Search PubMed⌕ Search

Biomedical subjects

P M Visscher

Publications and source records attributed to P M Visscher.

At least 19 recordsLinked to original sources
PubMed2007

Variation of estimates of SNP and haplotype diversity and linkage disequilibrium in samples from the same population due to experimental and evolutionary sample size.

Studies of genetic polymorphisms and diversity between and within human populations are increasingly characterised by a very large number of genetic markers but using a relatively small number of individuals from which DNA samples were taken. In this report we examine the limitations of a small experimental sample size relative to a large genomic sample size, and quantify the sampling variance of a number of measures of diversity and linkage disequilibrium. The relationship between sample size and observed levels of polymorphism and haplotype diversity at the level of a gene is investigated under a neutral model of sequence evolution, using coalescent simulations. It is shown that the effect of evolutionary sampling, as manifested by differences between samples (genes) in measures of diversity estimated using very large sample sizes, is substantial, with a coefficient of variation of the number of detected polymorphic SNPs or haplotypes in the order of 15%. The effect of experimental design (sample size) is also very large, and a number of 'significant' results reported in the literature can be explained by sampling alone. The expected correlation coefficient of measures of linkage disequilibrium across samples from the same population has been quantified and found to be consistent with empirical estimates from the literature.

Chromosomes, Human↗
PubMed2006

Genetic parameters for blood oxygen saturation, body weight and breast conformation in 4 meat-type chicken lines.

1. The objective of the study was to explore the genetic architecture of blood oxygen saturation (SaO) (an indicator trait, negatively correlated with ascites susceptibility), body weight (Weight) and fleshing score (Flesh, a measure of breast conformation) for 4 meat-type chicken lines reared in commercial conditions. 2. Genetic components, including heritabilities and genetic correlations, were estimated by Restricted Maximum likelihood for these traits measured at 6 weeks of age. 3. Data were collected over eight generations of selection and pedigrees comprised in excess of 130,000 birds. 4. Univariate analyses were performed to allow model definition and to obtain starting values for trivariate analyses. The basic model included a random animal effect and, in further models explored, a maternal environmental effect or a genetic maternal effect or both were fitted. Models were compared using likelihood ratio tests. 5. Estimated heritabilities for SaO ranged from 0.1 to 0.2, and there was no evidence of genetic maternal effects for SaO. The environmental maternal component was significant for one of the populations only. Estimated heritabilities for both Weight and Flesh were between 0.2 and 0.4, and there was evidence of environmental and genetic maternal effects for these traits in all populations. 6. Genetic correlations between SaO and Weight and between SaO and Flesh were low and negative. This suggests that, in principle, genetic selection to simultaneously increase SaO, and therefore decrease ascites susceptibility, and WEight and Flesh could be performed using traditional (marker-free) selection methods. We discuss how a putative interaction between ascites and production traits could jeopardise the success of such methods.

Animals↗
PubMed2006

Segregation analysis of blood oxygen saturation in broilers suggests a major gene influence on ascites.

1. Blood oxygen saturation (SaO) is a potential indicator trait for resistance to ascites in chickens. 2. The objective of the study was to investigate the genetic architecture of SaO in a meat-type chicken line reared in commercial conditions. 3. Data were collected over 15 generations of selection and were divided into two data sets on the basis of a change in recording age from 6 to 5 weeks of age, approximately halfway through the period. The resulting pedigrees comprised in excess of 90,000 birds each and, on average, 12% of these birds had SaO records. 4. Segregation analyses of SaO were carried out assuming a mixed inheritance model that included a major locus segregating in a polygenic background. 5. The analyses suggest that a major gene is involved in the genetic control of SaO in this line. The putative gene acts in a dominant fashion and has an additive effect of around 0.90 sigma(p), equivalent to a predicted difference in SaO between the two homozygous classes of more than 10%. The frequency of the allele that increases SaO changed from 0.53 to 0.65 from the first to the second set of data, consistent with selection on SaO scores. 6. Using estimated genotype probabilities at the putative major locus, we inferred that it acts in an overdominant fashion on body weight and fleshing score. If the low SaO allele leads to susceptibility to ascites, its combined effects are consistent with it being maintained in the population by a balance of natural selection on fitness nad artificial selection on growth and carcase traits. 7. Even with selection on both SaO and growth traits, the combined genotypic effects would make it difficult to remove the unfavourable low-SaO allele by means of traditional selection without the use of genetic markers.

