Genome-wide Admixture Mapping of eGFR and CKD Identify European and African Ancestry-of-Origin Loci in US Hispanics/Latinos

Genetic admixture has been utilized as a tool for identifying loci associated with complex traits and diseases in recently admixed populations such as African Americans. In particular, admixture mapping is an efficient approach to identifying genetic basis for those complex diseases with substantial racial or ethnic disparities. Though current advances in admixture mapping algorithms may utilize the entire panel of SNPs, providing ancestry-informative markers (AIMs) that can differentiate parental populations and estimate ancestry proportions in an admixed population may particularly benefit admixture mapping in studies of limited samples, help identify unsuitable individuals (e.g., through genotyping the most informative ancestry markers) before starting large genome-wide association studies (GWAS), or guide larger scale targeted deep re-sequencing for determining specific disease-causing variants. Defining panels of AIMs based on commercial, high-throughput genotyping platforms will facilitate the utilization of these platforms for simultaneous admixture mapping of complex traits and diseases, in addition to conventional GWAS. Here, we describe AIMs detected based on the Shannon Information Content (SIC) or Fst for African Americans with genome-wide coverage that were selected from ~2.3 million single nucleotide polymorphisms (SNPs) covered by the Affymetrix Axiom Pan-African array, a newly developed genotyping platform optimized for individuals of African ancestry.

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Genome-wide association study of asthma in individuals of African ancestry reveals novel asthma susceptibility loci

10.1101/112953 ◽

2017 ◽

Author(s):

Michelle Daya ◽

Nicholas Rafaels ◽

Sameer Chavan ◽

Henry Richard Johnston ◽

Aniket Shetty ◽

...

Keyword(s):

Complex Disease ◽

Genome Wide Association Study ◽

Rho Gtpase ◽

Meta Analysis ◽

African Ancestry ◽

Specific Effect ◽

Whole Genome Sequence ◽

Admixture Mapping ◽

Genome Wide ◽

A Genome

AbstractBACKGROUNDAsthma is a complex disease with striking disparities across racial and ethnic groups, which may be partly attributable to genetic factors. One of the main goals of the Consortium on Asthma among African-ancestry Populations in the Americas (CAAPA) is to discover genes conferring risk to asthma in populations of African descent.METHODSWe performed a genome-wide meta-analysis of asthma across 11 CAAPA datasets (4,827 asthma cases and 5,397 controls), genotyped on the African Diaspora Power Chip (ADPC) and including existing GWAS array data. The genotype data were imputed up to a whole genome sequence reference panel from n=880 African ancestry individuals for a total of 61,904,576 SNPs. Statistical models appropriate to each study design were used to test for association, and results were combined using the weighted Z-score method. We also used admixture mapping as a complementary approach to identify loci involved in asthma pathogenesis in subjects of African ancestry.RESULTSSNPs rs787160 and rs17834780 on chromosome 2q22.3 were significantly associated with asthma (p=6.57 × 10−9 and 2.97 × 10−8, respectively). These SNPs lie in the intergenic region between the Rho GTPase Activating Protein 15 (ARHGAP15) and Glycosyltransferase Like Domain Containing 1 (GTDC1) genes. Four low frequency variants on chromosome 1q21.3, which may be involved in the “atopic march” and which are not polymorphic in Europeans, also showed evidence for association with asthma (1.18 ×10−6 ≤ p ≤ 3.06 ×10−6). SNP rs11264909 on chromosome 1q23.1, close to a region previously identified by the EVE asthma meta-analysis as having a putative African ancestry specific effect, only showed differences in counts in subjects homozygous for alleles of African ancestry. Admixture mapping also identified a significantly associated region on chromosome 6q23.2, which includes the Transcription Factor 21 (TCF21) gene, previously shown to be differentially expressed in bronchial tissues of asthmatics and non-asthmatics.CONCLUSIONSWe have identified a number of novel asthma association signals warranting further investigation.

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A meta-analysis of genome-wide association studies of multiple myeloma among men and women of African ancestry

Blood Advances ◽

10.1182/bloodadvances.2019000491 ◽

2020 ◽

Vol 4 (1) ◽

pp. 181-190 ◽

Cited By ~ 2

Author(s):

Zhaohui Du ◽

Niels Weinhold ◽

Gregory Chi Song ◽

Kristin A. Rand ◽

David J. Van Den Berg ◽

...

