Changes in expression of VGF, SPECC1L, HLA-DRA and RANBP3L act with APOE E4 to alter risk for late onset Alzheimer’s disease

• Published in: Scientific reports 2024-06, Vol.14 (1), p.14954-13, Article 14954
• Main Authors: Branciamore, Sergio, Gogoshin, Grigoriy, Rodin, Andrei S., Myers, Amanda J.
• Format: Article
• Language: English
• Subjects: 631/114/2397; 692/617/375/132/1283; Adaptor Proteins, Signal Transducing - genetics; Adaptor Proteins, Signal Transducing - metabolism; Aged; Aged, 80 and over; Alleles; Alzheimer Disease - genetics; Alzheimer Disease - metabolism; Alzheimer's disease; APOE E4; Apolipoprotein E; Apolipoprotein E4; Apolipoprotein E4 - genetics; Apolipoproteins; Bayes Theorem; Bayesian analysis; Bayesian networks; Brain research; Dementia; Female; Gene expression; Genetic Predisposition to Disease; Genetics; Haplotypes; Histocompatibility antigen HLA; HLA-DR alpha-Chains - genetics; Humanities and Social Sciences; Humans; Late Onset Alzheimer's disease; Male; Medicine; multidisciplinary; Neurodegenerative diseases; Neuropathology; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; Risk Factors; Science; Science (multidisciplinary); Variables
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-024-65010-7

While there are currently over 40 replicated genes with mapped risk alleles for Late Onset Alzheimer’s disease (LOAD), the Apolipoprotein E locus E4 haplotype is still the biggest driver of risk, with odds ratios for neuropathologically confirmed E44 carriers exceeding 30 (95% confidence interval 16.59–58.75). We sought to address whether the APOE E4 haplotype modifies expression globally through networks of expression to increase LOAD risk. We have used the Human Brainome data to build expression networks comparing APOE E4 carriers to non-carriers using scalable mixed-datatypes Bayesian network (BN) modeling. We have found that VGF had the greatest explanatory weight. High expression of VGF is a protective signal, even on the background of APOE E4 alleles. LOAD risk signals, considering an APOE background, include high levels of SPECC1L , HLA-DRA and RANBP3L . Our findings nominate several new transcripts, taking a combined approach to network building including known LOAD risk loci.