To use, high-coverage whole genome sequencing in large cohorts to characterize C4/HLA allelic and structural variation within the major histocompatibility complex (MHC) to identify variants contributing to early-onset and late-onset Alzheimer’s Disease (EOAD/LOAD).

The MHC houses many immune genes and is the most gene-dense polymorphic region of the genome. While it has been strongly linked to Alzheimer’s Disease (AD) risk, its sequence complexity has limited investigations into how MHC variation influences AD.

In a ReDLat pilot cohort (13 samples: 4 EOAD, 4 LOAD, 5 controls), we did not replicate prior findings that C4A/B copy number is elevated in AD, finding no significant difference between EOAD, LOAD, and controls. Though there were no differences in C4A/B copy number between EOAD and LOAD in this cohort, we expect differences may emerge as we scale the pipeline. No novel structural variants (SVs) were found surrounding C4, but putative structural variants were identified near HLA genes, including three overlapping HLA-A and one upstream of HLA-DQB1. These preliminary findings underscore the locus’s complex contribution to AD.

We demonstrate the feasibility of utilizing MHConstructor to interrogate MHC variation in AD, identifying candidate SVs in individuals with EOAD/LOAD. Though we have yet proven their association with Alzheimer’s, this pilot cohort demonstrates our capacity to apply this approach to the full cohort, for robust association testing in larger cohorts (Memory and Aging Center cohort, ReDLat, and the Alzheimer’s Disease Sequencing Project). Beyond AD, this pipeline provides a framework for investigating MHC variation in other contexts, such as transplantation, immunotherapy, and adverse drug response.