Variance component model to account for sample structure in genome-wide association studies

Kang, Hyun Min; Sul, Jae Hoon; Zaitlen, Noah; Kong, Sit Yee; Freimer, Nelson B.; Sabatti, Chiara; Eskin, Eleazar

doi:10.1038/ng.548

Cited by 2,392 publications

(2,778 citation statements)

References 54 publications

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“…2014), we showed the numerical equivalence between the proposed SNP test, derived from GBLUP models, and a fixed SNP test derived from a model with a background random polygenic effect called EMMAX (Kang et al . 2010; Zhang et al . 2010).…”

Section: Discussionmentioning

confidence: 99%

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Meta‐analysis of genome‐wide association from genomic prediction models

Rubio

Duarte²,

Bates³

et al. 2015

Animal Genetics

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SummaryGenome‐wide association (GWA) studies based on GBLUP models are a common practice in animal breeding. However, effect sizes of GWA tests are small, requiring larger sample sizes to enhance power of detection of rare variants. Because of difficulties in increasing sample size in animal populations, one alternative is to implement a meta‐analysis (MA), combining information and results from independent GWA studies. Although this methodology has been used widely in human genetics, implementation in animal breeding has been limited. Thus, we present methods to implement a MA of GWA, describing the proper approach to compute weights derived from multiple genomic evaluations based on animal‐centric GBLUP models. Application to real datasets shows that MA increases power of detection of associations in comparison with population‐level GWA, allowing for population structure and heterogeneity of variance components across populations to be accounted for. Another advantage of MA is that it does not require access to genotype data that is required for a joint analysis. Scripts related to the implementation of this approach, which consider the strength of association as well as the sign, are distributed and thus account for heterogeneity in association phase between QTL and SNPs. Thus, MA of GWA is an attractive alternative to summarizing results from multiple genomic studies, avoiding restrictions with genotype data sharing, definition of fixed effects and different scales of measurement of evaluated traits.

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Section: Discussionmentioning

confidence: 99%

“…In particular, P ‐values and test statistics obtained with equation (6) are identical to those from the Efficient Mixed‐Model Association eXpedited (EMMAX; Kang et al . 2010; Zhang et al . 2010).…”

Section: Methodsmentioning

confidence: 99%

Meta‐analysis of genome‐wide association from genomic prediction models

Rubio

Duarte²,

Bates³

et al. 2015

Animal Genetics

View full text Add to dashboard Cite

show abstract

“…To understand patterns between chemical data and individual loci while controlling for sample structure and environmental variability, we employed a linear mixed model implemented in EMMAX (Kang et al., 2010). This model has been used in genomewide association (GWA) studies of Arabidopsis thaliana (Bac‐Molenaar, Fradin, Rienstra, Vreugdenhil, & Keurentjes, 2015; Fournier‐Level et al., 2011; Li, Huang, Bergelson, Nordborg, & Borevitz, 2010; Li et al., 2014; Strauch et al., 2015) because of its computational efficiency, and its ability to handle and control for population stratification (Price, Zaitlen, Reich, & Patterson, 2010) and environment.…”

Section: Methodsmentioning

confidence: 99%

Discovering variation of secondary metabolite diversity and its relationship with disease resistance inCornus floridaL.

Pais

Xiang

2018

Ecology and Evolution

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Understanding intraspecific relationships between genetic and functional diversity is a major goal in the field of evolutionary biology and is important for conserving biodiversity. Linking intraspecific molecular patterns of plants to ecological pressures and trait variation remains difficult due to environment‐driven plasticity. Next‐generation sequencing, untargeted liquid chromatography–mass spectrometry (LC‐MS) profiling, and interdisciplinary approaches integrating population genomics, metabolomics, and community ecology permit novel strategies to tackle this problem. We analyzed six natural populations of the disease‐threatened Cornus florida L. from distinct ecological regions using genotype‐by‐sequencing markers and LC‐MS‐based untargeted metabolite profiling. We tested the hypothesis that higher genetic diversity in C. florida yielded higher chemical diversity and less disease susceptibility (screening hypothesis), and we also determined whether genetically similar subpopulations were similar in chemical composition. Most importantly, we identified metabolites that were associated with candidate loci or were predictive biomarkers of healthy or diseased plants after controlling for environment. Subpopulation clustering patterns based on genetic or chemical distances were largely congruent. While differences in genetic diversity were small among subpopulations, we did observe notable similarities in patterns between subpopulation averages of rarefied‐allelic and chemical richness. More specifically, we found that the most abundant compound of a correlated group of putative terpenoid glycosides and derivatives was correlated with tree health when considering chemodiversity. Random forest biomarker and genomewide association tests suggested that this putative iridoid glucoside and other closely associated chemical features were correlated to SNPs under selection.

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“…The GWAS analysis was performed with a line mixed-effects model to determine the association between genotype and evaluated phenotype using EMMAX software (Kang et al 2010). The kinship matrix was calculated by EMMAX-kin to measure the genetic similarities between individuals.…”

Section: Gwas Analysis Of Cold Tolerance At the Bud Burst Stagementioning

confidence: 99%

Genome-wide association study of cold tolerance of Chinese indica rice varieties at the bud burst stage

Zhang

et al. 2018

Plant Cell Rep

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Key message A region containing three genes on chromosome 1 of indica rice was associated with cold tolerance at the bud burst stage; these results may be useful for breeding cold-tolerant lines. Abstract Low temperature at the bud burst stage is one of the major abiotic stresses limiting rice growth, especially in regions where rice seeds are sown directly. In this study, we investigated cold tolerance of rice at the bud burst stage and conducted a genome-wide association study (GWAS) based on the 5K rice array of 249 indica rice varieties widely distributed in China. We improved the method to assess cold tolerance at the bud burst stage in indica rice, and used severity of damage (SD) and seed survival rate (SR) as the cold-tolerant indices. Population structure analysis demonstrated that the Chinese indica panel was divided into three subgroups. In total, 47 significant single-nucleotide polymorphism (SNP) loci associated with SD and SR, were detected by association mapping based on mixed linear model. Because some loci overlapped between SD and SR, the loci contained 13 genome intervals and most of them have been reported previously. A major QTL for cold tolerance on chromosome 1 at the position of 31.6 Mb, explaining 13.2% of phenotypic variation, was selected for further analysis. Through LD decay, GO enrichment, RNA-seq data, and gene expression pattern analyses, we identified three genes (LOC_Os01g55510, LOC_Os01g55350 and LOC_Os01g55560) that were differentially expressed between cold-tolerant and cold-sensitive varieties, suggesting they may be candidate genes for cold tolerance. Together, our results provide a new method to assess cold tolerance in indica rice, and establish the foundation for isolating genes related to cold tolerance that could be used in rice breeding.

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Variance component model to account for sample structure in genome-wide association studies

Cited by 2,392 publications

References 54 publications

Meta‐analysis of genome‐wide association from genomic prediction models

Meta‐analysis of genome‐wide association from genomic prediction models

Discovering variation of secondary metabolite diversity and its relationship with disease resistance inCornus floridaL.

Genome-wide association study of cold tolerance of Chinese indica rice varieties at the bud burst stage

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