Analysis of Whole-Exome Sequencing Data for Alzheimer Disease Stratified by APOE Genotype.
JAMA Neurol. 2019 Jun 10. doi: 10.1001/jamaneurol.2019.1456.
Ma Y, Jun GR, Zhang X, Chung J, Naj AC, ... Farrer LA; Alzheimer’s Disease Sequencing Project and Alzheimer’s Disease Exome Sequencing–France Project.
But there's a good summary article at Alzforum: Sliced by ApoE Genotype, Whole Exome Data Yield New AD Variants
https://www.alzforum.org/news/research- ... d-variants. Some extracts from that article below (emphases mine)
... So far, Farrer noted, genetic studies point to six broad pathways in AD: inflammation, lipid metabolism, vesicular trafficking, neuronal signaling, Aβ, and tau.
...
In this study, first author Yiyi Ma and colleagues divvied the data by ApoE genotype. They sought variants that modulate the AD risk attributable to the E4 allele, as well as variants that affect risk independently of E4.
...
... In ApoE4 carriers, multiple hits within single genes combined to indicate gene-level association with AD for OR8G5, SLC24A3, and IGHV3-7; however, these associations did not repeat in subsequent analysis of other cohorts because the primary SNPs were not found. Even so, Farrer thinks IGHV3-7, which encodes immunoglobulin heavy variable chain, is notable, because variants in other members of this gene family have been tied to increased AD risk. A protective variant in the ISYNA1 gene encoding inositol-3-phosphate synthetase-1 did associate with AD in the discovery and two of three replication data sets.
Among ApoE4 carriers, the top SNP in ISYNA1, rs2303697, protected in all cohorts except CHARGE. Several other protective polymorphisms in this gene nearly reached statistical significance in the meta-analysis. The protein, inositol-3-phosphate synthetase-1, converts glucose-6-phosphate to myoinositol-1-phosphate. Brain myoinositol concentration has been correlated to tau pathology and cognitive impairment, and ApoE4 carriers reportedly have higher myoinositol levels than noncarriers (Mullins et al., 2018; Waragai et al., 2017; Voevodskaya et al., 2016). Scyllo-inositol, aka ELND005, which purportedly reduces myoinositol levels in the brain, did not pass muster in AD clinical trials.
In ApoE4 noncarriers, rs138412600, the GPAA1 variant found in the discovery data set, also reached significance in the replication cohorts. GPI anchor attachment 1 protein constitutes part of an enzyme complex that supports translational modification of GPI. In the meta-analysis, the GPAA1 minor A allele nearly doubled AD risk. The variant resides within the second exon of the gene, within a domain that binds FOXG1, a repressive transcription factor previously linked to Rett syndrome
