The sex chromosomes enable direct determination of haplotypes, and the analysis of 8 microsatellite markers from the FRAX region on Xq27-q28 contributes 7219 independent haplotypes from our study in Wessex. Allelic association increases with frequency of alleles, and is less for trinucleotide than dinucleotide repeats. The estimate of ε, the exponential decline of association with distance in kb, is 0.0023. The swept radius 1/ε estimates the distance at which disequilibrium falls to e−1 ≈ .37 of its initial value. The current study estimates the swept radius of association to be 433 kb, which is surprisingly close to estimates for SNPs, and suggests that a marker density of 1/100 kb should be powerful in regions such as FRAX. An explanation for these results is offered, and some speculations made about what will be found when SNPs are subjected to an equally intensive study in multiple regions.

Patterns of dystrophin gene deletions in DMD/BMD patients were compared in four populations: Turks (n = 146 deletions), Europeans (n = 838), North Indians (n = 89), and Indians from all over India (n = 103). Statistical tests revealed that there are differences in the proportions of small deletions. In contrast, the distribution of deletion breakpoints and the frequencies of specific deletions commonly observed in the four populations are not significantly different. The variations strongly suggest that sequence differences exist in the introns, and the differences are in agreement with genetic distances among populations. The similarities suggest that some intronic sequences have been conserved and that those will trigger recurrent deletions, since it is unlikely that gene flow would disperse the deleted chromosomes, which vanish from the gene pool in a few generations.

Several studies have indicated that additional genes in the major histocompatibility complex (MHC) region, other than the class II genes HLA-DQB1 and -DRB1 (the IDDM1 locus), may contribute to susceptibility and resistance to type 1 diabetes. The relative magnitude of these non- DR/DQ effects is uncertain and their map location is unknown owing to the extraordinary linkage disequilibrium that extends over the 3.5 Mb of the MHC. The homozygous parent test has been proposed as a method for detection of additional risk factors conditional on HLA-DQB1 and -DRB1. However, this method is inefficient since it uses only parents homozygous for the primary disease locus, the DQB1-DRB1 haplotype. To overcome this limitation, Conditional ETDT was used in the present report to test for association conditional on the DQB1-DRB1 haplotype, thereby allowing all parents to be included in the analysis. First, we confirm in UK and Sardinian type 1 diabetic families that allelic variation at HLA-DRB1 has a very significant effect on the association of DQB1 and vice versa. The Conditional ETDT was then applied to the HLA TNF (tumour necrosis factor) region and microsatellite marker D6S273 region, both of which have been reported to contribute to IDDM1 independent of the HLA-DQB1-DRB1 genes. We found no evidence for a major role for either of these two regions in IDDM1.

We typed 1801 males from 55 locations for the Y-specific binary markers YAP, DYZ3, SRY10831 and the (CA)n microsatellites YCAII and DYS413. Phylogenetic relationships of chromosomes with the same binary haplotype were condensed in seven large one-step networks, which accounted for 95% of all chromosomes. Their coalescence ages were estimated based on microsatellite diversity. The three largest and oldest networks undergo sharp frequency changes in three areas. The more recent network 3.1A clearly discriminates between Western and Eastern European populations. Pairwise Fst showed an overall increment with increasing geographic distance but with a slope greatly reduced when compared to previous reports. By sectioning the entire data set according to geographic and linguistic criteria, we found higher Fst-on-distance slopes within Europe than in West Asia or across the two continents.

