Deconvoluting complex correlates of COVID19 severity with local ancestry inference and viral phylodynamics: Results of a multiomic pandemic tracking strategy

The SARS-CoV-2 pandemic has differentially impacted populations of varied race, ethnicity and socioeconomic status. Admixture mapping and local ancestry inference represent powerful tools to examine genetic risk within multi-ancestry genomes independent of these confounding social constructs. Here, we leverage a pandemic tracking strategy in which we sequence viral and host genomes and transcriptomes from 1,327 nasopharyngeal swab residuals and integrate them with digital phenotypes from electronic health records. We demonstrate over-representation of individuals possessing Oceanian and Indigenous American ancestry in SARS-CoV-2 positive populations. Genome-wide-association disaggregated by admixture mapping reveals regions of chromosomes 5 and 14 associated with COVID19 severity within African and Oceanic local ancestries, respectively, independent of overall ancestry fraction. Phylodynamic tracking of consensus viral genomes reveals no association with disease severity or inferred ancestry. We further present summary data from a multi-omic investigation of human-leukocyte-antigen (HLA) typing, nasopharyngeal microbiome and human transcriptomics that reveal metagenomic and HLA associations with severe COVID19 infection. This work demonstrates the power of multi-omic pandemic tracking and genomic analyses to reveal distinct epidemiologic, genetic and biological associations for those at the highest risk.

Admixture mapping reveals loci for carcass mass in red deer x sika hybrids in Kintyre, Scotland

We deployed admixture mapping on a sample of 386 deer from a hybrid swarm between native red deer (Cervus elaphus) and introduced Japanese sika (Cervus nippon) sampled in Kintyre, Scotland to search for Quantitative Trait Loci (QTL) underpinning phenotypic differences between the species. These two species are highly diverged genetically (Fst between pure species, based on 50K SNPs, = 0.532) and phenotypically: pure red have on average twice the carcass mass of pure sika in our sample (38.7 kg vs 19.1 kg). After controlling for sex, age and population genetic structure we found ten autosomal genomic locations with QTL for carcass mass. Effect sizes ranged from 0.191 to 1.839 Kg and as expected, in all cases the allele derived from sika conferred lower carcass mass. The sika population was fixed for all small carcass mass alleles, whereas the red deer population was typically polymorphic. GO term analysis of genes lying in the QTL regions are associated with oxygen transport. Although body mass is a likely target of selection, none of the SNPs marking QTL are introgressing faster or slower than expected in either direction.

Admixture mapping reveals the association between Native American ancestry at 3q13.11 and reduced risk of Alzheimer’s disease in Caribbean Hispanics

Background Genetic studies have primarily been conducted in European ancestry populations, identifying dozens of loci associated with late-onset Alzheimer’s disease (AD). However, much of AD’s heritability remains unexplained; as the prevalence of AD varies across populations, the genetic architecture of the disease may also vary by population with the presence of novel variants or loci. Methods We conducted genome-wide analyses of AD in a sample of 2565 Caribbean Hispanics to better understand the genetic contribution to AD in this population. Statistical analysis included both admixture mapping and association testing. Evidence for differential gene expression within regions of interest was collected from independent transcriptomic studies comparing AD cases and controls in samples with primarily European ancestry. Results Our genome-wide association study of AD identified no loci reaching genome-wide significance. However, a genome-wide admixture mapping analysis that tests for association between a haplotype’s ancestral origin and AD status detected a genome-wide significant association with chromosome 3q13.11 (103.7–107.7Mb, P = 8.76E−07), driven by a protective effect conferred by the Native American ancestry (OR = 0.58, 95%CI = 0.47−0.73). Within this region, two variants were significantly associated with AD after accounting for the number of independent tests (rs12494162, P = 2.33E−06; rs1731642, P = 6.36E−05). The significant admixture mapping signal is composed of 15 haplotype blocks spanning 5 protein-coding genes (ALCAM, BBX, CBLB, CCDC54, CD47) and four brain-derived topologically associated domains, and includes markers significantly associated with the expression of ALCAM, BBX, CBLB, and CD47 in the brain. ALCAM and BBX were also significantly differentially expressed in the brain between AD cases and controls with European ancestry. Conclusion These results provide multiethnic evidence for a relationship between AD and multiple genes at 3q13.11 and illustrate the utility of leveraging genetic ancestry diversity via admixture mapping for new insights into AD.

Genetic Ancestry Inference and Its Application for the Genetic Mapping of Human Diseases

Admixed populations arise when two or more ancestral populations interbreed. As a result of this admixture, the genome of admixed populations is defined by tracts of variable size inherited from these parental groups and has particular genetic features that provide valuable information about their demographic history. Diverse methods can be used to derive the ancestry apportionment of admixed individuals, and such inferences can be leveraged for the discovery of genetic loci associated with diseases and traits, therefore having important biomedical implications. In this review article, we summarize the most common methods of global and local genetic ancestry estimation and discuss the use of admixture mapping studies in human diseases.

Genome-wide admixture mapping of eGFR and CKD identify European and African ancestry-of-origin loci in U.S. Hispanics/Latinos

Background Admixture mapping is a powerful approach for gene mapping of complex traits that leverages the diverse genetic ancestry in populations with recent admixture such as U.S. Hispanics/Latinos (HL), who have increased risk of chronic kidney disease (CKD). Methods Genome-wide admixture mapping was performed for CKD and estimated glomerular filtration rate (eGFR) in a sample of 12601 participants from the Hispanic Community Health Study/Study of Latinos, with validation in a sample of 8191 African Americans from the Women's Health Initiative (WHI). Results Three novel ancestry-of-origin loci were identified on chromosomes 2, 14 and 15 for CKD and eGFR. The chromosome 2 locus (2p16.3) consisted of two European ancestry regions encompassing the FSHR and NRXN1 genes, with European ancestry at this locus associated with increased risk for CKD. The chromosome 14 locus (14q32.2) located within the DLK1-DIO3 imprinted domain was driven by European ancestry, and was associated with lower eGFR. The chromosome 15 locus (15q13.3-14) included intronic variants of RYR3 and was within an African-specific genomic region that was associated with higher eGFR. These findings were compared to the conventional genome-wide association study that failed to identify significant associations in these regions. We validated the chromosome 14 and 15 loci for eGFR in the WHI African Americans. Conclusions This study provides evidence of shared ancestry-specific genomic regions influencing eGFR in HL and African Americans, and illustrates the potential for leveraging genetic ancestry in recently admixed populations for novel discovery of kidney trait loci.

Admixture mapping reveals loci for carcass mass in red deer x sika hybrids in Kintyre, Scotland

We deployed admixture mapping on a sample of 386 deer from a hybrid swarm between native red deer (Cervus elaphus) and introduced Japanese sika (Cervus nippon) sampled in Kintyre, Scotland to search for Quantitative Trait Loci (QTL) underpinning phenotypic differences between the species. These two species are highly diverged genetically (Fst between pure species, based on 50K SNPs, = 0.532) and phenotypically: pure red have on average twice the carcass mass of pure sika in our sample (38.7kg vs 19.1 kg). After controlling for sex, age and population genetic structure we found ten autosomal genomic locations with QTL for carcass mass. Effect sizes ranged from 0.191 to 1.839 Kg and as expected, in all cases the allele derived from sika conferred lower carcass mass. The sika population was fixed for all small carcass mass alleles, whereas the red deer population was typically polymorphic. GO term analysis of genes lying in the QTL regions are associated with oxygen transport. Although body mass is a likely target of selection, none of the SNPs marking QTL are introgressing faster or slower than expected in either direction.