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Peter M Visscher

Publications and source records attributed to Peter M Visscher.

14 recordsLinked to original sources
PubMed2024

The importance of family-based sampling for biobanks.

Biobanks aim to improve our understanding of health and disease by collecting and analysing diverse biological and phenotypic information in large samples. So far, biobanks have largely pursued a population-based sampling strategy, where the individual is the unit of sampling, and familial relatedness occurs sporadically and by chance. This strategy has been remarkably efficient and successful, leading to thousands of scientific discoveries across multiple research domains, and plans for the next wave of biobanks are underway. In this Perspective, we discuss the strengths and limitations of a complementary sampling strategy for future biobanks based on oversampling of close genetic relatives. Such family-based samples facilitate research that clarifies causal relationships between putative risk factors and outcomes, particularly in estimates of genetic effects, because they enable analyses that reduce or eliminate confounding due to familial and demographic factors. Family-based biobank samples would also shed new light on fundamental questions across multiple fields that are often difficult to explore in population-based samples. Despite the potential for higher costs and greater analytical complexity, the many advantages of family-based samples should often outweigh their potential challenges.

Humans↗
PubMed2004

Power of direct vs. indirect haplotyping in association studies.

Haplotype analysis is essential to studies of the genetic factors underlying human disease, but requires a large sample size of phase-known data. Recently, directly haplotyping individuals was suggested as a means of maximizing the phase-known data from a sample. Haplotyping, however, is much more labor-intensive than indirectly inferring haplotypes from genotypes (genotyping). This study uses simulations to compare the power of each methodology to detect associations between a haplotype and a trait or disease locus under conditions of varying linkage disequilibrium. The relative power of haplotyping over genotyping in association studies increases with decreasing sample size, decreasing linkage disequilibrium, increasing [corrected] numbers of marker loci, and decreasing numbers of different haplotypes. In addition, the frequency of the haplotype of interest and the magnitude of its association with the disease affect the power. From a cost-benefit standpoint, genotyping would be favored with large multiplicative risks (relative risk of haplotype >2.5). If case numbers are limiting rather than cost, haplotyping would maximize the information obtained. At small haplotype frequencies (e.g., <0.05), haplotyping is relatively more efficient, but there is little absolute power to detect associations under either methodology. Given the much larger laboratory resources required for direct haplotyping, genotyping would probably be favored under most conditions, but this must be balanced against the unit costs associated with recruitment and phenotyping. In the context of multipurpose, prospective cohort studies (e.g., the UK Biobank study), there may be a general value in establishing a series of directly haplotyped individuals to serve as controls for a number of alternative studies.

Algorithms↗
PubMed2003

Lack of association between polymorphisms in angiotensin-converting-enzyme and methylenetetrahydrofolate reductase genes and normal cognitive ageing in humans.

The hypothesis that polymorphisms at two candidate genes that code for angiotensin-converting-enzyme (ACE) and methylenetetrahydrofolate reductase (MTHFR) are associated with normal cognitive ageing was tested using a sample (n=536) of healthy 80-year-old people who were born in 1921 and whose cognitive ability at age 11 was measured in the Scottish Mental Survey 1932. Cognitive ability at age 11 and age 80 was assessed using the Moray House Test. Cognitive ageing was defined as the change in IQ from age 11 to 80. There was no significant association between the tested ACE and MTHFR polymorphisms and IQ score at age 11, IQ at age 80, and IQ change (all P>0.05). The ACE genotypes deviated significantly from Hardy-Weinberg equilibrium proportions (P=0.02), which could indicate that this gene is under selection. Polymorphisms at the two studied genes are unlikely to be risk factors for normal cognitive ageing.

Aged↗
PubMed2003

Genome scan meta-analysis of schizophrenia and bipolar disorder, part III: Bipolar disorder.

