transferability of tag SNPs in genetic association studies in multiple populations.

A general question for linkage disequilibrium-based association studies is how power to detect an association is compromised when tag SNPs are chosen from data in one population sample and then deployed in another sample. Specifically, it is important to know how well tags picked from the HapMap DNA samples capture the variation in other samples. To address this, we collected dense data uniformly across the four HapMap population samples and eleven other population samples. We picked tag SNPs using genotype data we collected in the HapMap samples and then evaluated the effective coverage of these tags in comparison to the entire set of common variants observed in the other samples. We simulated case-control association studies in the non-HapMap samples under a disease model of modest risk, and we observed little loss in power. These results demonstrate that the HapMap DNA samples can be used to select tags for genome-wide association studies in many samples around the world.

Breast Neoplasms↗
PubMed2006

A classical likelihood based approach for admixture mapping using EM algorithm.

Several disease-mapping methods have been proposed recently, which use the information generated by recent admixture of populations from historically distinct geographic origins. These methods include both classic likelihood and Bayesian approaches. In this study we directly maximize the likelihood function from the hidden Markov Model for admixture mapping using the EM algorithm, allowing for uncertainty in model parameters, such as the allele frequencies in the parental populations. We determined the robustness of the proposed method by examining the ancestral allele frequency estimate and individual marker-location specific ancestry when the data were generated by different population admixture models and no learning sample was used. The proposed method outperforms a widely used Bayesian MCMC strategy for data generated from various population admixture models. The multipoint information content for ancestry was derived based on the map provided by Smith et al. (2004) and the associated statistical power was calculated. We examined the distribution of admixture LD across the genome for both real and simulated data and established a threshold for genome wide significance applicable to admixture mapping studies. The software ADMIXPROGRAM for performing admixture mapping is available from authors.

Algorithms↗
PubMed2006

A common genetic variant is associated with adult and childhood obesity.

Obesity is a heritable trait and a risk factor for many common diseases such as type 2 diabetes, heart disease, and hypertension. We used a dense whole-genome scan of DNA samples from the Framingham Heart Study participants to identify a common genetic variant near the INSIG2 gene associated with obesity. We have replicated the finding in four separate samples composed of individuals of Western European ancestry, African Americans, and children. The obesity-predisposing genotype is present in 10% of individuals. Our study suggests that common genetic polymorphisms are important determinants of obesity.

Adult↗
PubMed2006

Increasing body mass index and obesity in the incident ESRD population.

An increase in obesity prevalence among patients who initiate dialysis may influence the growth of the total ESRD population as a result of improved survival and decreased likelihood for transplantation. Temporal trends in mean body mass index (BMI) and obesity prevalence were examined among incident patients with ESRD by year of dialysis initiation between 1995 and 2002, and these trends were compared with those in the US population during this same period. Among incident dialysis patients, BMI was calculated with the height and estimated dry weight collected from the Centers for Medicare and Medicaid Services End-Stage Renal Disease Medical Evidence Form. In the US population, self-reported height and weight were used. Prevalence of total obesity and obesity stage > or =2 were defined as a BMI > or =30 and > or =35 kg/m(2), respectively. Among incident patients with ESRD, mean BMI increased from 25.7 to 27.5 kg/m(2), and total obesity and obesity stage > or =2 increased by 33 and 63%, respectively, among incident patients with ESRD (P < 0.0001 for obesity trends). BMI slope was approximately two-fold higher in the incident ESRD population compared with the US population for all age groups. However, temporal increases in obesity prevalence were similar between the two populations. As a result of the survival advantage associated with obesity and decreased likelihood for transplantation, these trends most likely will influence the total number of patients who receive dialysis in the next decade.

Adult↗
PubMed2006

Drug-induced thrombocytopenia and thrombosis: evidence from patients receiving an oral glycoprotein IIb/IIIa inhibitor in the Orbofiban in Patients with Unstable coronary Syndromes- (OPUS-TIMI 16) trial.

