Dataset Information

Improved estimation of SNP heritability using Bayesian multiple-phenotype models.

ABSTRACT: Linear mixed models (LMM) are widely used to estimate narrow sense heritability explained by tagged single-nucleotide polymorphisms (SNPs). However, those estimates are valid only if large sample sizes are used. We propose a Bayesian covariance component model (BCCM) that takes into account the genetic correlation among phenotypes and genetic correlation among individuals. The use of the BCCM allows us to circumvent issues related to small sample sizes, including overfitting and boundary estimates. Using expression of genes in breast cancer pathway, obtained from the Multiple Tissue Human Expression Resource (MuTHER) project, we demonstrate a significant improvement in the accuracy of SNP-based heritability estimates over univariate and likelihood-based methods. According to the BCCM, except CHURC1 (h2 = 0.27, credible interval = (0.2, 0.36)), all tested genes have trivial heritability estimates, thus explaining why recent progress in their eQTL identification has been limited.

SUBMITTER: Elhezzani NS

PROVIDER: S-EPMC5945852 | biostudies-other | 2018 May

REPOSITORIES: biostudies-other

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Publications

Improved estimation of SNP heritability using Bayesian multiple-phenotype models.

Elhezzani Najla Saad NS

European journal of human genetics : EJHG 20180213 5

Linear mixed models (LMM) are widely used to estimate narrow sense heritability explained by tagged single-nucleotide polymorphisms (SNPs). However, those estimates are valid only if large sample sizes are used. We propose a Bayesian covariance component model (BCCM) that takes into account the genetic correlation among phenotypes and genetic correlation among individuals. The use of the BCCM allows us to circumvent issues related to small sample sizes, including overfitting and boundary estimat ...[more]

PMID: 29440776

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Project description:Height has an extremely polygenic pattern of inheritance. Genome-wide association studies (GWAS) have revealed hundreds of common variants that are associated with human height at genome-wide levels of significance. However, only a small fraction of phenotypic variation can be explained by the aggregate of these common variants. In a large study of African-American men and women (n = 14,419), we genotyped and analyzed 966,578 autosomal SNPs across the entire genome using a linear mixed model variance components approach implemented in the program GCTA (Yang et al Nat Genet 2010), and estimated an additive heritability of 44.7% (se: 3.7%) for this phenotype in a sample of evidently unrelated individuals. While this estimated value is similar to that given by Yang et al in their analyses, we remain concerned about two related issues: (1) whether in the complete absence of hidden relatedness, variance components methods have adequate power to estimate heritability when a very large number of SNPs are used in the analysis; and (2) whether estimation of heritability may be biased, in real studies, by low levels of residual hidden relatedness. We addressed the first question in a semi-analytic fashion by directly simulating the distribution of the score statistic for a test of zero heritability with and without low levels of relatedness. The second question was addressed by a very careful comparison of the behavior of estimated heritability for both observed (self-reported) height and simulated phenotypes compared to imputation R2 as a function of the number of SNPs used in the analysis. These simulations help to address the important question about whether today's GWAS SNPs will remain useful for imputing causal variants that are discovered using very large sample sizes in future studies of height, or whether the causal variants themselves will need to be genotyped de novo in order to build a prediction model that ultimately captures a large fraction of the variability of height, and by implication other complex phenotypes. Our overall conclusions are that when study sizes are quite large (5,000 or so) the additive heritability estimate for height is not apparently biased upwards using the linear mixed model; however there is evidence in our simulation that a very large number of causal variants (many thousands) each with very small effect on phenotypic variance will need to be discovered to fill the gap between the heritability explained by known versus unknown causal variants. We conclude that today's GWAS data will remain useful in the future for causal variant prediction, but that finding the causal variants that need to be predicted may be extremely laborious.

Project description:BackgroundTraditional breeding programs consider an average pairwise kinship between sibs. Based on pedigree information, the relationship matrix is used for genetic evaluations disregarding variation due to Mendelian sampling. Therefore, inbreeding and kinship coefficients are either over or underestimated resulting in reduction of accuracy of genetic evaluations and genetic progress. Single nucleotide polymorphism (SNPs) can be used to estimate pairwise kinship and individual inbreeding more accurately. The aim of this study was to optimize the selection of markers and determine the required number of SNPs for estimation of kinship and inbreeding.ResultsA total of 1,565 animals from three commercial pig populations were analyzed for 28,740 SNPs from the PorcineSNP60 Beadchip. Mean genomic inbreeding was higher than pedigree-based estimates in lines 2 and 3, but lower in line 1. As expected, a larger variation of genomic kinship estimates was observed for half and full sibs than for pedigree-based kinship reflecting Mendelian sampling. Genomic kinship between father-offspring pairs was lower (0.23) than the estimate based on pedigree (0.26). Bootstrap analyses using six reduced SNP panels (n = 500, 1000, 1500, 2000, 2500 and 3000) showed that 2,000 SNPs were able to reproduce the results very close to those obtained using the full set of unlinked markers (n = 7,984-10,235) with high correlations (inbreeding r > 0.82 and kinship r > 0.96) and low variation between different sets with the same number of SNPs.ConclusionsVariation of kinship between sibs due to Mendelian sampling is better captured using genomic information than the pedigree-based method. Therefore, the reduced sets of SNPs could generate more accurate kinship coefficients between sibs than the pedigree-based method. Variation of genomic kinship of father-offspring pairs is recommended as a parameter to determine accuracy of the method rather than correlation with pedigree-based estimates. Inbreeding and kinship coefficients can be estimated with high accuracy using ≥2,000 unlinked SNPs within all three commercial pig lines evaluated. However, a larger number of SNPs might be necessary in other populations or across lines.

Dataset Information

Improved estimation of SNP heritability using Bayesian multiple-phenotype models.

Publications

Improved estimation of SNP heritability using Bayesian multiple-phenotype models.

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