Genome scans of bipolar disorder (BPD) have not produced consistent evidence for linkage. The rank-based genome scan meta-analysis (GSMA) method was applied to 18 BPD genome scan data sets in an effort to identify regions with significant support for linkage in the combined data. The two primary analyses considered available linkage data for "very narrow" (i.e., BP-I and schizoaffective disorder-BP) and "narrow" (i.e., adding BP-II disorder) disease models, with the ranks weighted for sample size. A "broad" model (i.e., adding recurrent major depression) and unweighted analyses were also performed. No region achieved genomewide statistical significance by several simulation-based criteria. The most significant P values (<.01) were observed on chromosomes 9p22.3-21.1 (very narrow), 10q11.21-22.1 (very narrow), and 14q24.1-32.12 (narrow). Nominally significant P values were observed in adjacent bins on chromosomes 9p and 18p-q, across all three disease models on chromosomes 14q and 18p-q, and across two models on chromosome 8q. Relatively few BPD pedigrees have been studied under narrow disease models relative to the schizophrenia GSMA data set, which produced more significant results. There was no overlap of the highest-ranked regions for the two disorders. The present results for the very narrow model are promising but suggest that more and larger data sets are needed. Alternatively, linkage might be detected in certain populations or subsets of pedigrees. The narrow and broad data sets had considerable power, according to simulation studies, but did not produce more highly significant evidence for linkage. We note that meta-analysis can sometimes provide support for linkage but cannot disprove linkage in any candidate region.

Bipolar Disorder↗
PubMed2003

Novel multilocus measure of linkage disequilibrium to estimate past effective population size.

Linkage disequilibrium (LD) between densely spaced, polymorphic genetic markers in humans and other species contains information about historical population size. Inferring past population size is of interest both from an evolutionary perspective (e.g., testing the "out of Africa" hypothesis of human evolution) and to improve models for mapping of disease and quantitative trait genes. We propose a novel multilocus measure of LD, the chromosome segment homozygosity (CSH). CSH is defined for a specific chromosome segment, up to the full length of the chromosome. In computer simulations CSH was generally less variable than the r(2) measure of LD, and variability of CSH decreased as the number of markers in the chromosome segment was increased. The essence and utility of our novel measure is that CSH over long distances reflects recent effective population size (N), whereas CSH over small distances reflects the effective size in the more distant past. We illustrate the utility of CSH by calculating CSH from human and dairy cattle SNP and microsatellite marker data, and predicting N at various times in the past for each species. Results indicated an exponentially increasing N in humans and a declining N in dairy cattle. CSH is a valuable statistic for inferring population histories from haplotype data, and has implications for mapping of disease loci.

Animals↗
PubMed2003

Simple method to analyze SNP-based association studies using DNA pools.

Association studies using DNA pools are in principle powerful and efficient to detect association between a marker allele and disease status, e.g., in a case-control design. A common observation with the use of DNA pools is that the two alleles at a polymorphic SNP locus are not amplified in equal amounts in heterozygous individuals. In addition, there are pool-specific experimental errors so that there is variation in the estimates of allele frequencies from different pools that are from the same individuals. As a result of these additional sources of variation, the outcome of an experiment is an estimated count of alleles rather than the usual outcome in terms of observed counts. In this study, we show analytically and by computer simulation that unequal amplification should be taken into account when testing for differences in allele frequencies between pools, and suggest a simple modification of the standard chi(2) test to control the type I error rate in the presence of experimental error variation. The impact of experimental errors on the power of association studies is shown.

Case-Control Studies↗
PubMed2003

Power of QTL detection using association tests with family controls.

The power of testing for a population-wide association between a biallelic quantitative trait locus and a linked biallelic marker locus is predicted both empirically and deterministically for several tests. The tests were based on the analysis of variance (ANOVA) and on a number of transmission disequilibrium tests (TDT). Deterministic power predictions made use of family information, and were functions of population parameters including linkage disequilibrium, allele frequencies, and recombination rate. Deterministic power predictions were very close to the empirical power from simulations in all scenarios considered in this study. The different TDTs had very similar power, intermediate between one-way and nested ANOVAs. One-way ANOVA was the only test that was not robust against spurious disequilibrium. Our general framework for predicting power deterministically can be used to predict power in other association tests. Deterministic power calculations are a powerful tool for researchers to plan and evaluate experiments and obviate the need for elaborate simulation studies.

Analysis of Variance↗
PubMed2003

Quantitative trait loci variation for growth and obesity between and within lines of pigs (Sus scrofa).