OBJECTIVE: To assess etiology and impact of thrombocytopenia in a large oral glycoprotein (GP) IIb/IIIa inhibitor trial. BACKGROUND: Heparin is known to cause thrombocytopenia, and in some of these patients thrombosis. GP IIb/IIIa inhibitors are also associated with thrombocytopenia. METHODS: The Orbofiban in Patients with Unstable Coronary Syndromes (OPUS-TIMI 16) Trial randomized 10,392 patients with ACS to the oral GP IIb/IIIa inhibitor orbofiban or placebo. Patients were followed for a minimum of ten months. Thrombocytopenia was defined prospectively as a platelet count < 80,000. RESULTS: Thrombocytopenia was rare in the OPUS-TIMI 16 trial (0.68% at Day 30 and 0.80% at 1 year), but more common in patients treated with orbofiban (0.92%) compared with those treated with placebo (0.2%), p < 0.001. Patients who developed thrombocytopenia had higher rates of death (11.6% vs. 1.7%, p < 0.001), recurrent MI (12.1% vs. 2.8%, p < 0.001), intracranial hemorrhage (2.9% vs. 0.0%, p < 0.001), and major or severe bleeding (19.0% vs. 2.0%, p < 0.001) at 30 days (with similar results at one year). CONCLUSION: Thrombocytopenia, though uncommon, was associated with orbofiban use and an increased risk of bleeding, but also death and MI. This study provides further evidence that drugs that lead to thrombocytopenia are, in a significant proportion of patients associated with thrombotic events.

Aged↗
PubMed2006

Positive association between resting energy expenditure and weight gain in a lean adult population.

BACKGROUND: Weight gain in adulthood is common, from modest gains in developing countries to substantial increases in Western societies. Evidence of the importance of energy expenditure in adult weight change has been limited to studies conducted in Pima Indians, in whom resting energy expenditure (REE) was found to be inversely associated with weight gain. OBJECTIVE: The aim was to determine whether REE was predictive of weight change in lean Nigerian adults. DESIGN: Weight was measured in 744 adults on 2-4 occasions over 5.5 y. REE was measured in the second follow-up examination. Sex-specific, mixed-effects models with REE, fat-free mass, and age as fixed effects were used to test the association between REE and weight change. RESULTS: Adults aged >19 y (n = 352 men and 392 women) were included in these analyses. At baseline, the mean (+/-SD) age was 45.9 +/- 16.1 y for the whole population; the mean weight was 61.4 +/- 10.7 and 58.1 +/- 12.1 kg and body mass index (in kg/m(2)) was 21.4 +/- 3.2 and 23.1 +/- 4.0 for men and women, respectively. Over a mean 5.5 y of follow-up, the age-adjusted weight gain was 0.42 kg/y for the men and 0.59 kg/y for the women. In mixed-effects models, REE was positively associated with weight gain in both men and women (P < 0.001). No significant association was observed in participants who lost weight. CONCLUSIONS: In contrast with observations in overweight Pima Indians, REE adjusted for body size and composition was positively associated with weight gain in lean Nigerian adults. This suggests either that the potential for differential regulation of body weight in lean compared with overweight populations exists or that the increased REE in this population was the result, rather than cause, of weight gain.

Adult↗
PubMed2006

A combinatorial searching method for detecting a set of interacting loci associated with complex traits.

Complex diseases are presumed to be the results of the interaction of several genes and environmental factors, with each gene only having a small effect on the disease. Mapping complex disease genes therefore becomes one of the greatest challenges facing geneticists. Most current approaches of association studies essentially evaluate one marker or one gene (haplotype approach) at a time. These approaches ignore the possibility that effects of multilocus functional genetic units may play a larger role than a single-locus effect in determining trait variability. In this article, we propose a Combinatorial Searching Method (CSM) to detect a set of interacting loci (may be unlinked) that predicts the complex trait. In the application of the CSM, a simple filter is used to filter all the possible locus-sets and retain the candidate locus-sets, then a new objective function based on the cross-validation and partitions of the multi-locus genotypes is proposed to evaluate the retained locus-sets. The locus-set with the largest value of the objective function is the final locus-set and a permutation procedure is performed to evaluate the overall p-value of the test for association between the final locus-set and the trait. The performance of the method is evaluated by simulation studies as well as by being applied to a real data set. The simulation studies show that the CSM has reasonable power to detect high-order interactions. When the CSM is applied to a real data set to detect the locus-set (among the 13 loci in the ACE gene) that predicts systolic blood pressure (SBP) or diastolic blood pressure (DBP), we found that a four-locus gene-gene interaction model best predicts SBP with an overall p-value = 0.033, and similarly a two-locus gene-gene interaction model best predicts DBP with an overall p-value = 0.045.

