Linear mixed models (LMMs) are widely used for heritability estimation in genome-wide association studies (GWAS). In standard approaches to heritability estimation with LMMs, a genetic relationship matrix (GRM) must be specified. In GWAS, the GRM is frequently a correlation matrix estimated from the study population's genotypes, which corresponds to a normalized Euclidean distance kernel. In this paper, we show that reliance on the Euclidean distance kernel contributes to several unresolved modeling inconsistencies in heritability estimation for GWAS. These inconsistencies can cause biased heritability estimates in the presence of linkage disequilibrium (LD), depending on the distribution of causal variants. We show that these biases can be resolved (at least at the modeling level) if one adopts a Mahalanobis distance-based GRM for LMM analysis. Additionally, we propose a new definition of partitioned heritability -- the heritability attributable to a subset of genes or single nucleotide polymorphisms (SNPs) -- using the Mahalanobis GRM, and show that it inherits many of the nice consistency properties identified in our original analysis. Partitioned heritability is a relatively new area for GWAS analysis, where inconsistency issues related to LD have previously been known to be especially pernicious.
Recently, in independent work, @cite_0 proposed using the Mahalanobis kernel in a similar way for heritability esitmation with GWAS data. 's paper primarily focuses on empirical analysis, using both simulated and real datasets to illsutrate advantages of the Mahalanobis kernel. The present work contains more precise mathematical and statistical justification for much of the work in @cite_0 , and introduces statistical principles (e.g. @math -heritability in Section ) that can be extended to other targeted application areas and genetics (like partitioning heritability).
@cite_0
2289130514
We are interested in the large-scale learning of Mahalanobis distances, with a particular focus on person re-identification. We propose a metric learning formulation called Weighted Approximate Rank Component Analysis (WARCA). WARCA optimizes the precision at top ranks by combining the WARP loss with a regularizer that favors orthonormal linear mappings and avoids rank-deficient embeddings. Using this new regularizer allows us to adapt the large-scale WSABIE procedure and to leverage the Adam stochastic optimization algorithm, which results in an algorithm that scales gracefully to very large data-sets. Also, we derive a kernelized version which allows to take advantage of state-of-the-art features for re-identification when data-set size permits kernel computation. Benchmarks on recent and standard re-identification data-sets show that our method beats existing state-of-the-art techniques both in terms of accuracy and speed. We also provide experimental analysis to shade lights on the properties of the regularizer we use, and how it improves performance.