Keyword(s):

Multiple Myeloma ◽

Association Studies ◽

Meta Analysis ◽

African Ancestry ◽

Genome Wide Association ◽

European Ancestry ◽

Admixture Mapping ◽

Genome Wide Association Studies ◽

Risk Alleles ◽

Genome Wide

Abstract Persons of African ancestry (AA) have a twofold higher risk for multiple myeloma (MM) compared with persons of European ancestry (EA). Genome-wide association studies (GWASs) support a genetic contribution to MM etiology in individuals of EA. Little is known about genetic risk factors for MM in individuals of AA. We performed a meta-analysis of 2 GWASs of MM in 1813 cases and 8871 controls and conducted an admixture mapping scan to identify risk alleles. We fine-mapped the 23 known susceptibility loci to find markers that could better capture MM risk in individuals of AA and constructed a polygenic risk score (PRS) to assess the aggregated effect of known MM risk alleles. In GWAS meta-analysis, we identified 2 suggestive novel loci located at 9p24.3 and 9p13.1 at P < 1 × 10−6; however, no genome-wide significant association was noted. In admixture mapping, we observed a genome-wide significant inverse association between local AA at 2p24.1-23.1 and MM risk in AA individuals. Of the 23 known EA risk variants, 20 showed directional consistency, and 9 replicated at P < .05 in AA individuals. In 8 regions, we identified markers that better capture MM risk in persons with AA. AA individuals with a PRS in the top 10% had a 1.82-fold (95% confidence interval, 1.56-2.11) increased MM risk compared with those with average risk (25%-75%). The strongest functional association was between the risk allele for variant rs56219066 at 5q15 and lower ELL2 expression (P = 5.1 × 10−12). Our study shows that common genetic variation contributes to MM risk in individuals with AA.

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Ancestry-informative markers for African Americans based on the Affymetrix Pan-African genotyping array

10.7287/peerj.preprints.545v1 ◽

2014 ◽

Author(s):

Xu Zhang ◽

Wenbo Mu ◽

Cong Liu ◽

Wei Zhang

Keyword(s):

African Americans ◽

Complex Traits ◽

Association Studies ◽

African Ancestry ◽

Genetic Admixture ◽

Admixture Mapping ◽

Genome Wide Association Studies ◽

Ancestry Informative Markers ◽

Pan African ◽

Genome Wide

Genetic admixture has been utilized as a tool for identifying loci associated with complex traits and diseases in recently admixed populations such as African Americans. In particular, admixture mapping is an efficient approach to identifying genetic basis for those complex diseases with substantial racial or ethnic disparities. Though current advances in admixture mapping algorithms may utilize the entire panel of SNPs, providing ancestry-informative markers (AIMs) that can differentiate parental populations and estimate ancestry proportions in an admixed population may particularly benefit admixture mapping in studies of limited samples, help identify unsuitable individuals (e.g., through genotyping the most informative ancestry markers) before starting large genome-wide association studies (GWAS), or guide larger scale targeted deep re-sequencing for determining specific disease-causing variants. Defining panels of AIMs based on commercial, high-throughput genotyping platforms will facilitate the utilization of these platforms for simultaneous admixture mapping of complex traits and diseases, in addition to conventional GWAS. Here, we describe AIMs detected based on the Shannon Information Content (SIC) or Fst for African Americans with genome-wide coverage that were selected from ~2.3 million single nucleotide polymorphisms (SNPs) covered by the Affymetrix Axiom Pan-African array, a newly developed genotyping platform optimized for individuals of African ancestry.

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

10.1101/2021.05.06.442996 ◽

2021 ◽

Author(s):

Andrea R.V.R. Horimoto ◽

Jianwen Cai ◽

James P. Lash ◽

Martha L. Daviglus ◽

Nora Franceschini ◽

...

Keyword(s):

African Americans ◽

Complex Traits ◽

African Ancestry ◽

Genetic Ancestry ◽

European Ancestry ◽

Health Study ◽

Admixture Mapping ◽

Chromosome 14 ◽

Genome Wide ◽

Increased Risk

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.

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Eyes of Africa: The Genetics of Blindness: Study Design and Methodology

BMC Ophthalmology ◽

10.1186/s12886-021-02029-8 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Olusola Olawoye ◽

Chimdi Chuka-Okosa ◽

Onoja Akpa ◽

Tony Realini ◽

Michael Hauser ◽

...

Keyword(s):

Genome Wide Association Study ◽

Case Control Study ◽

African Ancestry ◽

Collaborative Study ◽

Data Set ◽

Human Heredity ◽

Genome Wide ◽

A Genome ◽

Multiplex Families ◽

Control Study

Abstract Background This report describes the design and methodology of the “Eyes of Africa: The Genetics of Blindness,” a collaborative study funded through the Human Heredity and Health in Africa (H3Africa) program of the National Institute of Health. Methods This is a case control study that is collecting a large well phenotyped data set among glaucoma patients and controls for a genome wide association study. (GWAS). Multiplex families segregating Mendelian forms of early-onset glaucoma will also be collected for exome sequencing. Discussion A total of 4500 cases/controls have been recruited into the study at the end of the 3rd funded year of the study. All these participants have been appropriately phenotyped and blood samples have been received from these participants. Recent GWAS of POAG in African individuals demonstrated genome-wide significant association with the APBB2 locus which is an association that is unique to individuals of African ancestry. This study will add to the existing knowledge and understanding of POAG in the African population.

