Biomedical subjects

L R Cardon

Publications and source records attributed to L R Cardon.

At least 55 records · Page 3Linked to original sources

PubMed1998

Genetic analysis of inflammatory bowel disease in a large European cohort supports linkage to chromosomes 12 and 16.

BACKGROUND & AIMS: Inflammatory bowel disease (IBD) is a complex disorder of unknown etiology. Epidemiological investigations suggest a genetic basis for IBD. Recent genetic studies have identified several IBD linkages. The significance of these linkages will be determined by studies in large patient collections. The aim of this study was to replicate IBD linkages on chromosomes 12 and 16 in a large European cohort. METHODS: Three hundred fifty-nine affected sibling pairs from 274 kindreds were genotyped using microsatellite markers spanning chromosomes 12 and 16. Affection status of the sibling pairs was defined as Crohn's disease (CD) or ulcerative colitis (UC). RESULTS: Nonparametric statistical analyses showed linkage for both chromosomes. Two-point results for chromosome 12 peaked at D12S303 (logarithm of odds [LOD], 2.15; P = 0.003) for CD and at D12S75 (LOD, 0.92; P = 0.03) for UC. Multipoint analyses produced a peak LOD of 1.8 for CD. Chromosome 16 showed linkage for CD at marker D16S415 (LOD, 1.52; P = 0.007). Multipoint support peaked above markers D16S409 and D16S411 (LOD, 1.7). CONCLUSIONS: These data are consistent with linkage of IBD to chromosomes 12 and 16. The replication of genetic risk loci in a large independent family collection indicates important and common susceptibility genes in these regions and will facilitate identification of genes involved in IBD.

Chromosomes, Human, Pair 12↗

PubMed1998

The future of genetic epidemiology.

Genetic epidemiology is a hybrid discipline whose ultimate aim is to identify and to characterize population-level factors that contribute to disease. Genetic epidemiologists often pursue this aim through the design and implementation of studies that simultaneously invoke principles in population genetics, epidemiology, molecular biology and biostatistics. However, traditional (and much contemporary) research in genetic epidemiology has barely tapped the potential that these disciplines have to work together. It is our view that future genetic epidemiology inquiry will benefit greatly from stronger integration of these disciplines and is likely to converge on themes in fields as diverse as demography, classical population and evolutionary genetics, pharmacoepidemiology, and ecology. The ultimate focus of this research will be evolution and maintenance of disease within and across populations.

Genetics, Population↗

PubMed1997

Homozygosity mapping at Alström syndrome to chromosome 2p.

Alström syndrome is a rare autosomal recessive disorder characterized by pigmentary retinal degeneration, sensorineural hearing loss, childhood obesity, non-insulin-dependent diabetes mellitus, hyperlipidemia and chronic nephropathy. Features occasionally observed include acanthosis nigricans, hypogonadism, hypothyroidism, alopecia, short stature and cardiomyopathy. We report here the results of a linkage study in a large French Acadian kindred, as a first step in identifying the molecular basis of Alström syndrome. Evidence of a founder effect made if feasible to use a homozygosity mapping strategy to identify the chromosomal location of the Alström gene. In a genome-wide screen, haplotype sharing for a region on chromosome 2 was observed in all affected individuals. Two point linkage analysis resulted in a maximum lod score of 3.84 (theta = 0.00) for marker D2S292. By testing additional markers, the disease gene was localized to a 14.9 cM region on chromosome 2p.

Abnormalities, Multiple↗

PubMed1997

A simple method for automated allele binning in microsatellite markers.

High-throughput fluorescent genotyping requires a considerable amount of automation for accurate and efficient processing of genetic markers. Automated DNA sequencers and corresponding software products are commercially available that contribute substantially to increased throughput rates for large-scale genotyping projects. However, some conceptually simple tasks still require time-consuming manual intervention that imposes bottlenecks on throughput capacity. One of these tasks is the conversion of imprecise DNA fragment sizes determined by commercial software programs to the underlying discrete alleles that the sizes represent. Here we describe a simple method for assigning allele sizes into their appropriate allele "bins" using least-squares minimization procedures. The method requires no special treatment of family data on plates, internal/external size standards, or electropherogram data manipulation. Tests of the method using the ABI 373A automated DNA sequencer and accompanying Genescan/Genotyper software resulted in accurate automatic classification of all alleles in >80% of 208 markers analyzed, with the remaining 20% being appropriately identified as requiring additional attention to laboratory conditions. Specific characteristics of different markers, including differences in PCR product size and inexact repeat lengths (e.g., 1. 9 bp for a dinucleotide repeat), are accommodated by the method and their properties discussed.

