Putting RFMix and ADMIXTURE to the test in a complex admixed population

Uren, Caitlin; Hoal, Eileen G.; Möller, Marlo

doi:10.1186/s12863-020-00845-3

Cited by 40 publications

(28 citation statements)

References 29 publications

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“…In particular, ADMIXTURE tends to infer an excess of Malay ancestry, even in southern and northern Chinese sampled from China. It has been shown by simulation studies that the haplotype-based RFMix method outperforms the frequency-based ADMXITURE method in determining the ancestry fractions in complex admixed populations ( Uren et al 2020 ). Therefore, we chose to report the RFMix estimates as our main results and included the ADMIXTURE estimates in the supplements.…”

Section: Resultsmentioning

confidence: 99%

Genetic Admixture in the Culturally Unique Peranakan Chinese Population in Southeast Asia

Pan

et al. 2021

Molecular Biology and Evolution

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The Peranakan Chinese are culturally unique descendants of immigrants from China who settled in the Malay Archipelago ∼300-500 years ago. Today, among large communities in Southeast Asia, the Peranakans have preserved Chinese traditions with strong influence from the local indigenous Malays. Yet, whether or to what extent genetic admixture co-occurred with the cultural mixture has been a topic of ongoing debate. We performed whole-genome sequencing (WGS) on 177 Singapore (SG) Peranakans and analyzed the data jointly with WGS data of Asian and European populations. We estimated that Peranakan Chinese inherited ∼5.62% (95% confidence interval [CI]: 4.75-6.46%) Malay ancestry, much higher than that in SG Chinese (1.08%, 0.69-1.53%), southern Chinese (0.86%, 0.57-1.31%), and northern Chinese (0.25%, 0.18-0.33%). A sex-biased admixture history, in which the Malay ancestry was contributed primarily by females, was supported by X chromosomal variants, and mitochondrial (MT) and Y haplogroups. Finally, we identified an ancient admixture event shared by Peranakan Chinese and SG Chinese ∼1,612 (95% CI: 1,345-1,923) years ago, coinciding with the settlement history of Han Chinese in southern China, apart from the recent admixture event with Malays unique to Peranakan Chinese ∼190 (159-213) years ago. These findings greatly advance our understanding of the dispersal history of Chinese and their interaction with indigenous populations in Southeast Asia.

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Section: Resultsmentioning

confidence: 99%

Genetic Admixture in the Culturally Unique Peranakan Chinese Population in Southeast Asia

Pan

et al. 2021

Molecular Biology and Evolution

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“…In addition, ancestral make-up between the discovery and target datasets is suggested to be a major PRS performance indicator ( Misganaw et al, 2019 ). Therefore, utilizing the overall summary statistics probably produced the lowest p -value because the dataset consists of genetic data from multiple ancestry groups, similar to the varying ancestral contributions to the South African Colored genome ( Uren et al, 2016 , 2020 ). However, this does not explain why we only observed an association between PTSD-PRS and MetS diagnosis when using the European subset of PGC-PTSD Freeze 2 summary statistics.…”

Section: Discussionmentioning

confidence: 99%

“…Participants were included if they were willing and able to provide informed consent; were 18 years or older; were able to read and write Afrikaans or English; were not pregnant; and were self-identified as being South African Colored. The South African Colored population is a five-way admixed population group, located in the Western Cape Province of South Africa ( Uren et al, 2016 , 2020 ). Participants were excluded if they had any major psychiatric disorder (e.g., severe psychotic or bipolar disorder), or any neurological disorder.…”