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Admixture mapping of anthropometric traits in the Black Women’s Health Study: evidence of a shared African ancestry component with birth weight and type 2 diabetes

Journal of Human Genetics ◽

10.1038/s10038-022-01010-7 ◽

2022 ◽

Author(s):

Yue Wu ◽

Julie R. Palmer ◽

Lynn Rosenberg ◽

Edward A. Ruiz-Narváez

Keyword(s):

Type 2 Diabetes ◽

Birth Weight ◽

Women’S Health ◽

Women's Health ◽

African Ancestry ◽

Health Study ◽

Admixture Mapping

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Genetic Determinants of Telomere Length in African American Youth

10.1101/310417 ◽

2018 ◽

Author(s):

Andrew M. Zeiger ◽

Marquitta J. White ◽

Sam S. Oh ◽

Jonathan Witonsky ◽

Maria G. Contreras ◽

...

Keyword(s):

African American ◽

Telomere Length ◽

Genome Wide Association Study ◽

African Ancestry ◽

African American Youth ◽

Genetic Associations ◽

Disease States ◽

Genome Wide ◽

Pediatric Populations ◽

Genetic And Environmental Factors

ABSTRACTTelomere length (TL) is associated with numerous disease states and is affected by genetic and environmental factors. However, TL has been mostly studied in adult populations of European or Asian ancestry. These studies have identified 34 TL-associated genetic variants recently used as genetic proxies for TL. The generalizability of these associations to pediatric populations and racially diverse populations, specifically of African ancestry, remains unclear. Furthermore, six novel variants associated with TL in a population of European children have been identified but not validated. We measured TL from whole blood samples of 492 healthy African American youth (children and adolescents between 8 and 20 years old) and performed the first genome-wide association study of TL in this population. We were unable to replicate neither the 34 reported genetic associations found in adults nor the six genetic associations found in European children. However, we discovered a novel genome-wide significant association between TL and rs1483898 on chromosome 14. Our results underscore the importance of examining these genetic associations with TL in diverse pediatric populations such as African Americans.

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PDTM-33. EUROPEAN GENETIC ANCESTRY ASSOCIATED WITH RISK OF CHILDHOOD EPENDYMOMA

Neuro-Oncology ◽

10.1093/neuonc/noz175.809 ◽

2019 ◽

Vol 21 (Supplement_6) ◽

pp. vi194-vi194

Author(s):

Chenan Zhang ◽

Quinn Ostrom ◽

Helen Hansen ◽

Adam de Smith ◽

Cassie Kline ◽

...

Keyword(s):

African American ◽

Native American ◽

Large Scale ◽

Genetic Ancestry ◽

European Ancestry ◽

Admixture Mapping ◽

Myxopapillary Ependymoma ◽

Central Nervous System Tumor ◽

Molecular Subgroup ◽

Genome Wide

Abstract BACKGROUND Ependymoma is a histologically-defined central nervous system tumor most commonly occurring in children. Incidence differs by race/ethnicity, with individuals of European ancestry at highest risk. No large-scale genomic analyses of ependymoma predisposition have been conducted to date. We aimed to determine whether extent of European genetic ancestry is associated with ependymoma risk. METHODS In a multi-ethnic study of Californian children (327 cases, 1970 controls), we estimated the proportions of European, African, and Native American ancestry among admixed Hispanic and African-American subjects and estimated European substructure among non-Hispanic white subjects using genome-wide data. We tested whether genome-wide ancestry differences were associated with ependymoma risk and performed admixture mapping to identify associations with local European ancestry. We also re-analyzed CBTRUS data to examine subtype-specific differences in ependymoma incidence across racial/ethnic groups. RESULTS Each 20% increase in European ancestry was associated with 1.31-fold greater odds of ependymoma among Hispanic and African-American subjects (95% CI: 1.08–1.59, Pmeta=6.7×10–3). Among non-Hispanic whites, European ancestral substructure was also significantly associated with ependymoma risk. Local admixture mapping revealed a peak at 20p13 associated with increased local European ancestry, and genotype association analysis in the region identified an association upstream of R-spondin 4 that survived Bonferroni correction (P=2.2x10-5) but was not validated in an independent set of posterior fossa type A (PF-EPN-A) patients. In complementary CBTRUS analyses, American Indian/Alaskan Natives were at reduced risk relative to non-Hispanic whites (RR=0.64, 95% CI:0.46–0.87), as were African-Americans (RR=0.67, 95% CI:0.60–0.74) and Asian/Pacific Islanders (RR=0.86, 95% CI:0.73–1.00). Although overall ependymoma rates were similar in U.S. Hispanics (RR=0.96, 95% CI:0.88–1.05), lower rates were observed for myxopapillary ependymoma and other spinal ependymoma. CONCLUSION Inter-ethnic differences in ependymoma risk vary by histopathologic and potentially molecular subgroup, and are recapitulated in the genomic ancestry of ependymoma patients.

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