Genome-Wide Association Studies in Africans and African Americans: Expanding the Framework of the Genomics of Human Traits and Disease

Peprah, Emmanuel; Xu, Huichun; Tekola‐Ayele, Fasil; Royal, Charmaine

doi:10.1159/000367962

Cited by 73 publications

(72 citation statements)

References 267 publications

(137 reference statements)

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“…Although GWAS in populations of African ancestry is challenging due to a less degree of LD, the high level of genetic diversity and weak LD with neighboring SNPs in Africans ancestry is considered a powerful tool for fine mapping causal disease or phenotype-associated variants globally (Campbell and Tishkoff, 2008;Peprah et al, 2015). Therefore, additional studies with a larger sample size using higher-density SNP array or next-generation sequencing may be required to discover susceptibility variants.…”

Section: Discussionmentioning

confidence: 99%

Genome-Wide Association and Replication Study of Hepatotoxicity Induced by Antiretrovirals Alone or with Concomitant Anti-Tuberculosis Drugs

Petros

Lee

Takahashi

et al. 2017

OMICS: A Journal of Integrative Biology

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Drug-induced hepatotoxicity (DIH) is a common adverse event that is associated with both antiretroviral (ARV) and anti-tuberculosis drugs (ATD). Moreover, the genetic variations predisposing ARV-and ARV-ATDinduced liver toxicity in African populations are not well investigated, despite the two diseases being the major global health problems in sub-Saharan Africa. We performed a genome-wide association study (GWAS) and replication study to identify the genetic variants linked to the risk of developing DIH due to ARV drugs alone, and ARV-ATD co-treatment in Ethiopian HIV-positive patients. Treatment-naïve newly diagnosed HIV patients (n = 719) with or without tuberculosis (TB) co-infection were enrolled prospectively and received efavirenz-based ARV therapy with or without rifampicin-based short course ATD, respectively. Whole-genome genotyping was performed by using the Illumina Omni Express Exome Bead Chip genotyping array with 951,117 single nucleotide polymorphisms (SNPs) on a total of 41 cases of DIH, and 452 people without DIH (treatment tolerants). The replication study was carried out for 100 SNPs with the lowest p-values (top SNPs) by using an independent cohort consisting of 18 DIH cases and 208 treatment tolerants. We identified a missense SNP rs199650082 (2756G/A, R919Q, p = 1.4 · 10 -6 , odds ratio [OR] = 18.2, 95% confidence interval [CI] = 7.1-46.9) in an endoplasmic reticulum to the nucleus signaling-1 (ERN1) gene on chromosome 17 to be associated with DIH in the ARV-only cohort. In the ARV-ATD co-treatment groups, rs4842407, a long intergenic noncoding RNAs (lincRNAs) transcript variant on chromosome 12, was associated with DIH ( p = 5.3 · 10 -7, OR = 5.4, 95% CI = 2.8-10.3). These genetic variants that are putatively associated with DIH due to ARV drugs alone and ARV-ATD co-treatment establish a foundation for future personalized medicine in people with HIV and TB and call for larger studies in independent populations.

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Section: Discussionmentioning

confidence: 99%

Genome-Wide Association and Replication Study of Hepatotoxicity Induced by Antiretrovirals Alone or with Concomitant Anti-Tuberculosis Drugs

Petros

Lee

Takahashi

et al. 2017

OMICS: A Journal of Integrative Biology

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“…Although the inclusion of multiple populations in GWAS is important to gain a comprehensive understanding of the genetic influences on disease risk, there are few studies of AD and other phenotypes in non-European ancestry populations, the most studied of which are African-ancestry populations, which account for only 3% of GWAS reported in the PubMed database (Peprah et al, 2015). To date, only one AD GWAS has identified GWS loci in AAs (Gelernter et al, 2014a), probably because the size of available African ancestry samples is generally much smaller than for European ancestry.…”

Section: Lessons Learned From Classical Ad Gwasmentioning

confidence: 99%

Alcohol Dependence Genetics: Lessons Learned From Genome-Wide Association Studies (GWAS) and Post-GWAS Analyses

