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Type I error rates and calculated using (A) the η statistic, (B) q-value, and (C) FDR value across various correction strategies. For each correction type, a vertical line has been drawn at the median value, although this is off the scale for the “No correction” approach in plots (B,C). Additionally, “Our methods” 1 and 2 have the same median value in plots (B,C). In (A), the scale on the x-axis is designed to demonstrate how the various correction methods all vastly outperform the model without any correction. In (B,C), the x-axis scale has focused in on the three correction methods to better demonstrate the gain resulting from our approach.
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Genome-wide association (GWA) studies have become a standard approach for discovering and validating genomic polymorphisms putatively associated with phenotypes of interest. Accounting for population structure in GWA studies is critical to attain unbiased parameter measurements and control Type I error. One common approach to accounting for populat...
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Clinical interpretation of human mitochondrial DNA (mtDNA) variants has been challenging for technical and biological reasons but the involvement of dysfunctional mitochondria in many diseases makes it imperative to have a validated assay for detecting pathogenic variants. We have tested several methods to identify those best suited to detect and c...
Citations
... Principal components calculated using autosomal SNPs are not applicable Potential overadjustment and loss of statistical power 1-Sensitivity analyses with and without genetic principal components 2-Sensitivity analyses with and without Y-DNA haplogroup information as a covariate in (male-only) GWASs and looking for SNPs with significant differences in effect sizes [117][118][119] Complex loci Many highly variable regions and repetitive sequences Variant calling may not be accurate Only include variants called with high confidence [17] ...
The Human Y chromosome (ChrY) has been demonstrated to be a powerful tool for phylogenetics, population genetics, genetic genealogy and forensics. However, the importance of ChrY genetic variation in relation to human complex traits is less clear. In this review, we summarise existing evidence about the inherent complexities of ChrY variation and their use in association studies of human complex traits. We present and discuss the specific particularities of ChrY genetic variation, including Y chromosomal haplogroups, that need to be considered in the design and interpretation of genetic epidemiological studies involving ChrY.
... In principle, these findings lend credibility to the argument that MR has the potential to disrupt co-adapted mitonuclear interactions. However, as noted above, the statistical associations were generally weak as would be expected given the limited amounts of population genetic structure found in humans [60,61] and the fact that mitochondrial haplotypes are only partially informative in predicting continental ancestry [93] or controlling for population stratification in association studies [99,100]. ...
There is extensive evidence from model systems that disrupting associations between co-adapted mitochondrial and nuclear genotypes can lead to deleterious and even lethal consequences. While it is tempting to extrapolate from these observations and make inferences about the human-health effects of altering mitonuclear associations, the importance of such associations may vary greatly among species, depending on population genetics, demographic history and other factors. Remarkably, despite the extensive study of human population genetics, the statistical associations between nuclear and mitochondrial alleles remain largely uninvestigated. We analysed published population genomic data to test for signatures of historical selection to maintain mitonuclear associations, particularly those involving nuclear genes that encode mitochondrial-localized proteins (N-mt genes). We found that significant mitonuclear linkage disequilibrium (LD) exists throughout the human genome, but these associations were generally weak, which is consistent with the paucity of population genetic structure in humans. Although mitonuclear LD varied among genomic regions (with especially high levels on the X chromosome), N-mt genes were statistically indistinguishable from background levels, suggesting that selection on mitonuclear epistasis has not preferentially maintained associations involving this set of loci at a species-wide level. We discuss these findings in the context of the ongoing debate over mitochondrial replacement therapy.
... Genotyping of several nuclear loci including HLA-B and HLA-C loci have been reported in previous REACH studies [24,25]. ...
... Self-report of population of origin and ethnicity was substantiated by discriminant analysis of a validated set of 150 ancestry informative markers (AIMs) typed in a previous REACH study [25]. ...
OBJECTIVE::
To evaluate the impact of mitochondrial DNA (mtDNA) haplogroups on virologic and immunological outcomes of HIV infection.
DESIGN::
HAART-naive African American adolescent participants to the Reaching for Excellence in Adolescent Care and Health study.
METHODS::
mtDNA haplogroups were inferred from sequenced mtDNA hypervariable regions HV1 and HV2 and their predictive value on HIV outcomes were evaluated in linear mixed models, controlled for human leukocyte antigen (HLA)-B27, HLA-B57 and HLA-B35-Px alleles and other covariates.