Alleles↗

PubMed1997

Heavy consumption of cigarettes, alcohol and coffee in male twins.

OBJECTIVE: To determine the relative contribution of environmental and genetic influences on the joint distribution of heavy smoking, heavy alcohol use and heavy coffee drinking. METHOD: Multivariate structural equation modeling in a large cohort of male twins (N = 2,220 monozygotic and 2,373 dizygotic twin pairs; mean age = 62.1 years) from the National Academy of Sciences-National Research Council's World War II Twin Registry. RESULTS: The best-fitting model identified two independent (i.e., uncorrelated) sets of genetic and environmental latent factors, with one set underlying joint heavy smoking and heavy alcohol use and the other set underlying joint heavy smoking and heavy coffee drinking (chi 2 = 14,13,22 df, p > .80). Heavy alcohol use and heavy coffee drinking were uncorrelated in this sample. While common genetic factors accounted for 35% to 78% of the total genetic variance in heavy substance use, a substantial amount of genetic variance remained specific to each of the three substances. CONCLUSIONS: Several hypotheses involving genetic and environmental factors are presented to account for the independent clustering of heavy smoking and heavy alcohol use and of heavy smoking and heavy coffee drinking.

Alcohol Drinking↗

PubMed1996

The consumption of tobacco, alcohol, and coffee in Caucasian male twins: a multivariate genetic analysis.

Despite the fact that epidemiologic studies demonstrate a consistent covariation between the use of tobacco, alcohol, and coffee, most previous behavioral genetic-studies have determined the contribution of genetic and environmental influences as if the consumption of these substances occurred independently of each other. In this study, we used multivariate structural equation modeling to determine the genetic and environmental overlap in the observed correlations between tobacco smoking and alcohol and coffee drinking in 173 monozygotic and 183 dizygotic male twin pairs (M age = 59 years; range = 52-66 years) who participated in a follow-up cardiovascular examination of the National Heart, Lung, and Blood Institute's Twin Study. Consistent with hypothesized psychoneurogenetic predispositions for the joint use of these substances, the most parsimonious model fitting these data identified a common genetic latent factor underlying the observed associations between smoking, alcohol, and coffee use in this cohort. This factor, herein called polysubstance use, underscores the role of genetic influence on the clustering of these behaviors in the same individual.

Aged↗

PubMed1996

Indication for linkage of the human OB gene region with extreme obesity.

Obesity is one of the most significant risk factors for hypertension, coronary heart disease, and NIDDM (Frayn KN, Coppack SW: Insulin resistance, adipose tissue and coronary heart disease. Clin Sci 82:1-8, 1992; Kaplan NM: The deadly quartet: upper-body obesity, glucose intolerance, hypertriglyceridemia, and hypertension. Arch Intern Med 149:1514-1520, 1989). While family segregation, adoption, and twin studies have indicated that degree of adiposity has a significant genetic component (Stunkard AJ, Harris JR, Pedersen NL, McClearn GE: The body-mass index of twins who have been reared apart. N Engl J Med 322:1483-1487, 1990; Bouchard C, Despres J-P, Mauriege P: Genetic and nongenetic determinants of regional fat distribution. Endocr Rev 14:72-93, 1993), the genes and predisposing mutations remain poorly understood. This is in contrast to several well-defined genetic models for obesity in rodents, particularly the mouse obese (ob) gene, in which loss-of-function mutations cause severe obesity. Recent studies have demonstrated a substantial reduction in body fat when recombinant ob protein (leptin) is administered to mice. To test the relevance of these observations to human obesity, the location of the human homologue (OB) was established by radiation hybrid mapping and eight microsatellite markers spanning the OB gene region (7q3l.3) were genotyped in 101 obese French families. Affected-sib-pair analyses for extreme obesity, defined by BMI >35 kg/m2, revealed suggestive evidence for linkage to three markers located within 2 cM of the OB gene (D7S514, D7S680, and D7S530). The OB gene is therefore a candidate for genetic predisposition to extreme obesity in a subset of these families.

Alleles↗

PubMed1995

Quantitative trait locus for reading disability: correction.

