Methods for Human Genetic Mapping

描述（由申请人提供）：复杂性状的遗传分析是生物医学研究人员在所谓的“后基因组时代”面临的主要挑战之一。“特别感兴趣的复杂特征包括常见疾病，如糖尿病，哮喘，高血压，精神疾病和癌症，这些疾病共同占美国医疗保健负担的很大一部分。它们是家族性的，但没有简单的传播模式，可能是多种遗传和环境因素的作用和相互作用的结果。这些特征的遗传结构是复杂的，仍然很难描述。确定和描述复杂疾病的遗传成分不仅有助于确定这些疾病的主要缺陷，而且有助于澄清环境风险因素的作用，这些因素也可能是具有成本效益的治疗和预防战略的目标。研究设计和分析方法对简单的孟德尔性状很有效，但对复杂性状的分析可能不够。 拟议研究的长期目标是开发用于人类复杂性状的绘图和遗传分析的统计方法。该提案特别侧重于开发质量性状的连锁不平衡作图方法，包括单倍型或多位点基因型数据。我们建议开发和测试统计模型和方法，并分发实现以下新方法的软件：（1）评估具有近交系的孤立建立者群体中的连锁不平衡;（2）评估具有近交系的孤立建立者群体中的连锁不平衡;（3）评估远交群体中的高分辨率单倍型结构;和（4）远交群体中连锁不平衡作图的方法，该方法利用高分辨率单倍型结构的信息。我们的初步研究表明，这些方法可以提高检测和定位复杂性状基因的能力，从而提高成功定位克隆的几率。

DESCRIPTION (provided by applicant): Genetic analysis of complex traits is one of the major challenges facing biomedical researchers in the so-called "'post-genomic era." Complex traits of particular interest include common diseases such as diabetes, asthma, hypertension, psychiatric illnesses, and cancer that together account for a large portion of the health care burden in the United States. They are familial, but do not have simple patterns of transmission and are likely to result from the actions and interactions of multiple genetic and environmental factors. The genetic architecture of such traits is complex and remains poorly characterized. Identifying and characterizing the genetic component to complex disorders should be useful in determining not only the primary defects for such disorders, but also in clarifying the role of environmental risk factors, which could also be targets of cost-effective treatment and prevention strategies. Study designs and methods of analysis that have worked well for simple Mendelian traits may not be sufficient for analysis of complex traits. The long-term objective of the proposed research is development of statistical methods for mapping and genetic analysis of human complex traits. The proposal is focused specifically on development of methods for linkage disequilibrium mapping of qualitative traits, with haplotype or multilocus genotype data. We propose to develop and test statistical models and methods and distribute software implementing new approaches in: (1) assessment of linkage disequilibrium in isolated founder populations with inbred pedigrees; 2) linkage disequilibrium mapping in isolated founder populations with inbred pedigrees; (3) assessment of high-resolution haplotype structure in outbred populations; and (4) methods for linkage disequilibrium mapping in outbred populations, that make use of information on high-resolution haplotype structure. Our preliminary studies indicate that these approaches can improve the ability to detect and localize genes for complex traits, thereby improving the odds for successful positional cloning.