Blood Pressure↗
PubMed2006

Common variants in the ENPP1 gene are not reproducibly associated with diabetes or obesity.

The common missense single nucleotide polymorphism (SNP) K121Q in the ectoenzyme nucleotide pyrophosphate phosphodiesterase (ENPP1) gene has recently been associated with type 2 diabetes in Italian, U.S., and South-Asian populations. A three-SNP haplotype, including K121Q, has also been associated with obesity and type 2 diabetes in French and Austrian populations. We set out to confirm these findings in several large samples. We genotyped the haplotype K121Q (rs1044498), rs1799774, and rs7754561 in 8,676 individuals of European ancestry with and without type 2 diabetes, in 1,900 obese and 930 lean individuals of European ancestry from the U.S. and Poland, and in 1,101 African-American individuals. Neither the K121Q missense polymorphism nor the putative risk haplotype were significantly associated with type 2 diabetes or BMI. Two SNPs showed suggestive evidence of association in a meta-analysis of our European ancestry samples. These SNPs were rs7754561 with type 2 diabetes (odds ratio for the G-allele, 0.85 [95% CI 0.78-0.92], P = 0.00003) and rs1799774 with BMI (homozygotes of the delT-allele, 0.6 [0.42-0.88], P = 0.007). However, these findings are not supported by other studies. We did not observe a reproducible association between these three ENPP1 variants and BMI or type 2 diabetes.

Asian People↗
PubMed2005

A genome-wide linkage and association study using COGA data.

BACKGROUND: Genome-wide association will soon be available to use as an adjunct to traditional linkage analysis. We studied alcoholism in 119 families collected by the Collaborative Study on the Genetics of Alcoholism and made available in Genetic Analysis Workshop 14, using genome-wide linkage and association analyses. METHODS: Genome-wide linkage analysis was first performed using microsatellite markers and a region with the strongest linkage evidence was further analyzed using single-nucleotide polymorphisms (SNPs). Family based genome-wide association test was also conducted using the SNPs. RESULTS: Nonparametric linkage analysis revealed weak linkage evidence on chromosome 7, and association analysis identified SNP tsc0515272 on chromosome 3 as significantly associated with alcoholism. CONCLUSION: Linkage analysis may require large sample sizes and high quality genotyping and marker maps to adequately improve power, while association analysis could hold more promise in efforts to identify variants responsible for complex traits.

Alcoholism↗
PubMed2005

Searching for signals of evolutionary selection in 168 genes related to immune function.

Pathogens have played a substantial role in human evolution, with past infections shaping genetic variation at loci influencing immune function. We selected 168 genes known to be involved in the immune response, genotyped common single nucleotide polymorphisms across each gene in three population samples (CEPH Europeans from Utah, Han Chinese from Guangxi, and Yoruba Nigerians from Southwest Nigeria) and searched for evidence of selection based on four tests for non-neutral evolution: minor allele frequency (MAF), derived allele frequency (DAF), Fst versus heterozygosity and extended haplotype homozygosity (EHH). Six of the 168 genes show some evidence for non-neutral evolution in this initial screen, with two showing similar signals in independent data from the International HapMap Project. These analyses identify two loci involved in immune function that are candidates for having been subject to evolutionary selection, and highlight a number of analytical challenges in searching for selection in genome-wide polymorphism data.

Algorithms↗
PubMed2005

Genome-wide linkage analysis for loci affecting pulse pressure: the Family Blood Pressure Program.

