家族性精神分裂症的定量性状与1号染色体的连锁分析

目的 探讨家族性精神分裂症的定量性状位点与1号染色体的分子遗传学关系。方法 在32个家族性精神分裂症家系中，选择以下量表对精神分裂症患者的性状进行定量，包括：阳性和阴性综合征量有、功能全面评定量表、病前分裂样和分裂型特质量表、病前社会适应量表，结合1号染色体上29个DNA多态标记位点的扫描数据，进行数量性状的遗传分析。结果 精神分裂症的阴性症状在147.64cM位置得到最大Trad H-E Lod值为1.73、最大EH H－E Lod值为1.65，此区域与质量性状连锁分析在1q21-23的峰值区域重叠。结论 提示精神分裂症阴性症状在1q21-23可能有独立的数量性状位点。     

Use of recombinant inbred strains to detect quantitative trait loci associated with behavior

Recombinant inbred (RI) strains are valuable not only for detecting major gene segregation and linkage but also for identifying associations between behavior and quantitative trait loci (QTL) that account for relatively small amounts of variation in behaviors for which strain distribution patterns are not bimodal. When applied to published data on genetic markers and on behavior for BXD RI strains, the RI QTL association approach suggests the presence of QTLs on chromosomes 6 and 12 for open-field activity and on chromosomes 1, 2, and 17 for high-pressure seizure susceptibility. Because the RI QTL approach does not require that the progenitor inbred strains of a particular RI series differ, researchers could focus on the BXD RI series, for which the greatest number of genetic markers are available. Focusing on BXD would capitalize on the cumulative nature of RI research which permits analyses of QTL sources of genetic correlations across studies.Support for our ongoing research on the RI QTL approach to alcohol-related behavior is provided by NIAAA Grant AA-8125 and the Hanley Foundation.     

Using multivariate genetic modeling to detect pleiotropic quantitative trait loci

Large numbers of sibling pairs or other relatives are needed to detect linkage between a quantitative trait locus (QTL) and a marker, especially if the variance of the QTL is low relative to the total phenotypic variance of the trait. One strategy to increase the power to detect linkage is to reduce the environmental variance in the trait under analysis. This approach was explored by carrying out a series of simulation studies in which multivariate observations were used to estimate individual genotypic values at a QTL, that pleiotropically affected more than one trait. Simulations for different QTL allele frequencies with a completely informative marker showed that the power to detect the QTL increased substantially when estimates of individual genotypic values at the QTL were used in the linkage analysis instead of phenotypic observations. An advantage of this approach is that, rather than employing phenotypic selection, individuals with extreme genotypes may be selected when ascertaining a sample of extreme families.     

Locating human quantitative trait loci: Guidelines for the selection of sibling pairs for genotyping

Simulation studies were conducted to assess the relative merits of different nonrandom sampling strategies for the selection of sibling pairs for genotyping in the attempt to locate individual loci (QTLs) contributing to variation in human quantitative traits. For a constant amount of variation contributed by a QTL (25% of the total) the frequencies and dominance relationships of a trait increasing allele were varied. Three strategies for selection of pairs for genotyping were based on the phenotypic values of the siblings: Concordant sib pairs (CSP) are pairs in which both individuals exceed a given threshold value; discordant sib pairs (DSP) are pairs in which one member exceeds a given upper threshold and the other is below a specified lower threshold; and most similar pairs (MSP) are pairs selected for falling below a specified percentile ranking of the within-pair mean square for the quantitative trait. Tests for linkage with markers at 1, 2, 5, 10, and 20 cM from each of the QTLs were conducted for each of the selected samples and compared with tests based on the regression, in the entire sample, of within pair variation on the proportion of alleles identical by descent (IBD) at each marker locus. Tests for the effect of the increasing allele at the QTL (candidate gene) were also conducted for the DSP pairs. No single nonrandom selection procedure yields as much as half the information realized in the total sample. However, a combined strategy which involves genotyping the 5% of MSP and DSP for the upper and lower quintiles of values of the quantitative trait (a further 3% of the sample approximately) yields lod scores which are usually more than 65% of the values realized for the entire sample. Tests comparing the proportion of increasing alleles in high- and low-scoring siblings from DSP samples are uniformly very powerful for detecting candidate loci. Even when it is not possible to measure the entire range of the phenotype with uniform precision, some attempt to differentiate among individuals in a common unaffected class of individuals can lead to considerable increase in power.     

