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.

PROJECT NARRATIVE Individuals of African descent tend to have greater disease burden but are underrepresented in genomics research. This study seeks to better characterize their genetic structure of the major histocompatibility complex (MHC) region; hence it addresses an important knowledge gap that has immediate and measurable health consequences for a population group that represents ~13% of the U.S. population. Its implication in suicide genomics is relevant to the public health because suicide accounts for more than 45,000 deaths each year in U.S. New resource in this project will also enable fine-mapping studies for other neuropsychiatric diseases.