Pulse pressure, the difference between systolic and diastolic blood pressure, is an independent risk factor for cardiovascular disease. Increased pulse pressure reflects reduced compliance of arteries and is a marker of atherosclerosis. To locate genes that affect pulse pressure, a genome-wide linkage scan for quantitative trait loci influencing pulse pressure was performed using variance components methods as implemented in sequential oligogenic linkage analysis routines. The analysis sample included 10 798 participants in 3320 families who were recruited as part of the Family Blood Pressure Program and were phenotyped with an oscillometric blood pressure measurement device using a consistent protocol across centers. Pulse pressure was adjusted for the effects of sex, age, age2, age-by-sex interaction, age2-by-sex interaction, body mass index, and field center to remove sources of variation other than the genetic effects related to pulse pressure. Significant linkage was observed on chromosome 18 (logarithm of odds [LOD]=3.2) in a combined racial sample, chromosome 20 (LOD=4.4), and 17 (LOD=3.6) in Hispanics, chromosome 21 (LOD=4.3) in whites, chromosome 19 (LOD=3.1) in a combined sample of blacks and whites, and chromosome 7 (logarithm of odds [LOD]=3.1) in blacks from the GenNet Network. Our genome scan shows significant evidence for linkage for pulse pressure in multiple areas of the genome, supporting previous published linkage studies. The identification of these loci for pulse pressure and the apparent congruence with other blood pressure phenotypes provide increased support that these regions contain genes influencing blood pressure phenotypes.

Adult↗
PubMed2005

The case for selection at CCR5-Delta32.

The C-C chemokine receptor 5, 32 base-pair deletion (CCR5-Delta32) allele confers strong resistance to infection by the AIDS virus HIV. Previous studies have suggested that CCR5-Delta32 arose within the past 1,000 y and rose to its present high frequency (5%-14%) in Europe as a result of strong positive selection, perhaps by such selective agents as the bubonic plague or smallpox during the Middle Ages. This hypothesis was based on several lines of evidence, including the absence of the allele outside of Europe and long-range linkage disequilibrium at the locus. We reevaluated this evidence with the benefit of much denser genetic maps and extensive control data. We find that the pattern of genetic variation at CCR5-Delta32 does not stand out as exceptional relative to other loci across the genome. Moreover using newer genetic maps, we estimated that the CCR5-Delta32 allele is likely to have arisen more than 5,000 y ago. While such results can not rule out the possibility that some selection may have occurred at C-C chemokine receptor 5 (CCR5), they imply that the pattern of genetic variation seen at CCR5-Delta32 is consistent with neutral evolution. More broadly, the results have general implications for the design of future studies to detect the signs of positive selection in the human genome.

Alleles↗
PubMed2005

Two major QTLs and several others relate to factors of metabolic syndrome in the family blood pressure program.

Genome-wide variance components linkage analysis was performed on 4 latent factors underlying metabolic syndrome derived from 10 risk factors. The latent factors represent obesity and insulin, blood pressure, lipids and insulin, and central obesity. The metabolic syndrome factor scores were derived in 4 ethnic groups recruited in 3 Networks of the Family Blood Pressure Program: GENOA (blacks, Hispanics, and whites), HyperGEN (blacks and whites), SAPPHIRe (Asians). Heritabilities of metabolic syndrome factors ranged from 66% for obesity and insulin to 11% for blood pressure factor. We observed higher heritabilities for obesity and insulin, and lipids and insulin, whereas those for blood pressure and central obesity were smaller. Linkage analysis detected two major quantitative trait loci. One of them linked to the obesity and insulin factor with a lod score of 3.94 (P=0.00001, marker GATA11A06, D18S53, 41.24 cM) at marker positions linkage (lod 4.71, at 46.84 cM at 1-cM-apart distances linkage), located on chromosome 18p11.21 in GENOA black. The other linked to the blood pressure factor with a lod score of 3.22 (P=0.000059, marker GATA49C09, D17S1290, 82 cM) at marker positions linkage (lod 3.56, at 84.63 cM for 1 cM apart distances linkage) located on chromosome 17q23.1 in Hispanics. These quantitative trait loci, together with 4 additional ones with lod scores >2.5, and 30 additional ones with lod score >1.7, offer hope for dissecting the genetic architecture of metabolic syndrome with beneficial implications for molecular diagnosis, prognosis, and in potential medical intervention.

