Extreme Discordant Sib Pairs Research Articles

Genetic Markers Regulating Blood Pressure in Extreme Discordant Sib Pairs.

Genome-wide scans performed in affected sib pairs have revealed small and often inconsistent clues to the loci responsible for the inherited components of hypertension. Since blood pressure is a quantitative trait regulated by many loci, two siblings at opposite extremes of the blood pressure distribution are more likely to have inherited different alleles at any given locus. Hence, we investigated an extreme discordant sib pair strategy to analyse markers from two previous loci of interest: (1) the Gordons syndrome locus that includes the WNK4 gene and (2) the ROMK locus identified in our first genome-wide scan. For this study, 24 sib pairs with strong family histories of essential hypertension were selected from the top and bottom 10% of the blood pressure distribution and genotyped for highly polymorphic microsatellite markers on chromosomes 11 and 17. The mean age of the population was 39.8 ± 7.8 years. A significant inverse correlation was found between the squared difference in pulse pressure and the number of alleles shared by IBD between the siblings for the DS11925 marker (r = -0.44, p = 0.031), systolic pressure and chromosome 17 markers (D17S250: r = -0.42, p = 0.040; D17S799 (r = -0.51, p = 0.011), and this relationship persisted after correcting for age and gender. Markers on chromosome 17 (D17S250, D17S928 and D17S1301) and 11 (D11S1999) also correlated with diastolic pressure. These results illustrate the successful use of discordant sib pair analysis to detect linkage within relatively small numbers of pedigrees with hypertension. Further analysis of this cohort may be valuable in complementing findings from the large genome wide scans in affected sib pairs.

A Novel Framework for Sib Pair Linkage Analysis

Sib pair linkage analysis of a dichotomous trait is a popular method for narrowing the search for genes that influence complex diseases. Although the pedigree structures are uncomplicated and the underlying genetic principles straightforward, a surprising degree of complexity is involved in implementing a sib pair study and interpreting the results. Ascertainment may be based on affected, discordant, or unaffected sib pairs, as well as on pairs defined by threshold values for quantitative traits, such as extreme discordant sib pairs. To optimize power, various domain restrictions and null hypotheses have been proposed for each of these designs, yielding a wide array of choices for the analyst. To begin, we systematically classify the major sources of discretion in sib pair linkage analysis. Then, we extend the work of Kruglyak and Lander (1995), to bring the various forms into a unified framework and to facilitate a more general approach to the analysis. Finally, we describe a new, freely available computer program, Splat (Sib Pair Linkage Analysis Testing), that can perform any sib pair statistical test currently in use, as well as any user-defined test yet to be proposed. Splat uses the expectation maximization algorithm to calculate maximum-likelihood estimates of sharing (subject to user-specified conditions) and then plots LOD scores versus chromosomal position. It includes a novel grid-scanning capability that enables simultaneous visualization of multiple test statistics. This can lead to further insight into the genetic basis of the disease process under consideration. In addition, phenotype definitions can be modified without the recalculation of inheritance vectors, thereby providing considerable flexibility for exploratory analysis. The application of Splat will be illustrated with data from studies on the genetics of diabetic nephropathy.

Detection of quantitative trait loci for carcass traits in the pig by using AFLP

For evaluation of the suitability of Amplified Fragment Length Polymorphism (AFLP) for detection of quantitative trait loci in farm animals, a combination of AFLP and selective genotyping has been applied as a rapid screening method for marker-QTL associations. Focusing on loci affecting eye muscle area, six extreme discordant sib pairs were selected from a Duroc x Berlin Miniature Pig F2 experimental cross and examined by using 48 AFLP primer combinations. Two prominent AFLP markers were converted into simple codominant PCR markers ( STS-Bo1 and STS-Bo3) and assigned to Sscr4 by physical and linkage mapping. Single marker analysis indicated association of the STS markers with a putative QTL influencing eye muscle area. Interval mapping confirmed the presence of a significant QTL for eye muscle area (Pgenomewide < 0.01) on the Sscr4, with STS-Bo1 being the closer marker. At the same location, significant effects (Pgenomewide < 0.01) on carcass length and backfat thickness were also detected. Our results demonstrate the capability of the combination of AFLP analysis and selective genotyping as a method for detection of genome regions containing QTL in livestock.

Ascertainment issues in variance components models.

One of the main concerns in the family studies of complex diseases is the effect that ascertainment and correction for it may have on test procedures and estimators. Elston and Sobel [1979] and Hopper and Mathews [1982] proposed two ways to correct for ascertainment in the study of quantitative trait data. For single ascertainment, using a variance components approach, we present results of simulation studies comparing estimates from these two methods for different selection criteria. We also show results from simulations when ascertained families are analyzed either at random or by correcting for ascertainment. For discordant sibpairs, we compare a variance components model that incorporates ascertainment correction with the extreme discordant sib pairs (EDSP) design proposed by Risch and Zhang [1995]. Our results show that there is minimal difference between the two methods of ascertainment correction. In the presence of effects from a large genetic background and the segregation of a rare gene, both ascertainment affected the polygenic and environmental components of variance but had rather little impact on the estimate of the linked major gene component of variance. The results also show the EDSP is slightly more powerful the variance components procedures for common alleles, and the variance components procedure is much more powerful than using EDSP when there is a rare allele segregating in the population.

