Dataset Information

Benchmarking Relatedness Inference Methods with Genome-Wide Data from Thousands of Relatives.

ABSTRACT: Inferring relatedness from genomic data is an essential component of genetic association studies, population genetics, forensics, and genealogy. While numerous methods exist for inferring relatedness, thorough evaluation of these approaches in real data has been lacking. Here, we report an assessment of 12 state-of-the-art pairwise relatedness inference methods using a data set with 2485 individuals contained in several large pedigrees that span up to six generations. We find that all methods have high accuracy (92-99%) when detecting first- and second-degree relationships, but their accuracy dwindles to <43% for seventh-degree relationships. However, most identical by descent (IBD) segment-based methods inferred seventh-degree relatives correct to within one relatedness degree for >76% of relative pairs. Overall, the most accurate methods are Estimation of Recent Shared Ancestry (ERSA) and approaches that compute total IBD sharing using the output from GERMLINE and Refined IBD to infer relatedness. Combining information from the most accurate methods provides little accuracy improvement, indicating that novel approaches, such as new methods that leverage relatedness signals from multiple samples, are needed to achieve a sizeable jump in performance.

SUBMITTER: Ramstetter MD

PROVIDER: S-EPMC5586387 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature

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Benchmarking Relatedness Inference Methods with Genome-Wide Data from Thousands of Relatives.

Ramstetter Monica D MD Dyer Thomas D TD Lehman Donna M DM Curran Joanne E JE Duggirala Ravindranath R Blangero John J Mezey Jason G JG Williams Amy L AL

Genetics 20170724 1

Inferring relatedness from genomic data is an essential component of genetic association studies, population genetics, forensics, and genealogy. While numerous methods exist for inferring relatedness, thorough evaluation of these approaches in real data has been lacking. Here, we report an assessment of 12 state-of-the-art pairwise relatedness inference methods using a data set with 2485 individuals contained in several large pedigrees that span up to six generations. We find that all methods ha ...[more]

PMID: 28739658

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Project description:Approaches based on linear mixed models (LMMs) have recently gained popularity for modelling population substructure and relatedness in genome-wide association studies. In the last few years, a bewildering variety of different LMM methods/software packages have been developed, but it is not always clear how (or indeed whether) any newly-proposed method differs from previously-proposed implementations. Here we compare the performance of several LMM approaches (and software implementations, including EMMAX, GenABEL, FaST-LMM, Mendel, GEMMA and MMM) via their application to a genome-wide association study of visceral leishmaniasis in 348 Brazilian families comprising 3626 individuals (1972 genotyped). The implementations differ in precise details of methodology implemented and through various user-chosen options such as the method and number of SNPs used to estimate the kinship (relatedness) matrix. We investigate sensitivity to these choices and the success (or otherwise) of the approaches in controlling the overall genome-wide error-rate for both real and simulated phenotypes. We compare the LMM results to those obtained using traditional family-based association tests (based on transmission of alleles within pedigrees) and to alternative approaches implemented in the software packages MQLS, ROADTRIPS and MASTOR. We find strong concordance between the results from different LMM approaches, and all are successful in controlling the genome-wide error rate (except for some approaches when applied naively to longitudinal data with many repeated measures). We also find high correlation between LMMs and alternative approaches (apart from transmission-based approaches when applied to SNPs with small or non-existent effects). We conclude that LMM approaches perform well in comparison to competing approaches. Given their strong concordance, in most applications, the choice of precise LMM implementation cannot be based on power/type I error considerations but must instead be based on considerations such as speed and ease-of-use.

Project description:Genome-wide association studies (GWASs) have the potential to reveal the genetics of microbial phenotypes such as antibiotic resistance and virulence. Capitalizing on the growing wealth of bacterial sequence data, microbial GWAS methods aim to identify causal genetic variants while ignoring spurious associations. Bacteria reproduce clonally, leading to strong population structure and genome-wide linkage, making it challenging to separate true 'hits' (i.e. mutations that cause a phenotype) from non-causal linked mutations. GWAS methods attempt to correct for population structure in different ways, but their performance has not yet been systematically and comprehensively evaluated under a range of evolutionary scenarios. Here, we developed a bacterial GWAS simulator (BacGWASim) to generate bacterial genomes with varying rates of mutation, recombination and other evolutionary parameters, along with a subset of causal mutations underlying a phenotype of interest. We assessed the performance (recall and precision) of three widely used single-locus GWAS approaches (cluster-based, dimensionality-reduction and linear mixed models, implemented in plink, pyseer and gemma) and one relatively new multi-locus model implemented in pyseer, across a range of simulated sample sizes, recombination rates and causal mutation effect sizes. As expected, all methods performed better with larger sample sizes and effect sizes. The performance of clustering and dimensionality reduction approaches to correct for population structure were considerably variable according to the choice of parameters. Notably, the multi-locus elastic net (lasso) approach was consistently amongst the highest-performing methods, and had the highest power in detecting causal variants with both low and high effect sizes. Most methods reached the level of good performance (recall >0.75) for identifying causal mutations of strong effect size [log odds ratio (OR) ?2] with a sample size of 2000 genomes. However, only elastic nets reached the level of reasonable performance (recall=0.35) for detecting markers with weaker effects (log OR ~1) in smaller samples. Elastic nets also showed superior precision and recall in controlling for genome-wide linkage, relative to single-locus models. However, all methods performed relatively poorly on highly clonal (low-recombining) genomes, suggesting room for improvement in method development. These findings show the potential for multi-locus models to improve bacterial GWAS performance. BacGWASim code and simulated data are publicly available to enable further comparisons and benchmarking of new methods.

Dataset Information

Benchmarking Relatedness Inference Methods with Genome-Wide Data from Thousands of Relatives.

Publications

Benchmarking Relatedness Inference Methods with Genome-Wide Data from Thousands of Relatives.

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