Hart

Kranzler

2015

Alcohol Clin Exp Res

110

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Background Alcohol dependence (AD) is a complex psychiatric disorder and a significant public health problem. Twin and family-based studies have consistently estimated its heritability to be approximately 50%, and many studies have sought to identify specific genetic variants associated with susceptibility to AD. These studies have been primarily linkage or candidate gene-based, and have been mostly unsuccessful in identifying replicable risk loci. Genome-wide association studies (GWAS) have improved the detection of specific loci associated with complex traits, including AD. However, findings from GWAS explain only a small proportion of phenotypic variance and alternative methods have been proposed to investigate the associations that do not meet strict genome-wide significance criteria. Methods This review summarizes all published AD GWAS and post-GWAS analyses that have sought to exploit GWAS data to identify AD-associated loci. Results Findings from AD GWAS have been largely inconsistent, with the exception of variants encoding the alcohol metabolizing enzymes. Analyses of GWAS data that go beyond single SNP association testing have demonstrated the polygenic nature of AD and the large contribution of common variants to risk, nominating novel genes and pathways for AD susceptibility. Conclusions Findings from AD GWAS and post-GWAS analyses have greatly increased our understanding of the genetic etiology of AD. However, it is clear that larger samples will be necessary to detect loci in addition to those that encode alcohol metabolizing enzymes, which may only be possible through consortium-based efforts. Post-GWAS approaches to studying the genetic influences on AD are increasingly common and could greatly increase our knowledge of both the genetic architecture of AD and the specific genes and pathways that influence risk.

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“…The vast majority of GWASs are using arrays designed for European ancestry. However, the SNP coverage of the arrays is low and the tag SNPs are less efficient for nonEuropeans, particularly for sub-Saharan African populations (Peprah et al, 2015). Black Africans are the most genetically diverse population characterized by extensive population substructure and less LD among chromosomal loci compared with non-African populations (Teo et al, 2010).…”

Section: Looking Ahead and Future Perspectivesmentioning

confidence: 99%

Genome-Wide Association Studies for Idiosyncratic Drug-Induced Hepatotoxicity: Looking Back–Looking Forward to Next-Generation Innovation

Petros

Makonnen

Aklillu

2017

OMICS: A Journal of Integrative Biology

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Idiosyncratic drug-induced hepatotoxicity is a formidable challenge for rational drug discovery and development, as well as the science of personalized medicine. There is evidence that hereditary factors, in part, contribute to drug toxicity. This expert analysis and review offer the insights gained, and the challenges ahead, for genome-wide association studies (GWASs) of idiosyncratic drug-induced hepatotoxicity. Published articles on genome-wide and subsequent replication studies were systematically searched in the PubMed electronic database. We found that the genetic risk variants that were identified genome-wide, and replication confirmed, are mainly related to polymorphisms in the human leukocyte antigen (HLA) region that include HLA-DQB1*06:02 for amoxicillin-clavulanate, HLA-B*57:01 for flucloxacillin, HLA-DRB1*15:01 for lumiracoxib, and HLA-DRB1*07:01 for lapatinib and ximelagatran-induced hepatotoxicity. Additionally, polymorphisms in ST6 b-galactosamide a-2, 6-sialyltranferase-1 (ST6GAL1), which plays a role in systemic inflammatory response, and variants in intron of family with sequence similarity-65 member-B (FAM65B) that play roles in liver inflammation displayed association with flucloxacillin and antituberculosis drug-induced hepatotoxicity, respectively. Taken together, these GWAS findings offer molecular leads on the central role that the immune system plays in idiosyncratic drug-induced hepatotoxicity. We conclude the expert review with a brief discussion of the salient challenges ahead. These include, for example, the need for discursive discovery paradigms that incorporate alternating GWASs and candidate gene studies, as well as the study of the environtome, the entire complement of environmental factors, including science and innovation policies that enact on global society and the human host, and by extension, on susceptibility for idiosyncratic drug-induced hepatotoxicity.

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Genome-Wide Association Studies in Africans and African Americans: Expanding the Framework of the Genomics of Human Traits and Disease

Cited by 73 publications

References 267 publications

Genome-Wide Association and Replication Study of Hepatotoxicity Induced by Antiretrovirals Alone or with Concomitant Anti-Tuberculosis Drugs

Genome-Wide Association and Replication Study of Hepatotoxicity Induced by Antiretrovirals Alone or with Concomitant Anti-Tuberculosis Drugs

Alcohol Dependence Genetics: Lessons Learned From Genome-Wide Association Studies (GWAS) and Post-GWAS Analyses

Genome-Wide Association Studies for Idiosyncratic Drug-Induced Hepatotoxicity: Looking Back–Looking Forward to Next-Generation Innovation

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