In the news article "Can risky mergers save hospital-based research?" by Wade Roush (19 May, p. 968), the statement that University Hospitals of Cleveland rose from 20th in the rankings of teaching hospitals funded by the National Institutes of Health (NIH) in 1991 to 12th at present was incorrect. In fact, it was Case Western Reserve University (CWRU), with which University Hospitals of Cleveland is affiliated, that received $69 million in NIH grants in 1993, making it the 20th largest recipient of such grants among medical centers; the university then received $97 million in 1994, raising its rank to 12th. About $15 million of the increase, or 53%, was attributable to CWRU's 1992 affiliation with Henry Ford Hospital in Detroit. Other hospitals affiliated with Case Western include MetroHealth Medical Center, Mount Sinai Medical Center, St. Luke's Medical Center, and Cleveland Veterans' Affairs Medical Center.

Chromosome Mapping↗

PubMed1995

Linkage analysis of a common oligogenic disease using selected sib pairs.

Sib pairs drawn from the simulated common oligogenic disease families were selected for extreme quantitative trait scores and analyzed using interval mapping and multipoint methods. Linkage analyses of 112 selected sib pairs, in which one or more members had trait values exceeding the disease threshold, were compared with analyses of the total unselected sib-pair sample (771 pairs). Selected sample regression models yielded comparable significance levels to those obtained from the unselected sample at most loci on the six simulated chromosomes, demonstrating the efficiency of selected sib-pair analysis for quantitative characters. Two of the three disease QTLs were detected in both selected and unselected samples. Interval mapping and multipoint analyses yielded location estimates close to the simulated positions of the QTLs. The combined strategy of using interval mapping and multipoint methods with selected sib pairs appears to provide improved accuracy and sensitivity over more traditional sib-pair methods for detecting quantitative trait loci.

Chromosome Mapping↗

PubMed1995

Genetic mediation in the relationship of education to cognitive function in older people.

We used data from 136 monozygotic and 125 dizygotic human, male twin pairs (M age = 64 years, range = 59 to 70 years) to test whether the previously observed association (r = .30, p < .01) between cognitive performance and education in this sample is genetically mediated. Biometric genetic modeling found that a common genetic latent variable accounted for 44% of the total variance in the Mini-Mental State Exam (MMSE: M. F. Folstein, S. E. Folstein, & P. R. McHugh, 1975), 40% of the variance in the Iowa Screening Battery for Mental Decline (P. J. Eslinger, A. R. Damasio, & A. L. Benton, 1984), and 21% of the variance in educational attainment. In addition, specific genetic and environmental variables contributed significantly to individual differences in education and cognitive performance of the participants.

Aged↗

PubMed1995

Multipoint interval mapping of quantitative trait loci, using sib pairs.

The sib-pair interval-mapping procedure of Fulker and Cardon is extended to take account of all available marker information on a chromosome simultaneously. The method provides a computationally fast multipoint analysis of sib-pair data, using a modified Haseman-Elston approach. It gives results very similar to those of the earlier interval-mapping procedure when marker information is relatively uniform and a coarse map is used. However, there is a substantial improvement over the original method when markers differ in information content and/or when a dense map is employed. The method is illustrated by using simulated sib-pair data.

Alleles↗

PubMed1994

Quantitative trait locus for reading disability on chromosome 6.

Interval mapping of data from two independent samples of sib pairs, at least one member of whom was reading disabled, revealed evidence for a quantitative trait locus (QTL) on chromosome 6. Results obtained from analyses of reading performance from 114 sib pairs genotyped for DNA markers localized the QTL to 6p21.3. Analyses of corresponding data from an independent sample of 50 dizygotic twin pairs provided evidence for linkage to the same region. In combination, the replicate samples yielded a chi 2 value of 16.73 (P = 0.0002). Examination of twin and kindred siblings with more extreme deficits in reading performance yielded even stronger evidence for a QTL (chi 2 = 27.35, P < 0.00001). The position of the QTL was narrowly defined with a 100:1 confidence interval to a 2-centimorgan region within the human leukocyte antigen complex.

Adolescent↗

PubMed1994

Pervasive CpG suppression in animal mitochondrial genomes.

All available complete mitochondrial genomes (21 species) are evaluated for dinucleotide over- and under-representation. The CpG dinucleotide is pervasively under-represented in all animal mitochondria, but it is of variable relative abundance in fungal, protist, and plant mitochondrial genomes. Interpretations and hypotheses are considered relative to mitochondrial genome organization, methylation, structural specificities, directed mutation, and evolutionary events. In particular, our results support Mycoplasma capricolum or a close relative as the most likely bacterial ancestor of the mitochondria.

Base Composition↗

PubMed1994

A model of developmental change in hierarchical phenotypes with application to specific cognitive abilities.