Section: Methodsmentioning

confidence: 99%

A Genome-Wide Association Study and Polygenic Risk Score Analysis of Posttraumatic Stress Disorder and Metabolic Syndrome in a South African Population

et al. 2021

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Posttraumatic stress disorder (PTSD) is a trauma-related disorder that frequently co-occurs with metabolic syndrome (MetS). MetS is characterized by obesity, dyslipidemia, and insulin resistance. To provide insight into these co-morbidities, we performed a genome-wide association study (GWAS) meta-analysis to identify genetic variants associated with PTSD, and determined if PTSD polygenic risk scores (PRS) could predict PTSD and MetS in a South African mixed-ancestry sample. The GWAS meta-analysis of PTSD participants (n = 260) and controls (n = 343) revealed no SNPs of genome-wide significance. However, several independent loci, as well as five SNPs in the PARK2 gene, were suggestively associated with PTSD (p < 5 × 10–6). PTSD-PRS was associated with PTSD diagnosis (Nagelkerke’s pseudo R2 = 0.0131, p = 0.00786), PTSD symptom severity [as measured by CAPS-5 total score (R2 = 0.00856, p = 0.0367) and PCL-5 score (R2 = 0.00737, p = 0.0353)], and MetS (Nagelkerke’s pseudo R2 = 0.00969, p = 0.0217). These findings suggest an association between PTSD and PARK2, corresponding with results from the largest PTSD-GWAS conducted to date. PRS analysis suggests that genetic variants associated with PTSD are also involved in the development of MetS. Overall, the results contribute to a broader goal of increasing diversity in psychiatric genetics.

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“…Running groups were created to ensure an equal number of reference populations and admixed populations whilst removing relatedness as a confounding factor during global ancestry assignment. After determining the correct k number of contributing ancestries through cross validation, the software RFMix was used to infer global ancestry proportions for downstream statistical analysis, since ADMIXTURE is not as accurate as haplotype-based analyses (Uren et al, 2020). The software PONG was used for visualisation of global ancestry proportions and amalgamation of multiple iterations into the major mode (Behr et al, 2016).…”

Section: Global Ancestry Inferencementioning

confidence: 99%

Local Ancestry Adjusted Allelic Association Analysis Robustly Captures Tuberculosis Susceptibility Loci

et al. 2021

Self Cite

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Pulmonary tuberculosis (TB), caused by Mycobacterium tuberculosis, is a complex disease. The risk of developing active TB is in part determined by host genetic factors. Most genetic studies investigating TB susceptibility fail to replicate association signals particularly across diverse populations. South African populations arose because of multi-wave genetic admixture from the indigenous KhoeSan, Bantu-speaking Africans, Europeans, Southeast Asian-and East Asian populations. This has led to complex genetic admixture with heterogenous patterns of linkage disequilibrium and associated traits. As a result, precise estimation of both global and local ancestry is required to prevent both false positive and false-negative associations. Here, 820 individuals from South Africa were genotyped on the SNP-dense Illumina Multi-Ethnic Genotyping Array (∼1.7M SNPs) followed by local and global ancestry inference using RFMix. Local ancestry adjusted allelic association (LAAA) models were utilized owing to the extensive genetic heterogeneity present in this population. Hence, an interaction term, comprising the identification of the minor allele that corresponds to the ancestry present at the specific locus under investigation, was included as a covariate. One SNP (rs28647531) located on chromosome 4q22 was significantly associated with TB susceptibility and displayed a SNP minor allelic effect (G allele, frequency = 0.204) whilst correcting for local ancestry for Bantu-speaking African ancestry (p-value = 5.518 × 10−7; OR = 3.065; SE = 0.224). Although no other variants passed the significant threshold, clear differences were observed between the lead variants identified for each ancestry. Furthermore, the LAAA model robustly captured the source of association signals in multi-way admixed individuals from South Africa and allowed the identification of ancestry-specific disease risk alleles associated with TB susceptibility that have previously been missed.

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Putting RFMix and ADMIXTURE to the test in a complex admixed population

Cited by 40 publications

References 29 publications

Genetic Admixture in the Culturally Unique Peranakan Chinese Population in Southeast Asia

Genetic Admixture in the Culturally Unique Peranakan Chinese Population in Southeast Asia

A Genome-Wide Association Study and Polygenic Risk Score Analysis of Posttraumatic Stress Disorder and Metabolic Syndrome in a South African Population

Local Ancestry Adjusted Allelic Association Analysis Robustly Captures Tuberculosis Susceptibility Loci

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