Animals↗
PubMed2005

Joint multi-population analysis for genetic linkage of bipolar disorder or "wellness" to chromosome 4p.

To test the hypothesis that the same genetic loci confer susceptibility to, or protection from, disease in different populations, and that a combined analysis would improve the map resolution of a common susceptibility locus, we analyzed data from three studies that had reported linkage to bipolar disorder in a small region on chromosome 4p. Data sets comprised phenotypic information and genetic marker data on Scottish, Danish, and USA extended pedigrees. Across the three data sets, 913 individuals appeared in the pedigrees, 462 were classified, either as unaffected (323) or affected (139) with unipolar or bipolar disorder. A consensus linkage map was created from 14 microsatellite markers in a 33 cM region. Phenotypic and genetic data were analyzed using a variance component (VC) and allele sharing method. All previously reported elevated test statistics in the region were confirmed with one or both analysis methods, indicating the presence of one or more susceptibility genes to bipolar disorder in the three populations in the studied chromosome segment. When the results from both the VC and allele sharing method were considered, there was strong evidence for a susceptibility locus in the data from Scotland, some evidence in the data from Denmark and relatively less evidence in the data from the USA. The test statistics from the Scottish data set dominated the test statistics from the other studies, and no improved map resolution for a putative genetic locus underlying susceptibility in all three studies was obtained. Studies reporting linkage to the same region require careful scrutiny and preferably joint or meta analysis on the same basis in order to ensure that the results are truly comparable.

Bipolar Disorder↗
PubMed2005

Mapping of quantitative trait loci affecting organ weights and blood variables in a broiler layer cross.

1. A genome scan was performed to locate genomic regions associated with traits that are known to vary in birds (most commonly broilers) suffering from heart, lung or muscular dysfunction and for weight of the dressed carcass and some internal organs. 2. The F2 population studied was derived from a cross between a broiler and a layer line and consisted of over 460 birds that were genotyped for 101 markers. 3. There was strong support for segregation of quantitative trait loci (QTL) for carcass and organ weights and blood variables. We identified 11 genome-wide significant QTL (most of them for dressed carcass weight) and several genome-wide suggestive QTL. 4. The results point to some genome regions that may be associated with health-related traits and merit further study, with the final aim of identifying linked genetic markers that could be used in commercial breeding programmes to decrease the incidence of muscular and metabolic disorders in broiler populations.

Animals↗
PubMed2004

Twin study of genetic and environmental influences on adult body size, shape, and composition.

OBJECTIVE: To investigate the genetic and environmental influences on adult body size, shape, and composition in women and men, and to assess the impact of age. MATERIALS AND METHODS: In this cross-sectional study of 325 female and 299 male like-sex healthy twin pairs, on average 38 y old (18-67 y), we determined zygosity by DNA similarity, and performed anthropometry and bioelectrical impedance analysis of body composition. The contribution to the total phenotypic variance of genetic, common environment, and individual environment was estimated in multivariate analysis using the FISHER program. Further, these variance components were analysed as linear functions of age. RESULTS: In both women and men genetic contributions were significant for all phenotypes. Heritability for body mass index was 0.58 and 0.63; for body fat%, 0.59 and 0.63; for total skinfolds, 0.61 and 0.65; for extremity skinfolds 0.65 and 0.62; for truncal skinfolds, 0.50 and 0.69; for suprailiac skinfolds, 0.49 and 0.48; for waist circumference, 0.48 and 0.61; for hip, 0.52 and 0.58; for lean body mass/height2, 0.61 and 0.56; and for height, 0.81 and 0.69, respectively. There was no strong evidence of common environmental effects under the assumptions of no nonadditive effect. The pattern of age trends was inconsistent. However, when significant there was a decrease in heritability with advancing age. DISCUSSION: These findings suggest that adult body size, shape, and composition are highly heritable in both women and men, although a decreasing tendency is seen with advancing age.

Adipose Tissue↗
PubMed2004

A genome scan and follow-up study identify a bipolar disorder susceptibility locus on chromosome 1q42.