The hypothesis that quantitative trait loci (QTL) that explain variation between divergent populations also account for genetic variation within populations was tested using pig populations. Two regions of the porcine genome that had previously been reported to harbor QTL with allelic effects that differed between the modern pig and its wild-type ancestor and between the modern pig and a more distantly related population of Asian pigs were studied. QTL for growth and obesity traits were mapped using selectively genotyped half-sib families from five domesticated modern populations. Strong support was found for at least one QTL segregating in each population. For all five populations there was evidence of a segregating QTL affecting fatness in a region on chromosome 7. These findings confirm that QTL can be detected in highly selected commercial populations and are consistent with the hypothesis that the same chromosome locations that account for variation between populations also explain genetic variation within populations.

Alleles↗
PubMed2002

SNP genotyping on pooled DNAs: comparison of genotyping technologies and a semi automated method for data storage and analysis.

We have compared the accuracy, efficiency and robustness of three methods of genotyping single nucleotide polymorphisms on pooled DNAs. We conclude that (i) the frequencies of the two alleles in pools should be corrected with a factor for unequal allelic amplification, which should be estimated from the mean ratio of a set of heterozygotes (k); (ii) the repeatability of an assay is more important than pinpoint accuracy when estimating allele frequencies, and assays should therefore be optimised to increase the repeatability; and (iii) the size of a pool has a relatively small effect on the accuracy of allele frequency estimation. We therefore recommend that large pools are genotyped and replicated a minimum of four times. In addition, we describe statistical approaches to allow rigorous comparison of DNA pool results. Finally, we describe an extension to our ACeDB database that facilitates management and analysis of the data generated by association studies.

Automation↗
PubMed2002

On the mapping of quantitative trait loci at marker and non-marker locations.

Previous studies have noted that the estimated positions of a large proportion of mapped quantitative trait loci (QTLs) coincide with marker locations and have suggested that this indicates a bias in the mapping methodology. In this study we predict the expected proportion of QTLs with positions estimated to be at the location of a marker and further examine the problem using simulated data. The results show that the higher proportion of putative QTLs estimated to be at marker positions compared with non-marker positions is an expected consequence of the estimation methods. The study initially focused on a single interval with no QTLs and was extended to include multiple intervals and QTLs of large effect. Further, the study demonstrated that the larger proportion of estimated QTL positions at the location of markers was not unique to linear regression mapping. Maximum likelihood produced similar results, although the accumulation of positional estimates at outermost markers was reduced when regions outside the linkage group were also considered. The bias towards marker positions is greatest under the null hypothesis of no QTLs or when QTL effects are small. This study discusses the impact the findings could have on the calculation of thresholds and confidence intervals produced by bootstrap methods.

Animals↗
PubMed2002

QTL Express: mapping quantitative trait loci in simple and complex pedigrees.

QTL Express is the first application for Quantitative Trait Locus (QTL) mapping in outbred populations with a web-based user interface. User input of three files containing a marker map, trait data and marker genotypes allows mapping of single or multiple QTL by the regression approach, with the option to perform permutation or bootstrap tests.

Chromosome Mapping↗
PubMedDate not supplied

QTL detection and allelic effects for growth and fat traits in outbred pig populations.

Quantitative trait loci (QTL) for growth and fatness traits have previously been identified on chromosomes 4 and 7 in several experimental pig populations. The segregation of these QTL in commercial pigs was studied in a sample of 2713 animals from five different populations. Variance component analysis (VCA) using a marker-based identity by descent (IBD) matrix was applied. The IBD coefficient was estimated with simple deterministic (SMD) and Markov chain Monte Carlo (MCMC) methods. Data for two growth traits, average daily gain on test and whole life daily gain, and back fat thickness were analysed. With both methods, seven out of 26 combinations of population, chromosome and trait, were significant. Additionally, QTL genotypic and allelic effects were estimated when the QTL effect was significant. The range of QTL genotypic effects in a population varied from 4.8% to 10.9% of the phenotypic mean for growth traits and 7.9% to 19.5% for back fat trait. Heritabilities of the QTL genotypic values ranged from 8.6% to 18.2% for growth traits, and 14.5% to 19.2% for back fat. Very similar results were obtained with both SMD and MCMC. However, the MCMC method required a large number of iterations, and hence computation time, especially when the QTL test position was close to the marker.

Animals↗