PDF(Pubmed)
Abstract：
Many families with clinical early-onset Alzheimer\'s disease (EOAD) remain genetically unexplained. A combination of genetic factors is not standardly investigated. In addition to monogenic causes, we evaluated the possible polygenic architecture in a large series of families, to assess if genetic testing of familial EOAD could be expanded.
Thirty-six pedigrees (77 patients) were ascertained from a larger cohort of patients, with relationships determined by genetic data (exome sequencing data and/or SNP arrays). All families included at least one AD patient with symptom onset <70 years. We evaluated segregating rare variants in known dementia-related genes, and other genes or variants if shared by multiple families. APOE was genotyped and duplications in APP were assessed by targeted test or using SNP array data. We computed polygenic risk scores (PRS) compared with a reference population-based dataset, by imputing SNP arrays or exome sequencing data.
In eight families, we identified a pathogenic variant, including the genes APP, PSEN1, SORL1, and an unexpected GRN frameshift variant. APOE-ε4 homozygosity was present in eighteen families, showing full segregation with disease in seven families. Eight families harbored a variant of uncertain significance (VUS), of which six included APOE-ε4 homozygous carriers. PRS was not higher in the families combined compared with the population mean (beta 0.05, P = 0.21), with a maximum increase of 0.61 (OR = 1.84) in the GRN family. Subgroup analyses indicated lower PRS in six APP/PSEN1 families compared with the rest (beta -0.22 vs. 0.10; P = 0.009) and lower APOE burden in all eight families with monogenic cause (beta 0.29 vs. 1.15, P = 0.010). Nine families remained without a genetic cause or risk factor identified.
Besides monogenic causes, we suspect a polygenic disease architecture in multiple families based on APOE and rare VUS. The risk conveyed by PRS is modest across the studied families. Families without any identified risk factor render suitable candidates for further in-depth genetic evaluation.
Thirty-six pedigrees (77 patients) were ascertained from a larger cohort of patients, with relationships determined by genetic data (exome sequencing data and/or SNP arrays). All families included at least one AD patient with symptom onset <70 years. We evaluated segregating rare variants in known dementia-related genes, and other genes or variants if shared by multiple families. APOE was genotyped and duplications in APP were assessed by targeted test or using SNP array data. We computed polygenic risk scores (PRS) compared with a reference population-based dataset, by imputing SNP arrays or exome sequencing data.
In eight families, we identified a pathogenic variant, including the genes APP, PSEN1, SORL1, and an unexpected GRN frameshift variant. APOE-ε4 homozygosity was present in eighteen families, showing full segregation with disease in seven families. Eight families harbored a variant of uncertain significance (VUS), of which six included APOE-ε4 homozygous carriers. PRS was not higher in the families combined compared with the population mean (beta 0.05, P = 0.21), with a maximum increase of 0.61 (OR = 1.84) in the GRN family. Subgroup analyses indicated lower PRS in six APP/PSEN1 families compared with the rest (beta -0.22 vs. 0.10; P = 0.009) and lower APOE burden in all eight families with monogenic cause (beta 0.29 vs. 1.15, P = 0.010). Nine families remained without a genetic cause or risk factor identified.
Besides monogenic causes, we suspect a polygenic disease architecture in multiple families based on APOE and rare VUS. The risk conveyed by PRS is modest across the studied families. Families without any identified risk factor render suitable candidates for further in-depth genetic evaluation.
摘要：
许多患有临床早发性阿尔茨海默病（EOAD）的家庭在遗传上仍无法解释。遗传因素的组合不是标准的调查。除了单基因原因，我们评估了一系列家庭中可能的多基因结构，评估家族性EOAD的基因检测是否可以扩展。
从更大的患者队列中确定了36个家系（77名患者），与遗传数据（外显子组测序数据和/或SNP阵列）确定的关系。所有家庭包括至少一名症状发作<70岁的AD患者。我们评估了在已知的痴呆相关基因中分离的罕见变异，和其他基因或变异，如果由多个家庭共享。对APOE进行基因分型，并通过靶向测试或使用SNP阵列数据评估APP中的重复。我们计算了多基因风险评分(PRS)与参考人群数据集的比较，通过输入SNP阵列或外显子组测序数据。
在八个家庭中,我们发现了一种致病变异,包括基因APP，PSEN1、SORL1和一个意外的GRN移码变体。APOE-ε4纯合性存在于18个家庭中，在七个家庭中显示出与疾病的完全隔离。八个家庭具有不确定意义（VUS）的变体，其中6个包括APOE-ε4纯合携带者。合并家庭的PRS与人群平均值相比并不高（β0.05，P=0.21），GRN家族的最大增加量为0.61(OR=1.84)。亚组分析表明，与其他患者相比，六个APP/PSEN1家庭的PRS较低（β-0.22vs.0.10；P=0.009）和所有八个单基因原因家庭的APOE负担较低（β0.29vs.1.15,P=0.010)。九个家庭仍然没有确定的遗传原因或危险因素。
除了单基因原因，我们怀疑基于APOE和罕见VUS的多基因疾病体系结构在多个家庭中。在研究的家庭中，PRS传达的风险不大。没有任何确定的风险因素的家庭为进一步深入的遗传评估提供了合适的候选者。
从更大的患者队列中确定了36个家系（77名患者），与遗传数据（外显子组测序数据和/或SNP阵列）确定的关系。所有家庭包括至少一名症状发作<70岁的AD患者。我们评估了在已知的痴呆相关基因中分离的罕见变异，和其他基因或变异，如果由多个家庭共享。对APOE进行基因分型，并通过靶向测试或使用SNP阵列数据评估APP中的重复。我们计算了多基因风险评分(PRS)与参考人群数据集的比较，通过输入SNP阵列或外显子组测序数据。
在八个家庭中,我们发现了一种致病变异,包括基因APP，PSEN1、SORL1和一个意外的GRN移码变体。APOE-ε4纯合性存在于18个家庭中，在七个家庭中显示出与疾病的完全隔离。八个家庭具有不确定意义（VUS）的变体，其中6个包括APOE-ε4纯合携带者。合并家庭的PRS与人群平均值相比并不高（β0.05，P=0.21），GRN家族的最大增加量为0.61(OR=1.84)。亚组分析表明，与其他患者相比，六个APP/PSEN1家庭的PRS较低（β-0.22vs.0.10；P=0.009）和所有八个单基因原因家庭的APOE负担较低（β0.29vs.1.15,P=0.010)。九个家庭仍然没有确定的遗传原因或危险因素。
除了单基因原因，我们怀疑基于APOE和罕见VUS的多基因疾病体系结构在多个家庭中。在研究的家庭中，PRS传达的风险不大。没有任何确定的风险因素的家庭为进一步深入的遗传评估提供了合适的候选者。
