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Principal Investigator: Hongsheng Gui
Organization: HENRY FORD HEALTH + MICHIGAN STATE UNIVERSITY HEALTH SCIENCES
Fiscal Year: 2024
Award: $157,000
Funding agency: National Institute of Mental Health
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.
Terms: <Address><African><African American group><African American individual><African American people><African American population><African Americans><African ancestry><African descent><All of Us Program><All of Us Research Program><All of Us Research Project><Alleles><Allelomorphs><Amino Acids><Antigen Variation><Antigenic Variability><Antigenic Variation><Antigens><AoURP><Area><Autoantigens><Autoimmune Diseases><Autologous Antigens><Behavior><Bipolar Affective Psychosis><Bipolar Disorder><Black><Black race><COVID-19 affected><COVID-19 consequence><COVID-19 effect><COVID-19 impact><COVID-19 impacted><Cessation of life><Chromosomes><Chronic><Code><Coding System><Data><Data Set><Death><Death Rate><Decrease health disparities><Diagnostic and Statistical Manual><Diagnostic and Statistical Manual of Mental Disorders><Diathesis><Diploid><Diploidy><Disease><Disease Pathway><Disease susceptibility><Disorder><European><Evaluation><Feeling suicidal><GWA study><GWAS><Genes><Genetic><Genetic Code><Genetic Predisposition><Genetic Predisposition to Disease><Genetic Structures><Genetic Susceptibility><Genetic propensity><Genetic study><Genomic Segment><Genomics><Genotype><Goals><Graft Rejection><Grain><HL-A Antigens><HLA Antigens><Haplotypes><Health><Health disparity mitigation><Health disparity reduction><Histocompatibility Complex><Histocompatibility Complices><Host Defense><Human><Human Genetics><Human Leukocyte Antigens><Hybrids><Immune Diseases><Immune Disorders><Immune Dysfunction><Immune System Diseases><Immune System Disorder><Immune System Dysfunction><Immune System and Related Disorders><Immune response><Immunochemical Immunologic><Immunodeficiency and Immunosuppression Disorders><Immunologic><Immunologic Diseases><Immunological><Immunological Diseases><Immunological Dysfunction><Immunological System Dysfunction><Immunological response><Immunologically><Immunologics><Individual><Individuals from minority><Individuals of minority><Inflammatory><Inflammatory Response><Inherited Predisposition><Inherited Susceptibility><International><Investigators><Knowledge><Leukocyte Antigens><Link><Linkage Disequilibrium><Long-term cohort><Longitudinal cohort><Longterm cohort><Lower health disparities><Major Depressive Disorder><Major Histocompatibility Complex><Major Histocompatibility Complices><Manic-Depressive Psychosis><Maps><Measurable><Mediating><Medical><Mental Health><Mental Hygiene><Mental disorders><Mental health disorders><Minority Groups><Minority People><Minority Population><Minority individual><Mitigate health disparities><Modern Man><Non-Hispanic><Nonhispanic><Not Hispanic or Latino><Participant><Pattern><Phase><Phenotype><Population><Population Group><Population Heterogeneity><Process><Proteins><Psychiatric Disease><Psychiatric Disorder><Psychological Health><Public Health><Reduce health disparities><Reporting><Research><Research Personnel><Research Resources><Researchers><Resolution><Resources><Risk Factors><Risk-associated variant><Role><Sampling><Schizophrenia><Schizophrenic Disorders><Self-Antigens><Shotgun Sequencing><Single Base Polymorphism><Single Nucleotide Polymorphism><Suicidal thoughts><Suicide><Suicide attempt><Technology><Transplant Rejection><Transplantation><Transplantation Rejection><United States><Variant><Variation><Viral Diseases><Virus Diseases><adaptive immune response><aminoacid><arm><autoimmune condition><autoimmune disorder><autoimmunity disease><biobank><biorepository><bipolar affective disorder><bipolar disease><bipolar illness><bipolar mood disorder><burden of disease><burden of illness><causal allele><causal gene><causal mutation><causal variant><causative mutation><causative variant><chronic mental illness><clinical care><clinical depression><co-morbid><co-morbidity><comorbidity><coronavirus disease 2019 consequence><coronavirus disease 2019 effect><coronavirus disease 2019 impact><coronavirus disease-19 impact><data mining><datamining><dementia praecox><disability><disease burden><diverse populations><emerging sequencing technology><entire genome><fatal attempt><fatal suicide><full genome><genetic architecture><genetic etiology><genetic mechanism of disease><genetic vulnerability><genetically predisposed><genome resource><genome segment><genome sequencing><genome wide association><genome wide association scan><genome wide association studies><genome wide association study><genomewide association scan><genomewide association studies><genomewide association study><genomic data><genomic data resource><genomic data-set><genomic dataset><genomic region><genomic resource><genomic sequencing resource><heterogeneous population><host response><immune system response><immunogen><immunoresponse><improved><inflammation marker><inflammatory marker><innovate><innovation><innovative><intent to die><liability to disease><major depression><major depression disorder><manic depressive disorder><manic depressive illness><mental illness><mortality rate><mortality ratio><neural inflammation><neuroinflammation><neuroinflammatory><neuropsychiatric disease><neuropsychiatric disorder><new sequencing technology><non fatal attempt><nonfatal attempt><novel sequencing technology><persistent mental illness><phenome><phenomics><phenotypic data><physical conditioning><physical health><population diversity><post-transplant><post-transplantation><posttransplant><posttransplantation><precision medicine><precision-based medicine><psychiatric illness><psychological disorder><resolutions><risk allele><risk gene><risk genotype><risk loci><risk locus><risk variant><schizophrenic><serious mental disorder><serious mental illness><severe mental disorder><severe mental illness><single nucleotide variant><social determinants><social role><sociodeterminant><suicidal><suicidal attempt><suicidal behavior><suicidal ideation><suicidal thinking><suicidality><suicide behavior><suicide ideation><suicides><thoughts about suicide><transplant><viral infection><virus infection><virus-induced disease><whole genome><whole genome association analysis><whole genome association studies><whole genome association study>