Parametric linkage analysis of simultaneous mapping of the two disease loci of a qualitative trait governed by a two-locus model has been shown to provide greater power in detecting linkage than standard lod-score analysis that maps a single disease locus. Despite its great potential for power gains, two-locus parametric analysis has not been used routinely in disease gene mapping, due to the computational intensity of currently available methods and programs. In this paper, we propose a Markov chain Monte Carlo (MCMC) method for performing lod-score analysis of qualitative traits governed by two-locus models. This method obtains lod-score estimates that can be arbitrarily close to their corresponding exact values. The algorithm implementing this MCMC method is linear in the number of markers. This feature enables us to perform two-locus analysis mapping each trait to a set of markers, instead of just to a single marker. We analyzed an alcohol dependence dataset composed of 105 pedigrees with various sizes and various degrees of missingness in the observed marker and disease data. The estimates from our MCMC procedure match up well with the lod scores from exact analysis, but it took much less time for the MCMC procedure to obtain the results. We also performed a simulation study to investigate power gains with additional markers. Our results indicate that an additional marker on each map can provide a great deal more information for linkage measured in terms of the magnitude of lod scores.

We present a new method for the fine scale mapping of disease loci based on samples of simplex families, each containing an affected child. The method is based on a generalisation of a single locus allele transmission model to multiple marker loci. The model is developed under the assumption of a single ancestral mutation and allows for the calculation of posterior probabilities that each allele at a particular marker was present on the founder chromosome. We illustrate the method using simulated family data for cystic fibrosis and Huntingtons disease, for which the locations of mutations in the disease genes are now known. For both diseases, our new method provides good estimates of the location of the mutations.

In a study based on 173 individuals drawn from three endogamous, co-resident communities in the province of Punjab, the Awan, Khattar and Rajpoot, an analysis of 10 autosomal single tandem repeats on chromosomes 13 and 15 revealed distinctive genetic profiles in each community. A total of 99 different alleles were detected, with 28 alleles (28.3%) shared by all three communities. The mean private allele frequency was 7.7%. There was a reduction in heterozygosity and high average inbreeding effects (FIS and/or HS), particularly in the Awan, indicating genetic isolation and a high cumulative level of autozygosity. Genotyping with eight Y-chromosome STRs resulted in the construction of six haplotypes, one each for the Awan and the Khattar but four for the Rajpoot, suggesting marked variation in the patterns of male founder effects in the history of each community. The lower than expected levels of homozygosity observed at a number of loci may be indicative of cosegregation of the STRs with nearby early development genes subject to selection.

We have analysed a linked microsatellite/Alu polymorphism at the CD4 locus (CD4/Alu) in 666 chromosomes from samples of the Iberian Peninsula, Northwest Africa, and West sub-Saharan Africa. The Iberian Peninsula differs from other European populations by its higher levels of haplotype diversity (0.75), and weaker association between the microsatellite allele 90 and Alu(−) chromosomes. These results are explainable by a substantial gene flow from Northwest Africa. Significant geographic clines for the five major haplotypes suggest a south to north migration from sub-Saharan Africa into Northwest Africa. In spite of this, the consistent presence of haplotype 110(−) in this area is congruent with an ancient and autochthonous human presence in Northwest Africa.

The history of Hungary starts in the 9th century with the arrival of the Magyars in the Carpathian Basin. They spoke, like modern Hungarians, an Uralic language belonging to the Finno-Ugric language group. Their original composition probably included Iranian and Turkish people, while other populations were already present in the territory (Avars, Slavs, Germans). Some of the Hungarian ethnic groups claim to be descendants of ancient Magyars settlers (such as the Örség), others of Huns, Turks or Iranians. We collected and compared the previously published gene frequencies of eight ethnic groups and seven hypothetical ancestral populations, including Uralics, applying a model of admixture. The results, most of which confirm historical hypotheses or the oral tradition, show that only one ethnic group (Örség) highly resembles the Uralic population.

For large numbers of marker loci in a genomic scan for disease loci, we propose a novel 2-stage approach for linkage or association analysis. The two stages are (1) selection of a subset of markers that are ‘important’ for the trait studied, and (2) modelling interactions among markers and between markers and trait. Here we focus on stage 1 and develop a selection method based on a 2-level nested bootstrap procedure. The method is applied to single nucleotide polymorphisms (SNPs) data in a cohort study of heart disease patients. Out of the 89 original SNPs the method selects 11 markers as being ‘important’. Conventional backward stepwise logistic regression on the 89 SNPs selects 7 markers, which are a subset of the 11 markers chosen by our method.

