Inference of Causative Genes for Alzheimer's Disease Due to Dosage Imbalance

Copy number variations (CNVs) have recently drawn attention as an important genetic factor for diseases, especially common neuropsychiatric disorders including Alzheimer's disease (AD). Because most of the pathogenic CNV regions overlap with multiple genes, it has been challenging to identify the true disease-causing genes amongst them. Notably, a recent study reported that CNV regions containing ohnologs, which are dosage-sensitive genes, are likely to be deleterious. Utilizing the unique feature of ohnologs could be useful for identifying causative genes with pathogenic CNVs, however its effectiveness is still unclear. Although it has been reported that AD is strongly affected by CNVs, most of AD-causing genes with pathogenic CNVs have not been identified yet. Here, we show that dosage-sensitive ohnologs within CNV regions reported in patients with AD are related to the nervous system and are highly expressed in the brain, similar to other known susceptible genes for AD. We found that CNV regions in patients with AD contained dosage-sensitive genes, which are ohnologs not overlapping with control CNV regions, frequently. Furthermore, these dosage-sensitive genes in pathogenic CNV regions had a strong enrichment in the nervous system for mouse knockout phenotype and high expression in the brain similar to the known susceptible genes for AD. Our results demonstrated that selecting dosage-sensitive ohnologs out of multiple genes with pathogenic CNVs is effective in identifying the causative genes for AD. This methodology can be applied to other diseases caused by dosage imbalance and might help to establish the medical diagnosis by analysis of CNVs.