In this study, we report a genome scan for psychiatric disease susceptibility loci in 13 Scottish families. We follow up one of the linkage peaks on chromosome 1q in a substantially larger sample of 22 families affected by schizophrenia (SCZ) or bipolar affective disorder (BPAD). To minimise the effect of genetic heterogeneity, we collected mainly large extended families (average family size >18). The families collected were Scottish, carried no chromosomal abnormalities and were unrelated to the large family previously reported as segregating a balanced (1:11) translocation with major psychiatric disease. In the genome scan, we found linkage peaks with logarithm of odds (LOD) scores >1.5 on chromosomes 1q (BPAD), 3p (SCZ), 8p (SCZ), 8q (BPAD), 9q (BPAD) and 19q (SCZ). In the follow-up sample, we obtained most evidence for linkage to 1q42 in bipolar families, with a maximum (parametric) LOD of 2.63 at D1S103. Multipoint variance components linkage gave a maximum LOD of 2.77 (overall maximum LOD 2.47 after correction for multiple tests), 12 cM from the previously identified SCZ susceptibility locus DISC1. Interestingly, there was negligible evidence for linkage to 1q42 in the SCZ families. These results, together with results from a number of other recent studies, stress the importance of the 1q42 region in susceptibility to both BPAD and SCZ.

Bipolar Disorder↗
PubMed2004

Mapping of quantitative trait loci for growth and carcass traits in commercial sheep populations.

Quantitative trait loci analyses were applied to data from Suffolk and Texel commercial sheep flocks in the United Kingdom. The populations comprised 489 Suffolk animals in three half-sib families and 903 Texel animals in nine half-sib families. Phenotypic data comprised measurements of live weight at 8 and 20 wk of age and ultrasonically measured fat and muscle depth at 20 wk. Lambs and their sires were genotyped across candidate regions on chromosomes 1, 2, 3, 4, 5, 6, 11, 18, and 20. Data were analyzed at the breed level, at the family level, and across extended families when families were genetically related. The breed-level analyses revealed a suggestive QTL on chromosome 1 in the Suffolk breed, between markers BM8246 and McM130, affecting muscle depth, although the effect was only significant in one of the three Suffolk families. A two-QTL analysis suggested that this effect may be due to two adjacent QTL acting in coupling. In total, 24 suggestive QTL were identified from individual family analyses. The most significant QTL affected fat depth and was segregating in a Texel family on chromosome 2, with an effect of 0.62 mm. The QTL was located around marker ILSTS030, 26 cM distal to myostatin. Two of the Suffolk and two of the Texel sires were related, and a three-generation analysis was applied across these two extended families. Seven suggestive QTL were identified in this analysis, including one that had not been detected in the individual family analysis. The most significant QTL, which affected muscle depth, was located on chromosome 18 near the callipyge and Carwell loci. Based on the phenotypic effect and location of the QTL, the data suggest that a locus similar to the Carwell locus may be segregating in the United Kingdom Texel population.

Adipose Tissue↗
PubMed2003

Extent of linkage disequilibrium in a Sardinian sub-isolate: sampling and methodological considerations.

The extent of linkage disequilibrium (LD) is an important factor when designing experiments for mapping disease or trait loci using LD mapping methods. It depends on the population history and hence is a characteristic of each population. Here, we have assessed the extent of LD in a sub-isolate of the general Sardinian population (775 members of one village) using 22 polymorphic markers on chromosome 19. We found high levels of disequilibrium that extended to 8 cM, when based on D', and 11 cM when based on the significance level of the allelic association. The fact that conclusions based on both methods are similar suggests that the estimates are quite robust. We have also shown, through a simple resampling technique, that small sample sizes can overestimate both the mean value of D' and its variance up to a factor of about 2 and 16, respectively, when the number of diplotypes (the pair of haplotypes that compose the genotype) decreased from 186 to 26. We evaluated the effect on D' of the depth of the pedigree available when using phased founders, and compared the estimates with those obtained when using unphased founders, and also the effect of grouping alleles on the value of D' and the significance level. Owing to the high sampling variance of LD, we recommend the use of at least 200 unrelated individuals when characterizing the extent of LD.

Alleles↗
PubMed2003

Twin study of genetic and environmental influences on glucose tolerance and indices of insulin sensitivity and secretion.

