A study comparing precision of the maximum multipoint heterogeneity LOD statistic to three model-free multipoint linkage methods.

This study compared the performance of the maximum lod (MLOD), maximum heterogeneity lod (MHLOD), maximum non-parametric linkage score (MNPL), maximum Kong and Cox linear extension (MKC(lin)) of NPL, and maximum Kong and Cox exponential extension (MKC(exp)) of NPL as calculated in Genehunter 1.2 and Genehunter-Plus. Our performance measure was the distance between the marker with maximum value for each linkage statistic and the trait locus. We performed a simulation study considering: 1) four modes of transmission, 2) 100 replicates for each model, 3) 58 pedigrees (with 592 subjects) per replicate, 4) three linked marker loci each having three equally frequent alleles, and 5) either 0% unlinked families (linkage homogeneity) or 50% unlinked families (linkage heterogeneity). For each replicate, we obtained the Haldane map position of the location at which each of the five statistics is maximized. The MLOD and MHLOD were obtained by maximizing over penetrances, phenocopy rate, and risk-allele frequencies. For the models simulated, MHLOD appeared to be the best statistic both in terms of identifying a marker locus having the smallest mean distance from the trait locus and in terms of the strongest negative correlation between maximum linkage statistic and distance of the identified position and the trait locus. The marker loci with maximum value of the Kong and Cox extensions of the NPL statistic also were closer to the trait locus than the marker locus with maximum value of the NPL statistic.

Finch SJ ，Chen CH ，Gordon D ，Mendell NR ... -  《GENETIC EPIDEMIOLOGY》

Determining trait locus position from multipoint analysis: accuracy and power of three different statistics.

Previous work using two-point linkage analysis showed that performing a lod score (LOD) analysis twice, once assuming dominant and once assuming recessive inheritance, and then taking the larger of the two values (designated MMLS) usually has more power to detect linkage than any other method tested. Using computer simulation for a variety of complex inheritance models, we demonstrated power for the MMLS comparable with analysis assuming the true model. However, reports in the literature suggested that the MMLS approach might fail to detect linkage using multipoint analysis due to genetic model misspecification. Here, we tested the robustness of the MMLS approach under multipoint analysis. We simulated data under complex inheritance models, including heterogeneity, epistatic, and additive models. We examined the expected maximum LOD, LOD assuming heterogeneity (HLOD), and nonparametric linkage statistics and the corresponding estimated position in a chromosomal interval of 10 markers with 10% recombination between markers. The mean estimates of position were generally good for all three statistics except when heterogeneity existed, where the LOD and the NPL did not perform as well as the HLOD. The MMLS approach was as robust using multipoint as using two-point linkage analysis. LOD and/or the HLOD generally had more power to detect linkage than NPL across a variety of generating models, even after correcting for the multiple tests. For finding linkage to one locus of several contributing to disease expression, assuming the dominant and recessive models with reduced penetrance is a good approximation of the mode of inheritance at that locus.

Greenberg DA ，Abreu PC 《GENETIC EPIDEMIOLOGY》

Lod scores for gene mapping in the presence of marker map uncertainty.

Multipoint lod scores are typically calculated for a grid of locus positions, moving the putative disease locus across a fixed map of genetic markers. Changing the order of a set of markers and/or the distances between the markers can make a substantial difference in the resulting lod score curve and the location and height of its maximum. The typical approach of using the best maximum likelihood marker map is not easily justified if other marker orders are nearly as likely and give substantially different lod score curves. To deal with this problem, we propose three weighted multipoint lod score statistics that make use of information from all plausible marker orders. In each of these statistics, the information conditional on a particular marker order is included in a weighted sum, with weight equal to the posterior probability of that order. We evaluate the type 1 error rate and power of these three statistics on the basis of results from simulated data, and compare these results to those obtained using the best maximum likelihood map and the map with the true marker order. We find that the lod score based on a weighted sum of maximum likelihoods improves on using only the best maximum likelihood map, having a type 1 error rate and power closest to that of using the true marker order in the simulation scenarios we considered.

Stringham HM ，Boehnke M 《GENETIC EPIDEMIOLOGY》

A genome screen of a large bipolar affective disorder pedigree supports evidence for a susceptibility locus on chromosome 13q.

Bipolar affective disorder is a severe mood disorder that afflicts approximately 1% of the population worldwide. Twin and adoption studies have indicated that genetic factors contribute to the disorder and while many chromosomal regions have been implicated, no susceptibility genes have been identified. In this present study, we undertook a 10 cM genome screen using 400 microsatellite markers in a large multigenerational bipolar pedigree consisting of 40 individuals, including six affecteds. We found strongest evidence for linkage to chromosome 13q14. A maximum NPL score of 4.09 (P = 0.008) was obtained between markers D13S1272 and D13S153 using GENEHUNTER. A maximum two-point LOD score of 2.91 (theta = 0.0) was found for marker D13S153 and a maximum three-point LOD score of 3.0 was obtained between markers D13S291 and D13S153 under a recessive model with 90% maximum age-specific penetrance and including bipolar I and unipolar individuals as affected. Several other markers in the region, D13S175, D13S218, D13S263, and D13S156 had two-point LOD scores greater than 1.5. These results meet the criteria for evidence of suggestive linkage. Haplotype analysis enabled us to narrow the likely disease region to a 6 cM region between markers D13S1272 and D13S1319, which contains the serotonin 2A receptor candidate gene. Two single nucleotide polymorphisms were identified in this gene but we did not detect any significant differences in allele frequency in a case-control sample. The region on chromosome 13q14-32 has previously been implicated in other bipolar and schizophrenia cohorts. Our results provide further support for the existence of a susceptibility locus on chromosome 13q14.

Badenhop RF ，Moses MJ ，Scimone A ，Mitchell PB ，Ewen KR ，Rosso A ，Donald JA ，Adams LJ ，Schofield PR ... -  《MOLECULAR PSYCHIATRY》

Multipoint development of the weighted pairwise correlation (WPC) linkage method for pedigrees of arbitrary size and application to the analysis of breast cancer and alcoholism familial data.

The weighted pairwise correlation (WPC) method is a simple and powerful model-free method of linkage analysis that has the advantages of being applicable to binary, ordered categorical, quantitative, or censored traits, and to consider all pairs of relatives in large pedigrees. The originally implemented approach was limited to the use of the identical by state (IBS) information, and we recently extended the WPC method to incorporate the identical by descent (IBD) information for two-point linkage analysis. Here, we develop a multipoint WPC method suitable for pedigrees of arbitrary size and large number of markers. The multipoint IBD estimation procedure for relative pairs is based on the efficient regression approach developed for pedigrees implemented in SOLAR. A robust and fast Monte-Carlo procedure is used to determine reliable P values. Application of the method to the 214 pedigrees from the Breast Cancer Linkage Consortium provided for the Genetic Analysis Workshop (GAW) 9 shows that multipoint WPC statistic values were not far from two-point maximum lod-score values obtained by the classical parametric linkage method and were higher than multipoint variance component analysis lod-scores obtained with SOLAR. The multipoint WPC method is also used to analyze the familial Collaborative Study of the Genetics of Alcoholism data on alcoholism released for GAW11. It allows a better specification of the linkage results previously obtained within the chromosome 4 region.

Zinn-Justin A ，Ziegler A ，Abel L 《GENETIC EPIDEMIOLOGY》