A Variance-Component Framework for Pedigree Analysis of Continuous and Categorical Outcomes

Variance-component methods are popular and flexible analytic tools for elucidating the genetic mechanisms of complex quantitative traits from pedigree data. However, variance-component methods typically assume that the trait of interest follows a multivariate normal distribution within a pedigree. Studies have shown that violation of this normality assumption can lead to biased parameter estimates and inflations in type-I error. This limits the application of variance-component methods to more general trait outcomes, whether continuous or categorical in nature. In this paper, we develop and apply a general variance-component framework for pedigree analysis of continuous and categorical outcomes. We develop appropriate models using generalized-linear mixed model theory and fit such models using approximate maximum-likelihood procedures. Using our proposed method, we demonstrate that one can perform variance-component pedigree analysis on outcomes that follow any exponential-family distribution. Additionally, we also show how one can modify the method to perform pedigree analysis of ordinal outcomes. We also discuss extensions of our variance-component framework to accommodate pedigrees ascertained based on trait outcome. We demonstrate the feasibility of our method using both simulated data and data from a genetic study of ovarian insufficiency.     

一般家系二分类性状的贝叶斯连锁分析方法

应用阈值模型和可逆的跳跃马尔可夫链方法提出一种适用于人类一般家系中复杂二分类性状基因定位的连锁分析方法,此方法可以同时估计易感基因位点的数目与位置。     

Analysis of Crossover Designs with a Categorical Response

In the analysis of two-period crossover designs, one frequently must consider the case of a categorical response with binary as a special case. These circumstances are considered in this paper and the proposed method—an extension of GART'S tests for the binary case—is similar to that of PIKE, CASAGRANDE and SMITH for the analysis of pair-matched case-control studies. The results are illustrated with a numerical example.     

The Effects of Selection on Linkage Analysis for Quantitative Traits

The effects of within-sample selection on the outcome of analyses detecting linkage between genetic markers and quantitative traits were studied. It was found that selection by truncation for the trait of interest significantly reduces the differences between marker genotype means thus reducing the power to detect linked quantitative trait loci (QTL). The size of this reduction is a function of proportion selected, the magnitude of the QTL effect, recombination rate between the marker locus and the QTL, and the allele frequency of the QTL. Proportion selected was the most influential of these factors on bias, e.g., for an allele substitution effect of one standard deviation unit, selecting the top 80%, 50% or 20% of the population required 2, 6 or 24 times the number of progeny, respectively, to offset the loss of power caused by this selection. The effect on power was approximately linear with respect to the size of gene effect, almost invariant to recombination rate, and a complex function of QTL allele frequency. It was concluded that experimental samples from animal populations which have been subjected to even minor amounts of selection will be inefficient in yielding information on linkage between markers and loci influencing the quantitative trait under selection.     

Statistics for Nonparametric Linkage Analysis of X-Linked Traits in General Pedigrees

We have compared the power of several allele-sharing statistics for "nonparametric" linkage analysis of X-linked traits in nuclear families and extended pedigrees. Our rationale was that, although several of these statistics have been implemented in popular software packages, there has been no formal evaluation of their relative power. Here, we evaluate the relative performance of five test statistics, including two new test statistics. We considered sibships of sizes two through four, four different extended pedigrees, 15 different genetic models (12 single-locus models and 3 two-locus models), and varying recombination fractions between the marker and the trait locus. We analytically estimated the sample sizes required for 80% power at a significance level of.001 and also used simulation methods to estimate power for a sample size of 10 families. We tried to identify statistics whose power was robust over a wide variety of models, with the idea that such statistics would be particularly useful for detection of X-linked loci associated with complex traits. We found that a commonly used statistic, S(all), generally performed well under various conditions and had close to the optimal sample sizes in most cases but that there were certain cases in which it performed quite poorly. Our two new statistics did not perform any better than those already in the literature. We also note that, under dominant and additive models, regardless of the statistic used, pedigrees with all-female siblings have very little power to detect X-linked loci.     

Genome-Wide Linkage Analysis Identifies Loci for Testicle and Ovary Traits in Chickens

Development of testes or ovaries is critical to chicken breeders. Understanding the genetic mechanisms influencing the development of the testes and ovaries could enhance selection efforts which target reproductive traits. The linkage analysis was conducted within an F2 population derived from Beijing-You chickens and a commercial broiler line. The results have identified one quantitative trait loci (QTL, designated T1) for bilateral testicular weight (TW) and the percentage of TW to carcass weight, and five QTLs (designated O1–O5) for ovary weight (follicle-free, OW) and the percentage of OW to carcass weight. For the testes traits, QTL T1 is located between 6.55 and 8.56 Mb on GGA13. Especially, the gene gamma-amino butyric acid A receptor, alpha 1 (GABRA1) located near the T1 peak. For ovarian traits, QTL O2 was located at 29.31 Mb on GGA7. G protein-coupled receptor 39 (GPR39) present at the O2 peak was expressed at higher levels within the reproductive tract. It is also involved in the regulation of several reproductive functions. Other QTL peaks and the genes’ function in the ovary and testes need to be evaluated. The QTLs and the genes identified in this study could provide valuable information for establishing reproductive traits in chickens, and need further investigation.     