An important design issue in allelic association studies for mapping disease genes is the choice of markers. We have used a simple model of a founder population, similar to those of Ott & Rabinowitz (1997) and Chapman & Wijsman (1998), to explore the effect of the number of alleles at a marker polymorphism on the power to detect linkage disequilibrium due to single or multiple ancestral disease mutations. We show that the optimal number of alleles is more than 2 even in the case of a single ancestral disease mutation, and much higher still if multiple ancestral mutations are present. In large samples, much power is lost by using too few alleles, but relatively little power is lost by using too many alleles. These results confirm the desirability of using highly polymorphic markers or multi-locus haplotypes for association analysis. They also show that multiple ancestral disease mutations do not necessarily preclude linkage disequilibrium mapping, if highly polymorphic markers or multi-locus haplotypes are used.

We report an analysis of allelic diversity at short tandem repeat polymorphisms within the fragile XA locus in 1069 male volunteers from twelve Indonesian sub-populations. An odd numbered allele of DXS548 was found at high frequency in all Indonesian populations. Greater allelic diversity was identified at the loci under study than has been previously reported for an Asian population. These differences distinguish the Indonesian population from all previously reported Asian, European and African populations. A high frequency of small premutation alleles, 4/120 (3.3%, 95% CI 0.9–8.3%), was identified in the Moluccan population of Hiri Island.

Complex segregation analysis was conducted in a sample of 171 pedigrees collected through probands affected by non-syndromic dysplasia of the hip (CDH) treated in Ferrara's CDH Centre in the period 1991–6. The analysis favoured a two-locus model, in which the accepted segregation model at the major locus was compatible with recessive transmission, with a gene frequency of the deleterious allele of around 0.20. For the other locus, among the Mendelian hypotheses tested, the recessive model turned out to be the most parsimonious. When ultrasonographic level was examined as an indication of severity, a significant improvement in the fit of the model was observed, giving clear evidence that information on the severity of CDH is important for a better definition of the hereditary transmission model.

Information on the age of a patient at disease onset, an important feature of complex diseases, is often collected in studies designed to map the disease genes. Penetrance-model-free methods, requiring no specification of penetrance functions, have been used extensively for detecting linkage and association between marker and disease loci. In this paper, we conduct an analytical study to examine the effects of incorporation of age at onset information on the power of two commonly used penetrance-model-free methods, the affected sib-pair (ASP) and transmission/disequilibrium tests (TDT). Assuming a Cox model with a major gene effect for the age at onset, we quantify analytically how age at onset affects the identity by descent (IBD) probabilities, the mean IBD values, and the expected numbers of alleles transmitted from heterozygous parents to affected children under various genetic models. We show that the power of the mean IBD test and the TDT can be greatly affected by the ages at onset of affected siblings or children used in the study. Generally, the most powerful test for ASPs is that based on affected sib pairs both having early disease onset and for TDT analyses is that based on trios with early-onset children. Naively combining affected sib pairs with different ages at onset or parent-children trios with different ages at onset of affected children can result in reduced power for detecting linkage or association. These results may be used to guide collection and analysis of sib pairs or families for diseases with variable age at onset.

When searching for trait loci along the genome, properly incorporating prior genomic information into the analysis will almost certainly increase the chance of success. Recently, we devised a method that utilizes such prior information in the mapping of trait genes for complex disorders (Vieland, 1998; Wang et al. 1999; Vieland et al. 2000). This method uses the posterior probability of linkage (PPL) based on the admixture model as a measure of linkage information. In this paper, we study the consistency of the PPL. It is shown that, as the number of pedigrees increases, the PPL converges in probability to 1 when there is linkage between the marker and a trait locus, and converges to 0 otherwise. This conclusion is shown to be true for general pedigrees and trait models, even when the likelihood functions are based on misspecified trait models. As part of the effort to prove this conclusion, it is shown that when there is no linkage, the maximum likelihood estimator of the recombination fraction in the admixture model is asymptotically 0.5, even when the admixture model misrepresents the true model.