Asian People↗
PubMed2005

An evaluation of the metabolic syndrome in a large multi-ethnic study: the Family Blood Pressure Program.

BACKGROUND: The Family Blood Pressure Program is an ongoing, NHLBI-sponsored, multi-center program to study the genetic determinants of high blood pressure. The goal of this particular study was to study patterns of metabolic syndrome (MetS) in four ethnic groups: African Americans, Caucasians, Hispanics, and Asians. METHODS: A major part of participants in three networks GENOA, HyperGEN and SAPPHIRe were recruited mainly through hypertensive probands. MetS was defined as a categorical trait following the National Cholesterol Education Program definition (c-MetS). MetS was also characterized quantitatively through multivariate factor analyses (FA) of 10 risk variables (q-MetS). Logistic regression and frequency tables were used for studying associations among traits. RESULTS: Using the NCEP definition, the Hispanic sample, which by design was enriched for type 2 diabetes (T2D), had a very high prevalence of MetS (73%). In contrast, its prevalence in Chinese was the lowest (17%). In African Americans and Hispanics, c-MetS was more prevalent in women than in men. Association of c-MetS with type 2 diabetes (T2D) was prominent in the Hispanics and African Americans, less pronounced in the Whites and Japanese, (although still significant), and weakest in the Chinese sample. Using FA without rotation, we found that the main factor loaded obesity (OBS) and blood pressure (BP) in African Americans; OBS and insulin (INS) in Hispanics, in Japanese, and in Whites; and OBS alone in Chinese. In Hispanics, Whites, and Japanese, BP loaded as a separate factor. Lipids in combination with INS also loaded in a separate factor. Using FA with Varimax rotation, 4 independent factors were identified: "Obesity-INS," "Blood pressure," "Lipids-INS," and "Central obesity." They explained about 60% of the variance present in the original risk variables. CONCLUSION: MetS ethnic differences were identified. Ascertaining for hypertension or T2D increased the MetS prevalence in networks compared with the one in the US general population. Obesity was the most prominent risk factor contributing to both c-MetS and q-MetS. INS contributed in two important factors (obesity and lipids). The information imbedded into c-MetS trait /q-MetS factors scores can contribute in future research of the MetS, especially its utilization in the genetic analysis.

Journal Article↗
PubMed2005

Urine albumin excretion and subclinical cardiovascular disease. The Multi-Ethnic Study of Atherosclerosis.

We examined the association between urine albumin excretion (UAE) and common and internal carotid artery intima-media thickness (IMT), end-diastolic left ventricular (LV) mass, and coronary artery calcification (CAC) scores using data from the Multi-Ethnic Study of Atherosclerosis (MESA), a population-based study of 6814 adults aged 45 to 85 years without clinical cardiovascular disease (CVD). The mean age of the MESA participants was 62.7 years, 47% were male, and 15% had diabetes mellitus (DM). Sex-specific spot urine albumin/creatinine ratios were used to define 4 UAE categories: normal, high normal, microalbuminuria, and macroalbuminuria. CAC scores were log-transformed after adding 1 to all scores. Mean values of subclinical CVD measures were computed by level of UAE after adjustment for blood pressure, DM, and other covariates. After adjustment for all covariates, geometric mean CAC scores were higher among participants with high normal UAE (8.8; P=0.07), microalbuminuria (9.9; P=0.002), and macroalbuminuria (13.1; P=0.02) compared with normal UAE (7.4), but only microalbuminuria reached statistical significance. Mean LV mass (g/m2.7) was significantly higher in participants with high normal UAE (37.0; P=0.001), microalbuminuria (38.3; P< or =0.0001), and macroalbuminuria (42.3; P< or =0.0001) compared with normal UAE (36.0) after adjustment for all covariates. No significant difference in mean carotid IMT was found after adjustment for all covariates. Similar results were noted in MESA participants with and without DM. In conclusion, higher UAE, including levels below microalbuminuria, may reflect the presence of subclinical CVD among adults without established CVD.

Aged↗