RESULTS::
We report data showing that the mtDNA L2 lineage, a group composed of L2a, L2b and L2e mtDNA haplogroups in the studied population, is significantly associated (beta = -0.08; Bonferroni-adjusted P = 0.004) with decline of CD4 T cells (median loss of 8 ± 1 cells per month) in HAART-naïve HIV-infected individuals of African American descent (n = 133). No significant association (P < 0.05) with set-point viral load was observed with any of the tested mtDNA haplogroups. The present data concur with previous findings in the AIDS Clinical Trials Group study 384, implicating the L2 lineage with slower CD4 T-cell recovery after antiretroviral therapy in African Americans.
CONCLUSIONS::
Whereas the present data show that the L2 lineage is associated with unfavorable immunological outcomes of HIV infection, its phylogenetic divergence from J and U5a, two lineages associated with accelerated HIV progression in European Americans, raises the possibility that interactions with common nucleus-encoded variants drive HIV progression. Disentangling the effects of mitochondrial and nuclear gene variants on the outcomes of HIV infection should be an important goal toward a better understanding of HIV/AIDS pathogenesis and pharmacogenomics.
... 3 Their work suggested that Y-SNP data from DNA chips-usually the byproduct of GWAS-provide opportunities to explore Y chromosome diversity within and among populations. Although Y-SNP data from DNA chips helped improve assessments of population stratification, 11 many GWAS do not consider or evaluate Y-SNPs. It is difficult to tease out Y-SNPs from bulk GWAS data and then to assign the Y chromosome to a haplogroup. ...
Phylogenetically informative Y chromosomal single-nucleotide polymorphisms (Y-SNPs) integrated in DNA chips have not been sufficiently explored in most genome-wide association studies (GWAS). Herein, we introduce a pipeline to retrieve Y-SNP data. We introduce the software YTool (http://mitotool.org/ytool/) to handle conversion, filtering, and annotation of the data. Genome-wide SNP data from populations in Myanmar are used to construct a haplogroup tree for 117 Y chromosomes based on 369 high-confidence Y-SNPs. Parallel genotyping and published resequencing data of Y chromosomes confirm the validity of our pipeline. We apply this strategy to the CEU HapMap data set and construct a haplogroup tree with 107 Y-SNPs from 39 individuals. The retrieved Y-SNPs can discern the parental genetic structure of populations. Given the massive quantity of data from GWAS, this method facilitates future investigations of Y chromosome diversity.
... AIMs are not limited to autosomal markers; ancestral markers have also been found in sex chromosomes and mitochondrial DNA (mtDNA). Given that mtDNA is inherited only through the maternal line and is not subject to recombination, it has been used for assessing population patterns such as sex-biased admixture [13] . Taking into consideration the historical context of an admixed population, AIMs are used to estimate ancestral proportions of each appropriate parental population (e.g. ...
The process of the colonization of the New World that occurred centuries ago served as a natural experiment, creating unique combinations of genetic material in newly formed admixed populations. Through a genetic admixture approach, the identification and genotyping of ancestry informative markers have allowed for the estimation of proportions of ancestral parental populations among individuals in a sample. These admixture estimates have been used in different ways to understand the genetic contributions to individual variation in obesity and body composition parameters, particularly among diverse admixed groups known to differ in obesity prevalence within the United States. Although progress has been made through the use of genetic admixture approaches, further investigations are needed in order to explore the interaction of environmental factors with the degree of genetic ancestry in individuals. A challenge to confront at this time would be to further stratify and define environments in progressively more granular terms, including nutrients, muscle biology, stress responses at the cellular level, and the social and built environments. © 2013 S. Karger AG, Basel.
Inherited DNA polymorphisms located within the non-recombing portion of the human Y chromosome provide a powerful means of tracking the patrilineal ancestry of male individuals. Recently, we introduced an efficient genotyping method for the detection of the basal Y-chromosome haplogroups A to T, as well as an additional method for the dissection of haplogroup O into its sublineages. To further extend the use of the Y chromosome as an evolutionary marker, we here introduce a set of genotyping assays for fine-resolution subtyping of haplogroups E, G, I, J and R, which make up the bulk of Western Eurasian and African Y chromosomes. The marker selection includes a total of 107 carefully selected bi-allelic polymorphsisms that were divided into eight hierarchically organized multiplex assays (two for haplogroup E, one for I, one for J, one for G and three for R) based on the single-base primer extension (SNaPshot) technology. Not only does our method allow for enhanced Y-chromosome lineage discrimination, the more restricted geographic distribution of the subhaplogroups covered also enables more finescaled estimations of patrilineal bio-geographic origin. Supplementing our previous method for basal Y-haplogroup detection, the currently introduced assays are thus expected to be of major relevance for future DNA studies targeting male-specific ancestry for forensic, anthropological and genealogical purposes. This article is protected by copyright. All rights reserved.
