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SAIGE-GPU: accelerating genome- and phenome-wide association studies using GPUs

Genome-wide association studies (GWAS) at biobank scale are computationally intensive, especially for admixed populations requiring robust statistical models. SAIGE is a widely used method for generalized linear mixed-model GWAS but is limited by its CPU-based implementation, making phenome-wide association studies impractical for many research groups. We developed SAIGE-GPU, a GPU-accelerated version of SAIGE that replaces CPU-intensive matrix operations with GPU-optimized kernels. The core innovation is distributing genetic relationship matrix calculations across GPUs and communication layers. Applied to 2068 phenotypes from 635 969 participants in the Million Veteran Program, including diverse and admixed populations, SAIGE-GPU achieved a 5-fold speedup in mixed model fitting on supercomputing infrastructure and cloud platforms. We further optimized the variant association testing step through multi-core and multi-trait parallelization. Deployed on Google Cloud Platform and Azure, the method provided substantial cost and time savings. Source code and binaries are available for download at https://github.com/saigegit/SAIGE/tree/SAIGE-GPU-1.3.3. A code snapshot is archived at Zenodo for reproducibility (DOI: [10.5281/zenodo.17642591]). SAIGE-GPU is available in a containerized format for use across HPC and cloud environments and is implemented in R/C++ and runs on Linux systems.

Rodriguez, Alex [Argonne National Laboratory (ANL)↗

CMPLE: Correlation Modeling to Decode Photosynthesis Using the Minorize–Maximize Algorithm

In plant genomic experiments, correlations among various biological traits (phenotypes) give new insights into how genetic diversity may have tuned biological processes to enhance fitness under diverse conditions. Consequently, knowing how the correlations are affected by genetic (G) and environmental (E) factors helps develop climate-resilient plants. However, the current literature lacks any method for assessing the effect of predictors on pairwise correlations among multiple phenotypes together with easily interpretable model parameters. To address this need, we propose to model pairwise correlations directly in terms of G and E and develop a computationally efficient inference procedure. Two major novelties in our methodology are (1) the use of a composite pairwise likelihood method to avoid the positive definiteness restriction on the correlation matrix and (2) the use of a novel Minorize–Maximize (MM) algorithm for the efficient estimation of a large number of parameters. The proposed method shows excellent numerical performance on synthetic datasets. Here, the analysis of the motivating data on cowpea reveals that the rates of solar energy storage by photosynthesis (the aggregate trait) are differentially affected by different genetic loci through two distinct processes: “photoinhibition” which results from photodamage caused by excess light, and “photoprotection” which protects plants from photodamage but also results in energy loss.

Correlation modeling↗

A multi-ancestry GWAS of Fuchs corneal dystrophy highlights the contributions of laminins, collagen, and endothelial cell regulation

Fuchs endothelial corneal dystrophy (FECD) is a leading indication for corneal transplantation, but its molecular etiology remains poorly understood. We performed genome-wide association studies (GWAS) of FECD in the Million Veteran Program followed by multi-ancestry meta-analysis with the previous largest FECD GWAS, for a total of 3970 cases and 333,794 controls. We confirm the previous four loci, and identify eight novel loci: SSBP3, THSD7A, LAMB1, PIDD1, RORA, HS3ST3B1, LAMA5, and COL18A1. We further confirm the TCF4 locus in GWAS for admixed African and Hispanic/Latino ancestries and show an enrichment of European-ancestry haplotypes at TCF4 in FECD cases. Among the novel associations are low frequency missense variants in laminin genes LAMA5 and LAMB1 which, together with previously reported LAMC1, form laminin-511 (LM511). AlphaFold 2 protein modeling, validated through homology, suggests that mutations at LAMA5 and LAMB1 may destabilize LM511 by altering inter-domain interactions or extracellular matrix binding. Finally, phenome-wide association scans and colocalization analyses suggest that the TCF4 CTG18.1 trinucleotide repeat expansion leads to dysregulation of ion transport in the corneal endothelium and has pleiotropic effects on renal function.

59 BASIC BIOLOGICAL SCIENCES↗