Current activities within the Center for research on genomics and global health (CRGGH) builds on the more than two decades of research dedicated to investigating the pathogenesis of metabolic disorders, with particular attention to health disparities (HD). An overarching concern of CRGGH investigators is that health inequities between ethnic groups within the US and between developed and developing countries will widen if these populations are not fully involved in genomic science. Estimates of the proportion of genomic research conducted in diverse populations are discouraging, with fully 96% of GWAS focusing on those of European descent2. The notion that these findings will be broadly applicable to all global populations is flawed given findings of ethnic-specific risk variants and significant inter-ethnic differences in allele frequencies across the genome, as demonstrated by the wide variation in GWAS-associated variants across populations. We and others have demonstrated that genetic ancestry can be leveraged in the search for genetic risk variants and for improving clinical care. Thus, CRGGH investigators are committed to conducting original research in diverse ancestral populations, developing publicly-available international genomic resources and analytical tools to increase trans-ethnic gene mapping, and to train scientists from diverse ethnic backgrounds (see the mission statement at http://crggh.nih.gov/mission.cfm). As these goals are multi-faceted, we take advantage of a variety of strategies across the breadth of the research spectrum, incorporating new advances, such as integration of omics data and CRISPR/Cas9 technology, into the Centers work. We advanced our science by developing and participating in the development of several active protocols including: 1) H3Africa Multi-Centre Study of the Prevalence and Environmental and Genetic Determinants of T2D in Africa (11 sites in 8 countries to recruit 6,000 cases and 6,000 controls); 2) Investigation of the Pathogenesis of Podoconiosis using RNA-seq and immunologic approaches (Ethiopia); 3) Genetics of T2D in Diverse Populations (African ancestry individuals); 4) Genetics of T2D among Han Chinese; 5) Genetics of Obesity, Diabetes, and Heart Disease in African Diaspora Populations (AA and recent African immigrants); 6) Genomics, Environmental Factors and Social Determinants of Cardiovascular Disease in AA; 7) Genetic Study of Myoclonic Epilepsy (whole exomes and genotyping of affected families from South Africa); 8) Active leadership and analyst roles in the multi-ethnic CHARGE Gene x Lifestyle Working Group, which has aggregated data on over 130,000 individuals, including almost 24,000 AA; 9) Global Human Ancestry (5,966 genotyped individuals in 282 samples from global ethno-linguistic groups); 10) Advanced genetic analyses of dbGaP datasets for the study of complex traits; and 11) continued participation in the 1000 Genomes Project, which led to a Nature publication A global reference for human genetic variation55. 12) We continue to play a leadership role in the implementation of the H3Africa initiative, including the design of a custom chip array and our publication of the first H3Africa consortium paper, Enabling the genomic revolution in Africa in Science . 13) We are a member of the Consortium on Asthma among African ancestry Populations in the Americas (CAAPA) that developed the African Power Chip for the identification of risk variants for asthma and other complex traits. This work contributed to the development of the Multi-Ethnic Genotyping Array (MEGA). Dyslipidemia: We sequenced lipid candidate genes in AA with extreme lipid profiles and genotyped the observed variation in a larger sample of AA. Notable among our findings were local ancestry-specific genetic effects at the LPL locus. Among AA with no African ancestry alleles for LPL variant rs328, the association between this variant and lipids was what has been previously observed among European Ancestry individuals, while among AA with 2 African ancestry alleles, the association was much smaller, similar to what was observed among West Africans, despite vastly different lifestyles and diets between AA and West Africans. Hypertension and related traits: a) In our African American project (HUFS), we showed that boys who grew up in two-parent homes are less likely to have elevated BP and HTN as adults compared to those raised by a single or neither parent. This is the first AA study to document an association between childhood family living arrangements and BP56. b) We contributed to the identification of novel variants (in EVX1-HOXA, RSPO3, and PLEKHG1) influencing BP and HTN susceptibility in AA57. c) We discovered an association of the -globin locus with serum uric acid levels in admixed AA. At rs2855126, the ancestral allele is associated with higher levels of serum uric acid and higher levels of reporter gene expression. We hypothesize that enhancer activity associated with the ancestral allele drives higher expression of -globin, leading to increased levels of fetal hemoglobin and conferring protection against malaria independent of hemoglobin S. We also hypothesize that higher expression of -globin leads to hemoglobin imbalance, in turn leading to increased hemolysis and higher levels of serum uric acid. Subsequently, higher levels of serum uric acid are associated with increased risk of hyperuricemia and hypertension. Diabetes and related traits: a) In our African diabetes project (AADM), we completed the first large-scale replication and fine mapping analysis of reported T2D-associated risk loci in Africans. Of 106 reported T2D GWAS loci, 41 showed transferability to our African sample and most of the 41 loci were localized to smaller haplotypes than in the original reports. Our lab provided leadership and statistical analysis for the largest (n>23,000) meta-analysis of the AA diabetes consortium (MEDIA). We identified two novel loci (HLA-B and INS-IGF2) that were genome-wide significant. c) We used transcriptomics of visceral adipose tissue from AA to profile differentially-expressed genes in T2D associated with morbid obesity. We detected 68 differentially expressed genes, including MYO10, which encodes an actin-based motor protein that has been associated with T2D. Our upstream regulator analysis predicted five miRNAs as regulators of the expression changes. d) We used shotgun proteomics to dissect the molecular mechanism underlying the metabolically healthy but obese (MHO) phenotype (obese people without comorbidities like diabetes, dyslipidemia or hypertension) in contrast to the metabolically abnormal obese phenotype (MAO). Genomics of neglected and rare diseases: Our 2012 NEJM publication shed light on the genetic basis of podoconiosis, a neglected tropical endemic non-filarial elephantiasis, and our research also led to the clinical staging of the disease. We identified a founder mutation in LEPRE1 that causes lethal recessive osteogenesis imperfecta (OI) in AA and West Africans; reported a lack of cyclophilin B in OI with normal collagen folding; and discovered two novel missense mutations in BBS5 with pathogenic properties and implications for screening for Bardet-Biedl syndrome in Africans. We were lead authors on the first publication of the AGVP, which found novel evidence of complex, regionally distinct hunter-gatherer and Eurasian admixture across sub-Saharan Africa and demonstrated improved imputation accuracy and presented an efficient genotype array design for GWAS in Africans. -Saharan Africa.We investigated ancestry of 3,528 modern humans from 163 global samples and identified 19 ancestral components, with 94.4% of individuals showing mixed ancestry; the ubiquity of mixed ancestry underscores the importance of accounting for ancestry in history, forensics, health, and drug labeling.
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