Multivariate multipoint linkage analysis of quantitative trait loci

Resolution of the genetic components of complex disorders may require simultaneous analysis of the contribution of individual quantitative trait loci (QTLs) to multiple variables. A likelihood approach is used to illustrate how the complexities of multivariate data may be resolved with multipoint linkage analysis. Sibling pair data were simulated from a model in which two QTLs and trait-specific polygenic effects explained all the sibling resemblance within and between five variables. Multipoint linkage analysis was used to obtain individual pair probabilities of having zero, one, or two alleles identical by descent, and these probabilities were applied in a weighted maximum-likelihood fit function. The results were compared with those obtained using conventional linear structural equation modeling to estimate the contribution of latent genetic factors to the genetic covariance in the multiple measures. Both analyses were conducted using the Mx package. Relatively poor agreement was found between genetic factors defined in purely statistical terms by varimax rotation of the first two factors of the genetic covariance matrix and the structure obtained by fitting a model jointly to the phenotypic and the multipoint linkage data.     

DNA markers associated with high versus low IQ: The IQ quantitative trait loci (QTL) project

General cognitive ability (intelligence, often indexed by IQ scores) is one of the most highly heritable behavioral dimensions. In an attempt to identify some of the many genes (quantitative trait loci; QTL) responsible for the substantial heritability of this quantitative trait, the IQ QTL Project uses an allelic association strategy. Allelic frequencies are compared for the high and low extremes of the IQ dimension using DNA markers in or near genes that are likely to be relevant to neural functioning. Permanent cell lines have been established for low-IQ (mean IQ=82;N=18), middle-IQ (mean IQ=105;N=21), and high-IQ (mean IQ=130;N=24) groups and for a replication sample consisting of even more extreme low-IQ (mean IQ=59;N=17) and high-IQ (mean IQ=142;N=27) groups. Subjects are Caucasian children tested from 6 to 12 years of age. This first report of the IQ QTL Project presents allelic association results for 46 two-allele markers and for 26 comparisons for 14 multiple-allele markers. Two markers yielded significant (p<.01) allelic frequency differences between the high- and the low-IQ groups in the combined sample—a new HLA marker for a gene unique to the human species and a new brain-expressed triplet repeat marker (CTGB33). The prospects for harnessing the power of molecular genetic techniques to identify QTL for quantitative dimensions of human behavior are discussed.     

SNP rs220028和STR HUMARA位点甲基化标记的时空稳定性研究

目的调查印记SNPrs220028和X-STRHUMARA位点甲基化标记的时空稳定性,评估其实用价值。方法采用甲基化敏感性限制酶消化后PCR技术,对SNPrs220028和STRHUMARA位点进行甲基化等位基因特异性分型。实验涉及10例不同年龄男女个体的血液、心、脑、肝、肾等主要组织以及不同程度降解的组织标本。结果SNPrs220028和STRHUMARA的甲基化等位基因特异性分型不受检材年龄、组织种类和一般程度降解的影响。结论SNPrs220028和X-STRHUMARA位点的甲基化标记稳定性良好,有实际应用价值。     

Quantitative trait loci (QTL) analyses and alcohol-related behaviors

Recombinant inbred (RI) strains can make an important contribution toward the merger of molecular genetics and quantitative genetics in the quest for quantitative trait loci (QTL). We present preliminary analyses of alcohol-related processes from our ongoing research using the BXD RI series. Issues concerning reliability, genetic correlations, and RI QTL analysis are discussed. Several strategies for replication and extension of QTL candidate regions are considered: F₁ crosses between RI strains, F₂ crosses, heterogeneous stock, interspecific backcrosses, QTL selection, and the use of murine QTL in chromosomal regions syntenic to human chromosomes as candidate chromosomal regions for human QTL.     

Hypothetical quantitative trait loci (QTL) for circadian period of locomotor activity in CXB recombinant inbred strains of mice

The locomotor activity of male mice (Mus musculus) of 13 CXB (BALB/cBy × C57BL/6J) recombinant inbred (RI) strains and their progenitor strains was monitored for 4 to 6 weeks by infrared photoelectric beams under constant dark. The circadian period (τ) of locomotor activity was calculated and used in quantitative trait locus (QTL) analysis of strains' means. Results were compared with potential QTL found in a previous study of the BXD RI series. The mean τ of 13 CXB RI mouse strains (three to six animals per strain) in constant dark had a unimodal distribution suggesting polygenic inheritance. A number of potential QTL were found for this trait. There were two associations atp<.001,H23 on chromosome 3 andPmv16 on chromosome 16. A region of chromosome 1 was associated with τ in both CXB and BXD RI series. There was also a conjunction with a locus determined from QTL analysis of the previously reported τ of wheel running activity in seven CXB RI strains (Schwartz and Zimmerman, 1990).