一个DMD家系的Bayes分析和RFLP连锁分析

本文对一个DMD家系中先证者之妹的致病基因携带者风险用3种方法进行估计。单纯根据系谱分析,其风险为50%;以CPK值为条件概率作Bayes分析,其风险为25%;用RFLP连锁分析,推断其风险仅为5%。将RFLP连锁分析的结果作为又一个条件概率进行Bayes分析,其风险估计又进一步准确到不超过2%。三者结合,得到了最佳的结果。     

Predicting Quantitative Traits With Regression Models for Dense Molecular Markers and Pedigree

The availability of genomewide dense markers brings opportunities and challenges to breeding programs. An important question concerns the ways in which dense markers and pedigrees, together with phenotypic records, should be used to arrive at predictions of genetic values for complex traits. If a large number of markers are included in a regression model, marker-specific shrinkage of regression coefficients may be needed. For this reason, the Bayesian least absolute shrinkage and selection operator (LASSO) (BL) appears to be an interesting approach for fitting marker effects in a regression model. This article adapts the BL to arrive at a regression model where markers, pedigrees, and covariates other than markers are considered jointly. Connections between BL and other marker-based regression models are discussed, and the sensitivity of BL with respect to the choice of prior distributions assigned to key parameters is evaluated using simulation. The proposed model was fitted to two data sets from wheat and mouse populations, and evaluated using cross-validation methods. Results indicate that inclusion of markers in the regression further improved the predictive ability of models. An R program that implements the proposed model is freely available.     

Statistical Methods for Linkage Analysis of Complex Traits from High-Resolution Maps of Identity by Descent

A multilocus model for complex traits is described that generalizes the additive and multiplicative models and hence allows simultaneously for both heterogeneity and gene interaction (epistasis). Statistical methods of linkage analysis are discussed under the assumption that identity by descent data from a dense set of polymorphic markers are available. Three methods, single locus search, simultaneous search and conditional search, are described and compared.     

Mutation in KERA Identified by Linkage Analysis and Targeted Resequencing in a Pedigree with Premature Atherosclerosis

Aims

Genetic factors explain a proportion of the inter-individual variation in the risk for atherosclerotic events, but the genetic basis of atherosclerosis and atherothrombosis in families with Mendelian forms of premature atherosclerosis is incompletely understood. We set out to unravel the molecular pathology in a large kindred with an autosomal dominant inherited form of premature atherosclerosis.

Methods and Results

Parametric linkage analysis was performed in a pedigree comprising 4 generations, of which a total of 11 members suffered from premature vascular events. A parametric LOD-score of 3.31 was observed for a 4.4 Mb interval on chromosome 12. Upon sequencing, a non-synonymous variant in KERA (c.920C>G; p.Ser307Cys) was identified. The variant was absent from nearly 28,000 individuals, including 2,571 patients with premature atherosclerosis. KERA, a proteoglycan protein, was expressed in lipid-rich areas of human atherosclerotic lesions, but not in healthy arterial specimens. Moreover, KERA expression in plaques was significantly associated with plaque size in a carotid-collar Apoe^−/− mice (r² = 0.69; p<0.0001).

Conclusion

A rare variant in KERA was identified in a large kindred with premature atherosclerosis. The identification of KERA in atherosclerotic plaque specimen in humans and mice lends support to its potential role in atherosclerosis.     

A Bayesian Nonparametric Approach for Mapping Dynamic Quantitative Traits

In biology, many quantitative traits are dynamic in nature. They can often be described by some smooth functions or curves. A joint analysis of all the repeated measurements of the dynamic traits by functional quantitative trait loci (QTL) mapping methods has the benefits to (1) understand the genetic control of the whole dynamic process of the quantitative traits and (2) improve the statistical power to detect QTL. One crucial issue in functional QTL mapping is how to correctly describe the smoothness of trajectories of functional valued traits. We develop an efficient Bayesian nonparametric multiple-loci procedure for mapping dynamic traits. The method uses the Bayesian P-splines with (nonparametric) B-spline bases to specify the functional form of a QTL trajectory and a random walk prior to automatically determine its degree of smoothness. An efficient deterministic variational Bayes algorithm is used to implement both (1) the search of an optimal subset of QTL among large marker panels and (2) estimation of the genetic effects of the selected QTL changing over time. Our method can be fast even on some large-scale data sets. The advantages of our method are illustrated on both simulated and real data sets.     

Testing Linkage Hypotheses in Hybrid Analysis of Alternatively Distributed Behavioral Traits with Incomplete Penetrance

The use of polymorphic microsatellite markers for mapping alternatively distributed behavioral traits with incomplete penetrance was studied with special reference to inheritance of predisposition to catalepsy in mice. Using only backcrosses as a segregating population, the major gene for catalepsy was with high likelihood mapped to region 30–75 cM of murine chromosome 13. It was also established that this gene determines 20% of the trait penetrance whereas the remaining 31% of the observed penetrance are accounted for by numerous polygenes.     

