The Human Brainome: changes in expression of VGF, SPECC1L, HLA-DRA and RANBP3L act with APOE E4 to alter risk for late onset Alzheimer's disease.

While there are currently over 40 replicated genes with mapped risk alleles for Late Onset Alzheimer's disease (LOAD), the 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 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 E4 carriers to non-carriers using scalable mixed-datatypes Bayesian network (BN) modeling. We have found that had the greatest explanatory weight. High expression of is a protective signal, even on the background of E4 alleles. LOAD risk signals, considering an APOE background, include high levels of and . Our findings nominate several new transcripts, taking a combined approach to network building including known LOAD risk loci.