AIMS/HYPOTHESIS: Family and twin studies have reported different estimates of the relative contribution of genetic and environmental factors to the quantitative traits glucose tolerance, insulin secretion, and insulin sensitivity. Our aims were to estimate these relative influences in a large sample of twins from the population and to assess the effect of age. METHODS: In this population-based, cross-sectional study we gave an oral glucose tolerance test to 317 women and 290 men who were same-sex healthy twin pairs between 18 to 67 years of age. The genetic, common environmental and individual environmental variance components for fasting and 120-min glucose and for fasting and 30-min insulin as well as the linear effects of age on these components were estimated by multivariate analysis (using the software FISHER). RESULTS: In women and men the heritability for fasting glucose was 12 and 38%, for 120-min glucose it was 38 and 43%, for fasting insulin it was 54 and 37%, and for 30-min insulin it was 57 and 47%, respectively. Under the assumption of no non-additive genetic effects (no intra- or inter-gene interaction) there was no strong evidence for common environmental effects, barring significant effects for fasting glucose in women. Heritability decreased with age for 120-min glucose in women and fasting insulin in men, whereas it increased for 120-min glucose in men. CONCLUSION/INTERPRETATION: This study indicates a limited additive genetic influence on the result of an OGTT, possibly with sex-specific age effects, and generally little or no influence of the common environment. Accordingly, there is a considerable individual environmental variation.

Adolescent↗
PubMed2003

Power of linkage disequilibrium mapping to detect a quantitative trait locus (QTL) in selected samples of unrelated individuals.

We considered a strategy to map quantitative trait loci (QTLs) using linkage disequilibrium (LD) when the QTL and marker locus were multiallelic. The strategy involved phenotyping a large number of unrelated individuals and genotyping only selected individuals from the two tails of the trait distribution. Power to detect trait-marker association was assessed as a function of the number of QTL and marker alleles. Two patterns of LD were used to study their influence on power. When the frequency of the QTL allele with the largest effect and that of the marker allele linked in coupling were equal, power was maximum. In this case, increasing the number of QTL alleles reduced the power. The maximum difference in power between the two LD patterns studied was approximately 30%. For low QTL heritabilities (h2QTL<0.1) and single trait studies we recommend selecting around 5% of the upper and lower tails of the trait distribution.

Chromosome Mapping↗
PubMed2003

Analyses for the presence of a major gene affecting uterine capacity in unilaterally ovariectomized rabbits.

The presence of a major gene for uterine capacity (UC), ovulation rate (OR), number of implanted embryos (IE), embryo survival (ES), fetal survival (FS), and prenatal survival (PS) was investigated in a population of rabbits divergently selected for UC for 10 generations. Selection was performed on estimated breeding values for UC up to four parities. UC was estimated as litter size in the remaining overcrowded horn of unilaterally ovariectomized does. OR and IE were counted by means of laparoscopy. Bartlett's test, Fain's test, and a complex segregation analysis using Bayesian methods were used to test for the presence of a major gene. All three tests showed that the data appeared consistent with the presence of a major gene affecting UC and IE. The results of the complex segregation analysis suggested the presence of a major gene with large effect on IE and ES (a > 1sigma(p)), at high frequency (p = 0.70 and 0.68, respectively), and with a large contribution to the total variance (R(g) = 0.39 and 0.47, respectively); and the presence of a major gene with moderate effect on each of OR, FS, PS, and UC. The results suggest that the studied reproductive traits are determined genetically by at least one gene of large effect.

Animals↗
PubMed2003

Estimation of linkage disequilibrium in a sample of the United Kingdom dairy cattle population using unphased genotypes.

The association between genetic marker alleles was estimated for two regions of the bovine genome from a random sample of 50 young dairy bulls born in the United Kingdom between 1988 and 1995. Microsatellite marker genotypes were obtained for six markers on chromosome 2 and seven markers on chromosome 6, spanning 38 and 20 cM, respectively. Two different methods, which do not require family information, were used to estimate population haplotype frequencies. Haplotype frequencies were estimated for pairs of loci using the expectation-maximization algorithm and for all linked loci using a Bayesian approach via a Markov chain-Monte Carlo algorithm. Significant (P = 0.0007) linkage disequilibrium was detected between pairs of loci in syntenic groups (that is, loci in the same linkage group), extending to about 10 cM. No significant linkage disequilibrium was detected between markers in nonsyntenic regions. Given the observed level of linkage disequilibrium, mapping methods based on population-wide association might provide a better resolution than traditional quantitative trait loci mapping methods in the U.K. dairy cattle population and may reduce the required sample sizes of the experiments.