多元性状同胞对连锁分析方法及其在原发性高血压基因定位数据中的应用

提出新的以广义最小二乘法原理处理同胞对数据间的相关性,以多元响应回归的方法处理多个性状数据间的相关性的多元性状同胞对连锁分析方法,模型的参数估计使用MCMC方法．并把此模型应用于原发性高血压基因定位的实际数据中．结果表明,与把多元性状拆成单一性状进行分析的方法相比,本文的方法可以提高估计的精度和检验的效能．     

ANOVA Designs for Estimating Heritability of Reproductive Traits in Medicinal Leech Hirudo medicinalisL.

ANOVA designs for estimating heritabilities of fecundity traits inHirudo medicinalis including batch size, the number of juveniles per cocoon, and juvenile weight. Accounting for reproduction mode of this species, different types of kinship were identified, which were taken into account in the ANOVA designs: juveniles from one batch and one cocoon were considered respectively full sibs and polyzygotic twins. Variation components were analyzed in the following kinship groups: for batch size, in full sibs; for the number of juveniles per cocoon, between sibships, full sins, and replicates; and for juvenile weight, in full sibs and polyzygotic twins. Using these designs, heritabilities of basic reproductive traits of H. medicinalis were obtained: for batch size, h ² = 0.35–0.40, H ² = 0.40–0.45; for the number of juveniles per cocoon, h ² = 0.33–0.36, H ² = 0.36–0.39; and for juvenile weight, h ² = 0.40–0.44, H ² = 0.44–0.48.     

Linkage of Bipolar Affective Disorder to Chromosome 18 Markers in a New Pedigree Series

Several groups have reported evidence suggesting linkage of bipolar affective disorder (BPAD) to chromosome 18. We have reported data from 28 pedigrees that showed linkage to marker loci on 18p and to loci 40 cM distant on 18q. Most of the linkage evidence derived from families with affected phenotypes in only the paternal lineage and from marker alleles transmitted on the paternal chromosome. We now report results from a series of 30 new pedigrees (259 individuals) genotyped for 13 polymorphic markers spanning chromosome 18. Subjects were interviewed by a psychiatrist and were diagnosed by highly reliable methods. Genotypes were generated with automated technology and were scored blind to phenotype. Affected sib pairs showed excess allele sharing at the 18q markers D18S541 and D18S38. A parent-of-origin effect was observed, but it was not consistently paternal. No robust evidence of linkage was detected for markers elsewhere on chromosome 18. Multipoint nonparametric linkage analysis in the new sample combined with the original sample of families supports linkage on chromosome 18q, but the susceptibility gene is not well localized.     

圈养大熊猫的系谱分析

应用Sparks Verl.4软件结合手工算法对现有的圈养大熊猫系谱进行了遗传分析。结果表明,圈养大熊猫群体规模小,漂变是导致遗传多样性丢失的主要因素。由于分散管理,现有群体正面临着近亲交配、种源枯竭的危险。因此,应统一遗传管理,加强各繁殖系之间的基因交流,使圈养大熊猫的遗传多样性能够保持在较高的水平之上。     

Score Tests for Association between Traits and Haplotypes when Linkage Phase Is Ambiguous

A key step toward the discovery of a gene related to a trait is the finding of an association between the trait and one or more haplotypes. Haplotype analyses can also provide critical information regarding the function of a gene; however, when unrelated subjects are sampled, haplotypes are often ambiguous because of unknown linkage phase of the measured sites along a chromosome. A popular method of accounting for this ambiguity in case-control studies uses a likelihood that depends on haplotype frequencies, so that the haplotype frequencies can be compared between the cases and controls; however, this traditional method is limited to a binary trait (case vs. control), and it does not provide a method of testing the statistical significance of specific haplotypes. To address these limitations, we developed new methods of testing the statistical association between haplotypes and a wide variety of traits, including binary, ordinal, and quantitative traits. Our methods allow adjustment for nongenetic covariates, which may be critical when analyzing genetically complex traits. Furthermore, our methods provide several different global tests for association, as well as haplotype-specific tests, which give a meaningful advantage in attempts to understand the roles of many different haplotypes. The statistics can be computed rapidly, making it feasible to evaluate the associations between many haplotypes and a trait. To illustrate the use of our new methods, they are applied to a study of the association of haplotypes (composed of genes from the human-leukocyte-antigen complex) with humoral immune response to measles vaccination. Limited simulations are also presented to demonstrate the validity of our methods, as well as to provide guidelines on how our methods could be used.     

系谱分析中概率问题的贝叶斯分析一例

《生物学通报》2007年第2期“遗传概率的一个认识误区”一文,给出了一个家系概率问题的答案,但没有详尽的分析过程,不利于初学者的学习掌握,本文对此予以补充和完善。[第一段]