Improvement of Mapping Accuracy by Unifying Linkage and Association Analysis

Abstract

It is well known that pedigree/family data record information on the coexistence in founder haplotypes of alleles at nearby loci and the cotransmission from parent to offspring that reveal different, but complementary, profiles of the genetic architecture. Either conventional linkage analysis that assumes linkage equilibrium or family-based association tests (FBATs) capture only partial information, leading to inefficiency. For example, FBATs will fail to detect even very tight linkage in the case where no allelic association exists, while a violation of the assumption of linkage equilibrium will result in biased estimation and reduced efficiency in linkage mapping. In this article, by using a data augmentation technique and the EM algorithm, we propose a likelihood-based approach that embeds both linkage and association analyses into a unified framework for general pedigree data. Relative to either linkage or association analysis, the proposed approach is expected to have greater estimation accuracy and power. Monte Carlo simulations support our theoretical expectations and demonstrate that our new methodology: (1) is more powerful than either FBATs or classic linkage analysis; (2) can unbiasedly estimate genetic parameters regardless of whether association exists, thus remedying the bias and less precision of traditional linkage analysis in the presence of association; and (3) is capable of identifying tight linkage alone. The new approach also holds the theoretical advantage that it can extract statistical information to the maximum extent and thereby improve mapping accuracy and power because it integrates multilocus population-based association study and pedigree-based linkage analysis into a coherent framework. Furthermore, our method is numerically stable and computationally efficient, as compared to existing parametric methods that use the simplex algorithm or Newton-type methods to maximize high-order multidimensional likelihood functions, and also offers the computation of Fisher's information matrix. Finally, we apply our methodology to a genetic study on bone mineral density (BMD) for the vitamin D receptor (VDR) gene and find that VDR is significantly linked to BMD at the one-third region of the wrist. T WO approaches are commonly used in pedigreeor family-based gene mapping, i.e., linkage analysis (e.g., Elston and Stewart 1971;Haseman and Elston 1972;Ott 1974;Lander and Green 1987;Risch 1990;Ward 1993;Amos 1994;Kruglyak and Lander 1995;O'Connell and Weeks 1995;Kruglyak et al. 1996;Gudbjartsson et al. 2000;Abecasis et al. 2002) and family-based association tests (FBATs) (e.g., Falk and Rubinstein 1987;Spielman et al. 1993;Lazzeroni and Lange 1998;Laird et al. 2000;Rabinowitz and Laird 2000). Linkage analysis focuses on gene cosegregation that can be characterized by inheritance vectors or gene concordance between related individuals (identical-bydescent, IBD, or identical-in-state, IIS) at each locus, while association tests (which, when due to linkage, are tests of gametic association, als...

Joint Linkage and Association Analysis Using GENEHUNTER-MODSCORE with an Application to Familial Pancreatic Cancer

“…We demonstrated by simulations that a JLA analysis based on MOD scores can substantially increase power as compared to the corresponding linkage-only test (Table 5). This observation was in accordance with the statement mentioned earlier, saying that a JLA analysis can substantially increase mapping accuracy and power because it makes use of both family and population information [4,5]. Moreover, we showed that there are LD scenarios, for which either the 2-or 3-marker JLA tests can be more powerful than the corresponding singlemarker test, which confirms another statement mentioned earlier, saying that haplotype-based association methods can outperform single-marker analyses [71], especially when the LD between the investigated test markers and the trait locus is rather weak [73].…”

“…Although these implementations offer the ability to include association information into the calculations, formal joint tests for linkage and association are less common. A parametric, likelihood-based approach to JLA analysis was presented by Lou et al [5,65], who also pointed out that neglecting association information can lead to a loss in statistical power of the linkage test and to biased estimates of the recombination fraction. Another JLA approach, implemented in the PSEUDOMARKER software package, exploits the equivalence of parametric and nonparametric linkage methods and offers various likelihood ratio tests with different null and alternative hypotheses including a JLA test for single markers using twopoint calculations [4,63,64].…”

Joint Linkage and Association Analysis Using GENEHUNTER-MODSCORE with an Application to Familial Pancreatic Cancer

“…We demonstrated by simulations that a JLA analysis based on MOD scores can substantially increase power as compared to the corresponding linkage-only test (Table 5). This observation was in accordance with the statement mentioned earlier, saying that a JLA analysis can substantially increase mapping accuracy and power because it makes use of both family and population information [4,5]. Moreover, we showed that there are LD scenarios, for which either the 2-or 3-marker JLA tests can be more powerful than the corresponding singlemarker test, which confirms another statement mentioned earlier, saying that haplotype-based association methods can outperform single-marker analyses [71], especially when the LD between the investigated test markers and the trait locus is rather weak [73].…”

“…Although these implementations offer the ability to include association information into the calculations, formal joint tests for linkage and association are less common. A parametric, likelihood-based approach to JLA analysis was presented by Lou et al [5,65], who also pointed out that neglecting association information can lead to a loss in statistical power of the linkage test and to biased estimates of the recombination fraction. Another JLA approach, implemented in the PSEUDOMARKER software package, exploits the equivalence of parametric and nonparametric linkage methods and offers various likelihood ratio tests with different null and alternative hypotheses including a JLA test for single markers using twopoint calculations [4,63,64].…”

Synteny analysis of genes and distribution of loci controlling oil content and fatty acid profile based on QTL alignment map in Brassica napus