Algorithms↗
PubMed2002

Simple deterministic identity-by-descent coefficients and estimation of QTL allelic effects in full and half sibs.

Accurate and rapid methods for the detection of quantitative trait loci (QTLs) and evaluation of consequent allelic effects are required to implement marker-assisted selection in outbred populations. In this study, we present a simple deterministic method for estimating identity-by-descent (IBD) coefficients in full- and half-sib families that can be used for the detection of QTLs via a variance-component approach. In a simulated dataset, IBD coefficients among sibs estimated by the simple deterministic and Markov chain Monte Carlo (MCMC) methods with three or four alleles at each marker locus exhibited a correlation of greater than 0.99. This high correlation was also found in QTL analyses of data from an outbred pig population. Variance component analysis used both the simple deterministic and MCMC methods to estimate IBD coefficients. Both procedures detected a QTL at the same position and gave similar test statistics and heritabilities. The MCMC method, however, required much longer computation than the simple method. The conversion of estimated QTL genotypic effects into allelic effects for use in marker-assisted selection is also demonstrated.

Animals↗
PubMed2002

Parental assignment in fish using microsatellite genetic markers with finite numbers of parents and offspring.

Deterministic predictions for the proportion of offspring assigned to different numbers of parent-pairs are developed in order to investigate the power of microsatellite loci for parental assignment in fish species. Comparisons with stochastic simulation results show that predictions based on exclusion probabilities are accurate, provided that the number of parents involved in the crosses is large. Accounting for sampling of parents gave very accurate predictions for a small number of parents and a single biallelic locus. For large numbers of loci or large numbers of alleles per locus stochastic simulations are, however, the only available method to predict the power of assignment of a particular set of loci when the number of parents is small. Nine 5-allele loci or six 10-allele loci with equifrequent alleles, are sufficient for assigning, with certainty, parents to 99% of the fish resulting from either 100 or 400 crosses. Results simulating a set of highly polymorphic microsatellites developed for Atlantic salmon show that the four most informative loci are sufficient to assign at least 99% of the offspring to the correct pair with 100 crosses involving 100 males and 100 females. An additional locus is required for correctly assigning 99% of the offspring when the 100 crosses are produced with 10 males and 10 females.

Animals↗
PubMed2002

A genome scan for quantitative trait loci in a wild population of red deer (Cervus elaphus).

Recent empirical evidence indicates that although fitness and fitness components tend to have low heritability in natural populations, they may nonetheless have relatively large components of additive genetic variance. The molecular basis of additive genetic variation has been investigated in model organisms but never in the wild. In this article we describe an attempt to map quantitative trait loci (QTL) for birth weight (a trait positively associated with overall fitness) in an unmanipulated, wild population of red deer (Cervus elaphus). Two approaches were used: interval mapping by linear regression within half-sib families and a variance components analysis of a six-generation pedigree of >350 animals. Evidence for segregating QTL was found on three linkage groups, one of which was significant at the genome-wide suggestive linkage threshold. To our knowledge this is the first time that a QTL for any trait has been mapped in a wild mammal population. It is hoped that this study will stimulate further investigations of the genetic architecture of fitness traits in the wild.

Animals↗
PubMed2002

Contrasting models for lactation curve analysis.

Several statistical models have been proposed for the genetic evaluation of production traits in dairy cattle based on test-day records. Three main approaches have been put forward in the literature: random regression, orthogonal polynomials, and, more recently, character process models. The aim of this paper is to show how these different approaches are related, to compare their performance for the genetic analysis of lactation curves, and to assess equivalence between sire and animal models for repeated measures analyses. It was found that, with an animal model, a character process model with 11 parameters performed better, regarding the likelihood criterion, than a quartic random regression model (with 31 parameters). However, although the likelihood was higher, the genetic variance was very different with the character process model from the unstructured model, which raises important issues concerning model selection criteria. There are advantages in combining methodologies. A quadratic random regression model for the environmental part, combined with a character process model for the residual, performed better than the quartic random regression model and had fewer parameters. A character process structure allowing for a correlation pattern modeled the residual better than a simple quadratic variance, and had only one extra parameter.

Animals↗