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      HOMINID: a framework for identifying associations between host genetic variation and microbiome composition

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          Abstract

          Recent studies have uncovered a strong effect of host genetic variation on the composition of host-associated microbiota. Here, we present HOMINID, a computational approach based on Lasso linear regression, that given host genetic variation and microbiome taxonomic composition data, identifies host single nucleotide polymorphisms (SNPs) that are correlated with microbial taxa abundances. Using simulated data, we show that HOMINID has accuracy in identifying associated SNPs and performs better compared with existing methods. We also show that HOMINID can accurately identify the microbial taxa that are correlated with associated SNPs. Lastly, by using HOMINID on real data of human genetic variation and microbiome composition, we identified 13 human SNPs in which genetic variation is correlated with microbiome taxonomic composition across body sites. In conclusion, HOMINID is a powerful method to detect host genetic variants linked to microbiome composition and can facilitate discovery of mechanisms controlling host-microbiome interactions.

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            Association mapping in structured populations.

            The use, in association studies, of the forthcoming dense genomewide collection of single-nucleotide polymorphisms (SNPs) has been heralded as a potential breakthrough in the study of the genetic basis of common complex disorders. A serious problem with association mapping is that population structure can lead to spurious associations between a candidate marker and a phenotype. One common solution has been to abandon case-control studies in favor of family-based tests of association, such as the transmission/disequilibrium test (TDT), but this comes at a considerable cost in the need to collect DNA from close relatives of affected individuals. In this article we describe a novel, statistically valid, method for case-control association studies in structured populations. Our method uses a set of unlinked genetic markers to infer details of population structure, and to estimate the ancestry of sampled individuals, before using this information to test for associations within subpopulations. It provides power comparable with the TDT in many settings and may substantially outperform it if there are conflicting associations in different subpopulations.
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              Individuality in gut microbiota composition is a complex polygenic trait shaped by multiple environmental and host genetic factors.

              In vertebrates, including humans, individuals harbor gut microbial communities whose species composition and relative proportions of dominant microbial groups are tremendously varied. Although external and stochastic factors clearly contribute to the individuality of the microbiota, the fundamental principles dictating how environmental factors and host genetic factors combine to shape this complex ecosystem are largely unknown and require systematic study. Here we examined factors that affect microbiota composition in a large (n = 645) mouse advanced intercross line originating from a cross between C57BL/6J and an ICR-derived outbred line (HR). Quantitative pyrosequencing of the microbiota defined a core measurable microbiota (CMM) of 64 conserved taxonomic groups that varied quantitatively across most animals in the population. Although some of this variation can be explained by litter and cohort effects, individual host genotype had a measurable contribution. Testing of the CMM abundances for cosegregation with 530 fully informative SNP markers identified 18 host quantitative trait loci (QTL) that show significant or suggestive genome-wide linkage with relative abundances of specific microbial taxa. These QTL affect microbiota composition in three ways; some loci control individual microbial species, some control groups of related taxa, and some have putative pleiotropic effects on groups of distantly related organisms. These data provide clear evidence for the importance of host genetic control in shaping individual microbiome diversity in mammals, a key step toward understanding the factors that govern the assemblages of gut microbiota associated with complex diseases.
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                Author and article information

                Journal
                Gigascience
                Gigascience
                gigascience
                GigaScience
                Oxford University Press
                2047-217X
                08 November 2017
                December 2017
                08 November 2017
                : 6
                : 12
                : 1-7
                Affiliations
                [1]Department of Genetics, Cell Biology, and Development, University of Minnesota, 321 Church St SE, 6-160 Jackson Hall, Minneapolis MN 55455, USA
                [2]Department of Ecology, Evolution, and Behavior, University of Minnesota, 1479 Gortner Ave, 140 Gortner Lab, Saint Paul MN 55108, USA
                [3]Departments of Statistical Science, Mathematics, and Computer Science, Duke University, 112 Old Chemistry, Box 90251, Durham NC 27708, USA
                [4]Department of Computer Science and Engineering, University of Minnesota, 200 Union St SE, 4-192 Keller Hall, Minneapolis MN 55455, USA
                [5]Biotechnology Institute, University of Minnesota, 1479 Gortner Ave, 140 Gortner Lab, Saint Paul MN 55108, USA
                Author notes
                Correspondence address. Ran Blekhman, Department of Genetics, Cell Biology, and Development, University of Minnesota, 420 Washington Avenue SE, Minneapolis, MN, 55455. Tel: 612-624-4092; E-mail: blekhman@ 123456umn.edu
                Correspondence address. Dan Knights, MCB 6-126, 420 Washington Avenue SE, Minneapolis, MN, 55455. Tel: 612-564-2762; E-mail: dknights@ 123456umn.edu
                [†]

                Current affiliation: Department of Agricultural and Biosystems Engineering, University of Arizona, Tucson, AZ, USA

                Article
                gix107
                10.1093/gigascience/gix107
                5740987
                29126115
                79c72b0e-3a7e-4625-a51e-04a20040da85
                © The Author(s) 2017. Published by Oxford University Press.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 31 October 2017
                : 07 November 2016
                : 19 July 2017
                Page count
                Pages: 7
                Funding
                Funded by: The Randy Shaver Cancer Research and Community Fund, Institutional Research
                Award ID: 124166-IRG-58-001-55-IRG53
                Categories
                Technical Note

                microbiome,host genetics,association,machine learning
                microbiome, host genetics, association, machine learning

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