Genetic epidemiology of complex diseases

National Human Genome Research Institute

Investigators

Linked publications, trials & patents

Abstract

Current activities within the Center for Research on Genomics and Global Health (CRGGH) build on the more than three decades of research dedicated to investigating the pathogenesis of metabolic disorders, with 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 over 90% of GWAS focusing on those of European descent. 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 Center's work. We continue to advance our science at the NIH through our work on the genetic epidemiology of complex disease, focusing on generating insights and contributions from studies of genetics of cardiometabolic disorders in African populations. The current longitudinal study in Nigeria, an extension of the African America Diabetes Mellitus (AADM) study, is collecting and analyzing phenotypic, biomarker, genomic, transcriptomic, metabolomic, and other data to build a comprehensive picture of the etiopathogenesis of T2D in Africa. In the current reporting period, we made substantial progress in these multi-omics studies of our deeply phenotyped T2D cohort in Africa. Whole genome sequencing of the samples is now at an advanced stage with over 400 samples already sequenced by NISC. We have RNA-seq data on primary tissue (adipose tissue, skeletal muscle, blood) on over 50 participants and have generated whole genome methylation array data on 600 samples. We also have proteomic and metabolomics data on this cohort. We are currently optimizing protocols for generating snRNA-seq and snATAC-seq data from our primary tissue collection from Africa. We presented several aspects of this project at the 14th International Congress of Human Genetics in Cape Town, South Africa, in February 2023. The first set of papers describing the results are currently under review. These data will fill several important gaps in our knowledge of the these molecular phenotypes in understudied populations and generate resources for use by scientists working in the field. We continue to participate in multiple active protocols including several H3Africa Consortium projects (including projects on type 2 diabetes, stroke, renal disorders and human papilloma virus infection), the multi-ethnic CHARGE Gene x Lifestyle Working Group and Research on Obesity and Diabetes among African Migrants (RODAM) study (among others). Our studies of T2D and related traits include an analysis of 9,232 individuals of European ancestry (PMID: 35657990) in which we showed that three known glucose-associated loci (in GCKR, G6PC2 and SLC30A8) were independently associated with fasting glucose at genome-wide significant levels. We replicated this association in a trans-ethnic analysis of 14,303 individuals and showed that the joint effect of the three SNPs was a reduced T2D risk. The findings indicate additive effects across pathophysiological pathways involved in type 2 diabetes, including glycolysis, gluconeogenesis, and insulin secretion. We reported an epigenome-wide association study of insulin resistance in African Americans (PMID: 35836279). Using DNA methylation profiles of blood samples obtained from the Illumina Infinium HumanMethylation450 BeadChip, we analyzed DNA methylation loci associated with insulin resistance among 136 non-diabetic, unrelated African American men from the Howard University Family Study. We identified three differentially methylated positions (DMPs) for homeostatic model assessment of insulin resistance (HOMA-IR) at 5% FDR, one of which is a known locus while the other two DMPs are novel. The two novel DMPS are either in genes previously associated with insulin resistance and T2D in Europeans or have been implicated in biological processes relevant to insulin resistance. We also found low transferability of HOMA-IR DMPs reported in other populations in this cohort of African Americans. The findings from our study suggest substantial differences in DNA methylation patterns associated with insulin resistance across populations. We participated in the largest genomic analyses for T2D globally (PMID: 37034649) that involved over 2.5 million individuals (39.7% non-European ancestry), including 428,452 T2D cases. The study identified 1,289 independent association signals (611 loci) at genome-wide significance of which 145 loci were novel. Eight non-overlapping clusters of T2D signals with distinct profiles of cardiometabolic trait associations were identified, and each cluster was differentially enriched for cell-type specific regions of open chromatin in pancreatic islets, adipocytes, endothelial, and enteroendocrine cells(PMID: 37034649). We participated in a massive international consortium that did multi-ethnic, multi-layer functional genomic analyses to understand noncoding genetic variation in lipids (PMID: 35931049). The effort involved integrating a large GWAS on blood lipids involving 1.6 million individuals from five ancestries with several functional genomic datasets to discover regulatory mechanisms. The findings confirmed the central role of the liver in lipid levels and showed the selective enrichment of adipose-specific chromatin marks in HDL-cholesterol and triglycerides. In our African cohort, we conducted a Mendelian randomization study for a causal relationship between adiponectin and LDL cholesterol (PMCID: PMC9643497). We utilized a polygenic risk score (PRS) for adiponectin levels as the instrumental variable in two-stage least-squares MR analysis to assess its association with insulin resistance, HDL, LDL, total cholesterol, triglycerides, blood pressure, T2D, and hypertension. The adiponectin PRS was causally related with LDL but not the other traits. This association was observed was only statistically significant among overweight/obese individuals. In normal weight individuals, the adiponectin PRS was also associated with T2D, and (in men only) with HDL. Thus study is the first MR study for adiponectin in sub-Saharan Africans and the findings support a causal relationship of adiponectin with LDL, with T2D in normal weight individuals only, and with HDL in men only. We also participated in other consortial studies that examined gene-by-lifestyle interactions with smoking and alcohol consumption (PMID: 36544485) and GWAS of physical activity and sedentary behavior (PMID: 36071172). We published the first epigenome-wide association study of plasma lipids in West Africans working with the RODAM study (PMID: 36791658) and We also published an important paper that showed ancestral and environmental patterns in the association between triglycerides and other cardiometabolic risk factors (PMID:370043).