Two popular and robust approaches to analysing affected sib pair (ASP) data for linkage are the traditional excess sharing methods and the transmission/disequilibrium test (TDT). Here we derive an overall test of linkage for multi-allelic ASP marker data which comprises two component tests: one for excess sharing and one for transmission disequilibrium. This method has several advantages. Firstly the overall test of linkage is often more powerful than either of the two component tests. Secondly the method makes it possible to determine the contribution of linkage disequilibrium (LD), in addition to linkage, to an overall positive linkage result. This is useful because the presence of LD in addition to linkage may suggest that the marker locus is in very close proximity to a disease susceptibility gene. Thirdly the method provides estimates of the risk associated with transmission of the different marker alleles.

The transmission/disequilibrium test (TDT) is a powerful method of locating disease genes. The TDT was originally proposed for use in studies of qualitative traits in families with both parents available. Recently, the TDT has been extended to studies of qualitative traits in sibships without parents available and in families with one parent available. It has also been extended for use in studies of quantitative traits in families with both parents available and in sibships with multiple offspring. In this paper, we first propose a new class of TDT-type tests for linkage in the presence of linkage disequilibrium for use in studies of families with both parents available. The TDT of Spielman et al. (1993) for qualitative traits and the TDT of Rabinowitz (1997) for quantitative traits are special cases of the new tests. Second, we propose a new class of TDT-type tests for linkage for use in studies of families with one parent available. Third, we study the validity and the power of the tests using simulations. Finally, we propose a method of combining data from different types of families. The combined test is valuable and allows researchers full use of the available data in detecting linkage between a marker locus and an unobservable quantitative trait locus. An important feature of the tests proposed in this paper is that no assumptions on the distribution of the quantitative traits are needed.

The proportions of affected sibs sharing 2, 1 or 0 identical by descent parental marker alleles have been shown to conform to the ‘triangle constraints’ (Suarez, 1978; Holmans, 1993). It has also been shown (Dudoit & Speed, 1999) that the constraints are verified provided certain assumptions hold. In this study we explore a realistic situation in which the constraints fail due to the presence of a factor in which the sibs differ, a factor on which penetrance depends. This factor may be a characteristic of the trait (severe vs. mild form), or the presence/absence of an associated trait or an environmental factor. We show that under such situations, using the triangle constraints may lead to important loss of power to detect linkage by the MLS test. We propose here an alternative approach in order to detect both linkage and heterogeneity.

There is good evidence from linkage analysis and mouse model knockouts that the endothelin-1 gene (EDN1) is a good candidate for non-syndromic orofacial cleft (OFC) disease. EDN1 maps to the chromosomal region of the OFC1 locus in 6p23. Therefore we have examined three other candidate genes in the endothelin pathway (ECE1, EDNRA and EDNRB, which map to chromosomes 1, 4 and 13 respectively) in a linkage study of 9 families with OFC, where the disorder is not linked to chromosome 6p23. The total lod score for these 9 multiplex families never exceeded −2.00 and thus our data suggest that EDN1 and related genes are not involved in non-syndromic familial OFC.

In the presence of gametic phase disequilibrium and inbreeding, multiple locus genotype frequencies cannot be written solely in terms of identity by descent (IBD) probabilities. Following Cockerham & Weir (1973) we introduce the concept of ‘equivalence by descent’ (EBD), an extension of the concept of IBD to include non-allelic genes. Two genes are said to be EBD if they derive ultimately from the same founding gamete of a pedigree. Allelic genes that are EBD are also IBD. For two loci 11 EBD probabilities, the ‘J-coefficients,’ are required and for three loci 117 J-coefficients are required to write genotype probabilities. It is shown how the 117 J-coefficients for three loci can be reduced to a basic set of 37. Computer programs, written in the algebraic programming language, MAPLE™, are described which are capable of calculating the two- and three-locus J-coefficients for any pedigree, subject only to size limitations. The MAPLE™ packages are available from the author upon request.