Abstract:
Disease-associated variants identified from genome-wide association studies (GWASs) frequently map to non-coding areas of the genome such as introns and intergenic regions. An exclusive reliance on gene-agnostic methods of genomic investigation could limit the identification of relevant genes associated with polygenic diseases such as Alzheimer disease (AD). To overcome such potential restriction, we developed a gene-constrained analytical method that considers only moderate- and high-risk variants that affect gene coding sequences. We report here the application of this approach to publicly available datasets containing 181,388 individuals without and with AD and the resulting identification of 660 genes potentially linked to the higher AD prevalence among Africans/African Americans. By integration with transcriptome analysis of 23 brain regions from 2,728 AD case-control samples, we concentrated on nine genes that potentially enhance the risk of AD: AACS, GNB5, GNS, HIPK3, MED13, SHC2, SLC22A5, VPS35, and ZNF398. GNB5, the fifth member of the heterotrimeric G protein beta family encoding Gβ5, is primarily expressed in neurons and is essential for normal neuronal development in mouse brain. Homozygous or compound heterozygous loss of function of GNB5 in humans has previously been associated with a syndrome of developmental delay, cognitive impairment, and cardiac arrhythmia. In validation experiments, we confirmed that Gnb5 heterozygosity enhanced the formation of both amyloid plaques and neurofibrillary tangles in the brains of AD model mice. These results suggest that gene-constrained analysis can complement the power of GWASs in the identification of AD-associated genes and may be more broadly applicable to other polygenic diseases.
摘要:
从全基因组关联研究(GWAS)中鉴定的疾病相关变体经常映射到基因组的非编码区域,例如内含子和基因间区域。对基因组研究的基因不可知方法的排他性依赖可能会限制与多基因疾病相关的相关基因的鉴定,例如阿尔茨海默病(AD)。为了克服这种潜在的限制,我们开发了一种基因约束分析方法,该方法仅考虑影响基因编码序列的中度和高风险变异.我们在这里报告了这种方法在公开可用的数据集的应用,该数据集包含181,388个没有和患有AD的个体,以及所得到的660个基因的鉴定,这些基因可能与非洲人/非裔美国人中较高的AD患病率有关。通过与来自2,728个AD病例对照样本的23个大脑区域的转录组分析整合,我们集中研究了9种可能增加AD风险的基因:AACS,GNB5,GNS,HIPK3、MED13、SHC2、SLC22A5、VPS35和ZNF398。GNB5是编码Gβ5的异三聚体G蛋白β家族的第五成员,主要在神经元中表达,并且对于小鼠脑中的正常神经元发育是必需的。人类GNB5功能的纯合或复合杂合缺失先前与发育迟缓综合征有关,认知障碍,和心律失常。在验证实验中,我们证实Gnb5杂合性增强了AD模型小鼠脑中淀粉样斑块和神经原纤维缠结的形成。这些结果表明,基因约束分析可以补充GWAS在鉴定AD相关基因方面的能力,并且可能更广泛地适用于其他多基因疾病。