“…In general, identification of candidate genes can be done via genome wide association studies (GWAS), linkage studies, expression studies but also it needs a prior understanding of the biological pathway. Lou et al (2006) affirmed that combining the candidate genes with linkage studies could effectively enhance the accuracy [ 74 ].…”

Statistical approaches in QTL mapping and molecular breeding for complex traits

“…Association mapping has been applied to analyze plant populations, although there are many limitations like the influence of population structure and non-random mating. To improve the accuracy of QTL mapping, some methods that combine interval mapping with association mapping have been proposed [90,91]. Currently, profiting from the rapid advance in high-throughput genotyping, transcriptional profiling and decreasing costs, it has become possible to measure many intermediate phenotypes in the chain of causation from genetic perturbation to phenotypic variation [12] for large mapping population, and even to sequence each individual in a population.…”

Joint Linkage and Association Analysis Using GENEHUNTER-MODSCORE with an Application to Familial Pancreatic Cancer

“…We demonstrated by simulations that a JLA analysis based on MOD scores can substantially increase power as compared to the corresponding linkage-only test (Table 5). This observation was in accordance with the statement mentioned earlier, saying that a JLA analysis can substantially increase mapping accuracy and power because it makes use of both family and population information [4,5]. Moreover, we showed that there are LD scenarios, for which either the 2-or 3-marker JLA tests can be more powerful than the corresponding singlemarker test, which confirms another statement mentioned earlier, saying that haplotype-based association methods can outperform single-marker analyses [71], especially when the LD between the investigated test markers and the trait locus is rather weak [73].…”

“…Although these implementations offer the ability to include association information into the calculations, formal joint tests for linkage and association are less common. A parametric, likelihood-based approach to JLA analysis was presented by Lou et al [5,65], who also pointed out that neglecting association information can lead to a loss in statistical power of the linkage test and to biased estimates of the recombination fraction. Another JLA approach, implemented in the PSEUDOMARKER software package, exploits the equivalence of parametric and nonparametric linkage methods and offers various likelihood ratio tests with different null and alternative hypotheses including a JLA test for single markers using twopoint calculations [4,63,64].…”

Synteny analysis of genes and distribution of loci controlling oil content and fatty acid profile based on QTL alignment map in Brassica napus

“…In general, identification of candidate genes can be done via genome wide association studies (GWAS), linkage studies, expression studies but also it needs a prior understanding of the biological pathway. Lou et al (2006) affirmed that combining the candidate genes with linkage studies could effectively enhance the accuracy [ 74 ].…”

Statistical approaches in QTL mapping and molecular breeding for complex traits

“…Association mapping has been applied to analyze plant populations, although there are many limitations like the influence of population structure and non-random mating. To improve the accuracy of QTL mapping, some methods that combine interval mapping with association mapping have been proposed [90,91]. Currently, profiting from the rapid advance in high-throughput genotyping, transcriptional profiling and decreasing costs, it has become possible to measure many intermediate phenotypes in the chain of causation from genetic perturbation to phenotypic variation [12] for large mapping population, and even to sequence each individual in a population.…”

Joint Linkage and Association Analysis Using GENEHUNTER-MODSCORE with an Application to Familial Pancreatic Cancer

“…We demonstrated by simulations that a JLA analysis based on MOD scores can substantially increase power as compared to the corresponding linkage-only test (Table 5). This observation was in accordance with the statement mentioned earlier, saying that a JLA analysis can substantially increase mapping accuracy and power because it makes use of both family and population information [4,5]. Moreover, we showed that there are LD scenarios, for which either the 2-or 3-marker JLA tests can be more powerful than the corresponding singlemarker test, which confirms another statement mentioned earlier, saying that haplotype-based association methods can outperform single-marker analyses [71], especially when the LD between the investigated test markers and the trait locus is rather weak [73].…”

“…Although these implementations offer the ability to include association information into the calculations, formal joint tests for linkage and association are less common. A parametric, likelihood-based approach to JLA analysis was presented by Lou et al [5,65], who also pointed out that neglecting association information can lead to a loss in statistical power of the linkage test and to biased estimates of the recombination fraction. Another JLA approach, implemented in the PSEUDOMARKER software package, exploits the equivalence of parametric and nonparametric linkage methods and offers various likelihood ratio tests with different null and alternative hypotheses including a JLA test for single markers using twopoint calculations [4,63,64].…”

Synteny analysis of genes and distribution of loci controlling oil content and fatty acid profile based on QTL alignment map in Brassica napus

“…In general, identification of candidate genes can be done via genome wide association studies (GWAS), linkage studies, expression studies but also it needs a prior understanding of the biological pathway. Lou et al (2006) affirmed that combining the candidate genes with linkage studies could effectively enhance the accuracy [ 74 ].…”

Statistical approaches in QTL mapping and molecular breeding for complex traits

“…Association mapping has been applied to analyze plant populations, although there are many limitations like the influence of population structure and non-random mating. To improve the accuracy of QTL mapping, some methods that combine interval mapping with association mapping have been proposed [90,91]. Currently, profiting from the rapid advance in high-throughput genotyping, transcriptional profiling and decreasing costs, it has become possible to measure many intermediate phenotypes in the chain of causation from genetic perturbation to phenotypic variation [12] for large mapping population, and even to sequence each individual in a population.…”