PROJECT SUMMARY/ABSTRACT
Technology is rapidly expanding our knowledge of the human genetic code and the alterations which
predispose to disease; however, minority populations (e.g., African Americans) are rarely included in the
discovery arms of genomic studies. As a particular genomic region, the major histocompatibility complex
(MHC) that encompasses the human leukocyte antigen (HLA) genes and variations are critically important for
their role in presenting foreign antigens and initiating adaptive immune responses. However, previous MHC
genomic resource and relevant disease gene findings were mostly enriched for non-Hispanic White individuals.
This area has been intractably difficult to decipher even with the most commonly used short-read shotgun
sequencing. This impedes the process for identification of functional HLA variants underlying immunologically
relevant mental health conditions in diverse populations. New sequencing technology (long-read) and
population-scale African samples are needed to address this knowledge gap. Recently we have gained
access to All of US (AoU) controlled tier data (e.g., long- and short-read whole-genome sequencing, WGS) and
UK Biobank (UKB) WGS data, consisting of >24,000 participants of African descent. Our overall goal is to
identify HLA long haplotypes and create the most detailed reference map of the MHC region for individuals of
African descent, and to leverage this new knowledge for fine-mapping HLA locus for suicidality phenotypes. In
the first aim, we hypothesize that a hybrid assembly approach with both short- and long-read sequencing data
provides a solution to the phasing ambiguity problem. We will generate African-specific HLA haplotype
assembly, then call, impute, and phase HLA variants and haplotypes for all African/Black samples in AoU and
UKB. In the second aim, we assume both direct and indirect HLA genetic effects are present in suicidal
thoughts and behaviors (STB). In addition to discover HLA variations and genes associated with STB and its
related inflammatory markers in AoU, we will further replicate top associations in UKB and annotate HLA
functional units by integrative omics approaches. More fully characterizing HLA variation in African populations
is both a significant and important innovation, and its implication for suicide genomics has never been done
before at such a resolution. The cloud-tailored analytical pipeline and MHC resources generated is expected
to support large projects in the AoU Researcher workbench that incorporates HLA effects in precision
medicine. In addition to our intended research goal of fine-mapping variants and genes which contribute to
STB, identifying HLA alleles that are exclusive to individuals of African descent also has the tangible benefit of
improving clinical care for transplantation and serious mental illness.
