Revealing Epistasis in Alzheimer Disease

阿尔茨海默病（Alzheimer disease，AD）是老年人痴呆的主要原因之一。 识别AD的易感基因将有助于风险评估、诊断和了解疾病的病因。 几个染色体区域已被确定为携带晚发性AD的基因，但只有一个基因，APOE，已被证明是一贯直接参与疾病的风险。 虽然APOE可以解释迟发性AD中高达一半的遗传效应，但其余的易感基因难以识别。 大量的候选基因已被测试的关联使用病例对照测试无关的个人或家庭为基础的关联测试，但结果有很大的差异研究。 我们的假设是，多个基因间的上位效应在决定AD的风险中起着比任何单个基因的独立效应更重要的作用。 许多候选基因关联研究的多个阳性和阴性报告实际上可能是由于研究设计仅评估每个候选基因的主效应，而这些主效应独立于所有其他基因。 本研究的目的是确定上位性或非加性基因-基因相互作用对晚发性AD风险的作用。 为了实现这一目标，我们建议在10个AD候选基因中识别和分型几个单核苷酸多态性，这些基因的关联研究存在冲突。 我们将使用一个家庭为基础的设计，使用受影响和未受影响的兄弟姐妹，并建议研究800兄弟姐妹约1600人。 我们将扩展最近开发的谱系不平衡检验（PDT）来测试基因型水平的关联，并将其纳入新的多因素降维（MDR）方法中。为了测试这些数据中复杂的遗传相互作用，我们将使用这种改进的MDR-PDT方法。 我们预计，这些结果将解释至少一些阿尔茨海默病候选基因关联研究中出现的不一致。此外，从拟议的研究中获得的知识将对预防和治疗阿尔茨海默病的开始，进展和严重程度的公共卫生工作非常宝贵。

Alzheimer disease (AD) is a leading cause of dementia in the elderly. Identifying susceptibility genes for AD will aid in risk assessment, diagnosis and understanding the etiology of the disease. Several chromosomal regions have been identified as harboring genes for late-onset AD, but only one gene, APOE, has been demonstrated consistently to be directly involved in disease risk. While APOE may explain up to half of the genetic effect in late-onset AD, the remaining susceptibility genes have been difficult to identify. A large number of candidate genes have been tested for association using either case-control tests in unrelated individuals or family-based association tests, but the results have varied greatly between studies. It is our hypothesis that epistatic effects among multiple genes play a more important role in determining risk of AD than the independent effects of any single gene. The multiple positive and negative reports for numerous candidate gene association studies may in fact be due to study designs that only evaluate each candidate gene for main effects that are independent of all other genes. The goal of this proposal is to determine the role of epistasis or nonadditive gene-gene interactions on the risk of late-onset AD. To accomplish this goal, we propose to identify and genotype several single nucleotide polymorphisms in ten AD candidate genes for which there have been conflicting association studies. We will use a family-based design using affected and unaffected siblings and propose to study 800 sibships containing approximately 1600 individuals. We will extend the recently developed pedigree disequilibrium test (PDT) to test for associations at the genotypic level and allow its incorporation into the new multifactor dimensionality reduction (MDR) method. To test for complex genetic interactions in these data, we will use this modified MDR-PDT method. We anticipate that these results will explain at least some of the inconsistency arising from Alzheimer disease candidate gene association studies. Further, knowledge gained from the proposed research will be invaluable for public health efforts to prevent and treat the initiation, progression, and severity of Alzheimer disease.