A hierarchical longitudinal path model is described for analysis of twin and sibling data. The model combines multivariate and longitudinal methodologies for assessment of continuity and change in the relationships among characters over time. Additionally, the model permits assessment of shared and independent etiologies for groups of measures at single and multiple occasions. The procedure is illustrated by application to specific cognitive ability data from 103 adopted and 109 nonadopted sibling pairs at ages 3, 4, 7, and 9 years, and 50 pairs of monozygotic and dizygotic twins at ages 3 and 4 years. The results suggest that much of the observed continuity in general intelligence measures is attributable to genetic influences common to specific abilities and indicate differential etiologies for specific abilities at different occasions in childhood.

Adoption↗

PubMed1994

Why is CpG suppressed in the genomes of virtually all small eukaryotic viruses but not in those of large eukaryotic viruses?

Dinucleotide over- and underrepresentation is evaluated in all available completely sequenced DNA or RNA viral genomes, ranging in size from 3 to 250 kb (available RNA viruses fall into the small-virus category). The dinucleotide CpG is statistically underrepresented (suppressed) in all but four of the small viruses (more than 75 with lengths of < 30 kb) but has normal relative abundances in most large viruses (> or = 30 kb). Most retrotransposons in eukaryotic species also show low CpG relative abundances. Interpretations, especially in some cases of DNA viruses or viruses with a DNA intermediate, might relate to methylation effects and modes of viral integration and excision. Other possible contributing factors relate to dinucleotide stacking energies, special mutation mechanisms, and evolutionary events.

Arginine↗

PubMed1994

Computational DNA sequence analysis.

This paper reviews several new developments in computer and statistical analysis of DNA and protein sequences. We present criteria and describe means for assessing and interpreting genomic inhomogeneities within and between sequences. These include: (a) characterizations of short oligonucleotide biases and general compositional tendencies; (b) molecular evolutionary reconstructions based on dinucleotide relative abundance distance measures and partial orderings; and (c) the application of r-scan statistics, quantile distributions, and score-based analyses to identify clustering, overdispersion, and excessive evenness in the distribution of a marker array along a sequence. These apply, for example, to restriction sites, microsatellite runs, regulatory motifs, and nucleosome placements. Furthermore, (d) the definition and determination of rare and frequent oligonucleotides and peptides provides another perspective on sequence heterogeneity, and (e) score methods are also applied in exon and gene locations. Most of the ideas and methods are illustrated with respect to bacteriophage genomes, to megabase amounts of several eukaryotic sequences, to a diverse collection of bacterial sets, to mitochondrial chromosomes, and to a broad assembly of viral genomes.

Amino Acid Sequence↗

PubMed1994

The power of interval mapping of quantitative trait loci, using selected sib pairs.

The interval-mapping procedure of Fulker and Cardon for analysis of a quantitative-trait loci (QTL) is extended for application to selected samples of sib pairs. Phenotypic selection of sib pairs, which is known to yield striking increases in power when a single marker is used, provides further increases in power when the interval-mapping approach is used. The greatest benefits of the combined approach are apparent with coarse maps, where QTLs of relatively modest (15%-20%) heritability can be detected with widely spaced markers (40-60 cM apart) in reasonably sized sibling samples. Useful information concerning QTL location is afforded by interval mapping in both selected and unselected samples.

Algorithms↗

PubMed1994

Genetic and environmental correlations between obesity and body fat distribution in adult male twins.

Genetic and environmental correlations between measures of obesity [body mass index (BMI)] and body fat distribution [waist/hip ratio (WHR) and subscapular/triceps ratio (SSTR)] were examined in 133 monozygotic and 129 dizygotic pairs of elderly white male twins, age 59 to 70 years, participating in the third cardiovascular examination of the National Heart, Lung, and Blood Institute Twin Study. The BMI, WHR, and SSTR fat measures were significantly correlated in these twins, with BMI more closely related to WHR (r = 0.52) than to SSTR (r = 0.18), and the WHR-SSTR association intermediate (r = 0.27). Multivariate genetic analyses of the three indexes using the LISREL modeling approach indicated a significant heritable component for each fatness variable, h2 = 0.66, 0.46, and 0.25 for BMI, WHR, and SSTR, respectively, and a significant correlation between genetic influences on BMI and WHR (genetic r = 0.51). The common genetic component accounted for 54% of the observed BMI-WHR correlation, suggesting that overall obesity and abdominal adiposity distribution are mediated to some extent by similar genetic influences. The genetic correlations between SSTR and BMI and between SSTR and WHR were not significantly different from zero, suggesting that genetic influences on skinfold distribution are independent of those on abdominal body fat and overall obesity. The genetic findings support the hypothesis that the WHR and SSTR indexes do not assess the same dimensions of fat patterning.

Adipose Tissue↗