A Unified Sampling Approach for Multipoint Analysis of Qualitative and Quantitative Traits in Sib Pairs

Recent advances in molecular biology have enhanced the opportunity to conduct multipoint mapping for complex diseases. Concurrently, one sees a growing interest in the use of quantitative traits in linkage studies. Here, we present a multipoint sib-pair approach to locate the map position (tau) of a trait locus that controls the observed phenotype (qualitative or quantitative), along with a measure of statistical uncertainty. This method builds on a parametric representation for the expected identical-by-descent statistic at an arbitrary locus, conditional on an event reflecting the sampling scheme, such as affected sib pairs, for qualitative traits, or extreme discordant (ED) sib pairs, for quantitative traits. Our results suggest that the variance about tau&d4;, the estimator of tau, can be reduced by as much as 60%-70% by reducing the length of intervals between markers by one half. For quantitative traits, we examine the precision gain (measured by the variance reduction in tau&d4;) by genotyping extremely concordant (EC) sib pairs and including them along with ED sib pairs in the statistical analysis. The precision gain depends heavily on the residual correlation of the quantitative trait for sib pairs but considerably less on the allele frequency and exact genetic mechanism. Since complex traits involve multiple loci and, hence, the residual correlation cannot be ignored, our finding strongly suggests that one should incorporate EC sib pairs along with ED sib pairs, in both design and analysis. Finally, we empirically establish a simple linear relationship between the magnitude of precision gain and the ratio of the number of ED pairs to the number of EC pairs. This relationship allows investigators to address issues of cost effectiveness that are due to the need for phenotyping and genotyping subjects.

Ascertainment issues in variance components models

One of the main concerns in the family studies of complex diseases is the effect that ascertainment and correction for it may have on test procedures and estimators. Elston and Sobel [1979] and Hopper and Mathews [1982] proposed two ways to correct for ascertainment in the study of quantitative trait data. For single ascertainment, using a variance components approach, we present results of simulation studies comparing estimates from these two methods for different selection criteria. We also show results from simulations when ascertained families are analyzed either at random or by correcting for ascertainment. For discordant sibpairs, we compare a variance components model that incorporates ascertainment correction with the extreme discordant sib pairs (EDSP) design proposed by Risch and Zhang [1995]. Our results show that there is minimal difference between the two methods of ascertainment correction. In the presence of effects from a large genetic background and the segregation of a rare gene, both ascertainment affected the polygenic and environmental components of variance but had rather little impact on the estimate of the linked major gene component of variance. The results also show the EDSP is slightly more powerful the variance components procedures for common alleles, and the variance components procedure is much more powerful than using EDSP when there is a rare allele segregating in the population.

Evaluation of a restricted likelihood ratio test for mapping quantitative trait loci with extreme discordant sib pairs.

Risch and Zhang recently proposed to use extreme discordant sib pairs for mapping quantitative trait loci. Here, it is shown that the set of genetically possible distributions of the number of marker alleles in such sib-pairs is described by two inequalities. Thus, a likelihood ratio test analogous to Holmans's possible triangle test for affected sib pairs can be defined. The performance of this test is compared to the mean test considered by Risch and Zhang. For most of the genetic models considered, the mean test is slightly more powerful than the restricted likelihood ratio test. However, for models with a rare recessive gene (or equivalently a common dominant gene), the restricted likelihood ratio test is much more powerful.

Evaluation of a restricted likelihood ratio test for mapping quantitative trait loci with extreme discordant sib pairs

Evaluation of a restricted likelihood ratio test for mapping quantitative trait loci with extreme discordant sib pairs

Effectiveness of extreme discordant sib pairs to detect oligogenic disease loci.

A method for the genomic screening of quantitative traits using extreme discordant sib pairs (EDSPs) has recently been described by Risch and Zhang [1995; 1996]. For many models relevant to common, genetically complex diseases, EDSPs are the most powerful siblings for detecting linkage. Thus, if such siblings can be identified and collected, powerful studies with reasonable genotyping budgets can be conducted. Using a subset of the GAW10 data, we have simulated a genomic screen using EDSPs. From the 4,780 total families in the first 20 replicates of 239 families, there were 100, 104, 155, 107, and 180 EDSP families for Q1, Q2, Q3, Q4, and Q5, respectively. EDSP data were analyzed for each trait using a modified version of MAPMAKER/SIBS capable of handling extreme discordant sib pairs. Four regions, one for Q1, one for Q2, and two for Q4, were able to exceed a threshold for linkage corresponding to a 0.001 pointwise significance level. In three cases, maximum lod score (MLS) peaks occurred within 3.8 cM of a major gene. In the fourth case, the MLS peak occurred 28.4 cM from a major gene. Omission of parents and an alternative definition of EDSP were also investigated.

A Clinically Orientated Approach for Combining Discordant and Concordant Sib Pairs

AbstractThe use of extreme discordant sib pairs (EDSP) or extreme concordant sib pairs (ECSP) has recently been proposed to increase power for mapping quantitative traits in humans (RISCH and ZHANG, 1995, 1996). In this paper we propose a test statistic to jointly analyze EDSP and ECSP based on a clinical sampling procedure. This test statistic does not fulfill any optimality criteria. However, this approach is useful for quantitative traits of clinical significance for which EDSP are rare and/or expensive to ascertain. We show how sample size calculations can be adjusted for recombination using single markers, multipoint analysis, incompletely polymorphic markers and varying proportions of ECSP. If the true genetic model is unknown, the combined approach appears to be more robust than sampling based on only EDSP or only ECSP. We discuss how to find the optimal proportion of EDSP and ECSP to be included in an analysis under power considerations.

The "possible triangle" test for extreme discordant sib pairs.

For the analysis of quantitative traits in nuclear families, extreme discordant sib pairs proved to be more powerful than unselected sib pairs. Here, we present a test that makes use of selected pairs and, in addition, restricts the parameters of the identical-by-descent distribution analogously to the "possible triangle" for affected sib pairs. In the Problem 2A data, extreme discordant sib pairs are selected. The analysis allowed the detection of most simulated major genes.